1. Issues and controversies— The pathophysiology and  imaging abnormalities of acute appendicitis are due to lumi-  nal obstruction, regardless of etiology. The advantage of pre-  operative imaging compared with clinical assessment alone  continues to be challenged by some studies. Several centers  have reported increased time to the operating room, operat-  ing time, length of stay, and cost without a reduction in neg-  ative appendectomy rate in patients whose surgery is  postponed for the performance of CT (or ultrasound). On  the other hand, even in patients with a high clinical proba-  bility of appendicitis, almost one third of those imaged will  be found to have another diagnosis or a normal scan  (Table 1-3). We believe the preceding discrepancies are  largely due to variability in institutional experience and rec-  ommend that cross-sectional imaging (CT, MRI, or ultra-  sound) be performed in all patients suspected of having  acute appendicitis, even those patients with high-probability  clinical presentations (see Figure 9-17).   CT scan with an appendicitis protocol is appropriate in  the majority of patients. The advantage of rectal contrast  remains a matter of continued discussion.   2. Ultrasound — Ultrasound has a sensitivity and negative  predictive value of nearly 98% and 100%, respectively, with a  specificity of 70-100%. Results are highly operator dependent.   Findings suggestive of acute appendicitis include a thick-  ened, blind-ended lumen (as opposed to an open-ended  salpinx or gonadal vein) with a diameter greater than 6 mm  that is noncompressible and fluid-filled, and the presence of  an appendicolith. There may be tenderness on compression.  Ultrasound should be used as the sole imaging modality  only for patients with a high probability of the disorder.  False-positive findings occur commonly (33% of the time) in  patients with inflammatory bowel disease, cecal diverticulitis,   and pelvic inflammatory disease. The value of ultrasound is  limited in morbidly obese patients, in the presence of perfo-  ration or a retrocecal position, and when there is inability to  compress the right lower quadrant (RLQ).   Ultrasound should be considered as the study of choice in  groups most vulnerable to ionizing radiation, especially chil-  dren and women of childbearing age. The additional infor-  mation gained about the female pelvic anatomy can also be  clinically valuable.   3. CT scan — A contrast-enhanced helical CT scan performed  for acute appendicitis is 96-98% sensitive and 83-89% spe-  cific, particularly with the demonstration of an appendicolith.  MDCT may improve specificity even more. Positive findings  include a diameter greater than 6 mm, thickened wall with  enhancement, periappendiceal fat stranding, and appendi-  colith. An air-filled appendix on CT essentially excludes acute  appendicitis.   Focal thickening of the terminal ileum or cecum may be  confused with Crohn disease and appendiceal dilation may  be falsely attributed to an infected right fallopian tube. An  ovoid fat-attenuation focus with hyperattenuating rim near  the colonic serosa distinguishes epiploic appendagitis.  Infectious enteritis should be easily differentiated by the dif-  fuse nature of bowel thickening and enhancement in the  presence of a normal appendix. Less common mimics  include mucocele of the appendix, ovarian disorders, and  endometriosis. Advantages of CT over ultrasound are its  ability to visualize the entire abdomen, demonstrating an  alternative diagnosis in 15% of cases. An additional 15% of  patients will be found to be normal.   A high clinical index of suspicion for acute appendicitis  mandates the use of a dedicated appendicitis protocol with  intravenous and rectal contrast alone, reducing the time of  study to only 15 minutes by eliminating the administration  of oral contrast. CT scan during pregnancy must be used   with great discretion; ultrasound or MRI is recommended.  The lack of a reduction in the published rate of negative  appendectomy since the introduction of CT most likely  reflects inconsistent performance standards.   Rettenbacher T, Hollerweger A, Gritzmann N, et al. Appendicitis:  Should diagnostic imaging be performed if the clinical presen-  tation is highly suggestive of the disease? Gastroenterology.  2002;123:992-998. [PMID: 12360459]   The differential diagnosis of acute appendicitis is broad,  reflecting classic and atypical presentations of the disorder. It  includes mesenteric lymphadenitis, bacterial enteritis, acute  diverticulitis, ureteral calculus, Crohn disease, cholecystitis,  appendagitis epiploica, Meckel diverticulitis, and several  gynecologic disorders including acute salpingitis (pelvic  inflammatory disease), ruptured ovarian follicle (mit-  telschmerz), and ruptured ectopic pregnancy. These disor-  ders are reviewed in ensuing chapters and only epiploic  appendagitis will be discussed below in detail.   Surgery has been recognized since 1886 as the definitive  treatment for appendicitis. Active debate continues regarding  the proper timing and choice of technique (ie, open appen-  dectomy vs laparoscopic appendectomy), and what variables  influence these decisions. The incidence of negative appen-  dectomy remains as high as 20% in some patient groups,  especially young women and patients with preexisting irrita-  ble bowel syndrome. Women aged 15-45 years have a 20%   negative appendectomy rate, two to five times that of the  general population, attributed to the multiple other causes  for acute pelvic pain and the atypical location of the appen-  dix in late pregnancy.   Clyde C, Bax T, Merg A, et al. Timing of intervention does not  affect outcome in acute appendicitis in a large community prac-  tice. Am J Surg. 2008;195:590-593. [PMID: 18367138]   Ditillo MF, Dziura JD, Rabinovici R. Is it safe to delay appendec-  tomy in adults with acute appendicitis? Ann Surg. 2006;244:  656-660. [PMID: 17060754]   Longstreth GF. Avoiding unnecessary surgery in irritable bowel  syndrome. Gut. 2007;56:608-610. [PMID: 17440179]   A third-generation intravenous cephalosporin may be initi-  ated preoperatively in patients who are mildly ill. Sicker  patients with signs of perforation and sepsis require broader  coverage for anaerobes, including bacteroides. Continuation  of antibiotics postoperatively will depend on the surgical  findings and the patient's clinical response. Antibiotic ther-  apy as the sole treatment for acute appendicitis must be  undertaken with great circumspection and extreme caution  based on the current literature.   Appendiceal rupture or abscess is found in 25% of patients at  presentation. When an abscess is found on imaging, CT-  guided drainage and dedicated parenteral antibiotic therapy  should be considered the preferred alternative to immediate  appendectomy. Interval appendectomy after resolution of  the collection should then be performed at a later date. The  final decision must be made by the surgeon after consulta-  tion with the gastroenterologist and radiologist.   Surgery remains the treatment of choice for acute appendici-  tis. The timing and type of surgical approach for acute  appendicitis is now the most debated aspect of management,  with a balance sought between the desire for accurate diag-  nosis and stabilization of the patient versus prevention of  perforation. Prevention of perforation remains a major goal,  and the rate of perforation has become a quality-of-care  indicator in some institutions. The identification of predic-  tors more reliable than patient age and gender has been a  challenge. A brief voluntary delay to perform diagnostic  studies, begin antibiotics, or accommodate staffing needs has  not been proven to increase the risk of complications,  including perforation. A patient with a late or atypical pres-  entation may actually benefit from a period of observation  with the administration of antibiotics, while the gastroen-  terologist obtains additional history and reviews the imaging   studies and the response to therapy with the surgeon, or  gynecologist/obstetrician. Primary therapy of acute appen-  dicitis with antibiotics has been utilized when surgical inter-  vention is not readily available or if antibiotics are deemed  necessary by a surgeon prior to operation.   Laparoscopic appendectomy has gained increasing sup-  port as the operation of choice. Patients have fewer wound  infections, less pain, and shorter hospital stays compared  with those undergoing open cholecystectomy. The surgeon  must first consider the degree of diagnostic certainty, imag-  ing evidence for complicating disease, stage of appendicitis,  and experience with the technique. Recent retrospective data  suggest that race and insurance status may affect the deci-  sion. Debate continues over which procedure is medically  appropriate, but in women, particularly during pregnancy,  there appears to be a clear advantage to laparoscopic  appendectomy associated with the ability to identify other  gynecologic pathology and reduce the rate of negative  appendectomy. Negative appendectomy rate, in women  inversely proportional to fetal health, is becoming another  benchmark for determining the proper procedure in any  given institution. In men, the benefit of laparoscopic appen-  dectomy is less well established. As noted earlier, the surgical  experience in an institution must always be considered  before a final choice of laparoscopic versus open cholecystec-  tomy is made.   The resected appendix may reveal unexpected and clini-  cally useful data in 2% of cases and therefore should always  be submitted for histologic analysis. It is recommended,  therefore, that surgeons continue to submit the resected  appendix for histologic analysis.   lones AE, Phillips AW, larvis JR, et al. The value of routine  histopathological examination of appendectomy specimens.  BMC Surg. 2007;7:17. [PMID: 17692116]   Paterson HM, Qadan M, de Luca SM, et al. Changing trends in sur-  gery for acute appendicitis. Br J Surg. 2008;95:363-368. [PMID:  17939131]   UNIQUE PRESENTATIONS OF APPENDICITIS  1. Appendicitis in Pregnancy (see Chapter 7)   Appendicitis occurs in approximately 1 in 800-1500 preg-  nancies and appendectomy is the most common nonob-  stetric operation performed during pregnancy. The presence  of the fetus and altered appendiceal location provide a major  clinical challenge. Preoperative diagnosis is inaccurate  25-50% of the time. Maternal death is now virtually zero but  fetal loss is 2-3% without and 20% with appendiceal perfo-  ration. Appendiceal rupture is reported in 12-55% of preg-  nant women.   The proper choice of imaging in women with appendici-  tis has been discussed earlier. The risk of fetal harm from  exposure to ionizing radiation of CT must be compared with  the relatively reduced accuracy of ultrasound, especially in   the third trimester. The imaging expertise in one's own insti-  tution, particularly in view of the increasing role of MRI,  remains very important and should factor into the clinician's  final choice of study.   Negative appendectomy is higher in pregnant (23%) than  nonpregnant (18%) women and carries a 2.69 increased odds  ratio for fetal loss. The goal of eliminating negative appen-  dectomy during pregnancy with improvement in preopera-  tive assessment must be balanced with the delay in surgical  therapy and expected increase in complicated appendicitis and  perforation. Laparoscopic appendectomy for the experienced  surgeon appears safe and effective.   McGory ML, Zingmond DS, Tillou A, et at. Negative appendec-  tomy in pregnant women is associated with a substantial risk of  fetal loss. J Am Coll Surg. 2007;205:534-540. [PMID: 17903726]   Retrocecal (ileal) appendicitis presents with less pain and  rigidity due to shielding from the abdominal wall. Localization  of discomfort may be ill defined as well due to the lack of  appendix contact with the peritoneum, and it is less common  in the RLQ.   Pelvic appendicitis is characterized by severe, constant  pain usually in the LLQ, with fecal and urinary urgency.  Abdominal tenderness is variable but severe tenderness on  pelvic and rectal examination may be present. Atypical  appendicitis is more common in the elderly but is considered  less frequently as a cause for acute abdominal pain. Pain is  vague and is present in the RLQ in only 20% of patients.  There may be no fever. The abdominal examination may  yield only a nontender mass. The white blood cell count can  be lower than expected.   Proper management relies on a high index of suspicion,  careful patient assessment, and CT findings.   Late appendicitis is defined as presentation following more  than 72 hours of symptoms. It occurs most often in the  young, the elderly, and in women of childbearing age since  accurate diagnosis is most difficult in these groups. A phleg-  mon may be palpable in the RLQ or be seen on CT, usually  with an abscess component. Accurate diagnosis is difficult  due to the surrounding inflammatory response. Crohn dis-  ease, infection, and neoplasm are part of the differential  diagnosis. Malignancy (carcinoid, colonic adenocarcinoma,  lymphoma, and ovarian cancer) may be present in 1% of  cases. Studies of late appendicitis are retrospective, occurring  before advanced CT imaging was widely available. Thirty  percent of patients required a drainage procedure as their  initial surgery and appendectomy was usually postponed  until abdominal sepsis could be controlled.   Patients should be kept NPO (nothing by mouth) with  intravenous fluids and antibiotics. A nontoxic patient  (without tachycardia, abdominal rigidity or oliguria) should  avoid immediate surgical intervention, if possible, to  improve diagnostic accuracy and prevent recurrent episodes.  The indications for percutaneous drainage of an abscess  depend on the collection, size, consistency and accessibility  as well as the patient's stability. Percutaneous drainage as the  sole treatment for delayed appendicitis is not recommended  because the recurrence rate for abscess without appendec-  tomy is 5-20%. Colonoscopy has a role in the preoperative  and postoperative management of patients who are stable  and have both clinical and radiographic features of ileo-  colonic Crohn disease. Note that the appendix can be  involved in ileocolonic Crohn disease and obfuscate the diag-  nosis in patients with acute RLQ abdominal pain.   No clinical criteria have been developed to predict the  clinical outcome of delayed appendectomy or the ideal timing  of appendectomy. Curative surgery, ideally by laparoscopy, is  usually performed within 2-3 months.   Five to ten percent of patients with a surgical diagnosis of  acute appendicitis may have had a previous attack, and 1.5%  will have had symptoms for more than 3 weeks. Such obser-  vations have led to the description of a subset of patients  with so-called chronic appendicitis. The literature is entirely  retrospective and no clinical distinction has been drawn  between patients found to have a normal appendix at appen-  dectomy and those with an inflamed appendix. Fibrosis with  luminal obliteration has been described but not fistula or  abscess. The role of appendectomy for such patients is con-  troversial as they appear to represent a distinct clinical group  without the poor prognosis associated with "late" or  "delayed" appendicitis.   Epiploic appendagitis is very uncommon. In 70% of patients,  illness is triggered by torsion with ischemia and pain in one  or more of the approximately 100 epiploic (or omental)  appendages that arise from the serosal surface of the colon.  These appendages are oriented in two rows and are com-  posed of adipose tissue and a vascular stalk, 0.5-5 cm in  length. Less common manifestations are incarceration (20%)  and obstruction (10%). The condition occurs more often in  men, primarily in the fourth to fifth decades, and mimics  acute appendicitis, diverticulitis, mesenteritis, and omental  infraction with the acute onset of RLQ or LLQ pain often  after eating or exercise in a previously healthy person. Risk  factors are obesity, hernia, and physical inactivity. Fever and  obstructive symptoms are uncommon. The white blood cell   count is normal. Preoperative diagnosis is uncommon even benign, but one study reported a 40% recurrence rate.   with the availability of sensitive ultrasound and CT technology.  CT findings, when present, consist of 2-4 cm oval fat-density  lesions with surrounding inflammation and central attenua-  tion. Unlike diverticulitis, colon wall thickness and diameter  are normal. It is important to make the diagnosis so as to  avoid unnecessary surgery. The prognosis is considered   Surgery, when performed for recurrent symptoms, involves  resection of the inflamed appendages.   Sand M, Gelos M, Bechara FG, et al. Epiploic appendicitis — clinical  characteristics of an uncommon surgical diagnosis. BMC Surg.  2007;7:11. [PMID: 17603914]   ► Gut-associated lymphoid tissues (GALT) are characterized  by a unique structure, physiologic inflammation, a ten-  dency to suppress immune responses (oral tolerance),  and production of secretory immunoglobulins.   ► The immune response has two major arms: innate (rapid,  hard-wired) and adaptive (delayed in onset with memory).   ► Inflammatory bowel disease (IBD) offers a paradigm for  understanding and treating intestinal inflammatory diseases.   ► IBD is a dysregulated immune response of GALT to normal  commensal microbes within the intestines of a geneti-  cally susceptible host; this response is modified by specific  environmental factors (eg, tobacco).   ► Numerous genetic loci defined as risk factors for IBD regu-  late innate immunity, adaptive immunity, the epithelial  barrier, and the relationships of each of these with normal  commensal bacteria.   ► IBD is ultimately caused by overproduction of proin-  flammatory mediators relative to anti-inflammatory  mediators, both of which are derived from cells associ-  ated with adaptive immunity (T helper [Th] cells) and  innate immunity (dendritic cells).   ► Crohn disease (CD) is primarily due to overactivity of  Th1 and Th17 cells, and ulcerative colitis (UC), possibly,  to overactivity of Th2 cells.   ► Excess production of cytokines derived from innate  immune pathways (tumor necrosis factor [TNF] and  interleukin-6 [IL-6]) occurs in both CD and UC.   ► T regulatory cells secrete anti-inflammatory cytokines  (eg, IL-10, TGF(3, and IL-35) that inhibit proinflammatory  cytokine responses.   ► Increased understanding of IBD immunopathogenesis  has led to development of anti-inflammatory therapeutic  agents that are increasingly being administered in a  logical, mechanism-based manner.   Clinically, inflammatory bowel disease (IBD) is a chronic inflam-  matory condition of the intestines that is marked by remission  and relapses and distills clinically into one of two major subtypes  of disease: ulcerative colitis (UC) and Crohn disease (CD).  Both diseases have a general commonality in their pathogenesis  and are derived from a dysregulated mucosal immune response  to antigenic components of the normal commensal microbiota  that reside within the intestine in a genetically susceptible  host (Figure 2-1).   This tripartite interaction between the genetic composition  of the host, the mucosal immune response (including that  associated with the epithelial barrier), and its relationship to  the commensal microbiota is likely further modified by specific  environmental factors that affect the lifetime risk of developing  this disorder. Although the influence of specific gene variations,  as endogenous risk factors that clearly define susceptibility to  this disease, is well accepted, only a limited number of environ-  mental factors have clearly been proven to either modify these  diseases or regulate the lifetime risk of developing them. These  include tobacco use, appendectomy, antibiotic use, and oral  contraceptive pills. These do not in and of themselves cause the  disease but likely modify the genetically defined or undefined  aspects of the most critical components that underlie the immuno-  pathogenesis of this disease: intestinal bacteria, epithelial barrier,  and mucosal immune response. Of the latter three factors, the  best understood influence — which has to date generated the  most information, resulting in novel and exciting new forms  of therapy — involves the immunobiology of these disorders.   ▲ Figure 2-1. Pathophysiologic mechanism of inflam-  matory bowel disease (IBD). IBD represents the dysregu-  lated mucosal immune response to commensal microbial  antigens in a genetically susceptible host that is modi-  fied by environmental factors. An exaggerated T-cell  response of polarized T cells that secrete T helper (Th)  1, 2, or 17 cytokines causes tissue injury and clinical  symptoms. An inadequate T regulatory cell response is  likely to be a significant contributor to IBD pathogenesis.  OCPs, oral contraceptive pills.   For this reason, a discussion of the immunopathogenesis of IBD  not only is important for understanding the pathophysiology of  these diseases but also provides a basis for understanding both  the mechanisms and the rationale for using the wide variety of  therapeutic approaches that have recently been developed or are  soon to be developed for the treatment of these diseases.   Friedman S, Blumberg RS. Inflammatory bowel diseases. In:  Braunwald E, Fauci AS, Kasper DL, et al (editors). Harrisons  Principles of Internal Medicine, 16th ed. McGraw-Hill, 2005:  1776-1789.   Loftus EV Jr. Clinical epidemiology of inflammatory bowel  disease: incidence, prevalence and environmental influences.  Gastroenterology. 2004;126:1504-1517. [PMID: 15168363]   Sartor RB, Blumberg RS, Braun J, et al. CCFA microbial-host inter-  actions workshop: highlights and key observations. Inflamm  Bowel Dis. 2007;13:600-619. [PMID: 17294437]   Strober W, Fuss II, Blumberg RS. The immunology of mucosal  models of inflammation. Annu Rev Immunol. 2002;20:495-549.  [PMID: 11861611]   Tuvlin JA, Raza SS, Bracamonte S, et al. Smoking and inflammatory  bowel disease: trends in familial and sporadic cohorts. Inflamm  Bowel Dis. 2007;13:573-579. [PMID: 17345609]   The normal intestine has an enormous surface area that is  exposed to a wide variety of exogenous, especially bacterial,  antigens (Figure 2-2). Consequently, the mucosal immune  system has had to develop a wide variety of very specific  modifications and developmental structures to deal with and  respond to these challenges. Importantly, the overwhelming  majority of initial antigen encounters for the host occur at  the mucosal surface, which is bathed by a heterogeneous  population of microorganisms, most of which are congre-  gated within the colon and distal small intestine where IBD  most commonly occurs (see Figure 2-1). Thus, the intestines  are confronted by a large number of antigenic stimuli that  must be deciphered for pathologic potential.   For the majority of antigenic challenges, a response that is  characterized by either ignorance or active suppression would  seem to be most appropriate in the intestine to avoid a non-  specific inflammatory response. Obviously for a few exposures  such as to pathogens, a robust immune response is appropriate.  The mucosal-associated lymphoid tissues associated with the  gut, or so called gut-associated lymphoid tissues (GALT), are  characterized by a unique organization and regulated state of  physiologic (or controlled) inflammation. Thus, the gut is  poised for but actively restrained from full action and  notable for a tendency to suppress responses, a characteristic  referred to as oral tolerance. Oral tolerance and physiologic  inflammation are unique hallmarks of the GALT and are both  manifestations of the tendency of mucosal-associated lymphoid  tissues to tightly regulate immune responses (Table 2-1).   These two functional hallmarks of the GALT are represen-  tative of the fact that the GALT is a very large immunologic  organ in addition to its obvious other functions associated with  digestion and endocrine secretion. Its functions are organized  anatomically and include two components. The first compo-  nent is the so-called organized GALT, which includes the  Peyer patches, isolated lymphoid follicles, and lymphocyte-  filled villi. The second component, the so-called diffuse GALT,  comprises anatomic structures that are diffusely contained  within the lamina propria.   The organized GALT structures are often characterized by  specialized types of epithelium such as the so-called micro-  fold cell (M cell). M cells are contained within the epithelium  that overlies the Peyer patches, with its rich content of asso-  ciated lymphocytes and dendritic cells that allows for selec-  tive uptake of and response to distinct types of antigens. The  Peyer patches and other organized lymphoid structures are  distributed throughout the gastrointestinal tract but are  especially congregated in the distal ileum. They are mainly   inductive sites where antigens, including bacterial antigens,  are taken up, processed, and presented by dendritic cells for  the education of the GALT-associated lymphocytes.   The diffuse GALT constitutes the majority of the small and  large intestine and is characterized by a single layer of epithelial  cells that separates the lumen of the intestines from the lamina  propria. This epithelium and its associated intraepithelial lym-  phocytes and dendritic cells are a major effector site for pro-  tecting the large surface of intestines that must be defended   from epithelial exposures to pathogens. In addition, this epithe-  lial surface is highly responsible for participating in the main-  tenance of a regulated immune response to the wide variety  of microbes associated with the normal commensal microbiota.   Both the epithelial compartment above the epithelial basement  membrane and the subepithelial compartment below the  epithelial basement membrane that is contained within  the lamina propria participate in the two major arms of the  immune system. These are the innate and adaptive (or specific)  immune systems.   The innate immune system is a pattern recognition system  that provides a hard-wired and rapid response system for  responding to microbial structures (Table 2-2). A classic  group of structures that are used by a wide variety of cell types  in an innate immune response are the so-called toll-like  receptors (TLRs) that respond to microbial structures as diverse  as lipopolysaccharide or DNA of microbes. Innate, pattern-  recognition receptors are distributed on virtually all cell types   CRP, C-reactive protein; HLA, human leukocyte antigen; IEC, intestinal epithelial cell; IL-23R, IL-23  receptor; LPS, lipopolysaccharide; NOD2, nucleotide oligomerization domain-containing protein 2;  TLR, toll-like receptor.   but are especially congregated on professional (dendritic cells,  macrophages, and B cells) and nonprofessional (intestinal  epithelial cells) antigen-presenting cells (APCs).   Adaptive or specific immunity has a delayed response and  is characterized by memory. This type of immunity is char-  acteristic of the immune response derived from T cells and  B cells and requires the uptake, processing, and presentation of  antigens by APCs to the lymphoid cell types (T and B cells)  associated with the adaptive immune response. Moreover, innate  and adaptive immunity interact with each other such that they  both promote and regulate each other in the generation of a  balanced and effective immune response.   Brandtzaeg P, Kiyono H, Pabst R, et al. Terminology: nomenciature  of mucosa-associated lymphoid tissue. Mucosal Immunol.  2008;1:31-37.   Kaparakis M, Philpott DJ, Ferrero RL. Mammalian NLR proteins: dis-  criminating foe from friend. Immunol Cell Biol. 2007;85:495-502.  [PMID: 17680011]   The major operating paradigm of our current understanding of  IBD is that this disease represents hyperreactivity or loss of (oral)  tolerance of the mucosal immune system to one's own mucosal  microbiota. This is consistent with the general localization of  the disease, both UC and CD, to the regions of the intestine  where microbes are most present. This concept is mainly  derived from observations with numerous animal models of  IBD, as well as a lesser number of human clinical studies. The   latter have revealed some response to antibiotics, especially  in CD, and the lack of any identifiable pathogens in both  clinical subtypes of IBD. Thus, IBD represents a dysregulated  mucosal immune response in a genetically susceptible host to  commensal microbial antigens.   It has been known for almost 50 years that IBD in humans  has a strong genetic basis. Specifically, 10-30% of patients  will have a positive family history. There is also an extremely  strong concordance of CD and, to a lesser extent (but which  is still significant), of UC in monozygotic twins. The risk that  both monozygotic twins will develop CD is up to a 60% (or  800-fold increased). Both CD and UC have been revealed as  complex, polygenic disorders as opposed to simple mendelian  disorders. That said, IBD is associated with a several simple  mendelian disorders such as Turner syndrome and glycogen  storage diseases. However, it is clear from genome-wide analyses  that multiple loci on multiple chromosomes are involved in  the development of these diseases. A genetic basis for IBD is  further supported by observations in animal models.   Genome-wide association studies have identified approxi-  mately three dozen genetic susceptibility loci throughout the  human genome (Table 2-3). Genetic risk is therefore the most  important, if not essential, variable in driving the causation of  IBD. It should be noted, however, that the mechanism by  which genetic risk factors impose risk for the development of  IBD remains largely unknown. It can be surmised but not  proven that any one of these genes alone cannot cause IBD,  as is strongly supported by the well-known observation that  deletion of NOD2/CARD15 (IBD1) in mice does not cause  inflammation.   Table 2-3. Summary of selected susceptibility loci  in Crohn disease. 3   Selected from more than three dozen genes identified to date.  ATG16L1, autophagy-related 1 6— like 1 gene; CD, Crohn disease; IBD,  inflammatory bowel disease; IL, interleukin; OCTN, organic cation  transporter; PTGE4, prostaglandin receptor EPR; UC, ulcerative colitis.   Several interesting observations have been derived from  the susceptibility loci identified to date. First, as predicted by  a wide variety of immunologic studies, the genetic evaluation  of humans shows very clearly that components of the immune  system associated with innate immunity (eg, NOD2) and  adaptive immunity (interleukin [IL]-23 receptor) are clearly  involved in the pathogenesis of these diseases. Moreover, the  genetic studies show that alterations of intestinal epithelial cell  function likely contributes to the pathogenesis of these diseases.   Kobayashi KS, Chamaillard M, Ogura Y, et at. Nod2-dependent regu-  lation of innate and adaptive immunity in the intestinal tract.  Science. 2005;307:371-374. [PMID: 15692051]   Van Limbergen J, Russell RK, Nimmo ER, et al. Genetics of the  innate immune response in inflammatory bowel disease.  Inflamm Bowel Dis. 2007;13:338-355. [PMID: 17206667]   Watanabe T, Kitani A, Murray PJ, et al. NOD2 is a negative regulator  of Toll-like receptor 2-mediated T helper type 1 responses. Nat  Immunol. 2004;5:800-808. [PMID: 15220916]   It remains incompletely understood how the previously noted  genetically imposed risk factors result in the development of  IBD. However, it can be reasonably predicted that these genetic  factors modify the intestinal epithelial cell barrier and have  major effects on the function of innate and adaptive immune  systems. They may also regulate the composition of the micro-  biota itself. Furthermore, these genetic risk factors resolve into   a final common pathway characterized by highly polarized  T-cell responses associated with excess cytokine production  derived from differentiated CD4-positive T helper cells and  aggressive APCs (dendritic cells and macrophages). Animal  models have shown the essential importance of the micro-  biota in these responses, as no disease is observed under germ-  free conditions (ie, in the absence of intestinal bacteria).  Finally, animal models have also revealed the importance of  regulatory (anti-inflammatory) pathways and T regulatory cells,  in particular, in both the prevention and resolution of IBD.  Given the importance of CD4-positive T helper cell polari-  zation in IBD pathogenesis, some discussion of this topic is  appropriate (Figure 2-3). T cells leave the thymus and migrate  into peripheral tissues, such as the intestines, as naive (antigen-  inexperienced) cells. As such, they are considered to be ThO  cells without a bias for cytokine production other than the  ability to secrete IL-2 upon stimulation through their anti-  gen-specific receptor, the T-cell receptor (TCR), together  with a co-stimulatory signal (so-called signal 2) that is clas-  sically delivered by cell surface molecules, such as CD80 or  CD86 on APCs, to CD28 on the T cell (see Figure 2-3). When  T cells are presented the antigen for which they are specific  through their TCR (signal 1) by professional APCs (eg, dendritic  cells in peripheral tissues such as the intestines) together with  signal 2, they are induced to deviate to one of several polarized  fates under the control of cytokines produced by the APC  (dendritic cell) itself or other surrounding cells, or both.  Importantly, these immune-deviating cytokines or other fac-  tors are typically regulated or induced by innate immune factors  (see Table 2-2 and Figure 2-3). Thus, cytokines associated  with innate immune responses (eg, IL-12, IL-23) guide the  adaptive immune response to one of several outcomes char-  acterized by the development of T cells that are polarized to  secrete a specific signature of cytokines, as shown in Figure  2-3 (eg, Thl, Th2, Thl7, or T regulatory).   Kim SC, Tonkonogy SL, Albright CA, et al. Variable phenotypes of  enterocolitis interleukin 10-deficient mice monoassociated  with two different commensal bacteria. Gastroenterology.  2005;129:891-906. [PMID: 15825073]   A wide variety of animal studies of mucosal inflammation  that model CD, as well as human CD itself, strongly support  an excess of Thl and Thl 7 cells and their respective cytokines  as important in the development of this form of IBD. Thus,  in human CD, increased IL-12, IL-23, interferon-y, IL-17,  and tumor necrosis factor (TNF) are present at high levels  (Figure 2-4). This is consistent with the presence of granulomas  in a subset of individuals with CD that is a well-known phe-  notypic consequence of Thl-related immune responses. Animal  models and humans exhibit increased activity of transcription  factors in T cells that are essential to development of these   ▲ Figure 2-3. Differentiation of T cells. Naive T cells that have never experienced an antigen (ThO) are stimulated  by an antigen-presenting cell (APC) such as a dendritic cell. The APC presents the antigen on a major histocompatibility  complex (MHC) class II molecule to the T-cell receptor (TCR) on a T cell (signal 1). In the presence of co-stimulatory signals  (so-called signal 2) provided by CD80 (B7.1) and CD86 (B7.2) on the APC to CD28 on the ThO cell, the T cell is properly  activated. The activated T cell is induced then to differentiate into one or more different fates that depend on the local  cytokine milieu. This cytokine milieu is mainly derived from the APC itself and thus the innate immune response (boxed  area in figure). In this manner, interleukin-12 (IL-12) induces Thl cells; IL-4 induces Th2 cells; IL-23 induces tissue growth  factor (TGFfS), IL-6 and IL-1 induce Th17 cells; TGF(3, IL-6, and retinoic acid induce natural (n) T regulatory (Treg) cells; and  interferon-a (IFN-a) induces T regulatory 1 cells (Tr1). Each T cell is maintained in its differentiated state by intracellular  transcription factors. These include t-bet (Th1), GATA-3 (Th2), RORgt (Th17), and FoxP3 (nTreg). The differentiated  T cells secrete a characteristic profile of cytokines (shown above the T cells). Cells in blue are effector cells and cells in  gray are regulatory cells that inhibit inflammation. nTreg, natural T regulatory cell (see Figure 2-6).   cytokine responses (eg, increased expression of t-bet, which  is associated with Thl cells). The most definitive evidence to  date that human CD is a Thl- or Thl 7 -mediated disorder is the  efficacy of biologic therapies directed at interferon-y, IL-12, and  IL-23 in the treatment of these diseases in human clinical studies.  IL-6 is another very significant proinflammatory cytokine  that is also secreted by Thl 7 cells and activated macrophages  and is highly present in human CD tissues. As will be discussed  below, IL-6 is an important cytokine in UC, but in that case,  it is mainly derived from innate immune cells. Human clinical  trials have also investigated the efficacy of neutralization of  IL-6 by blocking the IL-6 receptor in patients with CD.   When an activated Thl or Thl7 cell interacts with a pro-  fessional APC such as a macrophage or dendritic cell, a wide  variety of cell surface interactions between these cell types is  induced to occur that are often called co-stimulatory and  activate both cell types. These include the interaction between  CD40 on the dendritic cell and CD40-ligand (CD40L) on the  activated T cell, which leads to very high levels of secretion of  TNF from the APC as well as from the activated Thl T cell.  This interaction makes TNF a very important cytokine in CD,  although it is not strictly a Thl cytokine as it also secreted by   other cell types, such as the APC. Nonetheless, it is very clear  that TNF is a central mediator of CD that is derived from Thl  and innate immune cells, and is an important therapeutic target.  Not surprisingly, a wide variety of therapies have been devel-  oped that have shown significant efficacy in the treatment of  IBD through targeting of TNF. These include infliximab, adal-  imumab, and certolizumab pegol. The mechanism by which  the anti-TNF agents induce remission is not clear but may be  a combination of neutralization of TNF itself and reverse sig-  naling through membrane-bound TNF.   Hommes DW, Mikhajlova TL, Stoinov S, et al. Fontolizumab, a  humanised anti-interferon gamma antibody, demonstrates  safety and clinical activity in patients with moderate to severe  Crohn's disease. Gut. 2006;55:1131-1137. [PMID: 16507585]   Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a  human anti-interleukin-6 receptor monoclonal antibody in  active Crohn's disease. Gastroenterology. 2004;126:989-996.  [PMID: 15057738]   Kasran A, Boon L, Wortel CH, et al. Safety and tolerability of  antagonist anti-human CD40 Mab ch5D12 in patients with  moderate to severe Crohn's disease. Aliment Pharmacol Ther.  2005;22:111-122. [PMID: 16011669]   ▲ Figure 2-4. Role of the dendritic cell in IBD. Dendritic cells are always sensing the antigens within the bacterial  milieu of the intestines. Through their innate immune function, dendritic cells then secrete cytokines that are proin-  flammatory (eg, tumor necrosis factor [TNF] and interleukin-6 [IL-6]) and others such as IL-12, IL-23 and Epstein-Barr  virus— induced gene 3 (EBI3; IL-12-like protein) that promote the development of Th1 or Th17 cells in the case of Crohn  disease or Th2-like cells in ulcerative colitis. These Th1, Th17, and Th2-like (or natural killer T [NKT] cells) secrete a  variety of proinflammatory cytokines that are shown below the relevant cells.   Mannon PI, Fuss IJ, Mayer L, et al; Anti-IL-12 Crohn's Disease  Study Group. Anti-interleukin-12 antibody for active Crohn's  disease. N Engl J Med. 2004;351:2069-2079. [PMID: 15537905]   Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al; PRECISE 2  Study Investigators. Maintenance therapy with certolizumab  pegol for Crohn's disease. N Engl J Med. 2007;357:239-250.  [PMID: 17634459]   Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study  of chimeric monoclonal antibody cA2 to tumor necrosis factor  alpha for Crohn's disease. Crohn's Disease cA2 Study Group.  N Engl J Med. 1997;337:1029-1035. [PMID: 9321530]   Targan SR, Feagan BG, Fedorak RN, et al; International Efficacy of  Natalizumab in Crohn's Disease Response and Remission  (ENCORE) Trial Group. Natalizumab for the treatment of active  Crohn's disease: results of the ENCORE trial. Nat Clin Pract  Gastroenterol Hepatol. 2007;132:1672-1683. [PMID: 17484865]   UC is a diffuse superficial disease that is confined to the  mucosa and is more commonly characterized by the pres-  ence of epithelial apoptosis and superficial ulcerations than  is observed in CD. The immunologic profile in UC is also  quite different from CD. It is characterized by cytokines that  are more commonly associated with T cells that have been   immune deviated or differentiated into so-called Th2 cells  (which secrete IL-5 and IL-13) and cytokines derived from  the activation of professional APCs that occur in response to  these activated T-cell subsets (TNF and IL-6) (see Figure 2-4).  There is strong evidence that the origin of these Th2  cytokines in UC may be due to the activity of a unique sub-  set of T cells. Specifically, animal models of UC as well as  studies in humans show that IL-13 may be primarily derived  from a unique subset of T cells that carries on its cell surface  markers of both natural killer and T cells. These so-called  NKT cells recognize a major histocompatibility complex (MHC)  class I— like molecule, CD Id, which is structurally similar to  HLA-A, -B, and -C. In the presence of CDld on an APC,  these NKT cells, which represent approximately 1-2% of  peripheral blood lymphocytes and a similarly small set of  T cells in the intestines, respond to glycolipid antigens pre-  sented by the CD Id molecule on APC. This is in marked con-  trast to the presentation of peptide antigens in the case of  classical MHC class I (HLA-A, -B, and -C) and class II (HLA-  DR, -DP, and -DQ) molecules. These studies in humans and  animal models of IBD strongly support the hypothesis that  CD Id-restricted NKT cells are responsible for the elevated IL-13  observed in UC. IL-13 is a highly inflammatory cytokine that  has a strong tendency to disrupt the intestinal epithelial cell  barrier, as do TNF and IL-6, which are also increased in UC   due to the activity of inflamed macrophages and dendritic  cells in this disease. Disruption of the epithelial barrier in UC  may be due to collateral damage from the deleterious effects of  these cytokines (TNF and IL-13). These studies also suggest  that therapies that target CDld, the NKT cell, IL-13, TNF, and  IL-6 may be important future therapies in the treatment of UC.  Studies in humans have indeed shown the efficacy of TNF-  directed therapies in the treatment of UC.   Thus, the immune pathogenesis of IBD may be derived  from a decision making process initiated by dendritic cells  that take up and respond to bacterial antigens derived from  the normal commensal microbiota. In the context of signals  derived from innate immune responses by receptors (eg, TLRs)  on the cell surface of these professional APCs, cytokines and  other factors are secreted that drive the activity and differenti-  ation of T cells within the mucosal tissues and lamina propria  and damage the epithelium. In the case of CD, dendritic cells or  macrophages, or both, respond to bacterial antigens with excess  IL-12 and IL-23 secretion leading to excessive differentiation  and activation ofThl and Thl7 cells (see Figure 2-4). Moreover,  in the case of CD, this tendency to secrete IL-12 and IL-23 in  response to commensal bacteria is likely under the control of  innate immune receptors associated with risk for the devel-  opment of IBD. For example, genetic polymorphisms in the  NOD2 gene may increase the risk of developing exaggerated  secretion of cytokines that promote Thl and Thl7 cells.  Similarly, T cells in CD may be more sensitive to cytokines  secreted by dendritic cells (such as IL-12 and IL-23) given the  detection of polymorphisms of the IL-23 receptor expressed  on T cells that determine the responsiveness of this receptor.  In a similar manner, dendritic cells in UC likely sample and  respond to bacterial antigens in a manner that leads to the  excess secretion of other cytokines that would tend to pro-  mote a Th2-like response derived from the activity of a  unique subset of T cells, the NKT cells.   Zeissig S, Kaser A, Dougan S, et al. Role of NKT cells in intestinal  immunity. Am J Physiol Gastrointest Liver Physiol. 2007;293:  G1101-1105. [PMID: 17717040]   As noted earlier, an important attribute of intestinal tissues is  the tendency to suppress immune responses (see Table 2-1).  This has been associated with the phenomenon of oral toler-  ance. Oral tolerance is thus a functional manifestation of a more  general phenomenon of suppression of immune responses in  the intestinal tissues. This tendency of the intestines to sup-  press is due to the presence of very strong regulatory path-  ways and high concentrations of regulatory molecules  derived from these cells within the intestines. Regulatory cells  that have been shown to be present in normal intestine and  highly relevant to the development of IBD include natural T  regulatory cells (CD4-positive, CD25-positive T cells),  induced T regulatory cells, T regulatory 1 cells, Th3 cells,   B cells, and possibly NKT cells and CD8-positive T cells. These  cell types either through cell surface-dependent interactions  or the secretion of soluble mediators are able to both main-  tain normal homeostasis in the baseline state and promote  the inhibition of inflammation through the secretion of a  variety of regulatory (anti-inflammatory) cytokines such as  IL-10, TGFfS, and a recently identified IL-12 family member,  IL-35. Although multiple different types of regulatory cells  exist and may be operative in the intestines, the most important,  most thoroughly investigated, and most likely to be involved  in the regulation of IBD are the so-called natural and induced  T regulatory cells; therefore, this discussion focuses mainly  on these cells.   Natural T regulatory cells are CD4-positive, CD25 (IL-2  receptor a chain)-positive cells that are differentiated within  the thymus and dependent on the expression of a unique  transcription factor called FoxP3 (see Figure 2-3). FoxP3 is  a transcription factor that is homologous to the forked winged  transcription family and induces T regulatory cell development.  In the absence of FoxP3 expression, neither humans nor mice  develop natural T regulatory cells. The human disorder IPEX  (immune dysregulation, polyendocrinopathy, enteropathy,  X-linked) is caused by FoxP3 deficiency. IPEX is characterized  by autoimmune enteropathy, protein-losing enteropathy, insulin-  dependent diabetes mellitus, dermatitis, and protracted diar-  rhea that is unresponsive to gluten withdrawal. Once educated  in the thymus, FoxP3-positive T cells are exported into the  bloodstream where they suppress the activity of effector (proin-  flammatory) T cells that have been differentiated to secrete  Thl, Th2, or Thl7 cytokines (Figure 2-5). Thus, FoxP3-positive  T regulatory cells are important in preventing autoimmunity  (including IBD), and also play a role in allergy, tumor immunity,  organ transplantation, and microbial infection.   FoxP3-positive natural T regulatory cells can be detected  in human and mouse intestines and have been strongly linked  to the regulation of inflammation that is driven by both  innate and adaptive immune pathways. In the absence of an  adequate natural T regulatory response, spontaneous inflam-  mation of the intestines will develop, as shown in patients  with IPEX. It is important to note that FoxP3-negative T cells  can also develop in peripheral tissues within the intestines  themselves to become FoxP3 -positive cells when T cells are  exposed to high concentrations of TGF|3 and retinoic acid,  which is a metabolic product derived from vitamin A. Thus,  natural T regulatory cells can be induced and recruited into  action for the amelioration of inflammation from FoxP3-  negative T cells. Although T regulatory cells have been shown  to be extremely important in the development of IBD, there  is to date no guaranteed means to influence these important  regulatory cells in a therapeutic manner, although this is an  important goal of modern immunotherapy in these diseases.  Nonetheless, studies of these very important cells shows that  IBD can evolve from either an overly exuberant T-effector cell  response or a relatively inadequate T regulatory cell response,  or both. Thus, it is the balance between these various effector  and regulatory pathways that leads to either the tendency to   ▲ Figure 2-5. Development of natural T regulatory  (nTreg) cells. nTreg cells develop within the thymus and are  induced to express the transcription factor (Foxp3) that  results in their characteristic phenotypic and functional  characteristics. They are important suppressors of effector  T cells, which play an important role in many immune-  mediated pathways, including IBD. APC, antigen-presenting  cell. (Adapted, with permission, from Sakaguchi S. Naturally  arising Foxp3-expressing CD25+CD4+ regulatory T cells in  immunological tolerance to self and non-self. Nature  Immunol. 2005:6:345-352.)   develop or the inability to prevent and thus regulate the inflam-  mation that occurs in IBD.   Although it is important to discuss regulatory pathways  in the pathogenesis of IBD, it should be recognized that a  wide variety of other regulatory pathways are normally oper-  ative in the intestines under homeostatic conditions and pre-  sumably are of significance to the dampening or prevention  of inflammation. Arguably, virtually every process in the  immunologic cascade that leads to inflammation is regulated.  A wide variety of molecules with natural regulatory properties  have been described within intestinal tissues, including  endogenous anti-inflammatory or proresolution mediators  (eg, peroxisome proliferator activated receptor y [PPARy],  lipoxins, resolvins, opioids, and cannabinoids), antiadhesion  factors (eg, apoAIV), inhibitory cytokines and suppressors  (eg, TGF(3 and suppressor of cytokine signaling), and finally  an emerging group of co-inhibiting receptors on T cells and  APCs (eg, CTLA-4, PD-1, and CEACAM1). Mesalamine has  been proposed to work through PPARy-mediated inhibition  of the translocation of a potent proinflammatory transcription  factor, nuclear factor-KB, into the nucleus. Therefore, the  range of targets that might be useful for achieving regulation   and thus remission of human IBD is enormous and repre-  sents a great therapeutic opportunity.   Coombes IL, Robinson NJ, Maloy KJ, et al. Regulatory T cells and  intestinal homeostasis, tomimo/ .Rev. 2005;204:184-194. [PMID:  15790359]   Kunos G, Pacher P. Cannabinoids cool the intestine. Nat Med.  2004;10:678-679. [PMID: 15229512]   Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory  T cell differentiation mediated by retinoic acid. Science.  2007;317:256-260. [PMID: 17569825]   Sakaguchi S. Naturally arising Foxp3-expressing CD25 + CD4 + regu-  latory T cells in immunological tolerance to self and non-self.  Nat Immunol. 2005;6:345-352. [PMID: 17659825]   Weaver CT, Hatton RD, Mangan PR, et al. IL- 1 7 family cytokines  and the expanding diversity of effector T cell lineages. Annu Rev  Immunol. 2007;25:821-852. [PMID: 17201677]   This discussion has shown that IBD emerges from a very  specific immunologic cascade of events. The initial event is  the interaction between a T cell, an APC, and an antigen  (Figure 2-6). In this interaction, an APC responds to and  takes up an antigen that is primarily derived from the com-  mensal luminal microbiota, leading to innate receptor signaling  of the APC followed by processing and presentation of nom-  inal portions of this antigen to lymphocytes via the MHC-  related molecules.   As a consequence of the cellular dialogue that occurs  between T cells and APCs, both of these cells are activated to  produce the cytokines that are characteristic of their stage of  differentiation and are stimulated to display on their cell sur-  face a wide variety of new receptors that may either promote  or downregulate their activity. In turn, the cytokines and  other soluble mediators that the activated T cell and APC are  induced to express or secrete lead to the further activation of  the endothelium.   The activated endothelium is induced to become very  sticky for other leukocytes and thus encourages the so-called  homing of T cells, monocytes, B cells, and polymorphonu-  clear leukocytes to the intestines by inducing adherence of  these leukocytes to the endothelium and their diapedesis into  the lamina propria. It should be noted that the adherence of  T cells to the endothelium occurs through specific molecules  on their cell surface (eg, an integrin called a4p7 and a  chemokine called CCR9) and corresponding molecules on  the endothelium (eg, MadCAMl), all of which are potential  therapeutic targets.   In the context of an already inflammatory milieu, these  recruited leukocytes find themselves within a highly inflam-  matory matrix that is replete with inflammatory cytokines.  This leads to a further activation of the newly recruited  leukocytes and their production of inflammatory mediators  that further aggravate the tissue destruction through production    A Figure 2-6. The immunotherapeutic target in inflam-  matory bowel disease (IBD). IBD is initiated by a unique  group of bacterial antigens that possess special qualities  that allow them to interact with innate and adaptive  immune pathways. These antigens are taken up by  antigen-presenting cells (APCs) that both respond to the  antigens (via innate immune pathways) and present the  antigens (via adaptive immune pathways) to T cells. This  leads to secretion of cytokines and upregulation of  membrane receptors, activation of the endothelium and  recruitment of inflammatory cells, and release of inflam-  matory mediators. Each level of this target is amenable  to therapy, as described in the text and Table 2-4.   of metalloproteinases and other proteases, leading to degra-  dation of the matrix and tissue destruction. Most deleterious  perhaps are the ultimate effects of these inflammatory cytokines  and mediators, including proteases and reactive oxygen metabo-  lites, which lead to disruption and degradation of the epithelial  barrier resulting in more promiscuous uptake of inflamma-  tory antigens in the context of a highly active innate and  adaptive immune system.   Given this scenario, one can understand both the mecha-  nism of action of the therapeutic agents developed to date  and the rationale for the development of new generations of  agents to treat IBD (Table 2-4). Thus, one can understand  the rationale for using probiotics to challenge the "pathogenic"  commensal bacteria and their antigens that are driving the  disease in the first instance. Similarly, it is logical to block  so-called co-stimulatory molecules that are central to the ini-  tial interactions between a T cell and an APC, such as CD28  on the T cell, through the use of abatacept, for example.  Abatacept (CTLA4-Ig), which is currently approved for the  treatment of rheumatoid arthritis, binds to CD28 on a T cell  with high affinity and blocks its co-stimulatory effect.  Blockade of CD28 signaling may also be the mechanism by  which azathioprine/6-mercaptopurine induces remission in  IBD (see Table 2-4). It is therefore obvious why anticytokine  therapies that direct themselves at blocking proinflammatory  cytokines (eg, anti-TNF, anti-IL-6, anti-IL-12, and anti-IL-23)  or promotion of anti-inflammatory cytokines (eg, IL-35 or  IL-10) are of great significance. Moreover, it is clearly benefi-  cial to disrupt leukocyte homing (eg, targeting molecules on  the surface of the sticky endothelial cells such as MAdCAMl,  or homing molecules on the leukocytes such as a4(37 on  T lymphocytes) to treat these diseases. Finally, blocking proin-  flammatory signaling and the production of inflammatory   APC, antigen-presenting cell; IFNy, interferon-y; IL, interleukin; MP, mercaptopurine; TNF, tumor necrosis factor.   mediators by inhibition of the transcription factor, nuclear  factor-KB, through administration of mesalamines has  been shown to be highly effective, especially in UC. It is,  in conclusion, very instructive to consider the immunobiology  of IBD as a means to understand the rationale for the  mechanism of action and utility of the current and emerging  biologic therapies in IBD.   Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative  colitis with a humanized antibody to the a4p7 integrin. N Engl  I Med. 2005;352:2499-2507. [PMID: 15958805]   Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis  onset with probiotic therapy: a double-blind, placebo-controlled  trial. Gastroenterology. 2003;124:1202-1209. [PMID: 12730861]   Sandborn WJ, Colombel J, Enns R, et al. International Efficacy of  Matalizumab as Active Crohn's Therapy (ENACT-1) Trial Group;  Evaluation of Natalizumab as Continuous Therapy (ENACT-2)  Trial Group. Natalizumab induction and maintenance therapy  for Crohn's disease. N Engl J Med. 2005;353:1912-1925. [PMID:  16267322]   Tilg H, Moschen A, Kaser A. Mode of function of biological anti-  TNF agents in the treatment of inflammatory bowel diseases.  Expert Opin Biol Ther. 2007;7:1051-1059. [PMID: 17665993]   Crohn disease and ulcerative colitis are chronic inflam-  matory diseases with well-described epidemiologic and  clinical features.   Genetic factors, immune dysregulation, and microbial  gut flora all influence disease susceptibility.   No single symptom, physical finding, or test result can  diagnose inflammatory bowel disease (IBD); the diag-  nosis is a clinical one based on consistent findings  obtained from the history, physical examination, and  laboratory, endoscopic, histologic, and radiologic studies.   Multiple conditions can mimic IBD; infectious pathogens  are a particular concern.   Intestinal complications commonly occur in IBD, many of  which are predictable on the basis of disease type, loca-  tion, severity, or duration; extraintestinal complications  also occur, typically in association with active disease.   Patients with long-standing colitis are at increased risk  of developing colorectal cancer (CRC) and should be  evaluated for dysplastic changes predictive of subse-  quent or synchronous malignancy.   5-Aminosalicylates, steroids, antibiotics, and  immunomodulators have been mainstays of therapy;  the choice of appropriate medication is based on multi-  ple variables, including disease type, location, and  severity.   Biologic medications offer multiple powerful therapeu-  tic options; the optimal time to apply these medications  remains to be clarified.   The inflammatory bowel diseases, Crohn disease and ulcerative  colitis, are chronic inflammatory illnesses of the gastrointestinal   tract. Although significant advancements have been made in  our understanding of the pathogenesis of these conditions,  their ultimate cause remains idiopathic. The immunologic  basis of IBD is discussed in Chapter 2. This chapter addresses  the diagnosis and medical treatment of IBD. Surgical consider-  ations are discussed in detail in Chapter 4.   Crohn disease and ulcerative colitis have low incidences of  new diagnosis; however, as a chronic condition typically  diagnosed in the young, IBD has a relatively high prevalence.  Estimates of incidence and prevalence vary among studies,  with significant geographic and socioeconomic variations.  The incidence of ulcerative colitis in North America is esti-  mated to be 8-15 per 100,000 persons, with a prevalence of  170-230 per 100,000. Crohn disease has an estimated inci-  dence of 5-15 per 100,000 and a prevalence 140-200 per  100,000. An increased incidence and prevalence of both  forms of IBD is found in developed nations, northern locale  (at least within the northern hemisphere), and urban envi-  ronments; among Caucasians; and among persons of Jewish  ethnicity. In industrialized countries, the incidence of Crohn  disease has risen significantly over the past half century,  whereas that of ulcerative colitis has remained relatively  steady. In developing countries, the incidence of both forms  of IBD has dramatically risen.   IBD typically presents at a relatively young age, often in  adolescence. The median age of diagnosis for Crohn disease  and ulcerative colitis is the third and fourth decades of life,  respectively. Studies have suggested a second, smaller peak in  incidence of IBD in the sixth and seventh decades, although  this association is clearer for ulcerative colitis than for Crohn  disease.   Sandler RS, Loftus EV. Epidemiology of inflammatory bowel dis-  ease. In: Sartor RB, Sandborn WJ (editors). Inflammatory Bowel  Diseases. Saunders, 2004:245-262.   The cause of IBD remains elusive, although interplay of  genetic, microbial, and immunologic factors clearly exists.  Twin and familial studies demonstrate a component of  genetic susceptibility. However, the concordance rates among  monozygotic twins for ulcerative colitis (6-18%) and Crohn  disease (-50%) indicate that genetics play a relatively minor  role in disease manifestation. Presumably, specific mutations  confer susceptibility to IBD but are not sufficient per se.  Various susceptibility genes have been identified, including  NOD2/CARD15 on chromosome 16 and IL23R on chromo-  some 1, in Crohn disease. Both play integral roles in immune  regulation within the gut. At the same time, mutations in  these genes are present in only a minority of Crohn disease  cases. Clearly, other less well-described dysregulations in the  gut immune defense systems exist. A more complete discus-  sion of the immunopathology of IBD can be found in  Chapter 2.   Animal studies have demonstrated that the presence of  commensal gut bacteria is necessary for IBD to occur. In the-  ory, the subsequent enteritis or colitis results from a dysreg-  ulated or inappropriate immune response to flora tolerated  by healthy individuals. Other environmental factors appear  important as well. Cigarette smoking increases the risk for  Crohn disease but is protective for ulcerative colitis. Both  oral contraceptive and nonsteroidal anti- inflammatory med-  ications have been implicated as risk factors for IBD,  although the association remains controversial. Various diets  have been proposed as causes or remedies for IBD, but no  rigorous scientific evidence supports their use.   Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association  study identifies IL23R as an inflammatory bowel disease gene.  Science. 2006;314:1461-1463. [PMID: 17068223]   Podolsky DK. Inflammatory bowel disease. N Engl ] Med.  2002;347:417-429. [PMID: 12167685]   The inflammation in Crohn disease is typically transmural.  This frequently leads to complications from perforating dis-  ease or from progressive fibrosis and stricturing. Crohn dis-  ease can thus be thought of as fitting one of three  phenotypes: inflammatory, stricturing, or perforating disease  (the latter including abscesses and fistulae). Disease behavior  is not necessarily constant in an individual patient. Indeed,  inflammatory disease frequently progresses to penetrating  disease, and then to fibrosis and stricturing.   Unlike ulcerative colitis, Crohn disease may affect any  part of the alimentary canal, and may do so in a nonconflu-  ent (so-called skip lesion) pattern. Nearly half of all patients  with Crohn disease have inflammation localized to the ter-  minal ileum and cecum (Table 3-1). Isolated small bowel or   colonic involvement is also common. Crohn disease of the  esophagus, stomach, or duodenum is rare, and virtually  unheard of in the absence of small bowel or colonic disease.  Perianal disease, including abscesses and fistulae, is com-  monly encountered, particularly in conjunction with termi-  nal ileal disease.   1. Symptoms and signs — The onset of symptoms in Crohn  disease is typically insidious, and the subsequent clinical  course highly variable. For the majority of patients, the clin-  ical course is characterized by recurring episodes of sympto-  matic disease interspersed with periods of remission.  Abdominal pain and diarrhea are the most typical symp-  toms. Unlike ulcerative colitis, the diarrhea in Crohn disease  is often nonbloody. Fever and weight loss are common. As a  general rule, the location and phenotype of disease (inflam-  matory, stricturing, or perforating), along with the severity  of inflammation, dictate a patient's symptoms and signs.   Complications from fistulizing disease are common. Pain  and drainage of purulent or fecal material are characteristic  of perianal fistulae. Fistulae from the gut may cause a variety  of symptoms, depending on the sites of origin and other  organ(s) involved: gut — diarrhea, weight loss; skin — drainage;  vagina — drainage; bladder — pneumaturia. Stricturing disease  causes obstructive symptoms of pain, abdominal distention,  nausea, and vomiting. Extraintestinal manifestations are fre-  quently encountered with Crohn disease (as with ulcerative  colitis) and are discussed in more detail below.   Signs of Crohn disease include abdominal tenderness,  most classically in the right lower quadrant. An abdominal  mass may be palpable. Temporal wasting and cachexia indi-  cate significant malnutrition. Typical symptoms of small  bowel obstruction (distention, tympany, high-pitched bowel  sounds) may be present in stenosing disease. Perianal and  cutaneous fistulae are readily identified on a careful perineal  and skin examination.   2. Laboratory findings — No single laboratory test is diag-  nostic or specific for Crohn disease. Patients are typically at  least mildly anemic, often with iron deficiency. Leukocytosis  and thrombocytosis are common and typically reflect sys-  temic inflammation. Serum albumin may be low in the case   of protein-losing enterocolitis or in malnutrition.  Malabsorption due to inflammation, bacterial overgrowth,  or surgical resection may lead to diminished levels of various  minerals (serum calcium, magnesium) and vitamins (B 12 , D,  and folate). C-reactive protein (CRP) — and, to a lesser  extent, erythrocyte sedimentation rate (ESR) — are nonspe-  cific markers of inflammation that are frequently elevated in  Crohn disease.   Stool studies may reveal excess fat, indicative of malab-  sorption, or fecal leukocytes, indicative of gut inflammation.  Fecal lactoferrin has shown early promise as a marker of dis-  ease activity. Stool studies should be negative for infectious  pathogens, including standard bacterial pathogens, Clostridium  difficile, and ova and parasites.   Various serologic markers have been linked with Crohn  disease, including antibodies to the yeast Saccharomyces cere-  visiae (ASCA), to bacterial proteins Omp-C and 12, and to  pancreas (PAB). Antineutrophil cytoplasmic antibodies  (ANCA, P-subtype) are associated with both ulcerative coli-  tis and Crohn colitis. As individual tests, these markers have  limited diagnostic accuracy, but in select situations may be  helpful in distinguishing Crohn disease from other inflam-  matory conditions.   Targan SR, Karp LC. Serology and laboratory markers of disease  activity. In: Sartor RB, Sandborn WJ (editors). Inflammatory  Bowel Diseases. Saunders, 2004:442-450.   3. Imaging Studies — Standard abdominal plain films are  useful for detecting obstructive disease and megacolon, but  otherwise have a limited role in imaging Crohn disease.  Small bowel series are useful for imaging small bowel  mucosal disease, including strictures, ulcerations, and fistu-  lae. Enteroclysis, although more sensitive, is limited by  patient discomfort, increased radiation exposure, and its  technically demanding nature. Barium enema remains an  option for imaging colonic disease, especially to help delin-  eate obstructive or fistulizing disease.   Computed tomography (CT) of the abdomen and pelvis  has revolutionized the imaging of Crohn disease by allowing  imaging of the bowel wall itself, as well as extraluminal dis-  ease such as abscesses or inflammatory masses. Common  abnormalities of the gut include thickening and excessive  mesenteric fat proliferation (so-called creeping fat). CT  enterography, which uses a special low-density oral contrast,  combines the advantages of CT and small bowel series by  allowing detailed pictures of the small bowel mucosa, while at  the same time imaging the extraintestinal abdomen. Three-  dimensional CT reconstruction allows imaging of compli-  cated transmural disease (see Figure 9-10). CT colonography  has developed as a technology, but its role in Crohn disease  remains limited in comparison to colonoscopy.   Magnetic resonance imaging (MRI) is presently less useful  than CT for cross-sectional imaging of the bowel, although  this may change with technologic advances. The principal   advantages of MRI over CT lie in superior imaging of the  pelvis and lack of ionizing radiation. Along with endoscopic  ultrasound and examination under anesthesia, MRI remains  the modality of choice for imaging perianal disease.   Colonoscopy remains a mainstay in the assessment of  Crohn disease, as it allows direct visualization of the bowel  mucosa and sampling of tissue. Hallmark findings include  ulcerations, erythema, granularity, and strictures. Pseudopolyps  may be present. Ileal ulceration and skip lesions help distin-  guish Crohn disease from ulcerative colitis. The rectum is  often spared. Fistulae are often difficult to locate endoscopically,  and are best seen by contrast studies or MRI. Endoscopic  ultrasound, as previously mentioned, is useful in delineating  perianal disease. Enteroscopy occasionally allows visualization  of proximal small bowel lesions.   Capsule ("pill") endoscopy has been revolutionary in  terms of allowing direct visualization of the small bowel in  Crohn disease. The most common finding is ulceration,  ranging from shallow aphthous-type to deep "punched-out"  lesions. Strictures may also be encountered, occasionally  causing pill retention and subsequent obstruction.   Unlike Crohn disease, inflammation in ulcerative colitis is  limited to the mucosal layer of the colon. The rectum is vir-  tually always involved, with inflammation extending proxi-  mally in a confluent fashion. The extent of proximal  involvement is variable. A significant proportion of patients  have disease confined to the rectum (ulcerative proctitis).  Roughly one third of patients have proctosigmoiditis, and  the majority of patients have gross colitis only distal to the  splenic flexure. Approximately one third of patients have dis-  ease that extends proximal to the splenic flexure (extensive  colitis), often involving the entire colon (pancolitis or uni-  versal colitis).   On occasion a so-called cecal patch of periappendiceal  inflammation is encountered. This does not represent a true  skip lesion suggestive of Crohn disease. Similarly, limited  ileal involvement (backwash ileitis) can be seen in patients  with ulcerative colitis who have pancolonic disease. Deep  ileal ulcers, long segments of ileal involvement, or stricturing  disease are consistent with Crohn disease and not ulcerative  colitis. Although confluent disease involving the rectum is  the rule in ulcerative colitis, patients on medical therapy, par-  ticularly topical therapy, may have apparent skip lesions or  rectal sparing. This should be recognized as a treatment  effect and not a manifestation of Crohn disease.   Unlike Crohn disease, ulcerative colitis is frequently acute  or subacute in onset. Like Crohn disease, the subsequent  clinical course is one of recurring episodes of symptomatic  disease interspersed with episodes of relative (or complete)  quiescence.   1. Symptoms and signs— As with Crohn disease, the  symptoms of ulcerative colitis depend on the extent and  severity of inflammation. Overt rectal bleeding and tenesmus   are virtually universally present and may be the only symp-  toms in patients with proctitis alone. When the proximal  colon is involved, diarrhea and abdominal pain are more fre-  quent complaints. Nausea and weight loss portend more  severe disease. Severe abdominal pain or fever suggests ful-  minant colitis or toxic megacolon.   Signs of ulcerative colitis include mild abdominal tender-  ness, often most localized in the hypogastrium or left lower  quadrant. Digital rectal examination may disclose visible red  blood. As with Crohn disease, signs of malnutrition may be  evident. Severe tenderness, fever, or tachycardia heralds ful-  minant disease.   2. Laboratory findings — Patients with active disease are  generally anemic and often iron deficient. Hypoalbuminemia  suggests extensive disease with subsequent colonic protein  losses. Leukocytosis, thrombocytosis, ESR, and CRP are non-  specific markers of systemic inflammation. Elevations in ESR  and CRP are less common in ulcerative colitis than in Crohn  disease.   Stool studies should be sent and found negative for typi-  cal bacterial pathogens, C difficile, and ova and parasites.  Common positive findings in ulcerative colitis include fecal  leukocytes and fecal lactoferrin.   Serologic markers have also been studied for ulcerative  colitis. P-ANCA is the most commonly associated marker.  However, as previously mentioned, it is also present in Crohn  colitis, which limits its ability to distinguish the two condi-  tions. As with markers in Crohn disease, P-ANCA may be  helpful in predicting disease activity. Studies have suggested  that P-ANCA-associated ulcerative colitis is more likely to be  medically refractory, require early surgery, and result in  chronic pouchitis in patients who have undergone ileal  pouch anal anastomosis (IPAA).   Targan SR, Karp LC. Serology and laboratory markers of disease  activity. In: Sartor RB, Sandborn WJ (editors). Inflammatory  Bowel Diseases. Saunders, 2004:442-450.   3. Imaging Studies — Plain films of the abdomen are useful  predominantly in patients with symptoms of severe or fulmi-  nant colitis. So-called thumbprinting or thickening of the  colon wall indicates severe colitis with bowel wall edema. With  toxic megacolon, the bowel is dilated with loss of haustral  markings. Intestinal pneumatosis is a late finding and signals  bowel ischemia and infarction. Obstructive findings are less  common in ulcerative colitis than in Crohn disease and usu-  ally suggest malignancy. Barium enema is less commonly used  since the advent of flexible sigmoidoscopy and colonoscopy.  Nonetheless, it can be useful for detecting active ulcerative dis-  ease, polyps, or masses. In ulcerative colitis, the colon typically  appears granular and shortened, perhaps as a consequence of  chronic inflammation or fibrosis. Pouchography (contrast  study of the pouch) in patients who have undergone IPAA  permits assessment of diseases related to this operation,  including leaks, pouchitis, fistulae, or strictures.   CT of the abdomen typically reveals colonic wall thicken-  ing, as with other forms of colitis (see Figure 9-21). Small  bowel disease is not present, other than perhaps mild ileal  inflammatory changes. Once a diagnosis of ulcerative colitis  has been made, CT has only a limited role as an imaging  modality, because endoscopic examination is typically the  preferred modality for disease assessment.   Colonoscopy allows assessment of the extent of disease  and severity of involvement. Classic findings include conflu-  ent inflammation extending proximally from the anal verge,  with mucosal erythema, edema, and granularity and loss of  normal vasculature. With more severe disease, the mucosa  becomes overtly hemorrhagic, with ulcerations and a puru-  lent exudate. So-called backwash ileitis, characterized by  mild terminal ileal erythema, is seen in patients who have  pancolitis. Pseudopolyps are commonly encountered in  patients with long-standing disease. These are polypoid  nondysplastic colonic lesions of hypertrophied tissue, often  with surrounding atrophic mucosa. They are thought to rep-  resent the sequelae of chronic recurrent inflammation and  healing, and harbor no malignant potential. Dysplastic or  frankly malignant polyps or mass lesions are also encoun-  tered at higher rates in patients with ulcerative colitis. These  lesions are discussed in more detail under Complications,  below. Both pseudopolyps and colitis-associated neoplastic  lesions are also seen in patients with Crohn disease.   Flexible sigmoidoscopy is a useful tool for disease assess-  ment in the setting of flares of colitis. In this setting, a full  colonoscopy is typically overly cumbersome for the patient  and may carry an undue risk of perforation in patients with  severe colitis. Flexible colonoscopy can assist with assessment  of disease severity and help to exclude alternative diagnoses,  such as infectious or ischemic colitis.   No single symptom, physical finding, or test result can diag-  nose IBD. The diagnosis of both Crohn disease and ulcerative  colitis is a clinical one, based on compatible patient history;  physical examination; and laboratory, radiographic, endo-  scopic, and histological findings. Diagnostic tools have been  discussed at length in the preceding sections. A detailed dis-  cussion of the histologic findings of IBD is beyond the scope  of this chapter. Noncaseating granulomas and transmural dis-  ease both are highly specific to Crohn disease. Colonic biopsies  in both ulcerative colitis and Crohn colitis demonstrate evi-  dence of acute inflammation, characterized by neutrophilic  cryptitis, and chronic inflammation, such as crypt distortion  and a plasmacytic infiltration of the lamina propria. A skilled  pathologist is indispensable in helping to characterize the his-  tologic findings and make the diagnosis of IBD.   For both the initial diagnosis and subsequent flares, other  conditions that mimic IBD should be excluded (see next sec-  tion). Of particular importance is the exclusion of infectious  pathogens, as the treatment of active IBD frequently involves  immunosuppressive medications. For patients who do not   respond to medical therapy (or worsen despite it), the diag-  nosis of IBD should be rechallenged.   Abreu MT, Harpaz N. Diagnosis of colitis: making the initial diag-  nosis. Clin Gastroenterol Hepatol. 2007;5:295-301. [PMID:  17368227]   Many medical conditions can mimic IBD clinically, radi-  ographically, or endoscopically. Infectious diseases of the gas-  trointestinal tract are of particular concern (Table 3-2). First,  they are common; second, many of the immunosuppressive   therapies directed toward IBD are potentially deleterious if  given to a patient with an infectious illness. Common enteric  bacterial pathogens, such as Campylobacter, Salmonella,  Shigella, and Escherichia coli, can cause an infectious colitis  characterized by abdominal pain, diarrhea, and hema-  tochezia. The onset is usually acute with a self-limited course.  Colitis, suggestive of ulcerative colitis or Crohn colitis, is often  apparent by CT and colonoscopy. The E coli serotype  0157:H7 is of particular note due to its propensity to produce  a hemorrhagic colitis that may closely mimic fulminant ulcer-  ative colitis. Campylobacter, Salmonella, Shigella, and Yersinia  can cause an ileitis, which may mimic the radiographic  appearance of Crohn disease. Yersinia is particularly notable  for its predilection for the terminal ileum and cecum. Gram   stains and cultures of stool are helpful for establishing the  diagnosis of bacterial colitis. However, stool cultures have  limited sensitivity, and a negative Gram stain and culture does  not rule out a bacterial infection, particularly in the setting of  a suggestive clinical history.   Clostridium difficile infection is common in IBD patients,  even among those who have not been hospitalized or recently  received antibiotics. The symptoms of C difficile infection  may be the frequent, watery stools seen in non-IBD patients.  Alternatively, infection may trigger an IBD flare, with a  patient's typical symptoms of pain and bloody diarrhea.  Thus, any patient presenting with symptoms suggestive of an  IBD flare should be tested carefully for C difficile, and if ill,  treated empirically for this until infection is satisfactorily  excluded.   Mycobacterial infections of the gastrointestinal tract,  including Mycobacterium tuberculosis, have a predilection for  the terminal ileum and cecum, and thus may mimic Crohn dis-  ease. Active pulmonary disease may or may not be present. A  patient's history usually includes travel to or immigration from  endemic areas, exposure to infected patients, or immunosup-  pression. The diagnosis may be difficult to make, as histologic  stains and cultures have limited sensitivity. Polymerase chain  reaction amplification of biopsied tissue increases the yield and  should be ordered when the clinical suspicion is high. A missed  mycobacterial infection can have severe consequences, as the  therapies frequently used for Crohn disease (ie, steroids, anti-  tumor necrosis factor [anti-TNF] agents) suppress the immune  response to mycobacterial infection.   Appendicitis and diverticulitis are commonly encoun-  tered abdominal infections, and are typically readily distin-  guished from IBD by their acute nature. However,  occasionally they have subacute presentations, in which case  they may closely resemble Crohn disease both clinically and  radiographically.   Noninfectious colitides may also mimic ulcerative colitis  or Crohn colitis. Ischemic colitis may cause pain and bloody  diarrhea. However, it is typically acute in onset, self-limited,  and localized to a specific segment of the colon. Biopsies  readily identify acute ischemic injury. Radiation can cause  proctitis, colitis, or enteritis. The injury can be chronic or  acute, with symptoms similar to IBD. The diagnosis can usu-  ally be made on the basis of history, focal area of involve-  ment, and characteristic biopsy findings. Diversion colitis is  usually obvious by history, although distinguishing it from  IBD can be a challenge when a patient with preexisting IBD  (typically Crohn disease) undergoes a diversion. Segmental  colitis is an idiopathic, recently appreciated entity character-  ized by focal colitis surrounding diverticula. Cardinal symp-  toms include rectal bleeding, abdominal pain, and diarrhea.   Gastrointestinal malignancies can manifest with symp-  toms similar to those of IBD. Adenocarcinoma of the colon  or rectum may present with rectal bleeding, altered bowel  habits, pain, and anemia. Lymphoma frequently involves the  terminal ileum and cecum, creating a clinical picture similar  to Crohn disease.   Irritable bowel syndrome is very common, and — like  IBD — typically presents in younger patients. Hallmark  symptoms include abdominal pain and diarrhea, which may  make distinguishing irritable bowel syndrome from IBD  challenging on a historical basis alone. Objective findings  such as anemia, rectal bleeding, weight loss, or fever all point  to IBD. A colonoscopy or small bowel study is helpful in doc-  umenting organic disease.   Lastly, Crohn disease and ulcerative colitis can have suffi-  cient clinical overlap to make a definitive diagnosis difficult.  The distinguishing features have already been discussed at  length. Sometimes, however, a clear diagnosis of Crohn coli-  tis versus ulcerative colitis cannot be made despite  colonoscopy, biopsies, and other appropriate studies. In this  circumstance, the term indeterminate colitis is used.   Forcione DG, Sands BE. Differential diagnosis of inflammatory  bowel disease. In: Sartor RB, Sandborn WJ (editors). Inflammatory  Bowel Diseases. Saunders, 2004:359-379.   As previously discussed, Crohn disease frequently causes  complications from penetrating and stenosing disease,  including perforation, abscess, fistulae, and obstruction.  Active small bowel disease or extensive small bowel resection  may lead to complications from malabsorption, the severity  of which depend on the location and extent of nonfunction-  ing (or surgically excised) bowel. Deficiencies in iron, folate,  vitamin B 12 , and fat-soluble vitamins (A, D, E, and K) are  common, with resulting complications including anemia  and osteoporosis. Because Crohn disease has a predilection  for the ileum, bile salt reabsorption is frequently compro-  mised. Resection of 50-100 cm of ileum typically causes bile  salts to spill into the colon, resulting in a bile-salt-induced  diarrhea (responsive to bile-acid sequestrants). If more than  100 cm of ileum is resected or diseased, reabsorption of bile  salts may be so impaired that the total pool is depleted, caus-  ing fat maldigestion and steatorrhea. Extensive small bowel  disease or resection can also lead to short gut syndrome, with  protein-calorie and micronutrient deficiency and depend-  ence on parenteral nutrition. Small bowel bacterial over-  growth frequently complicates Crohn disease, particularly in  the setting of stricturing disease or after resection of the ileo-  cecal valve.   Malabsorption of fatty acids predisposes patients with  Crohn disease to renal calculi. Calcium readily binds unab-  sorbed fatty acids, allowing oxalate to be taken up by the  bowel in greater quantity. Subsequent renal excretion of this  excess oxalate promotes the precipitation of calcium oxalate  calculi.   The acute complications of ulcerative colitis (and Crohn  colitis) are similar to that seen with other severe colitides.  Severe, life-threatening hemorrhage occurs rarely. Toxic  megacolon with subsequent infarction and perforation is   also uncommon but requires a higher degree of clinical sus-  picion to diagnose. Colonic perforation bears a high mortal-  ity rate. Hence early diagnosis and treatment is critical.   Colorectal cancer (CRC) is the most feared long-term  complication for ulcerative colitis. Risk factors include dura-  tion and extent of disease, severity of inflammation, family  history of CRC, and concomitant primary sclerosing cholan-  gitis (PSC). Early age of onset has been suggested to be a risk  factor. The excess risk of CRC appears after 8-10 years of dis-  ease. Hence, a screening colonoscopy is recommended after  8 years for patients with extensive colitis, with surveillance  examinations every 1-2 years. Unlike sporadic CRC, colitis-  associated CRC does not typically arise from adenomatous  polyps. Premalignant dysplastic epithelium may be fiat and  less readily recognized. For this reason, guidelines suggest  random four-quadrant biopsies every 10 cm throughout the  colon. Polyps should be resected and the flat mucosa at their  base biopsied. Atypical polypoid lesions should also be biop-  sied. The presence of low-grade dysplasia in flat mucosa or  any mass lesion other than a typical sporadic adenoma por-  tends a high risk for synchronous or future CRC. In this sit-  uation, colectomy is advised, although in certain scenarios  intensive surveillance may be justified.   Although less well appreciated, Crohn colitis confers a risk  of CRC comparable to that of ulcerative colitis. As with ulcer-  ative colitis, the risk is proportional to the extent of colonic  involvement. Surveillance guidelines are less well defined, but  should roughly follow those for ulcerative colitis.   Other gastrointestinal malignancies occur with increased  frequency in Crohn disease. Adenocarcinoma of the small  bowel, although rare, is significantly more common among  patients with small bowel Crohn disease than in the general  population. Crohn patients also appear to have an excess risk  of lymphoma, although the precise reason for this is unclear.  Medications for treating Crohn disease have been implicated  (see later discussion).   Pouchitis is a condition unique to patients who have  undergone an IPAA. The etiology is unknown. Bacterial flora  play a role, as evidenced by the effectiveness of antibiotic  therapy. However, pouchitis is rare among non-IBD patients  who have undergone IPAA, suggesting that other variables  specific to IBD are at play. Typical symptoms include diar-  rhea, bleeding, urgency, incontinence, fever, and general  malaise. Antibiotics (metronidazole and ciprofloxacin,  among others), budesonide, and probiotics all have demon-  strated efficacy.   IBD may also cause extraintestinal complications  (Table 3-3). PSC is linked to both ulcerative colitis and  Crohn disease. The diagnosis of PSC may precede or follow  that of IBD; symptoms and signs may arise years after colec-  tomy. In addition to being at increased risk for CRC, these  patients carry a high risk for cholangiocarcinoma. Of the  dermatologic considerations, erythema nodosum is most  common and typically responds to therapy directed toward  active bowel disease. Pyoderma gangrenosum is rarer and   more worrisome. It may occur even when IBD is quiescent  and often does not respond to front-line IBD therapies.  Dapsone, thalidomide, calcineurin inhibitors, mycopheno-  late, and high-dose corticosteroids have been used.  Dermatologic referral is suggested. Uveitis is of special con-  cern, as it can lead to blindness if untreated. Patients with eye  pain, redness, and visual disturbance require urgent ophthal-  mologic evaluation.   Itzkowitz SH, Present DH; Crohn's and Colitis Foundation of  America Colon Cancer in IBD Study Group. Consensus confer-  ence: colorectal cancer screening and surveillance in inflamma-  tory bowel disease. Inflamm Bowel Dis. 2005;11:314-321.  [PMID: 15735438]   The primary goal of medical therapy for IBD is directed  toward the relief of clinical symptoms. For both Crohn dis-  ease and ulcerative colitis, medical therapy is generally con-  sidered as a two-step approach: (1) achieving remission from  symptoms of active disease, and (2) maintaining remission.  To a large extent, the clinical presentation dictates the choice  of pharmaceutical agent. Patients with severe disease gener-  ally require more aggressive therapy, whereas patients with  milder disease may do well with less potent medications, or  no therapy at all. All medical therapeutic options carry risks  of toxicity, and this risk must be considered carefully against  the potential benefit.   The secondary goal of preventing IBD-related complica-  tions has only recently become a serious consideration. Recent  studies have suggested that medical therapy may help prevent  postoperative recurrence of Crohn disease, or reduce the risk  of CRC in ulcerative colitis. Preventing complications may also   mean avoiding medical therapies. The goal of achieving  steroid-free remission is now well-recognized in IBD care.   Sands BE. Therapy of inflammatory bowel disease: past, present,  and future. / Gastroenterol. 2007;42:16-25. [PMID: 17322989]   1. 5-Aminosalicylates — The pharmacology of 5-aminosali-  cylate (5-ASA) medications is discussed in detail under  ulcerative colitis, for which their therapeutic benefit is better  established. Studies have indicated a modest benefit of sul-  fasalazine for achieving remission in patients with colonic  Crohn disease. Other 5-ASA drugs that lack the sulfa moiety  of sulfasalazine have yielded more equivocal results, with  some studies suggesting a modest clinical benefit. Neither  sulfasalazine nor other 5-ASA agents have been shown to be  effective in maintaining clinical remission in Crohn disease.  Certain mesalamine preparations allow release of the drug in  the small bowel, theoretically allowing therapy to be directed  there rather than the colon. Unfortunately, evidence that  such treatment alters disease course is lacking. Despite the  limited evidence supporting their use, the favorable safety  profile of 5-ASA medications has made them a popular  choice for the treatment of patients with mild to moderate  disease.   2. Antibiotics — Both ciprofloxacin (500 mg twice daily) and  metronidazole ( 1-1.5 g/day) are widely used in the treatment  of mild to moderate Crohn disease. As with 5-ASA agents,  studies regarding the utility of antibiotics have shown con-  flicting results. Uncontrolled trials have suggested a clinical  benefit for these two antibiotics in colonic and perianal  Crohn disease, but convincing randomized placebo-controlled  evidence is lacking.   3. Corticosteroids — Oral and intravenous corticosteroids  are effective in inducing clinical remission in Crohn disease.  Oral prednisone (40-60 mg/day) is a common option for  patients with moderate disease. For patients with severe dis-  ease or in whom enteric absorption is a concern, intravenous  methylprednisolone (40-60 mg/day) or hydrocortisone  (200-300 mg/day) is an option. Larger dosages of steroids  have a higher risk of side effects but offer no additional clin-  ical benefit. It should be noted that even though 75-80% of  patients respond to initial therapy with corticosteroids, only  25% of patients after 1 year are well without steroids.  Seventy-five percent become either steroid refractory or  steroid dependent. Steroids do not help to heal fistulae.   Although useful in achieving remission, steroids are not  effective in maintaining it. Therefore, once a satisfactory clin-  ical response has been achieved (usually within 2 weeks),  steroids should be tapered gradually but steadily. A common  approach is to reduce the daily dose of prednisone by 5 mg  every week. The risks of chronic steroid exposure have been  well-described (Table 3-4).   Budesonide is an oral corticosteroid with significant first-  pass hepatic metabolism. As such, it offers therapy to the gut  (typical dose 9 mg/day) with reduced systemic effect. Its pre-  dominant region of effect is the ileum and right colon; it is  generally not recommended for left-sided colonic disease. Its  role is typically reserved for patients with mild to moderate  ileocecal disease. As with other steroids, budesonide has not  been shown to be useful as a maintenance medication.  Furthermore, common corticosteroid side effects may occur  (eg, osteopenia and osteoporosis) but significantly less fre-  quently than with prednisone.   Lichtenstein GR, Abreu MT, Cohen R, et al. American  Gastroenterological Association Institute medical position state-  ment and technical review on corticosteroids, immunomodulators,  and infliximab in inflammatory bowel disease. Gastroenterology.  2006;130:940-987. [PMID: 16530532]   Azathiopurine and 6-mercaptopurine (6-MP) are purine  analogs that function as immunosuppressive agents.   Azathioprine is converted to 6-MP nonenzymatically. 6-MP  is then converted via three distinct metabolic pathways to  various metabolites, including the therapeutic metabolite, 6-  thioguanine nucleotides. Both medications have been  demonstrated to be effective for achieving and maintaining  remission in Crohn disease. Moreover, they can help to heal  fistulae and minimize steroid use. They are typically reserved  for use in patients with moderate to severe disease due to  their increased toxicity profile, which includes hepatitis, nau-  sea, and pancreatitis. Perhaps the most serious common side  effect is leukopenia, which can be life threatening. Several  studies have suggested an increased risk of lymphoma,  although the absolute risk appears to be well below 1%.   Standard therapeutic dosages for azathioprine and 6-MP  are 2-2.5 mg/kg/day and 1-1.5 mg/kg/day, respectively. Over  the past several years, studies have shown that 80% of  patients will have an appropriate response to azathioprine/  6-mercaptopurine (AZA/6-MP) if a serum level of the active  metabolite (6 thioguanine, 6TGN) of the drug achieves a  therapeutic range (235-450 pg/mL). Therefore, dosage  adjustment is no longer based solely on weight. Because  another metabolite of AZA/6-MP, 6-methylmercaptopurine  (6-MMP), is associated with abnormal liver tests, it has  become routine to check the metabolite levels of AZA/6-MP  after 3-4 weeks to be sure the dose is appropriate in regard to  a therapeutic level as well as risk for liver disease.   A minority of patients carry one or more mutant alleles  in one of the genes that regulate thiopurine metabolism —  thiopurine methyltransferase (TPMT). Patients carrying this  mutation are highly susceptible to leukopenia, even with  lower doses of drug. Therefore, it is common practice to test  for this mutation prior to starting therapy with these med-  ications. Patients homozygous for TPMT mutations (1%)  should not be treated with azathioprine or 6-MP. Regular  laboratory testing for leukopenia (every 1-2 weeks for first  3 months, then every 2-3 months indefinitely) is important for  all patients (including those homozygous wild-type for  TPMT), as leukopenia can occur late in the course of med-  ical therapy.   5. Methotrexate — Methotrexate is a folate antimetabolite  that has been shown to be effective for achieving remission  when delivered intramuscularly or subcutaneously (25 mg/  week). The drug is also effective at maintaining remission  at lower doses (15 mg/week). Oral therapy has not been  shown to be effective, possibly due to decreased absorption.  Common toxicities include nausea, pancytopenia, pneu-  monitis, hepatitis, and hepatic fibrosis. Methotrexate is an  abortifacient, and should be used only with extreme caution  in women of childbearing age.   6. Anti-TNF agents (infliximab, adalimumab, certolizumab  pegol) — The introduction of infliximab, a chimeric  immunoglobulin G monoclonal antibody directed against  TNF, revolutionized the medical therapy of moderate to   severe Crohn disease. The importance of TNF as a proin-  flammatory cytokine in IBD has long been appreciated  (see Chapter 2). Administered intravenously (starting dose  5 mg/kg) at weeks 0, 2, and 6, it is effective for achieving and  maintaining remission in Crohn disease, including disease  refractory to the standard medications discussed previously.  Like 6-MP, it is steroid sparing and effective in healing fistu-  lae. Infliximab also can maintain remission in Crohn disease  (dosed every 8 weeks). However, despite an initial response  rate of 80%, by the end of 1 year only 25% of patients  remain in a complete clinical remission. For patients who are  losing response to infliximab, the dose may be increased to  10 mg/kg with no change in the infusion interval or, alter-  nately, the interval to next infusion may be shortened to  every 6 weeks.   More recently, other anti-TNF biologic agents have been  introduced (adalimumab, certolizumab pegol). All share the  same putative mechanism of action and appear comparably  effective. Both adalimumab (induction dose of 160 mg sub-  cutaneously [SQ], followed by 80 mg SQ at week 2, then  40 mg SQ every 2 weeks) and certolizumab pegol (400 mg SQ at  weeks 0, 2, and 4, followed by 400 mg SQ every 4 weeks) pro-  vide a similar response and remission rates as infliximab.  Recent multicenter trials have demonstrated that both adali-  mumab (Table 3-5) and certolizumab pegol (Table 3-6) are  effective in maintaining a clinical response in 50-60% of  patients at either 6 months or 1 year and remission in  40-50% of patients. Additionally, among patients who have  lost their response to infliximab, approximately 35% of  patients will regain response with adalimumab or cer-  tolizumab therapy over 12 weeks. Adalimumab can heal fis-  tulae in 40% of patients, and this outcome is maintained in  90% of patients over 2 years. As foreign proteins, these agents  can generate an immune response in terms of antibody for-  mation against the drug itself, particularly if administered  intermittently. For this reason, continuous therapy is the cur-  rent standard of care. Loss of response to one medication  does not necessarily mean a loss of response to the class.   Infection is the most serious complication with anti-TNF  biologic agents. Patients are particularly vulnerable to tuber-  culosis and should be screened carefully for this prior to ini-  tial administration. Patients with latent hepatitis B are  vulnerable to reactivation. Anti-TNF therapy should be held  in the setting of pyogenic infections. Concern has been raised  about possible increased risk of lymphoma, although this  remains controversial. Less serious adverse effects include  infusion or injection reactions, lupus-like reaction, and  serum sickness.   Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-necrosis  factor monoclonal antibody (adalimumab) in Crohn's disease;  the Classic-I trial. Gastroenterology. 2006;130:323.   Sandborn WJ, Feagan BG, Stoinov S, et al. PRECISE 1 Study  Investigators. Certolizumab pegol for the treatment of Crohn's  disease. N Engl} Med. 2007;357:228-238. [PMID: 17634458]   Table 3-5. Response to adalimumab (ADL) for maintenance of clinical response and remission in patients  with Crohn disease.   Data from Colombel JF, Sandbom WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with   7. Other agents — The calcineurin inhibitor tacrolimus has  demonstrated efficacy in fistulizing disease but is rarely used  in adults due to its long-term risk of renal disease and oppor-  tunistic infections. Thalidomide appears effective, in part  through anti-TNF effects, but is similarly limited by its  known toxicities. Natalizumab is an antibody directed  against oc4 integrin, designed to inhibit trafficking of leuko-  cytes. Although effective for Crohn disease, initial enthusi-  asm for natalizumab has been tempered by an apparent  associated risk for developing progressive multifocal  leukoencephalopathy. The drug is available in a strictly mon-  itored setting for select patients. MLN-02, directed against   Table 3-6. Response of patients to maintenance therapy  with certolizumab pegol (CTZP) for Crohn disease.   Data from Schreiber S, Khaliq-Kareemi M, Lawrence IC, et al; PRE-  CISE 2 Study Investigators. Maintenance therapy with certolizumab  pegol for Crohn's disease. N Engl J Med. 2007;357:239-250.   a4|37 integrin, has shown early promise. Antibodies against  interleukin (IL)-12, IL-23, and IL-17, implicated in the  pathogenesis or Crohn disease, are currently being studied as  potential therapeutic agents.   8. Surgery — Surgery in Crohn disease is frequently required  to address complications of stricturing, penetrating, or fis-  tulizing disease. Because recurrence at anastomotic sites is  common, surgery is not recommended as a primary treat-  ment strategy. Refer to Chapter 4 for detailed discussion of  surgical considerations in the treatment of Crohn disease.   Achkar IP, Hanauer SB. Medical therapy to reduce postoperative  Crohn's disease recurrence. Am J Gastroenterol 2000;95:  1139-1146. [PMID: 10811318]   1. 5-Aminosalicytes — 5-ASA medications are the mainstay  of therapy for mild to moderate ulcerative colitis. Sulfasalazine,  the original drug in this class, consists of sulfapyridine  attached to the 5-ASA moiety. The sulfa component causes  the majority of side effects from sulfasalazine (nausea, vomiting,  dyspepsia, headache, malaise). Hence, formulations consisting  solely of the therapeutic 5-ASA compound have been deve-  loped, including both orally and rectally administered prepa-  rations. These formulations have used different mechanisms   to control the site of drug delivery (Table 3-7). Medications  that release 5-ASA at more than pH 7 selectively target the  terminal ileum and colon. Those that require cleavage of an  azo-bond by bacteria release 5-ASA only in the colon.   5-ASA medications have demonstrated efficacy in both  the induction and maintenance of remission for ulcerative  colitis. In the majority of patients, they are well tolerated.  Interstitial nephritis, pulmonitis, pericarditis, rash, pancre-  atitis, or worsening of colitis occurs rarely. Patient adherence  is a concern, as many formulations require three- to four-  times-daily dosage. Rectally administered topical therapy is  highly effective for distal ulcerative colitis but has similar  problems with patient adherence.   Recent evidence has suggested that 5-ASA medications  may decrease the risk for CRC. The mechanism is unclear  but may involve decreased colonic inflammation. This  apparent protective effect suggests that chronic 5-ASA ther-  apy may be warranted not just as a maintenance drug, but as  a chemopreventative agent.   2. Corticosteroids — Much as with Crohn disease, corticos-  teroids are useful for the acute treatment of moderate to  severe ulcerative colitis. Typical starting doses of prednisone  are 40-60 mg, with methylprednisolone (40-60 mg/day) or  hydrocortisone (200-300 mg/day) reserved for hospitalized  patients. Approximately one third of patients with ulcerative  colitis require steroids. Only about 50% of patients will achieve  a remission and about 30% will have a response. However, after  1 year about 20% of patients are steroid dependent and  about 30% require surgery. As with Crohn disease, steroids  are ineffective as maintenance medications. Therefore, they  should be tapered off once a satisfactory maintenance medi-  cation has been started. Rectally administered steroid enemas  offer the benefits of steroid therapy for flares of distal ulcer-  ative colitis without the systemic side effects.   3. Thiopurines — The efficacy of 6-MP and azathioprine for  ulcerative colitis has not been extensively studied. They are   effective medications for the maintenance of remission in  ulcerative colitis, although anecdotal experience suggests that  they are less so than when used in Crohn disease. Due to  their slow onset of action, they are not appropriate as solo  induction agents for patients with severe disease, especially  in light of other available medical or surgical options. Dosing  and adverse effects are as discussed earlier for Crohn disease.   4. Infliximab — Several years after infliximab had been in  wide use for Crohn disease, it was demonstrated to be effec-  tive both for the induction and maintenance of remission in  ulcerative colitis. It offers a valuable and less toxic alternative  to cyclosporine for patients with severe disease who other-  wise would be facing surgery. The appropriate time to initi-  ate infliximab vis-a-vis steroid and thiopurine therapy  remains controversial. However, infliximab may be consid-  ered in patients who are steroid refractory or steroid depend-  ent and definitely for patients who are failing AZA/6-MP.  Dosing and toxicity has previously been discussed.   5. Cyclosporine — Cyclosporine is a calcineurin inhibitor  used as last-line medical therapy to treat hospitalized  patients with severe ulcerative colitis. Given as a continuous  infusion (2-4 mg/kg/day), cyclosporine can induce a short-  term response in 50-80% of patients. It is best begun in a  hospitalized patient who has failed intravenous corticos-  teroids in hospital within 7 days. Toxicities limit its long-  term use. Nephrotoxicity and opportunistic infections are  prime concerns. Seizures are also possible; for this reason,  cyclosporine should be avoided in patients with low choles-  terol (<100 mg/dL) or hypomagnesemia. Moreover, long-  term data suggest that half of patients treated with  cyclosporine ultimately require colectomy within 1 year.  Therefore, the risks of toxicity must be weighed carefully  against the limited long-term benefit of even short-term  cyclosporine use. Cyclosporine is not appropriate as a long-  term maintenance medication.   6. Surgery — Unlike with Crohn disease, surgery offers a  therapeutic option in ulcerative colitis. Total proctocolec-  tomy removes the diseased tissue and eliminates the need  for further medical therapy directed toward colitis. It is  indicated in fulminant disease, severe disease refractory to  maximal medical therapy, and when colitis-associated dys-  plasia or malignancy is detected. As discussed previously,  colectomy does not preclude other complications, such as  PSC or pouchitis. IPAA is the current surgery of choice in  the elective setting. Total proctocolectomy with end ileostomy  is also a reasonable choice, and may be more appropriate  given the clinical setting. Surgical considerations in the  treatment of ulcerative colitis are discussed in detail in  Chapter 4.   Ulcerative colitis and Crohn diseases are chronic, relapsing ill-  nesses that can be managed for the most part with medical  therapy. However, 75% of patients with Crohn disease can  expect to have surgery over the course of the illness; this figure  may be somewhat less with the introduction of biologic thera-  pies. The majority of patients with ulcerative colitis can be  managed using medical therapy with the prospect of surgery  reaching 25%. It is important to remember that patients with  ulcerative colitis and extensive Crohn colitis are at increased  risk for CRC when the disease has been present for more than  8-10 years, and patients must be screened by colonoscopy  every 1-2 years, depending on the extent of disease.   ► Surgery is indicated when (1) chronic intractable dis-  ease is not controlled with medication, or drug side  effects are too severe; (2) patients with severe colitis  require an urgent procedure; or (3) dysplasia or cancer  is present.   ► Most patients needing surgery are candidates for an  ileoanal pouch anastomosis (IPAA); the main consider-  ations are age, gender, type of job, and lifestyle.   ► In most patients undergoing IPAA, a temporary divert-  ing loop ileostomy is constructed to decrease the likeli-  hood of pelvic sepsis.   ► In general, surgery is indicated for complications (ie,  abscess, fistula, perforation, obstruction); considera-  tions include symptom severity, medical treatment fail-  ure or side effects, and operative risk.   ► Most patients found to have Crohn disease at laparo-  tomy for suspected appendicitis require early ileocolic  resection.   ► Perianal Crohn disease activity can be assessed using  the Perianal Crohn Disease Activity Index.   ► Surgical procedures for treatment of fistula-in-ano  include fistulotomy, long-term draining setons, and  endoanal flap closure, if the rectal mucosa is normal.   ► Recent innovative therapy for anal fistula involves  adhesive products, fibrin glue, and bioprosthetic plugs  of porcine collagen.   The term inflammatory bowel disease (IBD) encompasses a  collection of gastrointestinal diseases that medical and surgi-  cal specialists treat in a collaborative fashion. Chapter 2 dis-  cusses genetic and immunologic factors influencing the  development of IBD. Chapter 3 describes medical therapy for  IBD. This chapter discusses the indications and types of sur-  gery used for ulcerative colitis and Crohn disease.   In general, these diseases are first treated with medica-  tions, and surgery is recommended after medical therapy has  been exhausted. However, with certain presentations (eg,  anal abscess, toxic colitis) surgery is the first line of therapy,  with medication often given after a procedure. Our purpose  in this chapter is to survey the surgical procedures used in the  treatment of IBD, and to discuss indications and timings  relating to their use.   Armuzzi A, Ahmad T, Ling KL, et al. Genotype-phenotype analy-  sis of the Crohn's disease susceptibility haplotype on chromo-  some 5q31. Gut. 2003;52:1133-1139. [PMID: 12864271]   Ulcerative colitis is usually successfully treated medically;  however, it is estimated that between 25% and 45% of  patients with ulcerative colitis will ultimately require surgery.  Surgical therapy is indicated in the following three cases:  (1) in patients in whom medication is not controlling the dis-  ease, or side effects of the medication are too severe to be  endured; (2) in patients with severe acute colitis requiring an  urgent procedure; and (3) in patients with either cancer or  dysplasia of the colorectal mucosa. Given that ulcerative coli-  tis is a disease limited to the colon and rectum, one needs to  remember that it is possible to "cure" this disease with surgi-  cal intervention. Further, in most patients, success rates of  surgical therapy are high, and sphincter-sparing options exist.   Before discussing the specific indications for surgery, sev-  eral general issues relating to the patient with colitis need to  be reviewed.   1. IPAA or ileostomy? — When surgery is recommended for  a patient with colitis, the surgeon needs to assess whether the  patient is ultimately a candidate for a sphincter-sparing sur-  gery that avoids a permanent ileostomy. Most patients are  candidates for an ileoanal procedure (see later discussion),  but some are not. The main considerations in determining  whether a patient should have an ileostomy or a sphincter-  sparing procedure include age, gender, type of job, and  lifestyle. For example, an older woman who has had several  children may at presentation to the surgeon already have  some fecal incontinence issues. As difficult as it may be for  the patient's body image, recommending an ileoanal proce-  dure in this patient would do her a disservice because it is  highly likely that there would be significant fecal leakage and  hygiene issues. Further, if a patient has a job or hobby that  does not allow for access to a bathroom, an ileostomy may  provide for a better quality of life than an ileoanal procedure.   2. Emotional support and education— When surgery is  recommended, the patient — and on occasion the medical  team — may feel a sense of failure. In addition, the patient  often has a significant fear of the procedure and the possible  need for a permanent ostomy. The medical team, surgeon,  and support staff need to be cognizant of this perception.  Reassurance and education about the upcoming process is  the best approach to the patient at this time. Availability of  support staff, such as an ostomy nurse, and discussions with  previous patients who have undergone the procedure are  extremely helpful in improving the patient's outlook on the  surgery.   3. Immunosuppression— The ill colitis patient is often  referred to the surgeon after all immunosuppressive options  have been exhausted. Surgical outcomes in avoiding infec-  tion and with wound healing can be significantly affected by  immunosuppressive medications. The gastroenterologist,  surgeon, and patient should discuss whether any medica-  tions can be stopped before the procedure without risk of a  significant disease flare. It is not realistic to wean a patient off  all immunosuppressive medications prior to surgery. In par-  ticular, many patients require and should remain on corti-  costeroids if these medications are necessary to avoid a  significant exacerbation of a flare.   4. Nutrition — IBD and especially severe colitis can lead to  weight loss, protein loss, and malnutrition. Intravenous  nutrition preoperatively and perioperatively is essential in  the most severe cases. Choice of operation is also affected by  the nutritional status of the patient.   5. Medical comorbidities— Although colitis usually affects  younger patients, the medical comorbidities of the patient need  to be reviewed because they may affect the type of procedure   recommended. In particular, patients with colitis seem to have  an increased incidence of thrombotic complications in the  postoperative period; therefore, a low threshold should be set  for investigating any preoperative risk for venous thrombosis  either of the extremities or the intestinal venous system.   6. Bowel preparation — Bowel preparation is recommended  in any patient undergoing a colon resection. Recent studies  have shown that mechanical preparation is not necessarily  associated with a decreased risk of infectious complications.  These studies, however, have been performed on the "average"  colon patient and not on the subset of colitis patients with the  issues already noted. We therefore recommend, when possi-  ble, that colitis patients undergo mechanical bowel prepara-  tion followed by administration of perioperative antibiotics  to cover aerobic and anaerobic bacteria.   Ideally operations for ulcerative colitis should be performed  in a staged and deliberate manner. However, some patients  develop severe acute colitis, requiring emergent surgical  intervention.   Acute colitis is a term used to describe a series of signs and  symptoms that include rapid onset of abdominal pain, bloody  diarrhea, abdominal distention and tenderness, anorexia,  fever, tachycardia, leukocytosis, and low urine output. It is  important to remember that most of these patients use corti-  costeroids, which may mask the severity of many clinical  symptoms. Severe colonic dilation or toxic megacolon is a  feared complication of therapy that can lead to perforation,  stool spillage, sepsis, and even death. Although acute colitis  may occur in patients with known ulcerative colitis, it can also  present as the heralding sign of colonic pathology in a patient  not previously diagnosed with ulcerative colitis. Surgery is  indicated for patients who exhibit signs of visceral perforation,  generalized peritonitis, sepsis, or massive gastrointestinal  bleeding. In addition, patients who do not improve despite  maximized medical therapy after approximately 72 hours  often require emergent operation. Other patients who  improve with medical treatment while NPO deteriorate once  an oral diet is resumed; surgery is often indicated in these  patients. The differential diagnosis of acute colitis includes  Clostridium difficile infection, infectious diarrhea, and  cytomegalovirus colitis. These conditions can coexist with and  complicate ulcerative colitis. It is important to rule out these  diseases, when possible, because their successful medical treat-  ment can avoid an urgent or emergent surgical procedure. At  times, however, the combination of baseline colitis and these  secondary colitides necessitates an emergency procedure.   The choice of operation for an emergent procedure is dis-  cussed later in this chapter. In most cases, the goal of the sur-  geon is to "get in and get out." Typically, a total colectomy   with ileostomy and Hartmann pouch (the oversewed rectum)  is performed. This procedure can be completed quickly,  removes about 90% of the large intestine, and avoids a com-  plex pelvic dissection and anastomosis. The procedure also  does not close off further treatment options for the patient;  for instance, a sphincter-sparing ileoanal anastomosis can  still be performed at a later date.   Subacute colitis describes a disease pattern in which the  patient is neither acutely ill with an unmistakable indication  for resection, nor in remission and symptom free. Patients  who experience symptoms of chronic intractable disease  such as recurring acute colitis, steroid dependence, chronic  fecal urgency, growth retardation, persistent active disease, or  complications of medical therapy (eg, diabetes, hyperten-  sion, peptic ulcer disease, psychosis, myopathy, osteonecro-  sis, and cataracts) often benefit from surgical intervention.  The long-term side effects of some of the new biologic med-  ications have not yet been determined, and the patient, gas-  troenterologist, and surgeon need to balance the risks of  long-term medical therapy against those of surgery. Again, it  should be emphasized that one can "cure" ulcerative colitis  with surgery, and most patients have an excellent quality of  life without the need for medications. However, a small per-  centage of patients fail surgical therapy with a sphincter-  sparing procedure and require an ileostomy, and some  develop pouchitis, a postoperative condition that is rarely  debilitating but can require chronic treatment.   In addition to failure of medical management, dysplasia or  cancer is an indication for surgery in patients with ulcerative  colitis. Patients with IBD are at increased risk of colorectal  cancer (CRC). The risk of CRC in ulcerative colitis depends  on the duration and extent of disease. A population-based  study in the United States estimated the risk was significantly  increased in those with extensive disease or pancolitis (stan-  dardized incidence ratio [SIR] 2.4, 95% CI 0.6-6.0). In addi-  tion, patients with ulcerative colitis complicating primary  sclerosing cholangitis (PSC) may be at increased risk for  CRC compared with those without PSC. A case control study  in which cases and controls were matched for the extent and  duration of disease found that the risk of CRC was reduced  with use of anti-inflammatory agents (including aspirin,  nonsteroidal anti-inflammatory drugs, and 5-aminosalicylic  acid [5-ASA] agents) and by surveillance colonoscopy while  it was increased in patients with a history of postinflamma-  tory pseudopolyps.   Patients with disease extending to the hepatic flexure or  more proximally have the greatest risk of CRC. Compared  with an age-matched population, the risk begins to increase  8-10 years after the onset of symptoms. The approximate  cumulative incidence of CRC is 5-10% after 20 years and  12-20% after 30 years of disease. Lower rates of CRC have   also been found. In a population-based study from  Copenhagen, the risk of CRC was not different from the gen-  eral population, a finding that the authors hypothesize may  have been due to an active surgical approach in medical treat-  ment failures and long-term use of 5-ASA drugs. The highest  cancer risks have been reported by medical centers that pre-  dominantly receive referral patients who may have more  severe or long-standing disease.   In one series, the absolute risk of CRC in patients with  pancolitis was 30% after 35 years of disease. The risk was  increased in those with the onset of symptoms prior to age  15. However, in other reports, the age of onset of colitis did  not increase the risk of CRC after adjusting for the longer  period of time that young patients were at risk and the extent  of the disease.   Most studies have found that the risk of CRC increases  after 15-20 years (approximately one decade later than in pan-  colitis) in patients with colitis confined to the left colon (ie,  distal to the splenic flexure). However, rates of CRC and dys-  plasia similar to those seen in patients with pancolitis have  been described. Patients with ulcerative proctitis and proc-  tosigmoiditis are probably not at increased risk for CRC.  Although optimal surveillance strategies for colon cancer in  patients with IBD have not been established, the following rec-  ommendations for patients with ulcerative colitis have been  issued by major national medical societies in the United States.   The AGA recommends that colonoscopic surveillance begin  after 8 years in patients with pancolitis, and after 15 years in  patients with colitis involving the left colon. Colonoscopy  should be repeated every 1-2 years.   ACG recommends annual surveillance colonoscopy begin-  ning after 8-10 years of disease in patients who are surgical  candidates. Multiple biopsies should be performed at regular  intervals. The finding of definite dysplasia (of any grade)  should be confirmed by an expert pathologist and is an indi-  cation for colectomy. Patients whose biopsy specimens are  indefinite for dysplasia after review by an expert pathologist  should undergo repeat surveillance colonoscopy at a shorter  interval. The ACG recommendations do not specify whether  surveillance can begin later in patients with disease limited to  the left colon.   Velayos FS, Loftus EV Ir, Jess T, et al. Predictive and protective factors  associated with colorectal cancer in ulcerative colitis: a case-control  study. Gastroenterology. 2006;130:1941-1949. [PMID: 16762617]   The choice of operation(s) for a patient with ulcerative coli-  tis is dependent on the presenting condition (emergent vs  urgent vs elective), general issues previously discussed, and  the experience of the surgeon. There are three eventual  choices for the patient: (1) proctocolectomy and creation of   an ileoanal anastomosis with a pouch (IPAA), (2) procto-  colectomy with end ileostomy, and (3) continent ileostomy  (Koch pouch or variation).   Another surgical issue is how to stage these procedures.  Can the procedure be completed in one operation or does it  require a two-stage or three-stage approach? Finally, in  patients undergoing IPAA, should the anorectal mucosa that  lines the sphincter complex and distal rectal wall just proxi-  mal to the dentate line be "stripped," or should 0-3 cm of  this mucosa be left intact and the pouch stapled to this  anorectal cuff?   Many factors are taken into account when the surgeon and  patient choose an operation, including age, comorbidities,  patient size, extent of disease, and patient preference.  Ultimately, however, surgery results in complete removal of  the colon and rectum, and near complete removal of the prox-  imal anal mucosa, which effectively eliminates the disease.   When an emergency operation is indicated, the best surgical  option consists of total colectomy, end ileostomy, and the  Hartmann pouch (stapling or sewing off the stump of the  rectum). As mentioned, this procedure avoids a pelvic dissec-  tion, removes most of the large intestine, avoids an anasto-  mosis, and does not eliminate any downstream options. The  procedure also is used in patients in whom the diagnosis of  ulcerative colitis is not clear. If the differential diagnosis  includes Crohn disease, indeterminate colitis, or C difficile or  other infectious colitis, this procedure should be performed;  the eventual surgical choice can then be discussed after the  pathologist has been able to examine the whole specimen. On  extremely rare occasions, the surgeon's only option is a divert-  ing ileostomy. The only indication for this procedure is a  patient who is hemodynamically unstable on the operating  room table.   In the ileoanal J pouch procedure, the colon and rectum are  removed in either one or two stages, and a reservoir is created  using the distal ileum. This reservoir or pouch is then anas-  tomosed to the anus in one of two ways: either with a hand-  sewn anastomosis combined with stripping of the distal  rectal mucosa down to the dentate line, or with a specialized  stapling device that leaves 0-3 cm of distal rectum. The  pouch procedure (IPAA) is a very attractive option because it  not only removes the diseased areas, but it also allows the  patient to remain continent and conduct anal defecation. It  is usually performed as a two-stage operation: the first stage  involves a complete proctocolectomy with ileoanal J pouch  anastomosis and temporary diverting ileostomy, and the sec-  ond (final) stage, removal of the diverting ileostomy and  restoration of intestinal continuity. The IPAA can also be  performed after a patient has had emergency surgery (see  later discussion). Once a patient has recovered sufficiently,  both medically and psychologically, from an emergency total   colectomy the surgeon can proceed to removal of the  remaining rectum and creation of the pouch.   The purpose of the pouch in the IPAA is to provide a  reservoir for stool as a means of decreasing the frequency of  bowel movements. When the ileoanal procedure was first  performed, creation of the pouch was not part of the proce-  dure. Instead, the patient would have a "straight" ileoanal  anastomosis. However, stool frequency during the first year  following surgery was extremely high — as many as 20 times  per day. Although the frequency diminished after 1 year, the  pouch procedure was added to the ileoanal anastomosis to  correct this functional problem.   There are several different configurations for an ileoanal  pouch. The most common shape is the J pouch, so named  because it resembles the letter "J." The J pouch is created by  folding the end of the oversewn ileum back on itself by 12-15 cm  and then creating a common channel between the limbs via  the apex of the J. The procedure can be performed with a sur-  gical stapling device, which is quick and reliable. The pouch  has an increased capacity which then allows for a decreased  frequency of bowel movements. The J pouch is anastomosed  to the anus or very distal rectum through the opening at the  apex that had been used to create the reservoir.   Several other pouch configurations (S, W, Q, etc) exist;  however, one pouch shape rarely has an advantage over  another. The S pouch is the only other configuration that is  commonly used. To create an S pouch, the distal ileum is  folded on itself three times for 8-10 cm, with the most distal  limb having a short "spout." The spout is anastomosed to the  anus. The key technical issue with the S pouch is to make  sure the spout is not too long, since this can lead to difficul-  ties in emptying of the pouch. Typically the spout is no  longer than 2 cm.   In most patients, after creation of the pouch and the  ileoanal anastomosis, a temporary diverting loop ileostomy  is constructed. The goal is to decrease the pelvic sepsis rate  from a suture line leak either at the ileoanal anastomosis or  along the suture or staple lines of the pouch. Pelvic sepsis  rates are decreased significantly when a temporary diverting  ileostomy is used. Because pelvic sepsis can lead to poor  pouch function and in woman can lead to significant rates of  infertility, the diversion is nearly always performed (ie, in  >95% of all patients undergoing IPAA). In carefully selected  patients, however, this temporary diversion can be elimi-  nated. These patients tend to be thin, well nourished, and not  receiving immunosuppressive medications.   The IPAA is not suitable for all patients. For example, in  patients who do not have sufficient anal sphincter function,  an ileoanal J pouch may lead to involuntary soilage and leak-  age of stool. In these patients, the best surgical option is  proctocolectomy with end ileostomy. This procedure  removes all of the large bowel, including the colon, rectum,  and anal glands, which are lined with columnar mucosa,   thereby removing any subsequent risk of inflammation or  carcinoma. It is usually performed as a one-stage procedure  and, because there are no suture or staple lines, is often per-  formed without major septic complications.   The disadvantage of the procedure is that it obligates the  patient to a permanent ileostomy. Any stoma can have an effect  on the patient's body image; however, this decrease in quality of  life is counterbalanced by the overall increase in well being that  results from elimination of the disease. Additionally, for  patients who have had problems with fecal incontinence, an  ostomy can bring a significant improvement in quality of life.   Total proctocolectomy and end ileostomy is indicated in  the following cases: poor anal sphincter control, those who  need postoperative chemoradiation for cancer treatment,  body habitus (ie, obese patients) that precludes an IPAA,  prior small bowel resection, severe dysplasia in the distal rec-  tal mucosa, and patient preference.   Another surgical option for patients with ulcerative colitis is  total proctocolectomy and continent ileostomy. This proce-  dure combines a total proctocolectomy with complex pouch  and nipple configuration of the distal ileum. The nipple valve  is sutured flush with the abdominal skin, and the pouch is  then emptied using a catheter at regular intervals. Although  ideal in theory, the continent ileostomy is associated with  many complications, including fistulization, valve necrosis,  prolapse of the valve, extrusion of the valve, dessusception,  and incontinence. Additionally, the continent pouch uses sig-  nificant amounts of distal ileum and if revised or removed,  can result in significant loss of small bowel. This procedure is  usually performed only at specialized centers, and its com-  plexity and complication rate make it the third choice for  patients who need surgery for colitis.   As with all colonic surgery, laparoscopic techniques can be  applied to surgery for ulcerative colitis. The use of laparo-  scopic instruments does not, however, lead to a significant  difference in hospitalization. Although the time to discharge  may be decreased in patients undergoing a segmental colon  resection, in those undergoing total colectomy or total proc-  tocolectomy, the length of stay is often the same for both  laparoscopic and open surgery. The laparoscopic procedure  does have some advantage in cosmesis. The overall length of  the small incisions is less than the incision length for open  surgery, and sometimes the main laparoscopic incision can  be placed low on the abdomen in a transverse manner so it  can been hidden below a belt or panty line. The laparoscopic  procedure usually takes longer than open surgery and is best  reserved for thin patients who are undergoing an elective  procedure. Larson and colleagues studied the functional out-  come of laparoscopic-assisted versus open IPAA and found  equivalent results for frequency and consistency of stool,  medication usage, daytime and nocturnal incontinence, and   quality of life in regard to social, home life, family, travel,  sports, recreation, and sex life.   Larson DW, Dozois EJ, Piotrowicz K, et al. Laparoscopic-assisted  vs. open ileal pouch-anal anastomosis: functional outcome in a  case-matched series. Dis Colon Rectum. 2005;48:1845-1857.  [PMID: 16175324]   Female patients requiring restorative proctocolectomy are  usually in their reproductive years at the time of surgery.  Cornish and colleagues reviewed the effect of restorative proc-  tocolectomy on sexual function, urinary function, fertility,  pregnancy, and delivery. They found that the incidence of dys-  pareunia increases after restorative proctocolectomy. There  was a decrease in fertility, although pregnancy was not associ-  ated with an increase in complications. Vaginal delivery is safe  after restorative proctocolectomy, and pouch function after  delivery returns to pregestational function within 6 months.   Cornish JA, Tan E, Teare J, et al. The effect of restorative procto-  colectomy on sexual function, urinary function, fertility, preg-  nancy and delivery: a systematic review. Dis Colon Rectum.  2007;50:1128-1138. [PMID: 17588223]   Crohn disease can affect the entire gastrointestinal tract,  from mouth to anus. It may be confined to the colon alone  or involve only the anal canal. Segmental involvement, rectal  sparing, fistulas, perianal disease, strictures, and abscess for-  mation are all characteristic of granulomatous colitis.  Characteristic "fat creeping" (subserosal extension of fat  around the surface of the bowel) and prominent vascularity  in the serosa are characteristics of the disease seen on gross  inspection. The disease usually affects the bowel in a seg-  mental fashion, leaving so-called skip lesions. Ulcerations  and bowel wall thickening occur with areas of sparing in  between pathologic areas. Fistulas often form in Crohn dis-  ease and may involve small or large bowel, bladder, vagina,  uterus, ureter, or skin, most commonly originating from the  mesocolic (rather than antimesocolic) border of the bowel.  Histologically, the three primary findings in Crohn colitis are  transmural inflammation and fibrosis, granulomas, and nar-  row, deeply penetrating ulcers or fissures.   Although the majority of patients with Crohn disease  require surgery during the course of their disease, the indica-  tions for surgery are not completely clear-cut. In general, sur-  gery is indicated primarily for complications of the disease,  including abscess, fistula, perforation, and obstruction. The  decision to operate involves consideration of symptom severity,  medical treatment failure or side effects, and operative risks.   Ileocecal Crohn disease may masquerade as appendicitis.  Traditionally, patients found to have terminal ileitis at   laparotomy for presumed appendicitis, and who have a nor-  mal cecum, undergo appendectomy, leaving the diseased  ileum in place. However, recent studies demonstrate that the  majority of patients found to have Crohn disease at laparo-  tomy for appendicitis required early ileocolic resection;  therefore, the traditional advice to leave the diseased bowel in  place may be reconsidered.   The ileocecal region is the most common site of Crohn  disease. The diagnosis of ileocolic Crohn disease may be  delayed up to 1 year. The second surgery rate for ileocolic dis-  ease is 44% over 10 years.   The rectum and anal region can be involved in this chronic  inflammatory bowel disease (Figure 4-1), either together (as  rectal and perianal Crohn disease) or as separate entities, and  the perianal disease often heralds the onset of intestinal  symptoms of Crohn disease (see Figure 9-23). Perianal dis-  ease on its own has a better prognosis than disease associated  with rectal involvement. However, it is important that defin-  itive diagnosis be confirmed by histologic examination, as  ulcerative colitis and Crohn disease share similar features.  Perianal involvement is present in 3.8-80% of patients, as  seen in literature reviews (refer to Armuzzi and colleagues;  McClane and Rombeau, listed later), and it recently has been  cited as a distinct phenotype of Crohn disease by identifica-  tion of a susceptibility locus on chromosome 5.   ▲ Figure 4-1. Common locations of chronic anal fissures  and other anal conditions.   There is a wide spectrum of presentation of perianal dis-  ease, with the perianal skin appearing bluish in active disease.  Superficial ulcers may extend into the anal canal or be present  on edematous fleshy tags protruding from the anal verge. These  ulcers may be painless, whereas deep cavitating ones in the  upper anal canal can be painful, causing abscesses and fistulas.  The anus can be distorted with fistulating disease and is some-  times described as a "watering can anus." Pain and swelling are  common findings, and individuals with fistulas have persistent  purulent discharge, pain, and possibly bleeding as well as fever  and a preceding history of abscess development. The external  opening on the skin is evident, and on digital rectal examina-  tion, anoscopy, or proctoscopy an indurated area in the anal  canal corresponding to the internal opening may be obvious.  The involved rectal mucosa has a characteristic thickened,  nodular feel and a congested and granular appearance.   Perianal lesions are classified as primary or secondary.  Primary lesions comprise anal fissure, ulcerated edematous pile,  cogitating ulcer, and aggressive ulceration. Secondary lesions  consist of skin tags, anal or rectal stricture, perianal abscess or  fistula, fistulas of the vagina or bladder, and carcinoma.   An assessment of perianal Crohn disease activity can be  made using the Perianal Crohn Disease Activity Index  (Table 4-1), which looks at discharge, pain, restriction of  sexual activity, type of perianal disease, and degree of  induration. Other scoring systems also are available that  require additional evaluation. A thorough assessment of  intestinal pathology should be undertaken to determine the  extent and severity of the disease, because terminal ileal dis-  ease sometimes manifests as a perianal fistula, and at other  times, medical treatment of intestinal disease improves the  outcome or healing of local surgery of perianal disease.   Armuzzi A, Ahmad T, Ling KL, et al. Genotype-phenotype analy-  sis of the Crohn's disease susceptibility haplotype on chromo-  some 5q31. Gut. 2003;52:1133-1139. [PMID: 12865271]   Basu A, Wexner SD. Perianal Crohn's disease. Curr Treat Options  Gastroenterol. 2002;5:197-206. [PMID: 12003714]   McClane SJ, Rombeau IL. Anorectal Crohn's disease. Surg Clin  North Am. 2001;81:169-183. [PMID: 11218163]   Pikarsky AJ, Gervaz P, Wexner SD. Perianal Crohn disease: a new  scoring system to evaluate and predict outcome of surgical  intervention. Arch Surg. 2002;137:774-777. [PMID: 12093328]   Traditionally, owing to poor or delayed healing, a conserva-  tive approach to the management of perianal Crohn disease  has been followed. Surgical procedures range from simple  suppurative drainage to proctocolectomy and ileostomy, the  latter reserved for intractable disease or complications asso-  ciated with intestinal disease.   Indications for local surgery in perianal Crohn disease are  limited to the drainage of pus in abscesses, bothersome fistulas-  in-ano that are refractory to medical or nonsurgical man-  agement, rectovaginal fistulas, and, in severe proctitis, anal  stenosis, or severe recurrent abscesses, proctectomy.   A common emergency presentation of perianal Crohn dis-  ease is abscess formation requiring incision and drainage to  allow maximum drainage of sepsis (Figure 4-2). Appropriate  antimicrobial cover is needed when significant cellulitis sur-  rounds the abscess, or the patient is immunocompromised  or has cardiac valvular pathology. A cruciate incision or an  elliptical excision of skin overlying the area of maximum  fluctuance is undertaken under general anesthesia if the  abscess cavity is large. Any loculations are then gently broken  up with a digit, and the wound is loosely packed (Figure 4-2A).  This approach should suffice for superficial abscesses. For  deep or high abscesses, placement of a mushroom or Malecot  catheter allows adequate drainage and thus prevents prema-  ture closure of the surgical incision (Figure 4-2B).   At this time an examination to find any fistulas is under-  taken under anesthesia. Usually a probe is inserted through  the external opening to delineate the fistulous tract. If any  resistance to the passage of the probe is encountered, care is  taken to avoid creating false passages. If the internal opening  is not evident, injection of dilute methylene blue dye, milk, or  hydrogen peroxide into the external opening with an angio-  catheter may facilitate visualization. The track, if found, is  curetted, and a loose seton is inserted to allow drainage. The  seton is a thread of foreign material that is passed through a  fistula tract and tied into a loop. (Silastic tubing or a vessel  loop is preferred because they are soft and can remain in place  for prolonged periods.) Drainage of sepsis decreases the risk  of further abscess formation and avoids iatrogenic inconti-  nence due to division of any sphincteric muscle, particularly  in high anal fistula.   These simple procedures alleviate pain and improve the  quality of life in most patients. They also permit magnetic  resonance imaging or endoanal ultrasonographic imaging of  the anus to delineate more complex fistula tracks or distorted  anorectal anatomy. Later, as the sepsis resolves, a more defin-  itive surgical procedure can be undertaken.   Some patients require long-term seton drainage because  of the risk of complications that may occur with surgery (eg,  delayed wound healing and incontinence). However, healing  of the perianal pathology occurs with removal of the seton in  some patients.   Surgical procedures for treating fistula-in-ano in patients  with Crohn disease vary, depending on the severity of symp-  tomatogy and the complexity of the fistulous track. The fol-  lowing guidelines are suggested: (1) Asymptomatic fistulas  need not be treated. (2) Simple, low fistulas may be treated by  fistulotomy. (3) Complex fistulas may be well palliated with  long-term draining setons. (4) Complex fistulas may be  treated with advancement flap closure if the rectal mucosa is  grossly normal.   ▲ Figure 4-2. Surgical approach to perianal abscess drainage. A: Simple incision and drainage procedure for an  abscess. B: Incision and drainage followed by placement of a mushroom drainage catheter for an abscess.   (Reproduced, with permission, from Schwartz DA, PembertonJH, Sandborn WJ. Diagnosis and treatment of perianal  fistulas in Crohn disease. Ann Intern Med. 2001;135:906-918.)   1 . Fistulotomy — Fistulotomy involves laying open of the fis-  tula tract and merging it with the anal canal. This allows the  tissues to heal from the inside out. Primary fistulotomy in  Crohn disease patients with low, simple fistulas demonstrates  excellent healing rates, particularly in the absence of rectal  disease. The procedure is contraindicated for complex and  high fistulas where division of a large proportion of the  anorectal sphincter would be necessary.   When a fistula occurs anterior to the anal canal in a  woman, primary fistulotomy almost invariably causes some  degree of fecal incontinence. Wound healing occurs in 3-6  months, and complications of fecal incontinence and anal  stenosis have been reported. In complex cases, a more con-  servative surgical approach is taken to minimize the risk of  incontinence, by using a noncutting or draining seton.  Medical therapy can also be instituted, thus reducing the   risk of recurrence. One report found that 85% of patients  treated with noncutting setons experienced fistula closure;  however, rates of fistula recurrence may be as high as 39%  after removal of noncutting setons, highlighting the need for  concomitant medical therapy with antibiotics, azathioprine,  or 6-mercaptopurine and infliximab. More than one seton  may be placed if multiple tracts are present, although fecal  seepage and drainage along the seton can be problematic.   In patients with rectal-sparing disease, endoanal or rectal  flaps are advocated. These flaps are advantageous because  they avoid the risk of incontinence, problems of open  wounds, and possibly poor healing that may occur in the  presence of sepsis. Apart from flap failure, few complications  are seen. Thus, fistulotomy can be performed as a primary  procedure or following seton drainage with the use of flaps  or interposition grafts.   Bahadursingh AM, Longo WE. Colovaginal fistulas. Etiology and  management. / Reprod Med. 2003;48:489-495. [PMID:  12953321]   Person B, Wexner SD. Management of perianal Crohn's disease.  Curr Treat Options Gastroenterol. 2005;8:197-209. [PMID:  15913509]   Rutgeerts P. Review article: treatment of perianal fistulizing  Crohn's disease. Aliment Pharmacol Ther. 2004;20(Suppl 4):  106-110. [PMID: 15352905]   Schwartz DA, Pemberton JH, Sandborn WJ. Diagnosis and treat-  ment of perianal fistulas in Crohn disease. Ann Intern Med.  2001:135:906-918. [PMID: 11712881]   Singh B, McMortenson NJ, Jewell DD, et al. Perianal Crohn's  disease. Br J Surg. 2004;91:801-814. [PMID: 15227686]   2. Endovaginal advancement flap— An endovaginal  advancement flap consists of anal mucosa, submucosa, and  usually part of the underlying circular muscle. The base of  the flap should be twice the width of its apex to ensure ade-  quate blood supply for healing. The optimal depth of the flap  is controversial; some surgeons believe that the flap should  entail the full thickness of the rectal wall to reduce the chance  of flap failure. The fistula tract is cored out or curetted before  mobilization and suturing of the flap distal to the internal  opening of the fistula is carried out. Any secondary tracts can  be treated by curetting or laying open the tract.   A curvilinear mucosal flap is most commonly used. It  involves a semicircular incision starting at the dentate line  and continuing proximally for 4-5 cm. The fistula tract is  cored out and the fistula is closed in layers, with mobilization  of the flap. The diseased distal portion of the flap is trimmed  before the flap is sutured to the mucosal edge of the anus.   If the location of the fistula is high, or there is too much  tension on the flap, a linear mucosal flap is used. In this  repair, the fistula tract is excised in a linear fashion perpen-  dicular to the dentate line. The defect is closed in layers. The  mucosa and submucosa are mobilized on each side and  sutured together.   An anocutaneous flap is another option for closing the  internal opening. It has the theoretical advantage of not  involving any sphincter and can be a more feasible option  than an endoanal flap if the internal opening is located dis-  tally or if the anal canal is changed by stenosis or scarring  after previous surgery or inflammation. The sleeve  advancement flap originally described by Berman has also  been used to treat anal stricture and a combination of rec-  tal and perianal fistulas.   Using these variations of flaps, healing rates of 68% have  been achieved for a curvilinear rectal flap in scenarios of  minimal rectal-sparing disease and for rectal ulceration, a  sleeve flap and a linear flap for high rectovaginal fistula.  Based on a literature review, Sher and colleagues advised  using a transvaginal approach to develop a vaginal flap with  a protective defunctioning ileostomy for the management of  rectovaginal fistula in patients with Crohn colitis. They  achieved a success rate of 93% in their series of patients. In   cases of high rectovaginal or colovaginal fistula, an approach  via the abdomen would be preferable. However, in intractable  disease some women may choose to accept residual fistula  drainage over proctectomy or stoma formation.   Bahadursingh AM, Longo WE. Colovaginal fistulas. Etiology and  management. / Reprod Med. 2003;48:489-495. [PMID:  12953321]   Hull TL, Fazio VW. Surgical approaches to low anovaginal fistula  in Crohn's disease. Am J Surg. 1997;173:95-98.[PMID:  9074371]   Sher ME, Bauer JJ, Gelernt I. Surgical repair of rectovaginal fistu-  las in patients with Crohn's disease: transvaginal approach. Dis  Colon Rectum. 1991;34:641-648. [PMID: 1855419]   Singh W, Draganov P, Valentine J. Efficacy and safety of endo-  scopic balloon dilation of symptomatic upper and lower gas-  trointestinal Crohn's disease strictures. / Clin Gastroenterol.  2005;39:284-290. [PMID: 15758621]   3. Fecal diversion — Diversion of the fecal stream by the cre-  ation of an ileostomy or a colostomy has been employed to  manage anal fistulas in Crohn disease, an approach first  reported by Truelove. A loop defunctioning stoma, which  should be easy to reverse, is constructed either laparoscopi-  cally or by open surgery. The decrease in fecal flow through  the rectum and across the fistula tract allows the rectal  mucosa to heal and the fistula to close. Creation of the stoma  may improve the results of subsequent anal procedures, and  also allows the patient to adjust to the prospect that life with  a stoma is feasible. Symptomatic improvement after diver-  sion is not predictable, and new manifestations of perianal  Crohn disease can develop. Approximately 50% of patients  with symptomatic perianal Crohn disease require permanent  fecal diversion.   There are limited indications for fecal diversion in Crohn  disease. These include severe perianal sepsis, deep persistent  anal ulceration, and complex anorectal or rectovaginal fistula,  as well as complications refractory to medical and local surgi-  cal measures. In some patients, fecal diversion can be consid-  ered before commencement of combination medical therapy.  Initially there is a high rate of perianal healing with reversal of  the stoma in patient with rectal-sparing disease. However, in  individuals with rectal or colonic Crohn involvement, restora-  tion of bowel continuity almost invariably leads to recurrence  of perianal symptoms, eventually necessitating proctectomy.   2005;241:796-801. [PMID: 15849515]  Yamamoto T, Allan RN, Keighley MR. Effect of fecal diversion alone   Patients with active anorectal disease that fails to respond to  medical and previous surgical therapy may require proctec-  tomy with end colostomy. Rates of 10-18% have been   reported. Patients who also have colonic involvement  require proctocolectomy with permanent end ileostomy. In  ill or high-risk patients, this may be performed in two  stages, with colectomy and end ileostomy comprising the  first procedure, followed by completion proctectomy. In  contrast to an abdominoperineal resection for rectal cancer,  an intersphincteric dissection may be considered for the  perineal component, as this leaves a smaller, more vascular-  ized wound that heals with less morbidity. However, deep  fistulating disease or sepsis may make this impossible. When  a tension-free closure is not possible, the use of rectus  abdominus, gluteal myocutaneous, and gracilis transposi-  tion flaps promote healing.   A recognized complication of proctectomy is a persistent  perineal sinus. In such cases, it is important to rule out pelvic  sepsis or an enteroperineal fistula, which would require  resection of the affected bowel. Some patients experience  phantom sensations post-proctectomy that are analogous to  those occurring after limb amputation. Explanation and  reassurance is usually sufficient to allay patients' concerns.  Persistent perineal pain post-proctectomy can be trouble-  some and may be caused by a neuroma.   Patients with long-standing Crohn disease, like those  with ulcerative colitis, are at increased risk (3.7%) of devel-  oping adenocarcinoma as well as squamous cell carcinomas.  This increased risk has been attributed to an early onset and  prolonged duration of disease. The incidence of carcinoma is  0.7% in patients with perineal Crohn disease. Patients with  adenocarcinoma require proctectomy. Those with squamous  cell carcinoma may be considered for chemoradiotherapy;  however, the functional outcome may be unsatisfactory.  Therefore, proctectomy may be the preferred option. The  diagnosis is usually made based on examination of biopsy  specimens and brushings of the curetted fistulous tract.   Rius J, Nessim A, Noguerasa JJ> et al. Gracilis transposition in com-  plicated perianal fistula and unhealed perineal wounds in Crohn's  disease. Eur J Surg. 2000;166:218-222. [PMID: 10755336]   Recent innovative therapy involves the use of adhesive prod-  ucts. Several studies have reported on fibrin glue treatment  of anal fistula using both autologous fibrin tissue adhesives  and commercially available fibrin glue. The adhesive is  instilled in the fistula tract after curetting, and sometimes  irrigation of the tract, to allow glue adhesion to the tissue.  Insertion of the fibrin glue is continued until glue appears at  the internal opening of the fistula. The sealant not only acts  as a closing plug for the fistula, but also as the substrate for  the in-growth of fibroblasts. The technique is not suitable for  fistulas with extensions.   The reported success rates in patients have varied from  40% to 85%, with a mean of 67% for the various materials.  Recently Buchanan and colleagues reported long-term healing  of only 14%, whereas Sentovich showed a healing rate of 60%   when all patients had a draining seton preoperatively and the  internal opening was closed with a suture at the time of glue  instillation. In a later review by Swinscoe and colleagues of  12 studies, the overall healing rate was 53%. However, in  patients with Crohn disease, fistula results have been consider-  ably lower. The use of human granulocyte colony-stimulating  factor instead of fibrin glue has been shown to heal perianal  Crohn-associated fistula in some patients.   Johnson and colleagues recently introduced a new  method of closure for anal fistula with a bioprosthetic plug.  The conically shaped plug, made of porcine collagen, is  pulled into the primary tract through the internal opening  until it fills out the whole length of the tract. Both ends of the  plug are secured with sutures and at the internal opening, the  end of the plug is covered with mucosa and also preferably  with internal sphincter. The remaining external opening is  left open for drainage. Champagne and colleagues reported a  success rate of 83% with a median follow-up of 12 months  for high cryptoglandular anal fistulas, and the method has  also been used in a smaller group of patients with Crohn fis-  tulas reported by O'Connor and colleagues. However the  exact place that these modalities have in the management of  Crohn fistula remains unclear, and their use does not pre-  clude surgical procedures should the treatment fail.   Asymptomatic fissures, hemorrhoids, and skin tags in  Crohn patients should be left alone and if surgery is  requested, the patient should be informed of complications  such as poor healing, stenosis, incontinence, and ulcer for-  mation. Anal ulcers are likely to be worsened by surgery, and  a trial with medical therapy should be instituted to promote  healing. In refractory symptomatic anal fissures without  proctitis, lateral sphincterotomy is indicated. Symptomatic  strictures should be cautiously dilated with Hegar dilators or  an endoscopic balloon, as perforation is a risk. The stricture  may be primary or occur as a complication of anorectal or  ileal pouch surgery performed on the basis of an incorrect  preoperative diagnosis of ulcerative colitis or indeterminate  colitis. Severe strictures that do not respond to dilation may  require an advancement flap (in low anal strictures) or ulti-  mately fecal diversion or proctectomy (in anorectal stenosis).   Given the unpredictable disease process of perianal  Crohn fistulas and the variety of surgical options, manage-  ment should be individually tailored, using a combined med-  ical and surgical approaches to offer the patient an improved  quality of life.   Buchanan GN, Bartram CI, Phillips RK, et al. Efficacy of fibrin  sealant in the management of complex anal fistula: a prospective  trial. Dis Colon Rectum. 2003;46:1167-1174. [PMID: 12972959]   Champagne BJ, O'Connor LM, Ferguson M, et al. Efficacy of anal fis-  tula plug in closure of cryptoglandular fistulas: long term follow-  up. Dis Colon Rectum. 2006;49:1817-1821. [PMID: 17082891]   Cintron IR, Park J J, Orsay CP, et al. Repair of fistulas-in-ano using  fibrin adhesive: long-term follow-up. Dis Colon Rectum.  2000;43:944-949. [PMID: 10910240]   Johnson EK, Gaw JU, Armstrong DN. Efficacy of anal fistula plug  vs. fibrin glue in closure of anorectal fistulas. Dis Colon Rectum.  2006;49:371-376. [PMID: 16421664]   Lindsey I, Smilgin-Humphreys MM, Cunningham C, et al. A ran-  domized, controlled trial of fibrin glue vs. conventional treatment  for anal fistula. Dis Colon Rectum. 2002;45:1608-1615. [PMID:  12473883]   Loungnarath R, Dietz DW, Mutch MG, et al. Fibrin glue treatment  of complex anal fistulas has low success rate. Dis Colon Rectum.  2004;47:432-436. [PMID: 14978618]   O'Connor L, Champagne BJ, Ferguson MA, et al. Efficacy of anal  fistula plug in closure of Crohn's anorectal fistulas. Dis Colon  Rectum. 2006;49:1569-1573. [PMID: 16998638]   Sentovich SM. Fibrin glue for anal fistulas: long-term results. Dis  Colon Rectum. 2003;46:498-502. [PMID: 12682544]   Swinscoe MT, Ventakasubramaniam AK, Jayne DG. Fibrin glue for  fistula-in-ano: the evidence reviewed. Tech Coloproctol.  2005;9:89-94. [PMID: 16007368]   High fever, frequent bloody stools, severe abdominal  pain, dehydration, and no improvement after 3-4 days  of initial supportive treatment are worrisome features.   Sigmoidoscopy and biopsy are indicated in patients  with bloody dysenteric stools and tenesmus lasting  more than 3-4 days.   Upper endoscopy and biopsy are indicated in patients  with persistent diarrhea and evidence of malabsorption.   Routine stool cultures aid in identifying Salmonella,  Shigella, and Campylobacter but rarely provide  useful information if diarrhea develops 2-3 days  after hospitalization.   Clinical features of shigellosis, salmonellosis, and  Campylobacter colitis (diarrhea, tenesmus, fever,  abdominal cramps) often overlap.   Consider Clostridium difficile infection after both recent  and remote (within 3 months) use of antibiotics and if  diarrhea develops during hospitalization.   Risk factors for severe C difficile infection include age  >65, renal failure, immunosuppression, and white  blood cell count >20,000/ul.   Consider enterohemorrhagic Escherichia coli (F coli  0157:H7) in patients with bloody diarrhea, abdominal  pain, leukocytes, and little or no fever, especially if uremia  or microangiopathic anemia develop; if suspected,  avoid antibiotics.   Giardiasis is best diagnosed using stool enzyme-linked  immunosorbent assay (ELISA) directed against Giardia  antigens.   Up to 10% of patients who have had traveler's diarrhea  may develop a postinfectious irritable bowel syndrome.   Acute diarrheal diseases remain a major global public health  problem, responsible for an estimated two million or more  deaths annually. Most deaths occur in developing countries  and many occur in infants and young children. The majority  of acute diarrheal episodes reflect gastrointestinal infections,  but medications, food intolerances, or the abrupt onset of  chronic disease may be causative (Table 5-1). In the United  States, acute diarrheal diseases are a major health and eco-  nomic problem resulting in between two million and four  million total episodes, 900,000 hospitalizations, and approx-  imately 6000 deaths per year.   Acute diarrheal diseases are second only to respiratory  infections as a cause of time lost from work in the United  States. As a symptom, diarrhea can be defined as an increase  in frequency, volume, and often urgency of the passage of  stool and as a decrease in stool consistency. More objectively,  as a sign diarrhea is an increase in stool mass to greater than  200 g/24 h, the upper limit of normal stool weight. Acute  diarrheal disease is generally defined as having begun within   Thielman NM, Guerrant RL. Clinical practice. Acute infectious diar-  rhea. N Engl J Med. 2004;350:38^7. [PMID: 14702526]   Under normal circumstances, adults ingest approximately 2 L  of fluid per day. An additional 7 L of endogenous secretions  from salivary, gastric, pancreatic, biliary, and enteric sources  enter the intestine for an approximate 24-hour load of 9 L.  Ingested nutrients are dissolved or suspended in this 9-L fluid   load. The healthy small intestine will absorb about 7.5 L,  largely in the duodenum and jejunum. Of the 1.5 L that tra-  verse the ileocecal valve, the colon absorbs approximately  1 . 3 L, resulting in a stool mass of no more than 200 g/24 h. The  maximum absorptive capacity of the small intestine is about  12 L and that of the colon, 4-6 L, for a total of 18 L; roughly  double the normal daily fluid load.   An increased fluid load sufficient to overwhelm the intestinal  and colonic absorptive capacity of about 12 L usually results  in diarrhea. Excessive endogenous fluid secretion is the usual  culprit, but excessive fluid intake may contribute. Examples  of diseases that cause diarrhea by excessive secretion include  cholera, toxigenic E coli infection, or a vasoactive intestinal  peptide-secreting tumor.   Epithelial cell absorptive and digestive function in the  small and large intestine is impaired and permeability of the  epithelial barrier is increased by the mucosal damage caused  by a variety of gastrointestinal viral, bacterial, and protozoal  infections and protozoal infestations. In addition, the available   absorptive surface may be reduced as in, for example,  rotavirus and norovirus enteritis and in giardiasis. Increased  intraluminal osmolality is a cause of acute diarrhea.  Ingestion of poorly absorbed or nonabsorbable laxatives  such as magnesium citrate or magnesium hydroxide or  polyethylene glycol 3350 are the classic examples, but  impaired nutrient absorption in some intestinal infections  contributes to diarrhea by increasing intraluminal osmolal-  ity. All of the mechanisms detailed above may be causative in  acute diarrheal diseases in which there is substantial  mucosal inflammation as occurs in most invasive and some  toxigenic bacterial enterocolitides. If mucosal inflammation  is mild or absent, as in cholera, enhanced fluid secretion,  altered permeability, enhanced motility, or, in the case of  laxative ingestion, increased intraluminal osmolality are the  major mechanisms.   A careful history and physical examination are crucial in the  evaluation of patients presenting with acute diarrhea and  should provide information as to the possible nature,  underlying cause, and severity of the diarrhea. Historical  points that should be explored include (1) any recent travels;  (2) the nature of recent food ingestion, including type and  preparation (fully cooked, rare or raw), location (home,  restaurant, street vendor); (3) occurrence of a similar illness  among recent contacts; (4) medication history, especially new  medications or past or current use of antibiotics; (5) sexual his-  tory; and (6) predisposing conditions, such as compromised  immune status.   The character of the diarrhea also provides clues as to the  site of involvement by the process causing the diarrhea. A  large stool volume with little urgency, no tenesmus, and only  a moderate increase in stool number suggests involvement  primarily of the small intestine and more proximal colon  whereas frequent, low-volume dysenteric stools containing  blood and mucus associated with urgency and tenesmus sug-  gest disease involving the rectum and distal colon. Although  a patient's subjective description of the nature of the diarrhea  is helpful, examination of the stool by the clinician is most  useful.   On physical examination, the presence or absence of  fever should be determined. Hypotension, orthostasis,  tachycardia, poor skin turgor, and dry mucous membranes  indicate dehydration, a major cause of morbidity and mor-  tality in acute diarrheal diseases, especially in the young and  the elderly. A careful abdominal examination is essential to  assess for evidence of localized abdominal infections (eg,  appendicitis or diverticulitis) that may be associated with  diarrhea. The abdomen should also be assessed for disten-  tion, which might suggest megacolon, and for the presence  of peritoneal signs.   Centers for Disease Control and Prevention. Diagnosis and man-  agement of foodborne illness, a primer for physicians. MMWR  Recomm Rep. 2004;53:1-40.   The majority of patients with acute diarrhea in developed  countries have relatively mild, self-limited illness, which  resolves in a day or two and requires no specific diagnostic  studies. A major goal of the initial assessment, including the  history and physical examination, is to identify patients who  have more serious disease meriting prompt and specific diag-  nostic studies and aggressive treatment (Figure 5-1).  Worrisome features include high fever, dehydration, frequent  bloody stools with tenesmus (dysentery), severe abdominal  pain, an immunosuppressed host, and no improvement in or  progression of symptoms after 3-4 days of supportive treat-  ment (see Figure 5-1). Useful tests for further evaluation  include assessment of stool for fecal leukocytes, stool culture,  blood culture, stool examination for ova and parasites, stool  testing for C difficile toxin, endoscopy and mucosal biopsy,  and, in highly selected cases, abdominal imaging studies.   1. Fecal leukocytes and stool lactoferrin— Examination  of stool suspensions stained with methylene blue for the  presence of fecal leukocytes is a time-honored test for evalu-  ation of patients with acute diarrhea. Neutrophils are usually  present in patients with dysenteric stools (containing blood  and mucus) caused by infection with invasive bacteria  (Table 5-3) and colitides unassociated with infection, as can  occur in acute onset or during acute exacerbations of inflam-  matory bowel disease (IBD). In other words, the presence of  neutrophils indicates the presence of an inflammatory colitis  or enterocolitis but not its cause. Thus, the test lacks speci-  ficity for infectious colitis and its reported sensitivities for  invasive bacterial infections is only in the range of 60-70%,  in part because the presence of neutrophils in stools is vari-  able in patients with diarrhea caused by Salmonella or  Yersinia infection. Fecal leukocytes are usually absent from  the watery stools caused by viral infections and toxin-  producing bacteria with exceptions being C difficile- and  cytomegalovirus -induced enterocolitis, in which fecal neu-  trophils may be present (see Table 5-3).   Despite its limitations, fecal leukocyte testing remains  worthwhile and, if positive, helps select patients who merit  more extensive diagnostic evaluation and possibly empiric  antibiotic therapy. Fecal lactoferrin, a surrogate marker for fecal  neutrophils, can be measured using a latex agglutination assay.  The test has been used most widely in assessing patients with  IBD. It appears to be more sensitive, less observer-dependent,  but more costiy than the conventional fecal leukocyte assay.  Falsely positive results may occur in breast-fed infants.   2. Stool culture — The indications for and cost-effectiveness of  obtaining stool cultures from patients with acute diarrhea are  still being debated. However, there is general consensus that too   Consider empiric  antiobiotics (see text)  or targeted therapy  when specific  diagnosis is made   ▲ Figure 5-1. Algorithm showing the approach to the  patient with acute diarrhea. O&P, ova and parasites.   many are obtained. Most surveys report an incidence of positive  stool cultures in only 1.5-3% of submitted stools with an esti-  mated cost of more than $ 1000 per positive culture. As indicated  earlier, most episodes of acute diarrhea are self-limited and  resolve within 48-72 hours, often before the results of a stool  culture are available. Stool cultures are rarely informative in  nonimmunosuppressed patients who develop diarrhea 3 or  more days after hospitalization.   a Fecal leukocytes are also present in noninfectious colitides such as active ulcerative colitis.   Stool cultures should be obtained from patients with  severe dehydration, fever exceeding 102°F (38.9°C), dysenteric  stools, and stools that contain neutrophils, and from those in  whom the culture may ultimately guide therapy. Stool cultures  should also be obtained from all immunosuppressed patients  who develop diarrhea or patients with other severe comor-  bidities, including idiopathic IBD. Stool cultures should be  obtained for epidemiologic purposes if an outbreak of diar-  rheal disease is suspected.   Once obtained, the stool specimen should be sent to the  laboratory as soon as possible to minimize false-negative  results. The clinician should also be cognizant of which  organisms are identified by the particular laboratory per-  forming the culture. In some laboratories, only Salmonella,  Shigella, and Campylobacter are identified during routine  processing. Hence, the clinician should specify other organ-  isms if suspected, such as Yersinia, enterohemorrhagic E coli  (EHEC), Aeromonas, or noncholera Vibrio, so that proper  media and culture conditions are used.   3. Blood culture — Blood cultures should be obtained from  patients with high fever, shaking chills, and those who are  immunosuppressed.   4. Stool examination for ova and parasites— The yield  of positive examinations for ova and parasites is low  among patients with acute diarrhea as most parasitic infes-  tations that cause diarrhea cause symptoms lasting several  weeks or more. Indications for assessment include diarrhea  that persists for more than 2 weeks, a history of travel to  areas endemic for parasitic disease, exposure to children in  daycare centers or summer camps, a concomitant history  of immunosuppression (HIV, chemotherapy, immunosup-  pressive drugs, known idiopathic IBD, homosexuals, and  unexplained peripheral eosinophilia). As ova and parasites  can be passed intermittently, optimal testing requires  prompt examination of each of three specimens collected  on separate days.   5. Clostridium difficile toxin— The recently reported ris-  ing incidence and increased morbidity and mortality of  C difficile colitis (see later discussion) underscores the importance  of C difficile toxin testing of the stool for timely diagnosis and  implementation of therapy for this important disease. Groups  at risk and, hence, indications for the test, include patients  who have received recent or even distant antibiotic therapy,  patients who develop diarrhea in a hospital or other institu-  tional setting, immunosuppressed patients, and patients with  idiopathic IBD.   The cytotoxicity assay using cultured fibroblasts remains  the gold standard for testing for C difficile toxin, with sensitiv-  ity exceeding 90% and almost absolute specificity. However, the  test is costly and requires 2-3 days for completion. Also avail-  able are several less-expensive enzyme-linked immunosorbent  assays (ELISAs) for stool C difficile toxin, which are somewhat  less sensitive but provide a result within 1 day.   Sigmoidoscopy and biopsy can be very useful in selected  patients with acute diarrhea. Sigmoidoscopy is indicated in  patients with bloody, dysenteric stools and tenesmus lasting  more than 3-4 days. The endoscopic appearance of the  mucosa is often indistinguishable in patients with acute  infectious diarrhea caused by invasive organisms compared  with patients with idiopathic IBD, but in such patients, it  provides some information as to extent and severity of dis-  ease. Additionally, rectosigmoid biopsies may help distinguish  acute infectious diarrhea from diarrhea caused by an acute flare  of IBD (Plates 1 and 2). Sigmoidoscopy can also help to exclude  ischemic colitis, which may present with abdominal pain and  bloody diarrhea. Sigmoidoscopy can provide a rapid, tentative  diagnosis of C difficile colitis if the characteristic pseudomem-  branous lesions are present. Additionally, sigmoidoscopy can  provide rapid diagnosis of amoebiasis if secretions from the  edge of ulcers are examined microscopically and the organism   is seen. Mucosal biopsy from immunosuppressed patients may  detect cytomegalovirus or herpetic proctocolitis. Upper  endoscopy is indicated in patients with persistent diarrhea and  malabsorption and, through examination of duodenal aspi-  rates and mucosal biopsies, may detect parasitic infections  including giardiasis, cryptosporidiosis, Isospora infection,  and occasionally strongyloidiasis.   Imaging studies are usually not required in patients with  uncomplicated acute diarrhea. An abdominal flat and upright  film maybe useful if there is worrisome abdominal distention  in order to screen for toxic megacolon, which can occur in  C difficile colitis and colonic amoebiasis. On occasion, com-  puted tomography (CT) or ultrasound scan of the abdomen  and pelvis may be indicated, if there is associated severe  abdominal pain, tenderness, or evidence of peritoneal irrita-  tion, to exclude a focal intra-abdominal or pelvic process.   Some general principles of treatment of acute diarrhea are  summarized next. When specific therapy of a defined cause  of acute diarrhea is indicated as, for example, for C difficile  colitis, such treatment is described later, in the section enti-  tled "Acute Diarrheal Disease Caused by Specific Infections."   Oral rehydration therapy will suffice in most patients who  develop acute diarrhea. In milder cases, juices, broth, and  water along with salted crackers usually suffice. If dehydra-  tion is more severe, oral rehydration fluids should be utilized.  The World Health Organization (WHO) recommends the  following formula per liter of water:   Several oral rehydration solutions in addition to that rec-  ommended by the WHO are commercially available.  Rehydrate closely mimics WHO oral rehydration solutions,  whereas others (Pedialyte, Enfalyte) contain less sodium and  may require intake of a larger volume. Maintaining a 1:1  molar ratio of sodium to carbohydrate facilitates sodium  transport in diarrheal diseases in which sodium-glucose co-  transport mechanisms remain intact as, for example, in  cholera or enterotoxigenic E coli (ETEC) infection. Some cli-  nicians favor preparations formulated with complex carbo-  hydrates such as rice-based solutions (CeraLyte).   Intravenous hydration is often overutilized in developed  countries such as the United States. However, if diarrhea is   massive and dehydration severe, especially in infants and young  children, the elderly, and patients unable to rehydrate orally  due to nausea, vomiting, or other comorbidities, intravenous  rehydration is indicated. Serum electrolyte levels should be  closely monitored and imbalances corrected.   Sentongo TA. The use of oral rehydration solutions in children and  adults. Curr Gastroenterol Rep. 2004;6:307-313. [PMID:  15245700]   The antimotility agent loperamide can be used with caution  to provide symptomatic relief in patients without high fever,  colonic distention, or dysenteric stools. The usual dose is 4 mg  initially followed by 2 mg every 4-6 hours, as required for  persistent diarrhea, not to exceed 10 mg/24 h. Absorption  may be increased by prolonging contact time of luminal con-  tents with mucosa, although oral fluid intake should be con-  tinued as fluid may pool in the gut lumen. Diphenoxylate has  also been used but is less desirable as it crosses the blood-  brain barrier and has central opiate actions. No antimotility  drug should ever be used if the possibility of toxic megacolon  is a concern. Moreover, there is some evidence that suggests  that the use of antimotility agents, while reducing the number  of stools, may prolong the course of some enteric infections,  including those caused by noroviruses and ETEC, perhaps by  prolonging the time required for clearance of causative  organisms and toxins from the gut. Bismuth subsalicylate  reduces stool number but there is no evidence that fecal fluid  losses are decreased significantly.   Although a controversial topic, antibiotics are overutilized in  acute infectious diarrhea. Most episodes are self-limited and  clear within 2-4 days or less without specific therapy; hence,  most patients would derive little or no benefit and risk poten-  tial harm were antibiotics indiscriminately prescribed. Their  use predisposes to the development of resistant organisms.  They provide no benefit in viral diarrhea caused by rotaviruses  or noroviruses and may be harmful in EHEC infections, pro-  long fecal excretion of nontyphoidal Salmonella, and precipi-  tate C difficile colitis. Their benefit in Yersinia, Campylobacter,  and Aeromonas infections is controversial.   Generally accepted indications for the use of an empiric  antibiotic (at this writing usually a quinolone) include fever  greater than 102°F (38.9°C) and chills, severe dysentery, trav-  eler's diarrhea that is severe or affects an individual in whom a  shortened duration of illness is critical, individuals with severe  dehydration and prolonged, severe diarrhea ( 1 week or more),  and the immunocompromised host.   Antibiotics should be avoided in patients with bloody  stools, abdominal pain, but little or no fever until EHEC has  been excluded from consideration.   Recommendations regarding antibiotic therapy for specific  pathogens that cause acute infections are discussed in the  next section.   As indicated previously, most acute diarrheal disease is  caused by transmissible infectious viruses, bacteria, or para-  sites. Infectious organisms cause disease by a number of  mechanisms (Table 5-4). Some actually invade and prolifer-  ate in the intestinal epithelium, underlying mucosa, and lym-  phoid follicles. Others produce tissue-damaging cytotoxins  while in the lumen and in contact with the epithelium. Still  others produce enterotoxins while in the lumen and in con-  tact with the epithelium that produce profound functional  alterations but no detectable histologic lesion. Some adhere  to the epithelial surface and induce epithelial damage and  mucosal inflammation without invasion. Finally, still others  produce toxins in vitro that, when ingested, induce sympto-  matic gastrointestinal illness.   The human host has defenses that resist enteric infec-  tions. Gastric acid secretion reduces bacterial colonization of  the proximal small intestine, and there is evidence that indi-  viduals who have had acid-reducing gastric surgery are more  susceptible to nontyphoidal salmonellosis and selected other  enteric infections. Normal gastric motility is a defense factor;  stasis predisposes to intestinal intraluminal bacterial prolif-  eration, and there is evidence that the use of antimotility  agents prolongs diarrhea caused by some enteric pathogens.  The normal intestinal flora itself is protective. Its alteration  by antibiotic therapy predisposes to C difficile colitis and   reduces the number of organisms required to produce non-  typhoidal salmonellosis. Antibodies secreted into the intes-  tinal lumen by the intestine and via the biliary tract appear to  play a protective role in reducing colonization of pathogens  in the gut.   Musher DM, Musher BL. Contagious acute gastrointestinal infec-  tions. N Engl J Med. 2004;351:2417-2427. [PMID: 15575058]   Noroviruses, which include Norwalk agent, Hawaii agent,  and Snow Mountain agent, are caliciviruses — small, single-  stranded RNA viruses that, despite extensive efforts, have  not been cultured (Table 5-5). It is estimated that these  viruses produce approximately 25 million episodes of ill-  ness annually worldwide. Epidemic outbreaks in hospitals  and nursing homes, from catered food and restaurants,  and on cruise ships have been widely publicized but  endemic cases also occur. Transmission is via the fecal-  oral route through contaminated food and water and  direct person-to-person contact. Histologic studies of  volunteers have shown that after ingestion, noroviruses  induce a mild to moderate mucosal enteritis that peaks in   severity approximately 48 hours after viral ingestion and  resolves completely within 4-6 weeks or earlier. Lesions  of the gastric mucosa were not detected after ingestion of  Norwalk agent.   The incubation period is usually 12-48 hours and clinical  symptoms may include nausea, vomiting, watery diarrhea,  and abdominal cramps. Fever, if present, is usually mild  (< 101. 5°F [38.6°C]). The duration of clinical symptoms is  short ranging from a few hours to no more than 3 days. The  characteristic histologic lesion has been observed in asymp-  tomatic volunteers after norovirus ingestion, providing evi-  dence that some infections are subclinical. Routine  laboratory studies remain normal unless severe dehydration  develops, in which case modest elevations of blood urea  nitrogen and creatinine may be seen.   The diagnosis depends on the epidemiology and clinical  features. A commercially available diagnostic immunoassay  has recently become available but it is used largely, together  with polymerase chain reaction-based testing, in the  research setting and to identify epidemics.   Treatment is supportive and consists of oral rehydration  with carbohydrate-electrolyte solutions (see earlier discus-  sion) and in a small minority of patients with severe dehy-  dration, by intravenous hydration. Symptomatic treatments  such as bismuth subsalicylate and loperamide can be used  but are usually not needed, and there is little evidence that  they significantly influence fecal fluid losses. There is no  effective antiviral agent and no available vaccine.   The prognosis is excellent for this generally self-limited  disease although deaths may occur in association with  norovirus gastroenteritis, largely in debilitated, elderly  patients with significant comorbidities.   Blanton LH, Adams SM, Beard RS, et al. Molecular and epidemio-  logic trends of caliciviruses associated with outbreaks of acute  gastroenteritis in the United States, 2000-2004. / Infect Dis.  2006;193:413-421. [PMID: 16388489]   Rotaviruses are a major cause of infectious diarrhea world-  wide (see Table 5-5). In the United States, approximately  2.7 million children develop rotavirus gastroenteritis yearly,  resulting in approximately 50,000 hospitalizations and an  estimated 30 deaths. Rotaviruses are double-stranded RNA  viruses whose classification is complex. There are several  groups, which, in turn, may contain subgroups and multiple  serotypes. Most but not all disease in humans is caused by  group A. The virus invades, proliferates in, and destroys ente-  rocytes, resulting in the passage of abundant virions in the  stool of infected individuals for 7-10 days; however, virions  can be shed for up to 3-4 weeks. Significant enteritis devel-  ops, with patchy shortening or even complete loss of villi,  crypt hyperplasia, and inflammation of the lamina propria.  Symptomatic illness is more common in winter and  occurs largely in infants and young children. Watery diarrhea,  which can be profuse, and vomiting are the major symptoms,   accompanied by fever in 50% or more cases. Reinfections in  older children and adults are usually asymptomatic or mild  but can occasionally cause severe symptoms. Dehydration is a  hazard — especially in infants, if diarrhea is accompanied by  vomiting that precludes adequate oral fluid intake — and is  the major cause of morbidity and death. The illness generally  lasts from 4-7 days but more protracted diarrhea has been  reported. The diagnosis can be confirmed by demonstrating  rotavirus antigen in the stool by specific ELISA or latex  agglutination assays.   Hydration is the cornerstone of therapy and can often be  achieved with oral rehydration regimens containing sugar, salt,  and water or commercial oral rehydration formulations unless  diarrhea is profuse and accompanied by vomiting, in which  case intravenous rehydration may be lifesaving. The American  Academy of Pediatrics does not recommend symptomatic  therapy, including antimotility drugs, bismuth subsalicylate,  and probiotics, for children younger than age 5 years.   The overall prognosis is excellent, with the vast majority  of patients recovering completely within 7-10 days, except as  noted earlier.   A pentavalent human-bovine reassortant rotavirus vaccine  (RotaTeq) is licensed in the United States and is recommended  for use in all infants without contraindications.   Widdowson MA, Bresee JS, Gentsch JR, et al. Rotavirus disease and  its prevention. Curr Opin Gastroenterol. 2005;21:26-31. [PMID:  15687881]   Enteric adenovirus causes a rotavirus-like endemic gastroen-  teritis primarily in children younger than 2 years of age. Its  incubation period is longer than that of rotavirus but it  appears to be less contagious. Astrovirus also causes endemic  gastroenteritis primarily in children but also among elderly  and immunocompromised adults; occasional multi-case  outbreaks have been described. Clinically, gastroenteritis  caused by adenovirus and astrovirus resembles that caused  by rotavirus and norovirus and the principles of therapy are  the same. Diarrhea may also accompany enterovirus and  coxsackievirus infections, although manifestations involving  other systems often overshadow any accompanying diarrhea.  Whereas cytomegalovirus infections of the gastrointesti-  nal tract notoriously affect immunocompromised patients, as  discussed in Chapter 10, occasional cases of cytomegalovirus  colitis have been described in apparently immunocompetent  adults. In one review, 15 cases over a wide age range were  described. Presenting features included diarrhea, hema-  tochezia, fever, and abdominal pain. Endoscopy generally  revealed colitis with frank ulcers and mortality (27%) was  high. When diagnosed, antiviral therapy with agents such as  ganciclovir or foscarnet is indicated.   Klauber E, Briski LE, Khatib R. Cytomegalovirus colitis in the  immunocompetent host: an overview. Scand f Infect Dis.  1998;30:559-564. [PMID: 10225382]   Although specific bacterial infections are discussed on the fol-  lowing pages, the presentation of patients with shigelloses,  invasive E coli and EHEC, Campylobacter, and nontyphoidal  Salmonella enterocolitis may be clinically indistinguishable.  As a result, the decision about whether or not to begin  empiric antibiotic treatment can be difficult. Although antibi-  otics may be of benefit in a few infections (shigelloses, inva-  sive E coli), they may have undesirable effects in others  (EHEC, uncomplicated nontyphoidal Salmonella enterocolitis)  and predispose to C difficile colitis. Hence, potential benefits  versus risks must be weighed carefully.   Shigella species are a major cause of dysenteric infectious coli-  tis, with an estimated annual incidence of 450,000 in the  United States. Four pathogenic species have been identified  (Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and  Shigella boydii). Disease is caused by ingestion of contami-  nated food, water, or direct person-to-person fecal-oral  spread. The Shigella species are acid-resistant; hence, a very  small inoculum (< 100 bacteria) can produce disease. The  bacteria invade and spread through the epithelium, produce  several enterotoxins, including shiga toxin, and induce severe,  acute inflammation of the mucosa (see Plates 1 and 2) proba-  bly by causing the release of proinflammatory cytokines.   After an average 3-day incubation period, patients usually  develop watery diarrhea, which rapidly progresses to dysen-  teric stools with mucus and blood, tenesmus, and, usually,  fever. Some patients also develop nausea and vomiting. The  severity varies and ranges from watery stools without dysen-  tery or significant fever to severe dysentery with more than  20 low-volume stools per day, and high fever. Sigmoidoscopy  in patients with dysentery caused by shigellosis is usually  grossly indistinguishable from that observed with other  dysenteric infections (Campylobacter, nontyphoidal  Salmonella) or a flare of idiopathic IBD. Biopsy can be useful  in distinguishing infectious proctocolitis from a flare of idio-  pathic proctocolitis in that chronic changes such as crypt dis-  tortion and dropout are absent despite the presence of  substantial inflammation, most prominently in the upper  half of the mucosa (compare Plate 1 with Plate 2). Stools  from the majority of patients contain neutrophils, and the  diagnosis is established by stool culture.   In previously healthy individuals who are not immuno-  suppressed, shigellosis is usually self-limited and clears  within about 1 week without treatment. Antibiotic therapy  shortens the duration of symptoms and the fecal shedding of  Shigella organisms by about 50% and should be considered if  fever is high and dysentery is severe or the stool cultures are  positive, especially in infants and young children but also in  adults. Antibiotic therapy is clearly indicated in patients with  bacteremia (< 10%), food handlers, elderly or malnourished  patients with comorbidities, and the immunosuppressed. If   possible, it should be guided by the antibiotic sensitivity of the  Shigella species isolated from stool or blood culture. If antibi-  otic susceptibility is unknown, the current treatment of choice  is a fluoroquinolone in adults and azithromycin in children  younger than 18 years of age. In all patients, supportive measures  such as hydration are important but antimotility agents are  not recommended.   Gastrointestinal complications are uncommon, but rectal  prolapse, toxic megacolon, and even intestinal perforation  have been reported. Systemic complications include a sterile  reactive arthritis occurring usually 1-2 weeks after the onset  of gastrointestinal symptoms and, in rare instances, the  hemolytic uremic syndrome with microangiopathic anemia,  thrombocytopenia, and acute renal failure. In addition,  seizures associated with high fever may occur, especially in  infants and young children.   Sivapalasingam S, Nelson JM, Joyce K, et al. High prevalence of  antimicrobial resistance among Shigella isolates in the United  States tested by the National Antimicrobial Resistance  Monitoring System from 1999 to 2002. Antimicrob Agents  Chemother. 2006;50:49-54. [PMID: 16377666]   Salmonella organisms that cause disease in humans are a  zoonosis widely distributed throughout the animal kingdom.  Most of the estimated two million annual cases that occur in  the United States result from ingestion of fecally contami-  nated, incompletely cooked food such as meat (especially  poultry and ground beef), eggs, milk and other dairy prod-  ucts, contaminated vegetables, and even processed foods such  as peanut butter. Direct person-to-person spread and spread  from common and exotic pets, especially reptiles, occurs.  Outbreaks from contaminated water have been described.   Salmonella typhimurium and Salmonella enteritidis are  the most common causes in the United States but other  serotypes may be isolated. Unlike Shigella organisms,  salmonellae are acid-sensitive; hence, a larger inoculum is  required for induction of clinical illness. Reduction of gastric  acid secretion through surgery, disease, or pharmacotherapy  and prior antibiotic treatment that disrupts the normal  intestinal flora reduce the number of organisms required to  produce infection. The extremes of age, immunosuppression,  and malignancy also predispose to infection, salmonellae  adhere to and invade the intestinal epithelium. They enter  macrophages, in which virulent forms can survive and then  may disseminate to distant sites.   The clinical features of Salmonella gastroenteritis are not  distinctive and vary from case to case. Nausea, vomiting, and  fever are common early in the course followed by abdominal  cramps and diarrhea, which may be voluminous. Dysentery  may occur but is less common than in shigellosis or  Campylobacter enterocolitis. In most healthy adults, the dis-  ease is self-limited, with fever abating within 2-3 days and  diarrhea lasting no more than 10 days. Clinical features are   often more severe in those with predisposing factors such as  immunosuppression, in neonates and the elderly, and in  those with other comorbidities. As there are no available tests  for rapid diagnosis, confirmation awaits a positive stool cul-  ture, which requires 2-3 days.   There is general agreement that antibiotics are not indi-  cated for individuals in good general health with mild to  moderate illness who are not at the extremes of age. There is  no convincing evidence that such treatment alters the clini-  cal course, and several studies indicate that antibiotic treat-  ment prolongs fecal shedding of nontyphoidal salmonellae.  Thus, supportive care with rehydration forms the basis of  treatment. Whether immunocompetent patients with more  severe and prolonged illness should be treated is somewhat  controversial. Some authorities favor a short course of  antibiotics, such as 4-7 days of a fluoroquinolone in that set-  ting. Also controversial is whether infected food handlers  and health care workers should be routinely treated.   More definite indications for antibiotic treatment  include the immunosuppressed host; those with sickle cell  disease or known atherosclerotic disease, in whom dissemi-  nation may cause osteomyelitis or infection of an athero-  sclerotic plaque; those with vascular grafts or orthopedic  prostheses; and the elderly, especially those with additional  comorbidities. Most authorities would recommend at least  2 weeks of treatment, with a choice of antibiotics guided by  the antibiotic resistance pattern of the infecting organism  and the patient's comorbidities.   2001;15:263-269. [PMID: 11170916]  Patrick ME, Adcock PM, Gomez TM, et al. Salmonella enteritidis   Like nontyphoidal Salmonella infections, Campylobacter  species that infect humans, notably Campylobacter jejuni  and Campylobacter coli, are carried by a wide array of  domestic and wild species. Hence, human Campylobacter  infections are a leading cause of foodborne disease, with  contaminated poultry responsible for approximately 50%  of infections. However, beef, lamb, and pork, as well as con-  taminated water or improperly pasteurized milk, have  caused major outbreaks. Like Salmonella and Shigella,  Campylobacter adhere to and then invade the intestinal  epithelium of the small intestine and colon, although the  exact mechanisms of adhesion and invasion differ. Like  Salmonella, Campylobacter species are acid-sensitive; as a  result, conditions that reduce gastric acid secretion predis-  pose to infection by reducing the number of ingested bac-  teria required to produce symptomatic disease. The  immunosuppressed, especially AIDS patients, and the eld-  erly with comorbid conditions are at risk of more severe  Campylobacter-induced illness.   The clinical features are not distinctive and often closely  resemble those seen with shigellosis or nontyphoidal salmo-  nellosis. After an average 3-day incubation period, a brief  prodromal phase with fever and malaise in some patients is  rapidly followed by crampy periumbilical abdominal pain  and diarrhea. Hematochezia occurs in 30-50% of patients,  and the abdominal cramps and diarrhea are often severe.  Fever occurs in 70-90% of patients. The disease is usually  self-limited, with recovery in 5-9 days, although a minority  (-10%) of patients suffer a relapse, usually within a few days  following apparent resolution. The abdominal pain in  patients with Campylobacter infection may be severe and  lead to consideration of other diagnoses, such as acute  appendicitis, especially in children. As with Salmonella and  Shigella infections, the clinical presentation and gross endo-  scopic appearance of the colonic mucosa in Campylobacter  enterocolitis can be indistinguishable from the acute onset  or an acute relapse of colitis caused by IBD, especially ulcer-  ative colitis.   Definitive diagnosis requires identification of  Campylobacter in stool culture. A tentative diagnosis can be  made more rapidly by microscopic examination of a stool  suspension using phase-contrast or darkfield optics in those  instances in which large numbers of Campylobacter organisms  are excreted in diarrheal stool. The rapidly motile spiral-shaped  organisms are characteristic.   Antibiotics may shorten the duration of symptoms if  given within 1-2 days of onset. However, as the diagnosis is  rarely established that rapidly, and the disease is self-limited  in otherwise healthy individuals, routine treatment is not  recommended. Rather, supportive therapy with rehydration  is recommended. Antibiotic treatment should be considered  in patients with prolonged or relapsing illness, the immuno-  suppressed, those with serious comorbidities, and the elderly.  A 3-5-day course of a macrolide such as erythromycin or  azithromycin is recommended. Fluoroquinolones are an  alternative, although increasing resistance to this group of  antibiotics is being reported.   Rarely, reactive arthritis or Guillain-Barre syndrome may  complicate C jejuni infection, with a range of onset of 1 week  to 2 months after the presentation with gastrointestinal  symptoms.   Ternhag A, Askikainen T, Giesecke J, et al. A meta-analysis on the  effects of antibiotic treatment on duration of symptoms caused  by infection with Campylobacter species. Clin Infect Dis.  2007;44:696-700. [PMID: 17278062]   Yersinia enterocolitica and Yersinia pseudotuberculosis pro-  duce enterocolitis with diarrhea in humans. Although  Yersinia species are widespread throughout the animal king-  dom, the strains pathogenic to humans do not produce dis-  ease in animals but may be carried by them, especially pigs.  Ingestion of contaminated food — especially undercooked   pork, but also vegetables grown in contaminated soil, dairy  products, and contaminated water — transmits the infection  to humans. Both outbreaks and sporadic infections occur in  the United States and, more commonly, in Europe.  Individuals with diseases that result in increased iron stores,  such as hemochromatosis and thalassemia, appear to be  more susceptible to infection. Yersinia organisms invade via  the epithelium overlying lymphoid follicles, which are most  abundant as aggregates in the ileum and cecum (Peyer  patches) but are present along the length of the alimentary  tract. The organisms then proliferate in the lymphoid tissues  and can spread to regional mesenteric lymph nodes.   After an incubation period of 1-10 days (median, 4 days),  two major patterns of clinical symptoms develop. A typical  acute enterocolitis with fever, abdominal cramps, diarrhea  (which may be bloody), and, in the minority of patients, nau-  sea and vomiting occurs. This presentation is nonspecific and  indistinguishable from that observed with Salmonella, Shigella,  or Campylobacter enteritis. However, the duration of symp-  toms among patients with Yersinia enterocolitis tends to be  longer, averaging 2 weeks in several reported outbreaks. Also,  in contrast to gastroenteritis caused by other invasive bacteria,  pharyngitis involving the lymphoid-rich tonsils may accom-  pany Yersinia enterocolitis. In the other pattern of illness seen  most often in adolescents and young adults, diarrhea may be  mild or absent whereas severe right lower quadrant abdominal  pain, fever, and leukocytosis predominate, often mimicking  acute appendicitis. If such patients undergo surgery, an acute  ileitis and mesenteric adenitis is usually observed.   Diagnosis is best established by culture of Yersinia from  stool, body fluids, or tissue, if surgical specimens are available.  Throat culture may be positive, especially if pharyngitis is pres-  ent. The laboratory should be alerted when Yersinia infection is  suspected as screening for Yersinia is usually not routine.  Serologic tests can be helpful; the presence of immunoglobulin  M antibodies to Yersinia and a significant rise in antibody titers  between acute and convalescent sera support the diagnosis of  recent infections, although the latter is of little help during  acute illness. In patients in whom symptoms mimic appendici-  tis, imaging of the right lower quadrant via CT or ultrasound is  important; ileitis and mesenteric adenitis are usually present  but the appendix generally appears normal.   Supportive therapy with hydration is the mainstay of  treatment. There is no convincing evidence that antibiotic  treatment alters the clinical course of uncomplicated Yersinia  enterocolitis. Indications for treatment are the immunosup-  pressed host, complications such as invasive infections and sep-  ticemia, and, perhaps, patients with conditions associated with  increased iron stores. If oral therapy suffices, in adults a fluoro-  quinolone and in children trimethoprim-sulfamethoxazole is  recommended for 5-7 days. If intravenous administration is  required, a third-generation cephalosporin is recommended  for 2-3 weeks. Complications include reactive arthritis, erythema  nodosum, and, rarely, other conditions with autoimmune over-  tones, including myocarditis, glomerulonephritis, thyroiditis,  and hepatitis.   Black RE, Slome S. Yersinia enterocolitica. Infect Dis Clin North Am.  1988;2:625-641. [PMID: 3074119]   Listeria monocytogenes is an invasive, gram-positive, rod-  shaped organism resembling diphtheroids in appearance.  Listeria monocytogenes is widely found in soil, many animal  species, and foodstuffs, most notably cheese, sausage, and other  processed delicatessen meats. L monocytogenes can proliferate  in refrigerated foods. Most infections occur sporadically but  foodborne outbreaks have also been well documented.   In otherwise healthy immunocompetent individuals, the  organism invades the intestinal mucosa and causes a self-  limited febrile gastroenteritis of relatively short duration,  usually 2 days or less. Symptoms are nonspecific and include  fever, malaise, muscle aches, nausea, vomiting, and diarrhea.  Pregnant patients commonly present with a flulike illness  with or without gastrointestinal symptoms. There is a  predilection for invasion of placental tissue, especially during  the last trimester, with spread of the organism to the fetus  and fetal death or birth of an infected neonate. In immuno-  suppressed hosts and the elderly, there is a predilection for  central nervous system invasion with resulting meningitis,  meningoencephalitis, and, rarely, brain abscess.   The diagnosis is usually made by culture of L monocyto-  genes from the blood and cerebrospinal fluid. The signifi-  cance of isolation of the organism from the stool is unclear  as it can be isolated occasionally from asymptomatic indi-  viduals. Blood cultures should routinely be obtained from  pregnant and immunocompromised patients with febrile  gastroenteritis.   There is no evidence that antibiotic therapy influences the  course of uncomplicated, febrile Listeria gastroenteritis in  otherwise healthy patients; in many instances, the diagnosis  is not established by bacterial isolation and, if it is, symptoms  will have resolved. On the other hand, infection in pregnancy  or immunosuppressed patients or in any individual with evi-  dence of spread to other tissues should be treated. Ampicillin,  penicillin G, and trimethoprim-sulfamethoxazole have been  effective.   Ooi ST, Lorber B. Gastroenteritis due to Listeria monocytogenes.  Clin Infect Dis. 2005;40:1327-1332. [PMID: 15825036]   Several Vibrio species distinct from Vibrio cholerae, including  Vibrio parahaemolyticus, can cause diarrheal disease in  humans. These organisms thrive in high salt concentrations  and are found in saltwater estuaries, especially in the summer  and fall, although they also can contaminate fresh water.  Most outbreaks and sporadic cases of diarrheal disease result  from ingestion of contaminated raw or improperly cooked  seafood, especially mollusks (eg, oysters, mussels, or clams)  and crustaceans, including crab and shrimp. Most noncholera   Vibrio species induce diarrhea by producing enterotoxins  similar to the heat-labile toxin produced by V cholerae or a  heat-stable toxin similar to that produced by ETEC.  Vibrio parahaemolyticus produces hemolysins, which appear  to correlate with virulence.   The clinical features of noncholera Viforio-induced gas-  troenteritis are nonspecific and include diarrhea, which may  be grossly bloody in 25-30% of patients, abdominal cramps,  fever, and, less commonly, nausea and vomiting. The duration  of illness ranges from an average of 3 days for V para-  haemolyticus to 6 days for the other noncholera Vibrio species.  Most species may also cause wound infections and, especially  in patients who are immunosuppressed or have liver disease,  septicemia, the latter with mortality as high as 20%.   Isolation from stool samples requires use of selective  media; hence, the laboratory should be alerted that infection  with noncholera Vibrio is suspected.   Supportive therapy and hydration are the mainstays of  treatment. Although controlled trials are lacking and diarrhea  is self-limited in immunocompetent individuals, doxycycline  or quinolones have been reported to reduce the duration of  diarrhea and shedding of Vibrio organisms in the stool.   Daniels NA, MacKinnon L, Bishop R, et al. Vibrio parahaemolyti-  cus infections in the United States, 1973-1998. / Infect Dis.  2000;981:1661-1666. [PMID: 10823766]   Cholera is endemic in developing countries in Asia, Africa,  and Central and South America and also causes epidemic  outbreaks in these continents largely through contamination  of water supplies and, less often, foodstuffs. In North  America, a few sporadic cases have occurred in recent years,  probably though ingestion of contaminated food, largely  shellfish. There are more imported infections among travel-  ers than indigenous infections in the United States.  Vibrio cholerae is acid-sensitive; hence, a large inoculum is  required to cause infection in individuals with normal gastric  acid secretion. Surviving organisms colonize the small intestine  by attaching to the epithelial surface via pili and subsequently  elaborate toxins that induce electrolyte and water secretion  and alter epithelial permeability.   Infections range from asymptomatic colonization to dev-  astating, watery diarrhea with fluid losses that can approach  1 L/h. Vomiting may accompany the diarrhea but a signifi-  cant fever is uncommon. Massive fecal fluid losses, if not  replaced, can rapidly lead to severe dehydration and pro-  found electrolyte disturbances, including hypokalemia and  metabolic acidosis, with associated renal failure. The epi-  demiologic history and clinical picture facilitate diagnosis.  Vibrio can often be seen in stool examined by phase-contrast  or darkfield microscopy and on Gram stain. Vibrio cholerae is  cultured on selective media.   Prompt rehydration is imperative. Oral rehydration  solution (see "General Principles of Treatment," earlier) is   sufficient for most infections and has saved hundreds of  thousands of lives and reduced mortality from cholera to less  than 1% in adults and older children. Ongoing stool fluid  losses should be measured to help guide the volume of oral  fluid administration. If dehydration is severe or nausea and  vomiting preclude adequate oral intake, intravenous hydra-  tion is indicated. If facilities or supplies needed for intra-  venous hydration are unavailable, oral solutions should be  administered via nasogastric tube although aspiration is a  hazard. Antibiotics (tetracycline, doxycycline, or azithromycin,  depending on susceptibility) reduce fluid losses and shorten  the duration of diarrhea. The rBS-WC vaccine, an oral,  killed, whole cell vaccine containing the nontoxic cholera  toxin B subunit, has recently been approved for traveler's diar-  rhea and provides significant protection against V cholerae  and ETEC infections.   Morris JG Jr, Wilson R, Davis BR, et al. Non-O group Vibrio  cholerae gastroenteritis in the United States: clinical, epidemio-  logic, and laboratory characteristics of sporadic cases. Ann  Intern Med. 1981;94:656-658. [PMID: 7235397]   Seas C, Gotuzzo E. Vibrio cholerae. In: Mandell GL, Bennett IE,  Dolin R (editors). Principles and Practice of Infectious Diseases,  6th ed. Churchill Livingston, 2005:2536.   Aeromonas species, like noncholera Vibrios, thrive in brack-  ish and freshwater environments but also cause disease in  fish as well as many land animals. They produce several tox-  ins, adhesins, hemolysins, and proteases, but the exact role of  these putative virulence factors in the pathogenesis of disease  in humans remains uncertain.   The role of Aeromonas species in human diarrheal disease  is somewhat controversial. Although small outbreaks among  travelers are described and the organisms are sporadically  cultured from patients with diarrheal disease, Aeromonas  have been isolated from 5 to 15% of asymptomatic individu-  als in developing countries. An effort to induce disease in  normal volunteers by oral challenge was inconclusive.  However, there is general consensus that some Aeromonas  species can cause diarrheal disease in some individuals.   Symptoms range from watery to dysenteric diarrhea and  may be accompanied by nausea and vomiting and, in the  minority of patients, fever. Although most cases are self-  limited, more protracted diarrhea lasting several weeks has  been observed. Aeromonas, like noncholera Vibrios, can also  cause wound infections. Gram-negative sepsis may occur in  immunosuppressed patients or patients with liver disease.  The diagnosis is made by stool culture but the laboratory  should be alerted that Aeromonas species are being sought as  identifying these organisms is not generally routine.   The disease is self-limited in most patients with Aeromonas-  associated diarrhea. Anecdotal reports suggest that patients  with protracted diarrhea merit antibiotic treatment with  trimethoprim-sulfamethoxazole or a fluoroquinolone,   depending on the results of susceptibility testing. Controlled  trials showing the benefit of antibiotic treatment are not  available.   Plesiomonas shigelloides, like Aeromonas species, is widely dis-  tributed in aquatic environments and among a broad range  of sea and land animals. Rare or undercooked shellfish,  notably oysters, as well as contaminated water have been  incriminated in outbreaks of human diarrheal disease.  Unlike Aeromonas, the carriage rate among asymptomatic  individuals is very low. However, like Aeromonas, an attempt  to induce disease in volunteers was inconclusive.   The pathogenesis of Plesiomonas-induced gastroenteritis  is poorly understood and specific disease-producing viru-  lence factors have not been identified. The clinical features  closely resemble those of Aeromonas-induced gastroenteritis  and range from watery to, in the minority of patients, dysen-  teric diarrhea. Nausea and vomiting are common and  abdominal cramps may be present. Fever is uncommon.  Although most cases are self-limited with only a few days of  symptoms, prolonged diarrhea has been reported. Diagnosis  is generally made by culture of P shigelloides from the stool,  but again, the bacteriology laboratory should be notified that  the organism is being sought.   There are no available controlled trials defining efficacy of  treatment with antibiotics. Most cases require no more than  supportive treatment. Patients who are immunocompro-  mised and those who have chronic liver disease, bacteremia,  extraintestinal infections, or prolonged diarrhea should be  treated. Trimethoprim-sulfamethoxazole, quinolones, and  cephalosporins are usually effective but the choice of antibi-  otic should be guided by sensitivity testing.   ETEC have been recognized for years as a major cause of diar-  rheal disease in infants and children younger than 2 years of  age in the developing world and, in some series, as the most  common cause of travelers' diarrhea at any age. In recent  years, outbreaks in the United States and Europe have also  been reported. Transmission generally is via contaminated  food or water, and a large inoculum is required. Important  virulence factors characterizing ETEC are heat-labile toxin  (LT) and a heat-stable toxin (STa). LT closely resembles  cholera toxin, stimulating cyclic adenosine monophosphate,  resulting in intestinal crypt chloride and water secretion and  reduced sodium chloride absorption by enterocytes. STa  stimulates cyclic guanosine monophosphate, which, much  like LT, causes enhanced chloride and water secretion and  impaired sodium chloride absorption by the small intestine.  The major clinical manifestation is diarrhea, which  ranges from just a few loose stools to severe, watery diarrhea  that may persist for several days and result in significant  dehydration. Fever is uncommon and, when present, low   grade. Nausea and abdominal cramps may accompany the  diarrhea but vomiting is uncommon.   As in cholera, the involved mucosa is not inflamed; hence,  fecal leukocytes are absent. ETEC require research techniques  (serotyping or bioassay) for identification; they cannot be  differentiated from nonpathogenic E coli by routine stool  culture. In the absence of research facilities, the diagnosis is a  clinical one.   Rehydration, again, is the cornerstone of therapy; short  courses of antibiotics, including fluoroquinolones and rifax-  imin, shorten the duration of illness by a day or so. Lack of a  definitive diagnosis in most instances and the self-limited  nature of the illness limit their therapeutic use. Prophylaxis is  discussed later in the section on travelers' diarrhea.   EPEC primarily cause disease in infants and children younger  than 2 years of age. Older children and adults may harbor the  causative organism but overt illness is uncommon. Both out-  breaks and sporadic episodes are most common in develop-  ing countries. EPEC attaches to the brush-border surface of  enterocytes, activating signal transduction pathways. These  activated pathways in turn alter cytoskeletal components,  resulting in the effacement of the absorptive surface as well  as increased epithelial permeability and altered epithelial  barrier function. The resulting diarrhea in neonates and  young children can be severe, may be associated with vom-  iting, and can cause severe dehydration. Most cases are  self-limited.   Some commercial laboratories offer a Hep-2 cell adherence  assay, but definitive diagnosis usually requires the resources of  reference or research laboratories. Rehydration therapy is critical.  Antibiotics appear effective; trimethoprim-sulfamethoxazole  and colistin have been used.   EAEC are a relatively recently recognized diarrhea-causing  phenotype of E coli. EAEC cause disease in all ages and have  been identified in both developing and fully industrialized  countries. EAEC adhere to cultured Hep-2 cells in a charac-  teristic "stacked brick" fashion; hence, the term aggregative  has been included in their name. Cytotoxin and enterotoxin  secretion and specific adherence factors together with still  other virulence factors have been incriminated, but the  pathogenesis of diarrhea caused by EAEC is incompletely  understood.   Watery diarrhea is a prominent clinical feature and may  be accompanied by low-grade fever. Bloody diarrhea has  been reported. Although many episodes of diarrhea are self-  limited, EAEC has been identified in stools of children in  developing countries and in adults with AIDS in the United  States and Europe with chronic diarrhea.   Identification of EAEC in stools requires use of the Hep-2  adherence assay, which is not performed in conventional   clinical laboratories. Ciprofloxacin, rifaximin, and azithromycin  have been reported to be effective therapy for diarrhea  caused by EAEC.   Huang DB, Nataro JP, DuPont HL, et al. Enteroaggregative  Escherichia coli is a cause of acute diarrheal illness: a meta-  analysis. Clin Infect Dis. 2006;43:556-563. [PMID: 16886146]   EIEC is a relatively uncommon cause of diarrhea found  largely in developing nations and, occasionally, among trav-  elers returning to industrialized nations. It shares virulence  factors with Shigella strains and invades intestinal epithelial  cells, causing mucosal inflammation. The clinical picture is  identical to that observed in shigellosis (see earlier discus-  sion), with watery diarrhea often progressing to dysentery  accompanied by fever and, in some patients, nausea and  vomiting. Diagnosis requires DNA-probe testing by reference  or research laboratories. Treatment guidelines follow those  for shigellosis; severe cases, especially in children or  immunocompromised adults, should be treated with fluoro-  quinolone (adults) or azithromycin (children) along with  vigorous rehydration as needed.   Since its description 25 years ago, EHEC has become recog-  nized as a major health problem. Over 50% of outbreaks are  foodborne. EHEC inhabit the intestinal tract of cattle, deer,  sheep, and goats and outbreaks have been traced to under-  cooked meat, especially ground beef, contaminated vegeta-  bles, fruit, and fruit products. Contaminated water and direct  animal contact, especially at petting zoos, have also been  incriminated in outbreaks. Person-to-person contact may cause  sporadic cases as only a small inoculum (<100 organisms)  can induce disease.   Following ingestion, EHEC adhere to gut epithelial cells  and cause epithelial apical surface effacement by mechanisms  similar to EPEC. All EHEC strains produce one or more shiga  toxins, which, on entering the systemic circulation, damage  endothelial cells, producing vascular damage that may con-  tribute to bloody diarrhea and predispose to hemolytic ure-  mic syndrome, thrombotic thrombocytopenic purpura, and  microangiopathic hemolytic anemia. Escherichia coli 0157:H7  is the most common EHEC serotype isolated in the United  States but other shiga toxin-producing serotypes have been  isolated from outbreaks in the United States and other  countries.   After an average incubation period of 3-5 days, the ill-  ness often begins with watery diarrhea for 2-5 days, pro-  gressing to bloody diarrhea in up to 90% of patients. Severe  cramps and abdominal pain are common, with right lower  quadrant tenderness in some patients. Notably, fever is  absent in most patients and, when present, is low grade.  Peripheral leukocytosis of 10,000-20,000/|iL is common.   The duration of gastrointestinal symptoms can be only a  few days to as long as 2 weeks. In some outbreaks, E coli  0157:H7 has been isolated from patients with much milder  or no symptoms further, suggesting a broad range of severity  of clinical manifestations.   Endoscopy, if performed, shows a friable, edematous, ery-  thematous colonic mucosa with superficial ulceration.  Imaging studies show colonic wall thickening, thumbprint-  ing, and, if contrast is used, mucosal hyperemia, which is  often most severe in the right colon. Fecal leukocytes may or  may not be present.   The diagnosis can often be suspected from the clinical  presentation (bloody stools, abdominal pain, leukocytosis,  but little or no fever) and is confirmed by stool cultures using  sorbitol-MacConkey agar. An ELISA that detects shiga toxins  in the stool is also available.   Treatment is supportive. Rehydration is important.  Antimotility agents should be avoided. There is no evidence  that antibiotic treatment provides any benefit in EHEC coli-  tis. Indeed, some series indicate that in children, antibiotic  treatment increases the risk of associated hemolytic uremic  syndrome. A trial of administration of a shiga toxin-binding  agent to children with diarrhea and hemolytic uremic syn-  drome showed no benefit when compared with placebo.   Hemolytic uremic syndrome, thrombotic thrombocy-  topenic purpura, and microangiopathic anemia are the  dreaded complications of EHEC infection and occur most  often in children younger than 10 years, although older chil-  dren and adults are not always spared. Details of treatment  for these conditions are beyond the scope of this chapter but  treatment is largely supportive, often requiring dialysis for  renal disease and, less often, plasma exchange for thrombotic  thrombocytopenic purpura.   Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic  uremic syndrome after antibiotic treatment of Escherichia coli  0157:H7 infections. N Engl } Med. 2000;342:1930-1936.  [PMID: 10874060]   Staphylococcus aureus gastroenteritis is a common cause of  food poisoning. The causative food is often contaminated by a  food handler. Foods rich in sugar and cream, such as custards,  cakes with creamy frostings, salty meat such as ham, and  mayonnaise- and cream-containing salads, favor Staphylococcus  growth and enterotoxin production at room temperature.  Within 6 hours of ingestion of foodstuffs containing sufficient  toxin, patients develop nausea and vomiting, which may be  severe; abdominal cramps; and subsequently, in some, diar-  rhea. Fever is uncommon. Duration of symptoms rarely  exceeds 24 hours and rapid recovery is the rule.   The diagnosis can best be established by isolating S aureus  or enterotoxin from the suspected food if an outbreak is sus-  pected. Additionally, vomitus or diarrheal stool can be tested  for enterotoxin but this in not routinely done. Treatment is   supportive, with hydration and correction of metabolic alka-  losis, if present, due to severe vomiting.   Bacillus cereus, a gram-positive, spore-forming bacillus, can pro-  duce two distinct types of food poisoning. Some strains produce  a heat-stable toxin in vitro that induces vomiting; other strains  produce a heat-labile enterotoxin that causes diarrhea.   The organisms that produce the vomiting syndrome have  largely been associated with ingestion of rice, notably fried  rice. The vegetative forms are destroyed when rice is boiled,  but the spores survive. If the rice is not refrigerated, the  spores germinate and toxin is produced that may not be inac-  tivated by flash frying as the fried rice is prepared. A short  2-3-hour incubation period follows toxin ingestion. Then  vomiting associated with abdominal cramping develops,  which may be associated with mild diarrhea. The illness is  self-limited, averaging about 8 hours, and can be treated with  antiemetics and, if needed, rehydration. The organisms that  produce the diarrheal syndrome have been associated with  contaminated meats, sauces, and dairy products. Their  longer incubation following ingestion of contaminated food  (6-18 hours) suggests that the enterotoxin is produced in  vivo. Major symptoms include diarrhea and abdominal  cramps; vomiting occurs in less than 25% of cases.  Symptoms usually clear within 24 hours and should be  treated supportively with rehydration, if needed.   Clostridium perfringens is a gram-positive, anaerobic, spore-  forming bacillus widely found in nature in the intestinal flora  of many animals and in soil. Type A strains produce a heat-  labile enterotoxin that causes intestinal fluid secretion and is  also cytotoxic to intestinal epithelium. Disease is caused almost  exclusively by ingested meat that is inadequately refrigerated  after cooking. After a 12-24-hour incubation, patients develop  watery diarrhea and abdominal crampy pain that may be  severe, usually in the absence of nausea, vomiting, or fever.  Symptoms generally last less than a day and treatment is sup-  portive; oral rehydration is usually sufficient. Type C strains can  produce a much more severe illness, which has been termed  enteritis necroticans or pigbel. It is characterized by intestinal  necrosis that may produce perforation requiring surgery.  Mortality rates as high as 40% have been reported. This disease  has been described largely in South Pacific islands after festive  consumption of large amounts of improperly cooked pork.   Clostridium difficile, a gram-positive, spore-forming bacillus,  is the major cause of hospital-acquired infectious diarrhea but  can also cause community-acquired diarrhea albeit less fre-  quently. Clostridium difficile spores are heat and alcohol resist-  ant and can remain infectious in vitro. They may colonize up  to 40% of hospitalized patients and 3% of healthy individuals.   Alteration of the normal enterocolonic bacterial flora by  prior antibiotic administration is required for the develop-  ment of C difficile colitis in almost all who develop the  disease. Antibiotics most often associated with C difficile-  induced disease include aminopenicillins, fluoroquinolones,  cephalosporins, and clindamycin, but virtually all antibiotics,  even metronidazole, have been incriminated. Occasionally,  cancer chemotherapy appears to trigger C difficile colitis and  in rare instances, the disease appears to develop in the absence  of antecedent antibiotic administration in otherwise healthy  individuals. Other risk factors for development of C difficile  infection include prolonged exposure in any health care facil-  ity, debilitating comorbidities, gastrointestinal surgery, old  age, and, perhaps, chronic acid suppression with proton  pump inhibitors or histamine 2 (H 2 )-receptor antagonists,  although the latter is controversial.   Upon colonizing the intestine, most virulent C difficile  strains produce toxin A and toxin B. These induce colonic  epithelial cytoskeletal damage, mucosal inflammation, and  mucosal fluid secretion, resulting in the clinical features  described below. The toxin-induced mucosal lesion is charac-  terized by damaged epithelium, mucosal inflammation, and  the exudative pseudomembrane, which consists of necrotic  debris, inflammatory cells, and mucus adherent to the  mucosal surface. Strains that produce only toxin B have been  isolated from patients with clinically manifest C difficile colitis.   Recently, highly virulent strains of C difficile have been  identified in North American and European outbreaks.  These toxinotype III strains have been shown to produce up  to 16- and 23-fold greater amounts of toxin A and B, respec-  tively. This has been ascribed to a partial deletion of the tcdC  gene that normally down-regulates toxin A and toxin B pro-  duction. These highly virulent strains have emerged in con-  cert with the wide use of fluoroquinolones, are frequently  resistant to fluoroquinolones, and have been implicated in  the increasing frequency and morbidity of C difficile entero-  colitis in North America and in Europe.   The clinical features of C difficile colonization may range,  at the one extreme, from total lack of symptoms in carriers  to, at the other extreme, fulminant diarrhea and toxic mega-  colon requiring emergency surgery. Symptoms usually begin  a few days to 2 weeks after initiation of antibiotic treatment  although the latency period may be as long as several  months. Malaise, watery diarrhea, lower abdominal pain and  tenderness, and low-grade fever are characteristic features.  Frank hematochezia is rare although occult blood loss is  common. Mild peripheral leukocytosis is common and fecal  leukocytes are often present, especially in patients with more  than mild colitis.   It should be stressed that many of the milder episodes of  diarrhea that occur in concert with antibiotic treatment are  not infectious in nature. Rather, alterations in the balance of  the colonic flora impair salvage carbohydrate digestion and  absorption. As a result, the amount of unabsorbed carbohy-  drates in the colonic lumen is increased, resulting in an  osmotic diarrhea.   Demonstration of C difficile diarrhea cytotoxin in stool  samples is the gold standard for establishing the diagnosis of  C difficile colitis. This test is performed by culturing fibrob-  lasts in the presence of stool supernate. If toxin is present, the  fibroblasts show evidence of cytotoxicity. Sensitivity and  specificity of this test range from 95% to 99% but the assay  requires 2-3 days. Available ELISA-based assays are more  rapid and less costly, but less sensitive, and may miss up to  10% of stool samples that are positive when tested using the  cytotoxicity assay.   An immediate, albeit only provisional, diagnosis can be  made at anoscopy or sigmoidoscopy if the characteristic  pseudomembrane is observed. However, the absence of  the pseudomembrane does not exclude C difficile colitis as  the disease may be confined to the more proximal colon  and the rectum and distal colon may be spared. Moreover,  not all patients with C difficile colitis develop the charac-  teristic pseudomembrane. Imaging studies including  abdominal flat films or abdominal CT are nonspecific and  may show colonic wall thickening. In patients with fulminant  colitis, ileus or toxic megacolon may be evident.   Worrisome signs suggesting fulminant, potentially life-  threatening colitis include florid diarrhea in excess of 9-10  stools per day; abrupt reduction of diarrhea in the absence of  other signs of clinical improvement, which may signal the  development of toxic megacolon; increasing abdominal pain  and distention; high fever; hypotension, especially if pressors  are required; hypoalbuminemia; a rising serum creatinine;  and colonic dilation on imaging. Patients showing such  symptoms and signs must be monitored closely in conjunc-  tion with a surgeon and may require vigorous therapeutic  intervention (see below).   Treatment recommendations depend on the severity of clin-  ical illness and host risk factors. Hospitalized patients should be  isolated and, in all cases, caregivers should wash their hands with  soap and water after patient contact. Purell and other alcohol-  based hand cleaners do not destroy C difficile spores.   Given the emergence of virulent C difficile strains,  treatment recommendations are now more aggressive. If  possible, causative antibiotics should be discontinued and  antimotility agents should be avoided. For patients with  mild disease, fewer than five stools per day, no fever, and  no or only mild leukocytosis, metronidazole (500 mg/day)  should be begun as the initial treatment. If there is no  response in 2 days or there is progression, oral vancomycin  (250 mg every 6 hours) should be added. In patients with  moderate disease characterized by more frequent diarrhea  (more than six stools per day), leukocytosis greater than  15,000/|lL, or low-grade fever, oral vancomycin (250 mg  every 6 hours) should be started. If there is no response in  2 days or if there is progression, metronidazole (500 mg  every 8 hours) should be added. For patients with severe disease  characterized by fulminant diarrhea (more than 10 stools  per day), fever greater than 101. 5°F (38.6°C), leukocytosis  greater than 25,000/n.L, marked abdominal pain or tenes-  mus, colonic dilation, or hemodynamic instability, both   oral vancomycin (250-500 mg every 6 hours) and intra-  venous metronidazole (300 mg every 6 hours) should be  begun. Additionally, these very ill patients should be  closely monitored with frequent abdominal examinations  and daily abdominal flat films to assess for developing  megacolon along with serial surgical assessment for the  possible need for colectomy. Metronidazole or vancomycin,  or both, should be continued for at least 14 days or for 10 days  after symptoms have disappeared. Emergency colectomy  may be lifesaving in those few patients who develop pro-  gressive fulminant diarrhea, severe ileus, and megacolon  with impending perforation or generalized sepsis.   Relapses after apparent complete resolution occur in  approximately 10-25% of treated patients, most likely  caused by reinfection or germination of residual spores  remaining in the colon. Retreatment should follow the  guidelines outlined above for initial therapy as there is no  evidence that antibiotic resistance plays a role. If there are  multiple relapses, tapering doses of vancomycin can be tried,  reducing the dose frequency by 50% every week until 250 mg  of vancomycin every 3 days has been administered for 2 weeks.  If that fails, other antibiotics, including bacitracin, rifampin,  or rifaximin can be tried. Saccharomyces boulardii given as  adjunctive therapy together with metronidazole or van-  comycin has been reported to be of benefit. As a last resort,  intravenous immunoglobulin G can be tried, as some responses  of refractory C difficile colitis to this treatment have been  reported.   Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-  institutional outbreak of Clostridium difficile-associated diar-  rhea with high morbidity and mortality. N Engl J Med.  2005;353:2442-2449. [PMID: 16322602]   Maroo S, Lamont IT. Recurrent Clostridium difficile. Gastro-  enterology. 2006;130:1311-1316. [PMID: 16618421]   McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin  gene-variant strain of Clostridium difficile. N Engl J Med.  2005;353:2433-2441. [PMID: 16322603]   Klebsiella oxytoca causes a relatively uncommon but distinc-  tive antibiotic-associated hemorrhagic colitis. Klebsiella  oxytoca has been shown to produce a cytotoxin that has been  implicated in the pathogenesis of colitis. Colitis generally  occurs during the first week after the introduction of antibi-  otic therapy, usually with a penicillin, although cases that  occurred in concert with administration of other antibiotics,  including cephalosporins and quinolones have been  described. Most reported patients have been relatively young  to middle aged. Bloody diarrhea (uncommon in C difficile  colitis), abdominal cramps, low-grade fever, and mild to  moderate leukocytosis are clinical features. The rectum is  often spared, and a patchy hemorrhagic colitis with superfi-  cial ulcers but without a pseudomembrane is observed in  colonic segments. Mucosal biopsies show an ulcerated  mucosa that resembles the lesion observed in patients with   EHEC with both inflammatory and ischemic features. The  condition is generally self-limited, resolving promptly after  the discontinuation of the causative antibiotic and requires  only supportive treatment.   Hogenauer C, Langner C, Beubler E, et al. Klebsiella oxytoea as a  causative organism of antibiotic-associated hemorrhagic coli-  tis. N Engl ] Med. 2006;355:2418-2426. [PMID: 17151365]   Giardia lamblia is the most common protozoal infestation in  the United States, where it occurs both endemically and in  epidemic outbreaks. It is a common cause of illness world-  wide, especially in the developing world where sanitation is  suboptimal and, hence, is a common cause of traveler's diar-  rhea. G lamblia infects other mammals, including beavers,  dogs, and cattle. The cyst form of Giardia can survive for pro-  longed periods in most environments. Once cysts are  ingested, the distinctive trophozoites are released in the upper  small intestine where they multiply by binary fission and col-  onize the host. The trophozoites attach to the intestinal  epithelium but do not invade the mucosa; however, they can  produce significant enteritis with mucosal inflammation and  architectural changes. Hence, biopsy specimens can range  from those revealing normal mucosal structure to a flat  mucosa architecturally reminiscent of a lesion of severe celiac  sprue.   Several factors increase the risk of contracting G lamblia  infection. These include travel to areas where the water sup-  ply may be contaminated, drinking mountain and forest  stream or lake water that has not been filtered or boiled,  attendance at day care or preschool, and swimming in pools  with improperly treated water or in contaminated lakes. The  risk of developing giardiasis is higher in patients with  immunoglobulin deficiencies and in homosexuals although,  interestingly, HIV infection by itself is not a risk factor.   Approximately 50% of individuals infested with G lamblia  have no symptoms and can be asymptomatic carriers of the  parasite for many months. Those that develop symptoms  commonly experience diarrhea, flatulence, abdominal  cramps, and epigastric pain and nausea. Approximately one  third of symptomatic patients experience vomiting.  Significant malabsorption with steatorrhea and weight loss  may develop. If left untreated, most symptomatic patients  recover spontaneously and eliminate the parasite within  3-4 weeks. However, up to a quarter develop chronic infection  if untreated.   Stool examination for ova and parasites has been used for  years to establish the diagnosis, but a single specimen has a  yield of only approximately 50% whereas examination of  three separate stool samples increases the yield of positive  examinations to 80-90%. The cysts and trophozoites may be  seen in diarrheal stools, but only cysts are usually observed in   formed stools. Stool immunoassays, including an ELISA with  reported sensitivities and specificities approaching 100%, are  now being widely used by clinical laboratories. Though  rarely needed now, sensitivity and specificity of examining  duodenal aspirates and mucosal biopsies for trophozoites  also approaches 100%. It is wise to exclude the diagnosis  among household members of symptomatic patients.   Metronidazole (250 mg three times daily for 5-7 days) is  the most commonly used treatment. Although the drug is  not approved by the U.S. Food and Drug Administration  (FDA) for treatment of giardiasis, reported efficacy rates  from a single course of therapy are in the 85-95% range. A  single 2-g dose of tinidazole has been reported to be 90%  effective. Nitazoxanide (500 mg twice daily for 3 days) is 85%  effective. Paromomycin is recommended for the treatment of  pregnant patients.   Rossingnol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused  by Giardia intestinalis and Entamoeba histolytica or E. dispar. a  randomized, double-blind, placebo-controlled study of nitazox-  anide. J Infect Dis. 2001;184:381-384. [PMID: 11443569]   Cryptosporidia are widely found in the animal kingdom.  Two coccidial species, Cryptosporidium hominis and  Cryptosporidium parvum, are responsible for most human  infections. Cryptosporidiosis is transmitted via contaminated  food or water, human-to-human contact, and, occasionally,  animal-to-human contact. Ingestion of a small number of  oocysts can produce colonization and disease. The oocysts  release sporozoites, which attach to and invade endodermal  epithelia. Ultimately, newly formed oocysts are excreted in  large numbers in stools of infected individuals. Both cellular  and humoral immune defects predispose to symptomatic dis-  ease; indeed, many of the earlier recognized cases of cryp-  tosporidial infection coincided with the recognition of HIV  infection.   Although Cryptosporidium can cause biliary tract, pan-  creatic, and respiratory tract disease (see Chapter 10), intes-  tinal infection is the most common manifestation. Infected  persons may remain asymptomatic or develop an enteritis  characterized by watery diarrhea, abdominal cramps, nausea,  and malaise, which usually resolves spontaneously in 2-3  weeks in immunocompetent hosts. The diarrhea can be  voluminous, especially in immunosuppressed patients in  whom chronic infections with debilitating secretory diarrhea  and weight loss may develop.   The diagnosis rests upon identification of Cryptosporidia  organisms in stool, bile, or tissue samples. A modified acid-  fast stain of stool has high specificity but mediocre sensitiv-  ity and requires the examination of at least three stool  specimens if initial specimens are negative. Use of a fluores-  cent ELISA test for stool examination has high specificity and  greatly increased sensitivity. Intestinal mucosal biopsy sam-  ples often reveal Cryptosporidia within the apical cytoplasm  of the enterocytes.   If treatment is required for immunocompetent patients,  nitazoxanide is the drug of choice, although spontaneous  resolution of symptoms is the rule. Immunosuppressed  patients can also be treated with nitazoxanide, although only  some respond. An attempt to restore immunologic compe-  tence with highly active antiretroviral therapy (HAART) in  HIV-infected patients is crucial. Other agents that have been  tried, with generally disappointing results, include paro-  momycin, metronidazole, clarithromycin, and other antibi-  otics. Supportive treatment with hydration and antidiarrheal  agents is important in the immunosuppressed, and par-  enteral nutrition may be required. Octreotide has been tried  but few patients respond.   Smith HV, Corcoran, GD. New drugs for the treatment for cryp-  tosporidiosis. Curr Opin Infest Dis. 2004;17:557-564.   C cayetanensis, like Cryptosporidium and Isospora, is a coc-  cidian that is widely distributed geographically and, hence, a  cause of traveler's diarrhea. In immunosuppressed patients,  it is a cause of protracted diarrheal illness. The major recog-  nized vectors for human infection in the United States have  been contaminated fruits and vegetables, although contami-  nated water is also likely in developing countries.   After a relatively prolonged 1-week incubation period,  patients develop watery diarrhea, flatulence, abdominal  cramps, and malaise. The illness even in immunocompetent  hosts may range from minimal to no symptoms to prolonged  illness lasting several weeks and even months if left  untreated. In immunosuppressed hosts, especially AIDS  patients, prolonged, debilitating illness virtually identical to  that caused by other coccidia (Cryptosporidium or Isospora)  may develop. Diagnosis is established by demonstrating  oocysts in the stool. The oocysts are autofluorescent; hence, flu-  orescence microscopy is useful. Alternatively, modified acid-  fast staining is used. Biopsies of the intestinal mucosa reveal  mucosal inflammation and protozoal epithelial invasion.   Trimethoprim-sulfamethoxazole (160 mg/800 mg twice  daily for 1 week) is effective treatment for otherwise healthy  hosts; larger doses and more prolonged treatment are indi-  cated for immunosuppressed patients. Ciprofloxacin or  nitazoxanide can be used for patients intolerant of  trimethoprim-sulfamethoxazole.   Herwaldt BL. Cyclospora cayetanensis: a review, focusing on the  outbreaks of cyclosporiasis in the 1990s. Clin Infect Dis.  2000;31:1040-1057. [PMID: 11049789]   Isospora belli, like the other coccidial pathogens, is widely dis-  tributed geographically. Ingestion of contaminated food or  water and person-to-person contact are probably important  in transmission. Travelers and immunosuppressed patients are   most likely to be infected, but sporadic illness in otherwise  healthy hosts occurs in the United States and other devel-  oped countries.   Clinical features are not specific and include diarrhea,  abdominal discomfort, steatorrhea, weight loss, nausea,  vomiting, and malaise. Symptoms are generally self-limited  in immunocompetent patients but may wax and wane for  months without specific treatment. Among AIDS and other  severely immunosuppressed patients, protracted illness with  severe diarrhea, malabsorption, and weight loss is the rule  without specific therapy.   The diagnosis is established by identifying oocysts in the  stool using autofluorescence or modified acid-fast staining.  Oocysts can also be identified in duodenal aspirates, and  examination of mucosal biopsy specimens reveals invasive  protozoal forms in the epithelium as well as severe enteritis  with marked architectural changes and a mixed inflamma-  tory infiltrate containing many eosinophils. Peripheral  eosinophilia may also be present.   Treatment with trimethoprim-sulfamethoxazole for 3-4  weeks is effective in most patients, but more prolonged and  even indefinite treatment may be required in AIDS and other  immunosuppressed patients to prevent frequent relapses.  Quinolones have been used successfully in those intolerant of  trimethoprim-sulfamethoxazole. Where possible, immune  reconstitution with HAART treatment is important for AIDS  patients.   Entamoeba histolytica infection occurs throughout the world,  but the highest prevalence rates are found in developing  countries in Asia, Africa, and Central and South America,  where sanitation is suboptimal. Simply finding amoeba by  microscopic examination in stool in the course of epidemio-  logic studies and clinical evaluation is compromised by the  fact that only 10% of E histolytica infections are symptomatic  and that two noninvasive, nonpathogenic species, Entamoeba  dispar and Entamoeba moshkovskii, colonize humans with far  greater frequency than does E histolytica.   Entamoeba histolytica cysts are ingested by consuming con-  taminated food or water or via fecal-oral contact, often during  sexual activity; hence, there is a higher prevalence among  homosexuals. Following excystation, trophozoites bind to the  colonic epithelial glycocalyx sugars via a trophozoite surface  lectin and subsequently invade the colonic mucosa, causing  inflammation and ulceration. Systemic dissemination may  occur, most often to the liver, resulting in abscess formation.   Clinically, colonic colonization by E histolytica produces a  wide spectrum of symptoms ranging from no symptoms in the  majority of patients to devastating pancolitis with toxic mega-  colon, requiring emergency colectomy and carrying a mortality  rate as high as 50%. In most symptomatic individuals, mild ini-  tial diarrhea progresses to dysentery with blood and mucus in  the stool and crampy abdominal pain, often with tenesmus.  Low-grade fever may be present in the minority of amoebic   colitis patients. Anemia and hypoalbuminemia may be present  depending on the severity and duration of the colitis. The clini-  cal features can closely mimic ulcerative colitis or Crohn colitis.  Indeed, it is crucial to exclude amoebiasis before administering  corticosteroids or other immunosuppressive drugs to presumed  ulcerative colitis patients to avoid precipitating fulminant  amoebic colitis with toxic megacolon or perforation.   Testing for E histolytica-speciiic antigen in the stool is now  available and has the advantage of selective identification of  E histolytica and not morphologically identical nonpathogenic  strains. Sensitivities and specificities in the range of 90% have  been reported. Stool microscopy is less sensitive and less spe-  cific. Using stool concentration techniques and special stains,  examination of three specimens results in a sensitivity of  approximately 85%. Sigmoidoscopy with collection of mucus  from ulcers for microscopy and biopsy samples from the edge  of ulcers may supplement antigen testing and stool  microscopy. Blood serologic testing is also useful in that  absence of antibodies in someone with 7-10 days of symp-  toms makes the diagnosis less likely. Because antibody levels  may persist for prolonged periods after exposure, a positive  serologic test does not necessarily indicate acute amoebiasis.   Patients with E histolytica colonization should be treated  whether symptomatic or not with metronidazole (750 mg  three times daily for 10 days). Alternatively, tinidazole (2 g  daily for 3 days) can be used. To eliminate residual cysts, this  should be followed by an intraluminally active drug such as  iodoquinol (650 mg three times daily for 20 days) or paro-  momycin (10 mg three times daily for 7 days). Patients with  severe colitis must be observed very closely for the develop-  ment of surgically emergent toxic megacolon or perforation  until a response to metronidazole treatment is evident.   Haque R, Huston CD, Hughes M, et al. Amebiasis. N Engl J Med.  2003;348:1565-1573. [PMID: 12700377]   Previously considered to be protozoa, microsporidia are now  classified as fungi. Numerous species infect many life forms  and over 10 species are known to cause disease in humans,  with Enterocytozoon bieneusi the most common. Involvement  of many organs in addition to the intestine has been reported  and will not be described here. The majority of clinically sig-  nificant infections occur in AIDS and other immunosup-  pressed patients although infections in travelers and  otherwise healthy individuals have been documented.   Ingestion of spores via person-to-person, animal-to-person,  foodborne, or waterborne routes has been incriminated as  sources of transmission. Microsporidia spores have been  isolated from the stools of asymptomatic, healthy, immuno-  competent individuals raising questions as to whether the  organisms are always the cause of gastrointestinal symptoms  ascribed to them. Nevertheless, both self-limited diarrhea  and occasionally chronic diarrhea have been reported,  especially in travelers and in the elderly.   In immunosuppressed AIDS patients and some immuno-  suppressed transplant patients, dehydration and malabsorp-  tion clinically indistinguishable from that associated with  coccidial infections such as cryptosporidiosis have been  noted in association with microsporidial organisms invading  intestinal mucosa and with identification of E bieneusi or  Enterocytozoon intestinalis in stool specimens. As in cryp-  tosporidiosis, biliary tract involvement can occur.   Diagnosis is established by stool examination, which is  facilitated by using special stains such as a modified  trichrome stain or identification of the organism in tissue  samples such as intestinal mucosal biopsies by light or elec-  tron microscopy.   Albendazole (400 mg twice daily for 2-4 weeks) is the  treatment of choice for microsporidiosis but is of limited  efficacy in the treatment of E bieneusi infections, the most  common form associated with diarrheal disease. Hence,  restoration of immunocompetence with HAART in AIDS  patients and reduced immunosuppression in transplant  patients is desirable if possible. Numerous other antibiotic,  antiparasitic, and antifungal agents have been tried in  immunosuppressed patients with chronic diarrhea who har-  bor these organisms without much benefit. Treatment with  the antibiotic fumagillin at 60 mg daily for 2 weeks showed  promising results in one small placebo-controlled trial and  in several uncontrolled reports, although worrisome bone  marrow depression was noted in some drug recipients.   Didier ES, Weiss LM. Microsporidiosis: current status. Curr Opin  Infect Dis. 2006;19:485-492. [16940873]   With increasing economic globalization and the increased  popularity of tourism to developing nations, travelers' diar-  rhea affects literally millions of travelers each year. A gener-  ally accepted definition for travelers' diarrhea is the passage  of three or more loose to diarrheal stools in 24 hours often  but not invariably associated with other symptoms, includ-  ing abdominal discomfort, nausea, vomiting, hematochezia,  and fever, depending on the cause. Symptoms most often  develop 2-10 days after arrival of the traveler but may occur  at any time during foreign exposure.   The incidence of travelers' diarrhea varies greatly with  geographic region and correlates with the level of sanitation  at the travelers' destination. Incidence rates as high as 50%  have been noted for selected Asian, Central African, and Latin  American countries whereas estimated rates are 10-20% in  Southern European countries, the Caribbean Islands, and  Northern African countries. Estimated rates among travelers  to and in Northern Europe, the United States and Canada,  Australia, and New Zealand are well under 10%. Risk factors  for the individual traveler other than destination are condi-  tions that interfere with host defenses against enteric infec-  tions, as discussed earlier in this chapter. In particular,  immunosuppressed patients and patients with hypochlorhydria   caused by pharmacologic agents or gastric surgery may be  especially vulnerable to developing traveler's diarrhea.   Virtually any of the specific organisms discussed individ-  ually in this chapter may be the causative agent for any given  case of traveler's diarrhea. Pathogenic bacteria have been  estimated to cause up to 90% of traveler's diarrhea in some  studies in which an etiologic agent was identified. ETEC and  EAEC appear as the most common causes, but invasive bac-  teria including Campylobacter, Salmonella, Shigella species,  and invasive E coli predominate among those with dysentery.  Both rotaviruses and noroviruses are established causes, the  latter being increasingly recognized among cruise passen-  gers. Protozoa, while less common, have been isolated from a  substantial number of travelers with more protracted diar-  rhea, especially among those who develop malabsorption.   The clinical features will not be belabored here and the  reader is referred to the descriptions of specific infections  earlier in the chapter. By far the most common presentation  is that associated with ETEC or EAEC infection, with abrupt  onset of watery diarrhea lasting a few hours to as long as  5 days. However, the entire spectrum of the clinical features  of gastrointestinal infections maybe seen, ranging from a few  loose stools to severe dysentery with fever or protracted diar-  rhea with malabsorption, depending on the cause of the  infection and the host's immune response capacity.   Because a specific diagnosis is rarely established during  travels, treatment is largely empiric. If diarrhea is severe,  rehydration is crucial, preferably using an oral rehydration  solution with a formula similar to that recommended by the  WHO or, if necessary, intravenous hydration. Loperamide  (2 mg up to four times daily) can provide symptomatic relief  but should be used with caution in patients with dysentery of  unknown cause and avoided in patients with possible C dif-  ficile (those taking prophylactic antibiotics) given the risk of  development of toxic megacolon. There is also some evi-  dence, though not conclusive, that antimotility agents can  prolong the duration of some enteric infections such as  shigellosis. Effective antibiotic therapy reduces the duration  of ETEC and EAEC, the most common causes of traveler's  diarrhea. Development of antibiotic resistance is a major  problem and has reduced the efficacy of trimethoprim-  sulfamethoxazole, aminopenicillins, and tetracyclines. Instead,  quinolones and azithromycin are now recommended. The  nonabsorbed antibiotic rifaximin is effective against ETEC  and may ultimately become the empiric antibiotic treatment  of choice for nondysenteric traveler's diarrhea.   Prevention is the most effective approach to reducing the  burden of travelers' diarrhea. Patient education is a crucial  component of this strategy. Travelers should be instructed  not to consume water that has not been thoroughly boiled,  filtered with iodine-containing filters, or chemically treated  with bleach or tincture of iodine. Drinks, especially those with  ice, should be avoided. Teeth should be brushed with bottled  or treated water and ingestion of water while showering   should be avoided. Only thoroughly cooked vegetables, fish,  shellfish, and meat should be eaten. Sauces and dips such as  guacamole are a frequent source of infection. Fruits, unless  freshly peeled, should not be eaten. Fruit-, vegetable-, and  meat-containing salads should be avoided.   Bismuth subsalicylate (two tablets or 30 mL of the liquid  preparation four times daily) can be taken as prophylaxis.  However, compliance is generally poor due to the inconven-  ience, and salicylate toxicity is a small risk especially if intake  is prolonged. Antibiotic prophylaxis for the casual, healthy  tourist, although often used, is not generally recommended  in view of cost and the risk of inducing antibiotic resistance  among pathogens. Undesirable side effects of antibiotic pro-  phylaxis may include allergic reactions, antibiotic-induced  diarrhea, C difficile colitis, and yeast infections. Antibiotic  prophylaxis can be justified for individuals who are  immunocompromised, who have IBD or other significant  comorbidities, or for those travelers whose responsibilities  and schedule are such that severe traveler's diarrhea would be  more than an inconvenience and would potentially negate  the purpose of their journey. Quinolones such as  ciprofloxacin (500 mg daily) are most widely used, although  resistance to these agents is increasing. Rifaximin (200 mg  twice daily) is promising, reducing diarrhea more than three-  fold among travelers to Mexico in one study with little appar-  ent alteration of the colonic flora.   Cheng AC, Thielman NM. Update on traveler's diarrhea. Curr  Infect Dis Rep. 2002;4:70-77. [PMID: 11853660]   DuPont HL, Jiang ZD, Okhuysen PC, et al. A randomized, double-  blind, placebo-controlled trial of rifaximin to prevent trav-  elers' diarrhea. Ann Intern Med. 2005;142:805-812. [PMID:  15897530]   Goodgame R. Emerging causes of traveler's diarrhea: Cryptospo-  ridium, Cyclospora, Isospora and Microsporidia. Curr Infect Dis  Rep. 2003;5:66-73. [PMID: 12525293]   Literally hundreds of medications can produce diarrhea. One  only has to peruse the adverse reaction sections related to  individual medications in the current Physician's Desk  Reference to appreciate the scope of the problem. Only a few  of the major causes are listed in Table 5-1. To that list could  be added antiarrhythmics, cholinergic agents, prokinetics,  prostaglandins, and many more. A careful history of all med-  ications, both prescription and nonprescription, as well as  herbal remedies and nutritional supplements — including  when they were begun — must be obtained if unnecessary and  costly evaluation seeking the cause of the diarrhea is to be  avoided. In the vast majority of cases, though not all,  medication-related diarrhea begins within a few days of the  initiation of treatment with or a change in dosage of the  offending agent.   ► Acute mesenteric ischemia (AMI) is a medical and sur-  gical emergency. Delay in diagnosis is associated with  high mortality.   ► Patients often present with abdominal pain out of pro-  portion to physical examination findings.   ► Clinical suspicion of AMI necessitates early radiologic  evaluation (computed tomographic [CT] angiography,  conventional angiography) or exploratory surgery in  patients with peritoneal signs.   ► Chronic intestinal ischemia is a clinical diagnosis; patients  report classic symptoms (eg, abdominal angina) and  have radiographic findings showing severe stenoses or  occlusion of two or more mesenteric arteries.   ► Colonic ischemia is rarely life-threatening and usually  resolves with supportive care.   Intestinal ischemia is caused by a reduction in intestinal blood  flow, most commonly as a result of occlusion, vasospasm, or  hypoperfusion of the mesenteric circulation. It is categorized  as acute or chronic, depending on the rapidity and the extent  to which blood flow is compromised and whether it is episodic  or constant, as might occur in chronic mesenteric ischemia.  Ischemia can involve the small intestine or colon. Acute small  intestinal ischemia is a medical and surgical emergency that  requires prompt diagnosis and a coordinated, interdiscipli-  nary approach. By contrast, acute colonic ischemia (ie, ischemic  colitis) is rarely an emergent condition. Acute intestinal  ischemia can be further categorized as arterial versus venous,  embolic versus thrombotic, and occlusive versus nonocclu-  sive. Other causes of bowel ischemia include strangulating   obstructions (adhesions, hernias, metastatic malignancy, intus-  susceptions) and vasculitis (systemic lupus erythematosus,  polyarteritis nodosa).   The vascular supply to the intestines includes the celiac artery,  the superior mesenteric artery (SMA), and the inferior  mesenteric artery (IMA) (Figure 6-1). The celiac axis supplies  blood to the stomach and duodenum. The SMA supplies  the small bowel from the distal duodenum to the mid-transverse  colon. The inferior mesenteric artery supplies the transverse  colon to the rectum. Anastomoses exist between branches of  the major vessels and if one artery is occluded some flow may  be maintained via a patent collateral vessel.   When a major vessel is occluded, collateral pathways open  immediately in response to a fall in arterial pressure distal to  the obstruction. The superior and inferior pancreaticoduo-  denal vessels are collaterals that connect the celiac axis to the  SMA. The phrenic artery connects the aorta to the celiac axis.  The marginal artery of Drummond and the arc of Riolan are  collaterals that connect the SMA and the IMA. The internal  iliac arteries provide collaterals to the rectum. Griffith point  in the splenic flexure and Sudek point in the rectosigmoid  area are watershed areas within the colonic blood supply and  common locations for ischemia.   The splanchnic circulation receives 25% of the cardiac  output under basal conditions and 35% or more postprandially.  Approximately 70% of splanchnic inflow goes to the mucosa,  which is the most metabolically active area of the gut. The  villus tips are the most vulnerable to ischemic injury. Intestinal  blood flow is under complex regulation controlled primarily by  resistance arterioles and precapillary sphincters. Several vasoac-  tive substances influence intestinal perfusion. Catecholamines,  angiotensin II, and vasopressin all can cause vasoconstriction,  whereas vasoactive intestinal peptide causes vasodilation.  Products of ischemia such as acidosis, hypoxemia, and hyper-  kalemia have been shown to cause vasodilation. Ischemic  damage is caused by both hypoxia and reperfusion injury.   ▲ Figure 6-1. Distribution of blood supply to the small intestine and colon from the celiac artery, superior mesenteric  artery (SMA), inferior mesenteric artery (IMA), and internal iliac artery (MA). (Reproduced, with permission, from Kasper DL,  Braunwald E, Fauci AS, et al (editors). Harrison's Principles of Internal Medicine, 17th ed. McGraw-Hill, 2008.)   2000;118:954-968. [PMID: 10784596]  Kirkpatrick ID, Kroeker MA, Greenberg HM. Biphasic CT with   ► Consider in patients >50 years who present with sud-  den onset of severe abdominal pain lasting >2 hours,  especially if a history of cardiovascular disease (conges-  tive heart failure, myocardial infarction, arrhythmia) is  present.   ► Consider in patients with abdominal pain out of proportion  to physical findings.   ► Angiography is the diagnostic procedure of choice and  is potentially therapeutic.   Acute mesenteric ischemia (AMI) remains a challenging  diagnosis with a mortality rate exceeding 50%. The incidence  of AMI has increased over the past 20 years due to longer life  expectancies, increased awareness of ischemic syndromes,  and enhanced diagnostic and therapeutic techniques. The  various causes of AMI include SMA embolism (50%), SMA  thrombosis (15-20%), nonocclusive mesenteric ischemia  (NOMI; 20-25%), and mesenteric venous thrombosis (5-10%).   Embolism to the SMA is most frequently due to a dislodged  thrombus originating from the left atrium, left ventricle, or  cardiac valves. One third of patients have a history of a prior  embolic event and 20% have synchronous emboli. The onset  of symptoms is abrupt and dramatic. SMA thrombosis usu-  ally occurs at the origin of the vessel, which is frequently an  area of severe atherosclerotic narrowing. Acute thrombosis  usually occurs in a patient with underlying chronic intestinal  ischemia. This process is analogous to plaque rupture in  acute coronary syndromes. Approximately 50% of patients  have a history of chronic mesenteric ischemia, and the acute  event occurs after closure of a collateral vessel.   Patients with AMI present with severe, acute, unremitting  abdominal pain strikingly out of proportion to the initial  physical findings. On examination the abdomen may be soft  and either nontender or minimally tender. Distention is  often the first sign. Later findings may include signs of peri-  tonitis, especially if infarction or gangrene has occurred.  Associated symptoms may include nausea, emesis, and tran-  sient diarrhea due to urgent bowel evacuation. Occult blood  is found in the stool in 50-75% of cases.   Leukocytosis with a white blood cell count greater than  15,000/uX is found in 75% of patients. However, most  patients with early intestinal ischemia do not have abnormal  laboratory findings. Lactic acidosis, hemoconcentration, and  raised serum aminotransferase levels are usually late findings  indicative of intestinal infarction.   Historically, standard radiologic imaging has not been useful  in diagnosing AMI, because most of the reported "classic"  findings (eg, bowel edema, pneumatosis intestinalis, portal  venous gas) are not seen until late in the course of the illness.  Plain films of the abdomen are usually normal, and the utility  of these studies is to exclude other acute abdominal processes  such as perforation or obstruction. Mesenteric angiography  has been the gold standard for making the diagnosis of AMI;  however, recent studies have demonstrated that CT scans  may have an overall sensitivity of 80% for AMI, thanks to  technical advances, including spiral CT, rapid intravenous bolus  injection of contrast, and multidetector-row CT (MDCT)  with three-dimensional reconstruction. CT findings may be  either more specific or nonspecific. More specific findings  include thromboembolism in mesenteric vessels, portal venous  gas, bowel wall intramural gas or pneumatosis, lack of bowel  wall enhancement, and signs of ischemia in other organs.  Less specific signs include diffuse bowel wall thickening,  striking vascular engorgement, dilated fluid-filled loops of  bowel, and mesenteric edema (Figure 6-2).   Initial evaluation should include radiographic imaging to  exclude other causes of acute abdominal pain such as perfo-  ration or obstruction. MDCT can provide detailed informa-  tion about the mesenteric vessels and small bowel and is  particularly sensitive in the diagnosis of mesenteric venous  thrombosis.   Angiography is important in both diagnosis and management  of AMI and remains the gold standard for evaluation of  patients with suspected AMI and no peritoneal signs. It is the   mainstay of diagnosis and treatment for both occlusive and  NOMI. It can be both diagnostic and therapeutic. Placement  of a catheter into the SMA allows visualization of obstructing  lesions and facilitates interventions such as infusion of  vasodilators into the SMA, angioplasty, stenting, or infusion of  thrombolytics (Figure 6-3).   The goal of treatment in AMI is to restore intestinal blood  flow as rapidly as possible. However, initial management must  include hemodynamic resuscitation and correction of precipi-  tating causes of AMI such as arrhythmias, congestive heart  failure, or volume depletion. Patients require aggressive hemo-  dynamic monitoring and support, correction of fluid and  electrolyte abnormalities, and treatment with broad-spectrum  antibiotics.   Patients with peritoneal signs or clinical suspicion of perfo-  ration or gangrene require emergent laparotomy, after hemo-  dynamic stabilization, to immediately restore mesenteric blood  flow and resect nonviable bowel. Patients who are hemo-  dynamically stable with no peritoneal signs should undergo  angiography to diagnose obstructive lesions and begin treatment  with vasodilators, such as papaverine, which when infused  directly into mesenteric vessels can help increase blood flow  by reversing vasospasm. Once an obstructing lesion is con-  firmed with angiography, patients can undergo either surgical  revascularization (through aortomesenteric bypass grafting,  embolectomy, or thromboendarterectomy) or endovascular  revascularization (using techniques such as balloon dilation  and angioplasty with or without stenting, or catheter-directed  thrombolytic therapy, in selected cases). The American  Gastroenterological Association algorithm for diagnosis  and management of acute intestinal ischemia is presented  in Figure 6-4.   [PMID: 15159262]  Segatto E, Mortele K, Ji H, et al. Acute small bowel ischemia: CT   [PMID: 14620718]  Wiesner W, Khurana B, li H, et al. CT of acute bowel ischemia.   Acute form— maintain a high index of suspicion in  patients with recent onset of acute abdominal pain  associated with a predisposing condition (ie, heritable  or acguired hypercoagulable states).   Diagnosed with 90% sensitivity by contrast CT, MDCT, or  vascular angiography.    ▲ Figure 6-2. CT scan findings of intestinal ischemia. A and B: Small bowel thickening. C: Small intestinal pneumatosis.  D: Portal venous gas. (Courtesy of Koenraad Mortele, MD.)   Mesenteric venous thrombosis (MVT) accounts for 5-10%  of all cases of AMI. The conditions responsible for the devel-  opment of MVT can be identified in over 80% of cases, and  risk factors are summarized in Table 6-1. The clinical pres-  entation of MVT can be acute, characterized by the sudden  onset of symptoms; subacute, in which symptoms occur for  days or weeks without bowel infarction; or chronic, involving  portal or splenic vein thrombosis and stigmata of portal  hypertension with or without variceal bleeding.   MVT leads to resistance to mesenteric venous blood flow and  intestinal ischemia, with resultant bowel wall edema, fluid efflux  into the bowel lumen, and systemic hypotension. As a conse-  quence of venous congestion, arterial inflow is diminished,   which can lead to bowel ischemia and, ultimately, infarction.  The extent of the venous collateral circulation is a key vari-  able influencing whether submucosal hemorrhage or bowel  infarction will develop following MVT.   As noted, the presentation of MVT can be acute, subacute, or  chronic. Symptoms of acute MVT usually begin a few days to  a few weeks (mean, 7 days) before presentation and in 25%  of patients have been present for 30 days before admission.  Nausea, vomiting, and diarrhea are common, and over 50%  of patients have occult blood in the stool. Examination  findings include fever (50%), abdominal distention with  mild to moderate tenderness and signs of dehydration, and   ▲ Figure 6-3. A: Volume-rendered three-dimensional CT scan showing narrowing of the celiac trunk (arrowhead) and  occlusion of the proximal SMA (arrow). B: Conventional angiogram showing SMA occlusion (arrow). (Reproduced, with  permission, from Kirkpatrick Kroeker MA, Greenberg HM. Biphasic CT with mesenteric CT angiography is the evaluation of  acute mesenteric ischemia: initial experience. Radiology. 2003;229:94.)   hypotension (25%). Hematochezia, found in 15% of  patients, usually signifies severe ischemia or bowel infarction.  Fever, guarding, rebound tenderness, lactic acidosis, and  increased transaminases are late findings that may be associ-  ated with bowel infarction.   In the subacute form of MVT, symptoms such as abdom-  inal pain can be present for several weeks along with an unre-  markable physical examination. Patients with chronic MVT  may not have experienced abdominal pain and often present  with stigmata of portal hypertension, varices (esophageal,  gastric, intestinal), and splenomegaly or bleeding from  varices. The latter can be manifested by hematemesis or fecal  blood loss.   Over 50% of patients with MVT have a personal or family  history of deep venous thrombosis or pulmonary embolism.  MVT should be suspected in patients with pain out of pro-  portion to physical findings, especially if there is a personal  or family history of such coagulation abnormalities.   The gold standard for the diagnosis of MVT is CT scan with  intravenous contrast. Classical findings with a sensitivity of  greater than 90% include a dilated superior mesenteric vein  with a clot or filling defect in the lumen (Figure 6-5). It should   be noted, however, that CT may be less reliable in early  thrombosis if small vessels are involved. Portal venous gas,  air in the small bowel, or free intraperitoneal air usually indi-  cates intestinal infarction.   The treatment of acute MVT depends on whether intestinal  infarction has occurred or is strongly suspected. For example,  persistent peritoneal findings such as guarding or rebound  tenderness should raise suspicion for gut infarction and war-  rant laparotomy (see Figure 6-4). By contrast, in patients  with clinical and radiologic evidence of MVT, but no infarc-  tion, and with good mesenteric blood flow demonstrated by  angiography, conservative management can be attempted  using anticoagulation therapy (ie, heparin). Anticoagulation  is usually continued for 6 months or longer if coagulation  abnormalities preceded MVT. Few data are available regarding  long-term follow-up or the need for treatment after 6 months.  Use of thrombolytics such as streptokinase, urokinase, and  tissue plasminogen activator has not been studied in a large  group of patients; however, catheter- directed thrombolysis has  been performed in some cases.   When there is suspicion of bowel infarction, laparotomy is  required to restore mesenteric blood flow and resect gangrenous   perfusion of the  distal, mesenteric  vascular bed, after  bolus of vasodilator   ▲ Figure 6-4. Algorithm for diagnosis and management of acute intestinal ischemia. DVT, deep venous thrombosis; SMA, superior mesenteric artery. (Reproduced,  with permission, from American Gastroenterological Association Medical Position Statement: guidelines on intestinal ischemia. Gastroenterology. 2000;1 18:951.)   bowel segment(s). In cases in which there is extensive  ischemic damage, massive intestinal resection followed by  long-term parenteral nutrition may be required.   Amitrano L, Brancaccio V, Guardascione MA, et al. High preva-  lence of thrombophilic genotypes in patients with acute mesen-  teric vein thrombosis. Am ] Gastroenterol. 2001;96:146-149.  [PMID: 11197244]   Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis.  NEnglJMed. 2001;345:1683-1688. [PMID: 11759648]    A Figure 6-5. Acute superior mesenteric vein thrombosis;  arrow points to a large thrombus in the proximal superior  mesenteric vein. (Courtesy of David Stockwell, MD.)   Accounts for -20% of cases of AMI and results from  intense mesenteric vasoconstriction, leading to splanchnic  hypoperfusion.   Suspect in patients with diffuse atherosclerotic disease  under conditions of hemodynamic stress (hypotension),  in the setting of vasoconstrictive agents (vasopressin,  cocaine), and in patients with vasculitis (eg, systemic  lupus erythematosus, polyarteritis nodosa).   Signs and symptoms of NOMI may be similar to those of  AMI. Patients who develop NOMI are typically elderly with  diffuse vascular disease, but NOMI can also be seen in patients  with vasculitis or who are on vasoconstricting medications.  Predisposing factors include conditions such as myocardial  infarction with decreased cardiac output, congestive heart fail-  ure, cardiac arrhythmias, sepsis, dehydration, and shock; med-  ications such as diuretics, digoxin, and adrenergic agonists; and  therapies such as dialysis. Vasopressin and angiotensin are the  most likely mediators of the marked vasoconstriction. NOMI  has also been reported after cocaine use.   The mortality rate from NOMI is high for several reasons,  including advanced patient age, comorbidities, and difficulty  in making the diagnosis and reversing ischemia once it has  started. When NOMI is suspected, angiography is the gold  standard for diagnosis and management (Figure 6-6).   Treatment of NOMI includes hemodynamic resuscitation,  antibiotics, and intra-arterial infusion of papaverine, a smooth  muscle dilator, which reverses vasoconstriction and restores  mesenteric blood flow.   Am. 1997;97:319-326. [PMID: 9146715]  Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia.   Survival of patients with AMI depends on early diagnosis  and treatment. Reviewing outcomes of 21 patients with SMA  embolism, Lobo Martinez and colleagues found intestinal  viability was 100% in patients whose symptoms had lasted    ▲ Figure 6-6. Angiogram of the superior mesenteric artery in a patient with nonocclusive mesenteric ischemia (NOMI).  A: Initial angiogram demonstrating diffuse vasoconstriction in setting of hypotensive shock. B: Angiogram after 48 hours  of papaverine infusion, showing dilation. (Reproduced, with permission, from Boley SJ, Brandt LJ. Mesenteric ischemia. In:  Baum S (editor). Abrom's Angiography, 4th ed. Little, Brown, 1997:1627.)   less than 12 hours, 56% when symptoms lasted 12-24 hours,  and only 18% when symptoms lasted more than 24 hours.  Survival was 90% in the setting of early angiography in  patients with no peritonitis; however, among patients in  whom intestinal infarction had already occurred, mortality  was 80%.   In summarizing data from 3692 patients with AMI from  1966-2002, Schoots and colleagues found that while overall  survival has improved over the past four decades, in-hospital  mortality remains high at 88% for SMA thrombosis, 86%  for NOMI, 70% for SMA embolism, and 44% for SMV  thrombosis.   To recapitulate, mortality rates from AMI are 70-90% if  diagnosis is delayed and intestinal gangrene develops. In  patients with angiographically proven AMI who do not have  peritonitis, survival rates now approach 90%. Early diagnosis  and prompt intervention with angiography, or surgery, or  both, are of critical importance for improving outcomes for  patients with AMI.   Lobo Martinez E, Merono Carvajosa E, Sacco O, et al. [Embolectomy  in mesenteric ischemia.] Rev Esp. Enferm Dig. 1993;83:351-354.  [PMID: 8318278]   Schoots IG, Koffeman GI, Legemate DA, et al. Systemic review of  survival after acute mesenteric ischaemia according to disease  aetiology. Br } Surg. 2004;91:17-27. [PMID: 14716789]   Post-prandial abdominal pain, avoidance of eating  (which triggers pain), weight loss, abdominal bruit (50%  of patients).   Angiography shows involvement of at least two of  three major splanchnic blood vessels.   Chronic mesenteric ischemia (CMI) is the result of reduced  blood flow due to atherosclerotic narrowing of at least two of  three major vessels (ie, celiac axis, SMA, or IMA). Usually, an  adequate collateral circulation has developed that prevents  intestinal infarction. However, acute on chronic mesenteric  ischemia and infarction can develop suddenly if thrombosis  or embolism occurs in a severely narrowed artery.   The classic diagnostic triad for CMI consists of post-prandial  abdominal pain, weight loss, and an abdominal bruit. Pain  from abdominal angina is typically recurrent, dull, crampy,  epigastric, and periumbilical, occurring 10-30 minutes after  meals and lasting 1-3 hours. Because eating consistentiy triggers  pain, food fear causes patients to eat progressively less, resulting  in weight loss and often cachexia. Most patients have a history  of peripheral vascular disease (PVD). It is important to note  that some patients with PVD develop abdominal angina after  undergoing surgical repair of peripheral vascular lesions because  of so-called steal syndrome (ie, increased blood flow to the  extremities and away from the mesenteric circulation).   Physical examination of CMI patients usually reveals a soft  abdomen without tenderness during episodes of pain, hence the  classic description of pain disproportionate to physical findings.  As many as 50% of CMI patients have an epigastric bruit, espe-  cially post-prandially, and nausea, emesis, and early satiety are  common associated symptoms. The average duration of symp-  toms prior to diagnosis is 1 year. Diagnosis is often difficult  because of the vague nature of complaints, absence of physical  findings, and lack of an accurate noninvasive test.   Angiography is the diagnostic test of choice for CMI; how-  ever, the diagnosis of CMI remains a clinical rather than an  anatomic one. Angiograms in patients with CMI typically  demonstrate high-grade stenosis in at least two vessels. CT  angiography, magnetic resonance angiography, and Doppler  ultrasound measuring mesenteric blood flow are noninvasive  imaging modalities. However, it is important to correlate  angiographic findings with symptoms, because some indi-  viduals who have complete occlusion of all three major  mesenteric arteries may remain asymptomatic because of  collateral blood flow. Although there have been preliminary  reports of "stress tests" for abdominal angina, at present there  is no functional test with high sensitivity or specificity for  confirming a clinical diagnosis of CMI.   Once the diagnosis of CMI is made based on symptoms and  high-grade stenosis or occlusion of two or more mesenteric  arteries, the goal is to restore mesenteric arterial flow. Although  surgical revascularization using aortomesenteric grafting is  the gold standard, recent studies suggest that endovascular  therapy using percutaneous angioplasty with or without  stenting may be effective in treating CMI, albeit with a higher  risk of symptom recurrence.   Otte JA, Geelkerken RH, Oostveen E. Clinical impact of gastric  exercise tonometry on diagnosis and management of chronic  gastrointestinal ischemia. Clin Gastroenterol Hepatol. 2005;  3:660-666. [PMID: 16206498]   ► Typically, sudden onset of left lower quadrant pain  followed by hematochezia within 24 hours.   Colonic ischemia, also referred to as ischemic colitis, is the  most frequent form of mesenteric ischemia, accounting for  75% of all intestinal ischemia and affecting primarily the eld-  erly. It is estimated that colonic ischemia accounts for 1 in  2000 hospital admissions. Findings of colonic ischemia are  seen in one of every 100 colonoscopies and may be misdiag-  nosed as inflammatory bowel disease or infectious colitis  (Plate 3). Colonic ischemia has been described in several  clinical settings (Table 6-2), although in many instances no  specific cause can be identified. Many cases are initially mis-  diagnosed as inflammatory bowel disease or infectious coli-  tis, especially in individuals younger than age 50 years. The  risk of colonic ischemia appears to be highest for patients  who have recently undergone cardiovascular surgery, and  these patients may experience more severe episodes.   Aortoiliac surgery  Cholesterol emboli  Dehydration  Precipitants in patients <50 years  Vasculitis (eg, systemic lupus erythematosus)  Hypercoagulable states (factor V leiden), phospholipid antibody syndrome  Sickle cell crisis  long-distance running  Medications (estrogens, danazol, vasoconstrictors [pseudoephedrine,   ▲ Figure 6-7. Distribution of colonic ischemia in 250 cases. (Reproduced, with permission, from Brandt L, Boley SJ. Colonic  ischemia. Surg Clin North Am 1992,72:212. Copyright Elsevier.)   Ischemic injury to the colon usually occurs as a consequence  of a sudden and transient reduction in blood flow, resulting  in a low- flow state. In the majority of cases a specific occluding  anatomic lesion cannot be identified. Although it may occur  anywhere, colonic ischemia most commonly affects the so-  called watershed areas with a limited collateral blood supply,  such as the splenic flexure and left colon (Figure 6-7).  Ischemia is usually mucosal and rarely transmural; conse-  quently, gangrenous colitis and colonic strictures are infre-  quent. Eighty- five percent of cases of colonic ischemia resolve  spontaneously within 2 weeks.   Patients with colonic ischemia usually present with abrupt  onset of crampy left lower quadrant abdominal pain, and mild  to moderate rectal bleeding or bloody diarrhea within the  first 24 hours. Over 90% of patients are older than 60 years.  Cardiovascular disease is common, and frequent precipitating   factors include hypotension, cardiovascular surgery (coronary  artery bypass grafting, aortic aneurism repair), dialysis, and  dehydration. Physical examination reveals mild to moderate  abdominal tenderness over the affected bowel, most often  left-sided.   In contrast to patients with AMI, those with colonic  ischemia do not usually appear acutely ill. Bleeding is usually  mild, and patients rarely require blood transfusion. Peritoneal  signs, if present, would suggest perforation or peritonitis.  Ischemic colitis is usually a singular event, and only 5% of  patients develop a recurrence.   The diagnosis is usually established on the basis of clinical  history, physical examination, and endoscopic or radiologic  studies. Although most patients who develop colonic ischemia  are elderly, the condition can also occur in younger patients.  For patients who are younger than age 50, several precipitants  of colonic ischemia should be considered (see Table 6-2). In  young women, the triad of smoking, use of oral contraceptives,  and carriage of the factor V Leiden mutation may be associated  with increased risk of colonic ischemia. Recent reports indicate  that giving penicillin derivatives to patients who harbor  Klebsiella oxytoca may precipitate hemorrhagic colitis.    A Figure 6-8. CT scans demonstrating findings in colonic  ischemia. A: Colonic thickening. B: Pneumatosis. (Courtesy  of Koenraad Mortele, MD.)   Diagnostic modalities include flexible sigmoidoscopy or colo-  noscopy, plain films of the abdomen, and CT scan. Colo-  noscopy with biopsies makes the definitive diagnosis; however,  endoscopy should be avoided in patients with significant  abdominal pain or distention because air insufflation may  precipitate perforation in cases of severe ischemia. Endoscopic  findings frequently include petechial bleeding, pale mucosa,  and, in more severe cases, hemorrhagic ulceration (see Plate 3),  and biopsy specimens show characteristic findings. Plain films  of the abdomen are usually nondiagnostic, but thumbprinting  representing submucosal hemorrhage and edema may be seen  in 20-25% of cases. The use of plain films has been largely  superseded by the ready availability and accuracy of CT scans.  CT scans can demonstrate wall thickening, mucosal and sub-  mucosal hemorrhage, and pericolic fat stranding, and occa-  sionally bowel wall pneumatosis (Figure 6-8).   Angiography is usually not necessary in the evaluation of  colonic ischemia; however, it should be considered if the  clinical findings raise concern for concomitant small bowel  ischemia or infarction.   Stool studies should be performed to exclude infections  such as Escherichia coli 0157:H7, Campylobacter enteritis,  Klebsiella oxytoca, Shigella, or Clostridium difficile, which can  be associated with hemorrhagic colitis.   Patients with colonic ischemia are usually placed on bowel  rest. Patients should be followed with serial abdominal exami-  nations and monitored for bleeding, fever, leukocytosis, and  electrolyte abnormalities. Although there are no controlled  randomized trials proving the effectiveness of antibiotics in  reducing morbidity and mortality, broad-spectrum intra-  venous antibiotics are recommended. Any medications that  can cause vasoconstriction and promote ischemia should be  withdrawn (ie, digitalis, glycosides, vasopressin, and diuretics).  Marked colonic distention is treated with rectal tubes and  nasogastric decompression if necessary. There is no role for  anticoagulation or corticosteroids. Prognosis is favorable, and  most patients improve within a few days and demonstrate  clinical and radiologic resolution within 2 weeks.   Indications for surgery include peritoneal signs suggesting  perforation, gangrenous colitis, massive bleeding, toxic  megacolon, and recurrent sepsis. Long-term complications,  including persistent recurrent colitis and colonic structures,  are infrequent but may require resection of the affected  colonic segment.   In contrast to small bowel ischemia, colonic ischemia is  rarely life threatening. However, the development of colonic  ischemia in the setting of recent cardiovascular surgery  deserves special mention, as the natural history of colonic  ischemia in these patients may be more severe. Prolonged  colonic ischemia, such as can occur in patients with ruptured  abdominal aortic aneurysms or prolonged aortic cross-  clamp time, can lead to acute gangrenous colitis and trans-  mural infarction of the colon. Although emergent operative  intervention may be necessary in the setting of sepsis and  peritoneal signs, most cases of colonic ischemia resolve with  conservative management.   Hogenauer C, Langner C, Beubler E, et al. Klebsiella oxytoca as a  causative organism of antibiotic-associated hemorrhagic colitis.  N Engl] Med. 2006;355:2418-2426. [PMID: 17151365]   ► Pregnancy can exacerbate many chronic gastrointestinal  disorders; the central goal of evaluation is to control  symptoms and rule out an urgent need for surgery while  minimizing exposure to excessive tests and medications.   ► Pregnancy does not affect the course of inflammatory  bowel disease (IBD), and most IBD medications are safe  in pregnancy.   ► Appendicitis is the most common indication for surgery  during pregnancy.   ► Indications for urgent surgery are the same in pregnant  as in nonpregnant patients.   ► Efforts should be made to minimize risk to mother and  fetus when performing diagnostic endoscopic and radi-  ologic tests.   The management of gastrointestinal disease during preg-  nancy poses multiple challenges. First, gastrointestinal dis-  eases are common during pregnancy, and many predisposing  gastrointestinal disorders are aggravated by pregnancy.  Second, diagnostic options are often limited in pregnancy as  there is a need to minimize testing out of concern for both  maternal and fetal exposure. Finally, the management of  these diseases is more complex due to the need to consider  additional risks to both the pregnant mother and the fetus  incurred by medications, endoscopic procedures, and surger-  ies. Data on safety and efficacy of both medications and pro-  cedures during pregnancy are often scarce or inadequate; few  controlled trials have included pregnant women, and fewer  still were designed specifically to study gastrointestinal dis-  ease in this population. Table 7-1 summarizes the U.S. Food   Biertho L, Sebajang H, Bamehriz F, et al. Effect of pregnancy on  effectiveness of laparoscopic Nissen fundoplication. Surg  Endosc. 2006;20:385-388. [PMID: 16391963]   Cohen-Kerem R, Railton C, Oren D, et al. Pregnancy outcome fol-  lowing non-obstetric surgical intervention. Am J Surg. 2005;  190:467-473. [PMID: 16105538]   Malangoni MA. Gastrointestinal surgery and pregnancy.  Gastroenterol Clin North Am. 2003;32:181-200. [PMID:  12635416]   Heartburn symptoms attributed to gastroesophageal reflux  occur in nearly two thirds of pregnancies and in women with  no preexisting gastroesophageal reflux disease (GERD), often  resolve following delivery. Symptoms are more common and  more severe during the third trimester. Risk factors for heart-  burn during pregnancy include a history of heartburn before  pregnancy or during previous pregnancies, multiparity, and  younger maternal age. Reduced lower esophageal sphincter  (LES) pressure and decreased gastric and small bowel motil-  ity, possibly mediated by progesterone and to a lesser extent  by estrogen, and increased abdominal pressure secondary to  the gravid uterus are all implicated in the pathogenesis.   Heartburn is the predominant symptom of GERD, and  regurgitation may accompany it. Symptoms are exacerbated  by reclining and eating, and patients may also report hoarse-  ness, cough, and asthma-like symptoms. Diagnosis is based  on symptoms. Esophageal manometry and pH studies are  rarely needed, and barium studies should be avoided in preg-  nancy. If required for severe symptoms, esophagogastroduo-  denoscopy (EGD) can be performed during pregnancy with  careful monitoring (see later discussion on endoscopy during  pregnancy).   Table 7-1. FDA categories for the use of medications  in pregnancy.    Controlled studies in animals and women have  shown no risk in the first trimester, and possible  fetal harm is remote    Either animal studies have not demonstrated a  fetal risk but there are no controlled studies in  pregnant women, or animal studies have  shown an adverse effect that was not con-  firmed in controlled studies in women in the  first trimester    No controlled studies in humans have been  performed, and animal studies have shown  adverse events, or studies in humans and  animals are not available; give if potential  benefit outweighs the risk    Positive evidence of fetal risk is available, but  the benefits may outweigh the risk if life-  threatening or serious disease   Reproduced, with permission, from Mahadevan U, Kane S. American  Gastroenterological Association Institute technical review on the  use of gastrointestinal medications in pregnancy. Gastroenterology.  2006;131:283-311.   Lifestyle modification should be the first line of therapy. This  includes avoidance of alcohol, caffeine, mint, chocolate,  tobacco, and fatty and spicy foods. Avoiding late night meals  and raising the head of the bed can also prevent nighttime  symptoms.   Medications used in the treatment of GERD during  pregnancy are listed in Table 7-2. Limited data are available  about either the efficacy or the safety of antacids; however,  aluminum- and calcium-containing antacids are consid-  ered acceptable in normal therapeutic doses during preg-  nancy, and limited studies have not shown evidence of  teratogenicity in animals. Calcium-based antacids are con-  sidered the first line of pharmacologic therapy. All magnesium-  containing compounds should be avoided during the last  few weeks of pregnancy, as magnesium can slow or arrest  labor and may cause convulsions. Antacids containing  alginic acid or magnesium trisilicate should be avoided, as  these chemicals have been associated with nephrolithiasis,  hypotonia, respiratory distress, and cardiovascular impair-  ment. Antacids containing sodium bicarbonate should not  be used because they can cause maternal or fetal metabolic  acidosis and fluid overload. Finally, antacids should be   taken separately from iron preparations as they can interfere  with absorption of iron.   Overall, sucralfate, histamine-2 blockers (H,-blockers)  and the majority of proton pump inhibitors (PPIs) have been  found to be safe in pregnancy even when used in the first  trimester. Sucralfate, like antacids, is a nonabsorbable med-  ication and has been studied in a randomized controlled trial  in pregnancy and found to be effective in the treatment of  heartburn and regurgitation without presenting any risk to  the fetus of pregnant women with normal renal function.  H 2 -receptor blockers are commonly used and considered safe  in pregnancy. Ranitidine has demonstrated safety and effi-  cacy and is probably the H 2 -blocker of choice. Cimetidine is  also considered safe; however, some authorities recommend  avoiding its use in pregnancy because of feminization seen in  some animal and human studies. Fewer data are available for  famotidine and nizatidine.   Although PPIs are more effective than H 2 -blockers for  controlling symptoms of GERD and healing esophagitis,  they are not as well studied in pregnancy. Some investigators  suggest documenting failure with H 2 -blockers and consider-  ing upper endoscopy before empiric trial. Observational  studies suggest omeprazole can be used safely during pregnancy;  however, increased fetal toxicity in animal studies and some  evidence of cardiac malformations in human studies have led  to class C categorization by the FDA. Animal studies support  the safety of lansoprazole and rabeprazole; pantoprazole and  esomeprazole also appear to be safe based on animal data,  although studies in humans are limited.   Antireflux surgery during pregnancy should be avoided  and is often not necessary as symptoms resolve or improve  with delivery. Metoclopramide can be used in very refrac-  tory cases and may help treat pregnancy-related bowel  hypomotility, which is hypothesized to contribute to  pregnancy-related reflux. It is used to treat pregnancy-  associated nausea and vomiting, and one study shows no  association with fetal malformations. For patients who have  already undergone antireflux surgery prior to pregnancy,  these methods appear to be effective in controlling GERD  symptoms during and after pregnancy, and pregnancy does  not appear to affect long-term outcomes and failure rates of  antireflux surgery.   For patients experiencing symptoms in the postpartum  period, antacids and sucralfate are considered safe because  of limited maternal absorption. All H,-blockers are excreted  in breast milk; however, cimetidine, ranitidine, and famoti-  dine are felt to be safe during breast feeding. Nizatidine  has been associated with growth retardation in one animal  study.   Gonzalez R, Bowers SP, Swafford V, et al. Pregnancy and delivery   Table 7-2. Medications used in the treatment of gastroesophageal reflux and peptic ulcer disease.    Embryonic and fetal toxicity reported, but  large data sets suggest low risk   Reproduced, with permission, from Mahadevan U, Kane S. American Gastroenterological Association Institute technical review on the use of  gastrointestinal medications in pregnancy. Gastroenterology. 2006;131:283-311.   Almost 80% of women experience nausea during the first  trimester, and for some this is the symptom that leads to the  diagnosis of pregnancy. In a prospective study of 160 preg-  nant women, 80% of the women reporting nausea stated that  it lasted all day, suggesting that "morning sickness" may be a  misnomer. The average duration of the nausea was 35 days  and only half of the women had relief of nausea by the 14th  week of gestation, although symptoms disappeared in 90%  of women by week 22.   Nausea and vomiting during pregnancy has been associ-  ated with decreased risks of miscarriage, perinatal death, low  infant birth weight, and preterm birth. Although it has been  suggested that nausea and vomiting is a sign that hormonal  levels and physiologic changes appropriate for gestation have  been achieved, this has not been demonstrated. The patho-  genesis of nausea and vomiting in pregnancy is not well   understood; hormonal changes during pregnancy (estro-  gens, progesterone, prostaglandin E, human chorionic  gonadotropin [hCG] ) are believed to contribute to this phe-  nomenon either directly or by altering gastric neuromuscu-  lar function.   A careful evaluation to exclude other disorders and con-  tributing factors is important (Figure 7-1). The presence of  heartburn suggests the coexistence of GERD and should  prompt treatment with antacid medications (see the discus-  sion of GERD, earlier). Although patients can experience  soreness of the abdominal muscles and ribs in the setting of  recurrent vomiting and retching, abdominal pain is not typ-  ically associated with nausea and vomiting during pregnancy.   ▲ Figure 7-1. Evaluation of nausea and vomiting during pregnancy. AFLP, acute fatty liver of pregnancy; CBC, complete blood  count; LFT, liver function tests; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; UA, urinalysis.   Epigastric, periumbilical, or right-sided pain can suggest  gallstone disease, peptic ulcer disease (PUD), pancreatitis, or  appendicitis and an appropriate workup should be per-  formed to exclude these disorders. Vomitus typically contains  recently ingested food or yellow juice. Bilious vomitus or  severe periumbilical pain can suggest bowel obstruction.   The patient with uncomplicated pregnancy-associated  nausea and vomiting should have normal findings on physical  examination. The presence of dehydration or orthostatic  hypotension can suggest hyperemesis gravidarum (see later  discussion). The presence of abdominal tenderness, rebound,  palpable masses, abdominal distention, or a succussion splash  should prompt laboratory evaluation and imaging to rule out  other causes.   An elevated white blood cell count (beyond physiologic  leukocytosis of pregnancy or accompanied by a neutrophilia)  can suggest the presence of cholecystitis, pancreatitis, appen-  dicitis, or pyelonephritis. A urine specimen for urinalysis and  urine culture to exclude urinary tract infection should be  obtained. Other relevant testing includes thyroid function  testing, liver blood tests (chronic hepatitis C infection can be  associated with a high incidence of nausea), hepatitis serolo-  gies, and fasting glucose level. Severely abnormal serum elec-  trolytes resulting from vomiting suggest the diagnosis of  hyperemesis gravidarum.   The medical and nonmedical literature is replete with  dietary suggestions for women suffering from this problem.  Medical treatment is directed toward control of symptoms  (Figure 7-2).   Typically, fatty foods are avoided because these can delay  gastric emptying. Small, frequent meals of bland carbohy-  drates (starches such as noodles, potatoes, and rice), chicken,  and fish are recommended. For patients with severe nausea  and vomiting, small sips of salty liquids such as sports bever-  ages or broth are recommended. Juices and creamy or dairy  beverages are not advised as these can exacerbate symptoms.  Some authors also recommend avoidance of vegetables or  high-fiber foods, which can form bezoars. Acupressure is  often performed with the use of wrist bands (Seabands) worn  continuously for a period of a few days, followed by a hiatus  of few days; it is noninvasive and many women report a  reduction in the number of episodes of nausea, although data  are equivocal about whether this benefit is actual or partially  a placebo effect. Most studies did not show a significant ben-  efit in the treatment of severe vomiting. A recent Cochran  review supports the use of pyridoxine (B ) for control of nau-  sea symptoms, and another small trial comparing 1.05 g of  ginger daily for 3 weeks with 75 mg of pyridoxine found a  similar modest benefit in reducing symptoms of nausea.   Antihistamines such as meclizine have been used with no  reports of teratogenicity. Studies of dimenhydrinate and   diphenhydramine during pregnancy have shown conflicting  results on safety and efficacy. Phenothiazines such as  promethazine, prochlorperazine, and trimethobenzamide  are considered low-risk drugs based on studies in pregnant  women and also have clinical efficacy in this setting.  Metoclopramide is used frequently in Europe for this indica-  tion, and one study shows no association with fetal malfor-  mations. Other prokinetics such as domperidone (used in  Canada), bethanechol, and erythromycin have not been  studied. Ondansetron is considered low risk in pregnancy,  although its use is typically limited to cases of hyperemesis  gravidarum. Granisetron and dolasetron have not been stud-  ied in human pregnancies.   Jewell D, Young G. Interventions for nausea and vomiting in early   [PMID: 14583914]  Koch KL, Frissora CL. Nausea and vomiting during pregnancy.   Gastroenterol Clin North Am. 2003;32:201-234. [PMID: 12635417]  Smith C, Crowther C, Willson K, et al. A randomized controlled   trial of ginger to treat nausea and vomiting in pregnancy. Obstet   This condition is characterized by severe vomiting with con-  current dehydration, electrolyte abnormalities, or weight loss.  The incidence is roughly 5 per 1000 pregnancies and symp-  toms nearly always begin in the first trimester, although  hyperemesis can sometimes be indicated by vomiting that  persists after the first trimester. Hyperemesis gravidarum is  associated with high estrogen levels and is more likely to  occur with multiple gestations, gestational trophoblastic dis-  ease, and fetal abnormalities such as triploidy, trisomy 21, and  hydrops fetalis. It has also been associated with hyperthy-  roidism, preeclampsia, eclampsia, HELLP syndrome (hemoly-  sis, elevated liver enzymes, and low platelets), and acute fatty  liver of pregnancy (AFLP). Although overall, patients with  hyperemesis have good fetal outcomes, one study found that  patients who experience a loss of 5% or more of body weight  have a greater risk of growth retardation or fetal anomalies.   Patients may report dry mouth, sialorrhea, hyperolfaction, dys-  geusia (altered or metallic taste), and decreased taste sensation.  Physical examination may reveal signs of dehydration, includ-  ing dry mucous membranes and poor skin turgor. The pres-  ence of epigastric or right upper quadrant pain, headache, and  diplopia can suggest preeclampsia or eclampsia. Blood pressure  should be measured and urinalysis performed; hypertension  and proteinuria support the diagnosis of preeclampsia.  Hyperreflexia and edema may also be present in preeclampsia,  and the development of seizures defines eclampsia.   Admit for IV hydration  IV antiemetics, nutritional  support if no improvement   ▲ Figure 7-2. Management of nausea and vomiting in pregnancy. GERD, gastroesophageal reflux disease;  IV, intravenous; PPI, proton pump inhibitor.   Blood chemistries should be evaluated as hypochloremic  metabolic alkalosis, hypokalemia, hypomagnesemia, and  hyponatremia are common. Complete blood count and liver  blood tests should also be checked to evaluate for HELLP  syndrome (elevated transaminases without significant ele-  vation of alkaline phosphatase or bilirubin, often with low  platelets). AFLP can present with fulminant hepatic failure  (elevated prothrombin time, jaundice, and elevated  transaminases) and sometimes concurrent renal failure and   hypoglycemia. These patients must be transferred to an  intensive care unit and a hepatologist should be consulted  immediately. HELLP syndrome and AFLP typically occur  late in pregnancy, usually in the third trimester. Other dis-  eases associated with severe vomiting include hepatic vein  thrombosis or Budd-Chiari syndrome, which can be diag-  nosed with a Doppler ultrasound. Celiac sprue can be diag-  nosed by tissue transglutaminase immunoglobulin A (IgA)  and antiendomysial IgA or endoscopy, or both. Helicobacter  pylori can be diagnosed by serology, endoscopy, or hydrogen  breath test. Hyperemesis does not typically cause elevation   Pregnancies of women with hyperemesis gravidarum can be  complicated by low birth weight if the mother has experi-  enced weight loss; however, fetal fatality is rare. Severe vom-  iting can rarely cause Mallory- Weiss tears or esophageal  rupture. The most serious complication is Wernicke  encephalopathy resulting from thiamine deficiency. Poor  dietary intake can also result in deficiency of other vitamins  and nutrients such as iron, calcium, and folate.   Oral and intravenous hydration and repletion of electrolytes  is the primary treatment. Thiamine should be administered  prior to dextrose to avoid Wernicke encephalopathy. After  24 hours of aggressive intravenous hydration, the infusion  should be adjusted to maintain urine output. Once oral  hydration is tolerated, broth or salty liquids should be  started, followed by small carbohydrate meals such as crack-  ers and noodles. In some cases nasogastric or nasojejunal  feeding may be required. In rare cases, parenteral nutrition  has been used, but this should be avoided if possible due to  risks of infection, diabetes, cholelithiasis, and risks associated  with central line placement. Four cases have been reported of  placement of percutaneous endoscopic gastrostomy tubes  with jejunal extensions for this indication, during which fetal  monitoring and anesthesia support were provided. Although  procedure-related adverse fetal outcomes were not reported,  this procedure should be reserved for patients at high nutri-  tional risk, after nasoenteric feeding has failed and parenteral  nutrition is contraindicated (hyperglycemia, hypercoagula-  bility, or inadequate venous access). Medications used to  control nausea and vomiting are often effective for hyper-  emesis. One study demonstrated some benefit of powdered  root of ginger (20 mg orally, four times daily) in controlling  symptoms. A few case reports describe benefits of erythro-  mycin in controlling hyperemesis. Another study showed  some efficacy of methylprednisolone, but steroids can be  associated with adverse fetal outcomes.   Irving PM, Howell RIS, Shidrawi RG. Percutaneous endoscopic  gastrostomy with a jejunal port for severe hyperemesis gravi-  darum. Eur J Gastroenterol Hepatol. 2004;16:937-939. [PMID:  15316422]   New-onset constipation and exacerbation of chronic consti-  pation are common complaints during pregnancy. Several  physiologic changes are believed to contribute to this prob-  lem, including poor fluid intake in the setting of nausea and  vomiting, iron supplementation, bed rest or decreased exer-  cise, and hormonal changes such as increased progesterone   and estrogen, which is thought to depress the migrating motor  complex and slow orocecal transit time.   In uncomplicated constipation, the physical examination  should be normal. Fever, abdominal pain, tenderness, disten-  tion, nausea or vomiting, or obstipation should prompt eval-  uation for other causes such as bowel obstruction or volvulus.   The treatment of constipation during pregnancy is similar to  its treatment in nonpregnant patients. First-line therapy con-  sists of dietary fiber, which is the safest and most physiologic  way to treat constipation; however, many patients will not  respond to dietary fiber alone.   Psyllium, calcium polycarbophil, and methylcellulose are  bulk laxatives that can be used as an alternative or adjunct to  dietary fiber. These agents should be diluted and taken with  food during meals. Fiber increases fecal water content,  increases stool weight, decreases colonic transit time, and  improves stool consistency. The laxative effect may be delayed  for days. Pregnant patients should be warned that fiber can  cause bloating and flatulence and instructed to consume suf-  ficient fluids with it. Docusate, a stool softener, can be used  alongside fiber supplements and is used routinely in preg-  nancy; however, there is one case report of neonatal hypo-  magnesemia associated with maternal oral administration of  sodium docusate.   Osmotic laxatives can be used if fiber supplementation  fails. Sorbitol and lactulose are poorly absorbed sugars that  stimulate fluid accumulation in the colon by an osmotic  effect. Lactulose is more expensive and should not be used in  diabetic patients because it contains galactose. In addition, it  can exacerbate nausea in pregnant patients with this symp-  tom. Polyethylene glycol has been used to treat chronic con-  stipation during pregnancy and causes less abdominal  bloating and flatulence than other osmotic laxatives. It is  now available over-the-counter and is recommended by  many obstetric societies.   Stimulant laxatives are generally reserved for patients who  do not respond to fiber or osmotic laxatives. If used chroni-  cally, electrolytes should be monitored as hypokalemia, Hypo-  magnesemia, hyponatremia, and dehydration can result.  Senna is generally safe in pregnancy and can be used in com-  bination with bulk laxatives. It can be used at bedtime with  fluids up to three times per week. Cascara is milder and is less  often associated with abdominal discomfort. Bisacodyl is also  safe in pregnancy as tablets or suppository, but can produce  some abdominal discomfort when administered orally.   Fecal impaction should be treated with digital disim-  paction. Mineral oil, tap water, or retention enemas can be  used to soften stool. Bisacodyl suppository can then be used  along with oral agents to treat constipation.   Agents to avoid during pregnancy include castor oil,  which can initiate premature uterine contractions; aloe,  which has been associated with congenital malformations;  and saline hyperosmotic agents such as magnesium laxatives  and phosphosoda, which can promote sodium and water  retention. Orally administered mineral oil should also be  avoided because it prevents absorption of fat-soluble vita-  mins. Tegaserod is no longer available for use in either preg-  nant or nonpregnant patients.   Wald A. Constipation, diarrhea, and symptomatic hemorrhoids  during pregnancy. Gastroenterol Clin North Am. 2003;32:  309-322. [PMID: 12635420]   Acute or chronic diarrhea can occur in pregnant women, and  it is believed that pathogenesis and differential diagnosis are  similar in pregnant and nonpregnant patients. Most cases of  acute diarrhea are caused by viral infections such as rotavirus  and Norwalk virus and are associated with large volume,  watery diarrhea that is self-limited. Bacterial illness often  produces more frequent stools of small volume, abdominal  pain, occasional fever, and blood and leukocytes in the stool.   Evaluation of diarrhea is typically warranted only if diarrhea  is profuse, leads to dehydration, is bloody, is associated with  high fevers, or if the illness persists for 48 hours without  improvement or becomes chronic. Noninfectious causes of  acute and chronic diarrhea include functional diarrhea, food  intolerance, use of sugar substitutes such as sorbitol and man-  nitol, and IBD. A careful dietary and family history should be  obtained.   Stool cultures for bacterial pathogens, ova and parasites, and  toxin or enzyme-linked immunosorbent assay (ELISA) for  Clostridium difficile are the next step in evaluation. Flexible  sigmoidoscopy with biopsy is considered safe in pregnancy  and can be performed if needed to evaluate bloody or per-  sistent diarrhea.   Uncomplicated diarrhea should be treated with oral rehydra-  tion using juices, noncaffeinated beverages, and broth.  Orange juice and bananas provide potassium, and salted  crackers and broth can provide sodium. Small, frequent  meals and avoidance of high-fat, caffeine, dairy and artificial  sweeteners are recommended.   Antibiotics should be used only in the setting of docu-  mented infection with bacterial or parasitic microbes.  Albendazole is teratogenic in animals, but in the setting of   helminthic infections during pregnancy the benefit is felt to  be greater than the theoretical risk. Metronidazole can be  used for C difficile, Giardia lamblia, and Entamoeba histolyt-  ica, but should be avoided during the first trimester and  should not be administered long term because there are no  data supporting its use more than 2-3 weeks at a time.  Ampicillin and erythromycin stearate have been used for  bacterial causes of diarrhea, the latter specifically for  Campylobacter jejuni infection. Less data are available on  vancomycin, but it is also considered a low-risk drug.  Azithromycin is not associated with congenital defects but  may cause maternal gastrointestinal discomfort during preg-  nancy. Second-generation cephalosporins such as cefurox-  ime and cefixime can be used for acute shigellosis.  Fluoroquinolones, tetracycline, doxycycline, erythromycin  estolate, and trimethoprim-sulfamethoxazole should not be  used based on current data available. Rifaximin is a nonab-  sorbable antibiotic with a wide spectrum of gram-negative  and anaerobic coverage that is currently FDA approved for  traveler's diarrhea. Although it should eventually be useful  during pregnancy, no data are currently available regarding  its use in pregnant women.   Antidiarrheal agents can be used to control symptoms in  severe or persistent disease once active infection has been  excluded. Kaolin and pectin are not absorbed and are proba-  bly safe although impairment of iron absorption is a possi-  bility. Loperamide in small doses has been used in and is  rated category B during pregnancy. Codeine can also be used  in small amounts. Agents to avoid include bismuth subsali-  cylate (contained in Kaopectate), mainly because of the ter-  atogenicity of salicylates. Diphenoxylate with atropine has  also been found to be teratogenic. Alosetron should be  avoided as well, because there are few data on its use during  pregnancy. Cholestyramine has been used to treat cholestasis  of pregnancy safely; however, its use can result in fat-soluble  vitamin deficiencies including coagulopathy, which can lead  to neonatal intracerebral hemorrhage.   Hemorrhoids are common in the U.S. adult population and  often become symptomatic or worsen during pregnancy.  Pregnancy-associated constipation, poor venous return,  increase in circulating blood volume, and extended time in  the sitting position are all believed to contribute to this  problem.   The perianal area should be inspected to rule out other con-  tributions to pain and pruritus such as pinworms, fissures, fis-  tulas, or ulcers. Other causes of rectal bleeding should be  evaluated for, and a flexible sigmoidoscopy performed if  needed. Internal hemorrhoids should be graded: first-degree  hemorrhoids bleed but do not prolapse and can be visualized   by anoscopy; second-degree hemorrhoids protrude during  defecation or with straining but revert when straining stops;  third-degree hemorrhoids are continuously prolapsed but eas-  ily reduced; fourth-degree hemorrhoids cannot be reduced.   External hemorrhoids require treatment if they become  thrombosed, which often results in pain or discomfort with  sitting. If conservative measures such as stool softeners, daily  warm sitz baths, and mild analgesics are not effective, surgi-  cal excision under local anesthesia is safe during pregnancy  and does not affect the fetus. Clot incision and removal is  generally only a temporizing measure as thrombosis usually  recurs.   Internal hemorrhoids can cause bleeding, pain, or pruri-  tus that may require treatment. Treatment of constipation is  essential. Topical therapies such as witch hazel, hydrocorti-  sone cream, and topical anesthetics (eg, benzocaine, dibu-  caine, or pramoxine) can help treat pruritus. Products  containing epinephrine or phenylephrine should be avoided,  especially in women with hypertension, diabetes, or fluid  overload. If topical measures fail, band ligation for first-,  second-, or third-degree internal hemorrhoids or injection  sclerotherapy for first- or second-degree hemorrhoids is safe  in pregnancy. Band ligation carries the associated risk of acute  necrotizing perianal sepsis; however, this complication is rare.  Infrared photocoagulation or laser coagulation of first- and  second-degree hemorrhoids is also minimally invasive,  although safety in pregnancy has not been demonstrated. For  patients who fail office-based procedures or those with  fourth-degree lesions, closed excisional hemorrhoidectomy  using local anesthesia has been reported to be safe and effec-  tive in pregnancy.   Wald A. Constipation, diarrhea, and symptomatic hemorrhoids  during pregnancy. Gastroenterol Clin North Am. 2003;32:  309-322. [PMID: 12635420]   The symptom complex and defining criteria of irritable bowel  syndrome is described in Chapter 24. Irritable bowel syn-  drome is common in pregnancy, partly because it is a common  syndrome in women of childbearing age and partly because  pregnancy seems to exacerbate gastrointestinal symptoms  associated with the syndrome. Many women experience an  increase in constipation, or conversely, an increase in stool fre-  quency. Abdominal pain, bloating, flatulence and nausea are  also exacerbated by pregnancy, it is thought because of the  impact of female hormones on gastrointestinal motility.   In patients with preexisting irritable bowel syndrome, evalua-  tion mainly consists of ruling out other causes of constipation,   irregular stools, and abdominal discomfort. Failure to respond  to medical management or alarm symptoms such as bleeding,  weight loss, or fever should prompt a search for other causes.  In patients who present with irritable bowel syndrome during  pregnancy, the diagnosis of irritable bowel syndrome is sug-  gested by the combination of pain, flatulence, irregular defeca-  tion, and mucus in stools, and the exacerbation of symptoms by  eating and relief by defecation. (See Chapter 24.)   Dietary measures are the safest way to treat irritable bowel syn-  drome in pregnancy. Fiber supplementation can be imple-  mented for constipation-predominant, diarrhea-predominant,  and alternating irritable bowel syndrome. Patients can add  bran to each meal or purchase supplements such as psyllium.  Patients should be warned that an increase in bloating and flat-  ulence occurs initially with fiber but may improve with time.   Medications used in the treatment of irritable bowel  syndrome are outlined in Table 7-3. For patients with con-  stipation-predominant symptoms who do not respond to  bulk laxatives, osmotic laxatives such as polyethylene glycol,  sorbitol, or lactulose can be used and are considered low  risk in pregnancy. Tap-water enemas can be used to treat  fecal impaction. Magnesium citrate and sodium phosphate  should be avoided. For a full discussion of laxatives that can  be used in pregnancy, see the earlier discussion of constipa-  tion. For patients with diarrhea-predominant symptoms, a  low-fat, nondairy diet should be tried first. After this, lop-  eramide or codeine can be used in small doses after infec-  tion is ruled out. For information about antidiarrheal  agents for use during pregnancy, see the earlier section on  treatment of diarrhea in pregnancy.   Antispasmodic agents such as anticholinergics, calcium  channel blockers, and direct gut smooth muscle relaxants are  used in patients whose irritable bowel syndrome is associated  with severe pain, but these agents have not been well studied  in pregnancy, and there is a lack of efficacy data to support use.  Dicyclomine has been associated with phocomelia in animals  and is a category B drug in pregnancy. Most other anticholin-  ergics such as hyoscyamine, and calcium channel blockers  such as nifedipine are category C drugs and are not well-studied  in pregnancy. Antidepressant drugs have been used during  pregnancy for treatment of depression, but have not been  studied for the treatment of irritable bowel syndrome in preg-  nancy. Tricyclic antidepressants and selective serotonin reup-  take inhibitors (SSRIs) have been associated with short-term  neonatal withdrawal symptoms, and cases of neonatal heart  failure and electrocardiographic abnormalities have been  reported with tricyclic antidepressants. SSRIs such as fluoxe-  tine, paroxetine, sertraline, and citalopram are FDA category C.  Paroxetine is associated with increased congenital malforma-  tion. The tricyclic agents nortriptyline and imipramine are  category D drugs, but desipramine and amitriptyline are  category C. Narcotics should be avoided because of the risk of  tolerance, and benzodiazepines are category D in pregnancy.   Table 7-3. Medications used in the treatment of irritable bowel syndrome.   Reproduced, with permission, from Mahadevan U, Kane S. American Gastroenterological Association Institute technical review on the use of   Hasler WL. The irritable bowel syndrome during pregnancy.  Gastroenterology Clin North Am. 2003;32:385-406. [PMID:  12635423]   Fecal incontinence following vaginal delivery can be caused  by anal sphincter tears, denervation injury, or rectovaginal  fistulas. Risk factors for anal sphincter tears after vaginal  delivery include third- or fourth-degree perineal lacerations  (those that extend into the muscular layers of the anal  sphincter), incomplete repairs of these lacerations, nerve  injury or partial dehiscence following laceration repair, epi-  siotomies (particularly midline episiotomies), a history of  anal tears from previous deliveries, and forceps or vacuum  delivery. The incidence of anal sphincter tears is lower in  elective caesarean deliveries, but fecal incontinence is still  common following emergency caesarean deliveries, presum-  ably because some injury to the pelvic floor has already  occurred. Anovaginal and rectovaginal fistulas are more  common in pregnant women in underdeveloped countries  and are felt to be partly due to prolonged labor leading to  pressure necrosis. Fistulas can also be seen after laceration  repair or in infected episiotomy sites. Nerve injury, particu-  larly pudendal nerve injury during delivery, has also been  implicated in fecal incontinence, but this has not been  demonstrated conclusively.   Patients can present with pregnancy-related fecal inconti-  nence immediately after or many years following delivery. In  most patients, the rectal examination will be normal and rec-  tal tone will be grossly normal; in some cases, it is possible to  palpate a defect in the anterior wall.   The mainstay of evaluation is the endoanal ultrasound  (EAUS). Defects in either the external or internal anal  sphincter are seen as asymmetries in concentric rings of tis-  sues that surround the anal canal. The internal anal sphinc-  ter appears hypoechoic, and defects in this layer appear  hyperechoic. The external anal sphincter appears hypere-  choic and defects appear hypoechoic. Typically, pregnancy-  related trauma from tears or episiotomies is located  anteriorly. Fistulas appear as hypoechoic tracts; air within  these tracts appears as focal hyperechoic areas. Findings on  EAUS have been validated by anorectal manometry and cor-  relate with anal squeeze pressure and surgical findings and  histology. Other studies of EAUS performed before and after  surgical repair of sphincter defect show that EAUS docu-  mentation of closure of the sphincter defect predicts  improvement in fecal incontinence. Anorectal manometry  can demonstrate changes in resting and squeeze pressure due   to sphincter trauma but is less sensitive in being able to  detect tears than anorectal manometry. Pelvic magnetic res-  onance imaging (MRI) may be a useful and noninvasive  modality but is currently not widely available and has not  been well studied for this indication. Pudendal nerve injury  can be documented by pudendal nerve terminal motor  latency measurements, but the role of pudendal nerve injury  in fecal continence is controversial.   The treatment of sphincter tears and rectovaginal fistulas is  surgical. Sphincteroplasty, when closure of the defect is suc-  cessful, often leads to improvement in symptoms   GastrointestEndoscCHnNAm. 2006;16:71-81. [PMID: 16546024]  Mimura T, Kaminishi M, Kamm MA. Diagnostic evaluation of   Initial presentation of IBD during pregnancy is rare. For  patients with existing IBD, severity of disease at the time of  conception is the strongest predictor of disease activity dur-  ing pregnancy. Only one third of women who are in remis-  sion at the beginning of pregnancy will experience a flare  during pregnancy, whereas two thirds of women with active  disease at the time of conception will have continued or  worsened symptoms during their pregnancy. Pregnancy out-  comes are also related to severity of disease. Patients in  remission or with mild disease typically have normal preg-  nancies; however, poor outcomes have been reported in 60%  of pregnancies complicated by severe Crohn disease or ful-  minant ulcerative colitis requiring surgery. Patients with  active disease should be considered to have high-risk preg-  nancies and should be followed by the appropriate obstetric  service. Unlike many other diseases in pregnancy, IBD flares  are rarely cured by delivery, although early delivery in some  situations may protect the fetus and allow for more aggres-  sive treatment of the mother.   Disease activity should be monitored carefully prior to con-  ception and throughout the pregnancy. Patients should be in  remission on stable doses of medications at least 3-6 months  before conception. Patients should be encouraged to be com-  pliant with treatment if needed for flares or for maintenance,  as active disease is the greatest threat to normal pregnancy,  not the medications used to treat it. As patients with IBD can  develop other gastrointestinal complications during preg-  nancy, a careful evaluation for infection, ulcer disease, nausea  and vomiting associated with pregnancy, and biliary disease   should be undertaken before starting treatment for a flare.  Tuberculin skin test placement (PPD) is generally done prior  to administering most of the immunosuppressive agents  described later under "Treatment."   Flexible sigmoidoscopy is generally safe during pregnancy  and can be performed if needed to evaluate the severity of a  flare or to rule out hematochezia or diarrhea from another  source. Colonoscopy is generally avoided in pregnancy (see  later discussion of endoscopy during pregnancy). If radi-  ographic studies are needed, testing using low-dose (< 25 rad)  ionizing radiation is preferred. MRI does not involve ionizing  radiation and has been used to establish the diagnosis or to  evaluate the activity of Crohn disease in the second and third  trimesters. The indications for performing sigmoidoscopy in  pregnant patients are similar to indications in nonpregnant  patients and include evaluation of diarrhea, hematochezia,  and abdominal pain or mass. In one study, 15 of 17 patients  with IBD who underwent sigmoidoscopy during pregnancy  had a change in management based on findings. When lower  endoscopy is required, flexible sigmoidoscopy is much lower  risk than colonoscopy and should be considered first, partic-  ularly in patients with left-sided disease.   Treatment of IBD during pregnancy is similar to that of non-  pregnant patients.   Tables 7-4 and 7-5 outline considerations relating to med-  ication use in pregnant and breast-feeding women.   1. Sulfasalazine — Sulfasalazine is useful for colonic Crohn  disease and ulcerative colitis, particularly in the treatment of  mild disease and maintenance of remission. It is category B in   pregnancy but has a high rate of side effects in both pregnant  and nonpregnant patients (nausea, vomiting, rash, fever,  anorexia, heartburn, epigastric pain, diarrhea, pancreatitis,  interstitial nephritis, hepatotoxicity). For patients starting this  medication, a low dose of 500 mg/day should be prescribed  initially due to high rate of side effects; if tolerated, this can be  increased to the goal of 4-6 g/day over several days. Patients  taking sulfasalazine should take higher amounts of folic acid  than normally recommended (2 g/day).   2. 5-AcetylsaIkylic acid— 5-Acetylsalicylic acid (5-ASA) com-  pounds are more expensive than sulfasalazine, but have mini-  mal side effects, and mesalamine may be effective in treating  small bowel Crohn disease. Side effects reported are the same in  pregnant as in nonpregnant patients and include renal toxicity,  headache, abdominal pain, nausea, fever, IBD flare, pancreatitis,  leukopenia, and hepatocellular toxicity. Asacol (mesalamine)  releases 5-ASA in the distal ileum and colon and can be used in  doses of 4.8 g/day orally or as enemas or suppositories in  patients with distal disease. Pentasa (mesalamine), used in oral  doses of 4 g/day, is a formulation that contains coated micro-  granules that release 5-ASA throughout the gastrointestinal  tract; it is effective in gastric and small bowel Crohn disease.  Balsalazide releases 5-ASA into the colon and is also safe in preg-  nancy. Few data are available on slow-release Lialda (MMX  mesalamine) and olsalazine sodium.   3. Antibiotics — Antibiotics are often used in Crohn disease  and can be effective as an alternative to immunosuppression  in patients with active disease. Metronidazole and  ciprofloxacin are most commonly used in this capacity in  nonpregnant patients. Metronidazole is pregnancy category  B; however, its use has been associated with cleft lip and  palate. It should be avoided in the first trimester as well as in  nursing mothers, as it is excreted into breast milk.  Ciprofloxacin and other quinolones are contraindicated in  pregnancy. Alternatives that are safer in pregnancy include  ampicillin and cephalosporins. Amoxicillin-clavulanate can  be used in the treatment of pouchitis.   b Studies in women with IBD and renal transplants have shown that these medications are relatively safe during   4. Azathioprine and 6-mercaptopurine— Azathioprine  (AZA) and 6-mercaptopurine (6-MP) are used to treat  patients whose disease is unresponsive to 5-ASA agents alone  and who require long-term immunosuppression. These  agents are pregnancy category D; however, extensive data are  available proving their safety in patients with IBD and in  renal transplant patients during pregnancy. Use of these  agents during pregnancy carries no increased risk of congen-  ital abnormalities, stillbirths, or spontaneous abortions;  however, there may be an increased risk of premature or  lower birth weight infants. Only one study has evaluated  breast-feeding infants whose mothers were taking AZA and  6-MP; it found that no to minimal metabolites are excreted  into breast milk. However, standard practice has been to stop  these agents prior to nursing or forgo nursing the infant. Side  effects in pregnancy and in nonpregnant patients include  leukopenia, pancytopenia, pancreatitis, nausea, vomiting,  and hepatotoxicity.   5. Glucocorticoids — Glucocorticoids are generally reserved  for acute flares of disease often presenting as diarrhea, hema-  tochezia, and abdominal pain. They are believed to be safe  during pregnancy and nursing, although one uncontrolled  human study did demonstrate a possible increased risk of  cleft palate (and there is also the risk of premature rupture of  membranes). Patients with left-sided colitis or proctosig-  moiditis may benefit from once- or twice-daily steroid ene-  mas (hydrocortisone enemas, 100 mg/60 mL), foam  (10% hydrocortisone acetate), or suppositories (hydrocorti-  sone acetate, 30 mg). For those who require systemic steroids  the standard dose for acute flares is 40 mg/day of oral pred-  nisone. For those with severe flares or who fail a trial of  oral steroids, the next step is intravenous hydrocortisone,  300 mg/day in divided doses, or the equivalent dose of  methylprednisolone for 7-10 days or until there is improve-  ment in symptoms (solid stool, absence of blood or abdom-  inal pain). Patients are then transitioned to oral prednisone.  Side effects are the same in pregnant as in nonpregnant  patients (weight gain, fluid retention, hypertension, avascu-  lar necrosis, mood swings, psychosis, PUD, diabetes, obesity,  myopathy, immunosuppression, metabolic bone disease);  however, electrolyte abnormalities such as hypernatremia,  volume overload, and hypokalemia are more common in  pregnancy and can produce preeclampsia. Careful monitoring  of electrolytes is required, and dietary salt restriction may be   needed. Budesonide is an orally administered synthetic  steroid with limited systemic absorption that is particularly  effective in right-sided Crohn disease, but data in pregnancy  are currently lacking.   6. Immunosuppressants— Cyclosporine (2-4 mg/kg intra-  venously to maintain a level of 200-400 ng/mL) has been  used rarely in severe steroid-refractory ulcerative colitis dur-  ing pregnancy, but there is an association with low birth-  weight and prematurity when used for both colitis and renal  transplant, and it is a pregnancy category C drug. Side effects  include renal dysfunction, immunosuppression, tremor,  hypertension, nausea, vomiting, paresthesias, leukopenia, and  hirsutism. In addition patients who are hypomagnesemic are  at risk for seizures, necessitating careful monitoring of preg-  nant and nonpregnant patients. Use of cyclosporine during  pregnancy should be reserved for patients with severe disease,  and the drug may be a better option than colectomy in severe  colitis. Cyclosporine is passed in high levels in breast milk and  should not be used during nursing.   Tacrolimus is another agent to consider if immunosup-  pression is required, and at least one case report supports its  use as maintenance therapy during pregnancy. Methotrexate  is also used in nonpregnant patients with steroid-refractory  disease; however, it is an abortifacient, is contraindicated  in pregnancy, and should be stopped 3 months prior to  conception.   Infliximab (5-10 mg/kg intravenous infusion) is another  option in steroid-refractory disease and is particularly effective  for patients with inflammatory or fistulizing Crohn disease. It is  also effective in some patients with ulcerative colitis. It has been  used in over 100 pregnancies and no increases in miscarriages or  instances of teratogenicity have been observed. It can be initi-  ated and maintained during pregnancy if necessary, although  long-term experience is lacking. Side effects include infusion  reactions and anaphylaxis (this is a contraindication to contin-  ued use), as well as reactivation tuberculosis, lupus-like syn-  drome, nausea, abdominal pain, and fatigue. Infliximab levels  have been measured in infants up to 7 months of age and live  vaccines should be avoided until the drug is out of the infant's  system. Some pediatricians recommend checking titers of child-  hood vaccinations. Infliximab is probably not passed in breast  milk but more data are needed to state this with certainty.  Several case reports show the safety of adalimumab and cer-  tolizumab pegol during pregnancy but more data is needed.   Maintaining adequate nutrition, hydration, and electrolyte  balance is critical for the patient and the fetus. Antidiarrheal  therapy can be used as an adjunct in the treatment of IBD to  help avoid hospitalization in refractory diarrhea. The safest  agent is loperamide, but codeine has also been used (see the  discussion of antidiarrheal agents, earlier). Parenteral nutri-  tion is safe in pregnancy and should be used in patients  requiring bowel rest.   Indications for surgery during pregnancy include uncontrol-  lable bleeding, obstruction, perforation, fulminant disease  refractory to medical management, or intra-abdominal  abscess that cannot be drained by other methods. Surgery  during the second trimester carries a lower rate of miscar-  riage than during the first trimester and is technically less  complicated than during the third trimester. Total colectomy  for fulminant ulcerative colitis has a 50-60% fetal mortality  rate and if possible, intravenous cyclosporine, possibly inflix-  imab, or early delivery is preferable.   In general, the method of the delivery should be dictated by  obstetric indication. Vaginal delivery and cesarean delivery are  safe for patients with an ileal pouch-anal anastomosis, and  episiotomy is not contraindicated in IBD. Many patients with  active perianal disease report worsening of their disease after  vaginal delivery; therefore, it is generally recommended that  these patients undergo cesarean deliveries. Patients with ful-  minant ulcerative colitis should also undergo cesarean deliv-  ery. Women in remission or with mild disease without  perianal activity generally deliver vaginally unless the circum-  stances of pregnancy dictate otherwise.   Friedman S, Regueiro MD. Pregnancy and nursing in inflamma-  tory bowel disease. Gastroenterol Clin North Am. 2002;31:  265-273. [PMID: 12122737]   Tilson RS, Friedman S. Inflammatory bowel disease during preg-  nancy. Curr Treat Options Gastroenterol. 2003;6:227-236.  [PMID: 12744822]   The differential diagnosis of abdominal pain in pregnant  patients, just as in nonpregnant patients, is extensive and  deserves careful evaluation. Because imaging tests are often  avoided during pregnancy, there is often heavy reliance on the  history, physical examination, and laboratory testing.  Location and severity of pain are critical to evaluation.  Diffuse pain can suggest intestinal obstruction, peritoneal  inflammation from pancreatitis, appendicitis, or intra-  abdominal abscess, metabolic abnormalities such as uremia,  porphyria, and diabetes. Upper abdominal pain can suggest  biliary disease, PUD, or mediastinal pathology such as   esophageal rupture, pneumonia, rib fracture, pulmonary  embolism, Mallory-Weiss tear, esophageal stricture, and  myocardial infarction. In addition, some diseases may present  with epigastric pain or localize to the left side, such as PUD,  splenic infarcts or abscess, splenic artery aneurysm (more  common in pregnancy), gastric volvulus, and incarcerated  paraesophageal hernia. Right upper quadrant pain can sug-  gest hepatitis, hepatic vascular engorgement, hepatic  hematoma, hepatic malignancy, preeclampsia, or HELLP syn-  drome. Biliary diseases such as biliary colic, choledocholithi-  asis, cholangitis, and cholecystitis may also present with  epigastric discomfort or localize to the right side. Right lower  quadrant pain can indicate appendicitis, ruptured Meckel  diverticulum, Crohn disease, intussusception, bowel infection  or perforation, or colon cancer. Left lower quadrant pain can  indicate diverticulitis, sigmoid volvulus, colon cancer, bowel  infection or perforation, IBD, and irritable bowel syndrome.  Any lower abdominal discomfort can suggest gynecologic or  obstetric causes such as ruptured ectopic pregnancy (severe  pain), ovarian cyst rupture, pelvic inflammatory disease,  tubo-ovarian abscess, uterine fibroids, impending abortion,  adnexal mass, salpingitis, endometriosis, ruptured corpus  luteum, or cervical or ovarian cancer. Nephrolithiasis and  pyelonephritis can manifest right- or left-sided, upper or  lower abdominal pain.   Vascular causes such as mesenteric ischemia and abdomi-  nal aortic aneurysm can cause diffuse or localized pain and  should always be considered in the differential as they may  present as medical or surgical emergencies. Spontaneous  hepatic rupture is an abdominal emergency unique to preg-  nancy. It typically occurs late in pregnancy; is associated with  subcapsular hematoma, preeclampsia, and HELLP syndrome;  and presents with severe right-sided or epigastric pain, some-  times radiating to the right shoulder. It can be diagnosed with  ultrasound, and when signs of rupture or expanding subcap-  sular hematoma are seen, the patient should undergo imme-  diate cesarean delivery; intraoperative packing, hepatic  resection, or hepatic artery ligation are often needed to control  bleeding.   A careful history of pain onset, character, severity, and loca-  tion is critical. Important signs on physical examination  include the presence of fever, hypotension, and tachycardia;  these findings should prompt a search for causes of abdomi-  nal infection or acute abdomen. Classic physical examination  findings of peritonitis may be absent due to abdominal wall  laxity in pregnancy; however, the presence of a rigid  abdomen is a likely indicator of peritonitis.   Any patient presenting with significant abdominal pain  should undergo laboratory tests, including complete blood   count and differential, serum electrolytes, liver function tests,  coagulation profile, and amylase and lipase levels. Physiologic  changes in these values that occur normally during pregnancy  such as elevation in white blood cell count, anemia, elevated  alkaline phosphate, elevated erythrocyte sedimentation rate,  and mild hyponatremia, all should be kept in mind during  evaluation.   Ultrasound is considered low risk and should be the imag-  ing study of choice if needed. Abdominal radiographs are  avoided if possible due to radiation exposure to the fetus, but  may be indicated when bowel perforation or obstruction is  suspected. MRI is preferable to computed tomography (CT)  scanning to avoid ionizing radiation, but gadolinium should  be avoided during the first trimester if possible. Any radio-  logic testing should be preceded by counseling of the patient.   Treatment is based on the disorder. Evaluation and treatment  of common biliary and gastrointestinal problems in preg-  nancy are discussed in later sections of this chapter. Liver dis-  eases of pregnancy are discussed in Chapter 8.   Capell MS, Friedel D. Abdominal pain during pregnancy.  Gastroenterol Clin North Am. 2003;32:1-58. [PMID: 12635413]   There is no evidence to support an increased incidence of  PUD during pregnancy, and in fact many studies suggest a  decreased incidence. Nevertheless, both gastric and duodenal  ulcers do occur and detection is difficult, as avoidance of inva-  sive testing is desirable during pregnancy.   The symptoms of PUD are the same in pregnant as in non-  pregnant patients and include epigastric pain, abdominal dis-  tention, eructation, postprandial nausea and vomiting,  anorexia, and rarely, hematemesis, melena, hematochezia, or  peritonitis. Differentiating ulcer disease from other conditions  that present with similar symptoms is an important part of  evaluation. Nausea and vomiting associated with pregnancy  are often most pronounced in the first trimester, whereas PUD  worsens during the third trimester. The physical examination  may reveal signs of complications from PUD; heme-positive  stool or visible blood on rectal examination may suggest  bleeding from an ulcer. Peritoneal signs should prompt surgi-  cal consultation for possible perforated ulcer.   leukocytosis can suggest cholecystitis, which can also be diag-  nosed by ultrasound. Pancreatitis can be suggested by pain  that is exacerbated with eating, pain radiating to the back, a  history of alcoholism, gallstones, prior pancreatitis, leukocy-  tosis, and fever; amylase and lipase levels should be checked.  An electrocardiogram should be obtained to exclude myocar-  dial ischemia. Urinalysis and urine culture should also be  obtained to exclude urinary tract infection.   Abdominal radiographs are avoided in pregnancy but  should be obtained in suspected perforation. Barium studies  are also avoided, but upper endoscopy should be performed  when symptoms are severe and refractory to intensive med-  ical therapy, when complications including hemorrhage and  gastric outlet obstruction occur, or when gastric adenocarci-  noma or lymphoma is suspected. The safety of endoscopy in  pregnancy is discussed separately, later in this chapter.   The symptoms of PUD are difficult to distinguish from  GERD; however, the medical treatment for both is identical  and should be attempted first unless indications for  endoscopy, discussed earlier, are present. Medical treatment  for suspected PUD and GERD includes antacids, sucralfate,  H 2 -blockers, and if needed PPIs (see earlier discussion of  treatment of GERD in pregnancy). Misoprostol is con-  traindicated in pregnancy. Triple-drug therapy for treatment  of H pylori should be deferred if possible until after delivery  due to the low risk of complications from PUD and possible  fetal risk from antibiotics. Treatment of H pylori associated  with mucosa-associated lymphoid tissue tumor is indicated,  however, and should not be deferred. Amoxicillin (class B),  metronidazole (class B), and clarithromycin (class C), can be  used, although treatment during the first trimester should be  avoided if possible. Both tetracycline and bismuth subsalicy-  late are relatively contraindicated during pregnancy.   Endoscopy is indicated in patients with gastrointestinal  bleeding suspected to be from PUD. Very little is known  about the risks of therapeutic endoscopic therapy for PUD or  hemostasis for other disorders such as variceal bleeding or  Mallory- Weiss tear. Therapeutic endoscopy is currently an  experimental procedure during pregnancy but is justifiable  when the only alternative is surgery. The indications for sur-  gery for PUD are the same in pregnant as in nonpregnant  patients and include uncontrollable hemorrhage, perfora-  tion, and gastric outlet obstruction.   Capell MS. Gastric and duodenal ulcers during pregnancy.  Gastroenterol Clin North Am. 2003;32:263-308. [PMID:  12635419]   Liver blood tests and an ultrasound scan should be obtained  to evaluate for cholelithiasis, choledocholithiasis, viral hepati-  tis, AFLP, and HELLP syndrome. Right upper quadrant ten-  derness, a history of fatty food intolerance, fever, and   Pregnancy predisposes to gallstone formation; increased bile  lithogenicity mediated by estrogen and decreased gallbladder  contractility mediated by progesterone are implicated in the  causality. The incidence of cholelithiasis in pregnancy has   been reported to be between 2.5% and 12.5%, but most  patients with gallstones remain asymptomatic. Obesity,  prepregnancy weight gain, Hispanic ethnicity, and maternal  age are risk factors for gallstone disease during pregnancy.   Symptomatic patients may present with anorexia, nausea,  vomiting, right upper quadrant or epigastric pain, and a his-  tory of symptoms exacerbated by fatty foods. The pain can  radiate to the back or right shoulder. Although termed  "biliary colic," severe pain from gallstones can last several  hours. The presence of fever, tachycardia, leukocytosis, ele-  vated neutrophil count, right upper quadrant tenderness,  and Murphy sign may indicate the presence of cholecystitis.   Abnormal liver blood tests may indicate the presence of chole-  docholithiasis (keeping in mind physiologic elevation of alka-  line phosphatase in pregnancy). Elevated amylase and lipase  can indicate pancreatitis. A right upper quadrant ultrasound is  safe in pregnancy and has a high degree of accuracy in detect-  ing gallstones. The presence of sonographic Murphy sign, gall-  bladder wall thickening, pericholecystic fluid, or stranding can  suggest cholecystitis. Common bile duct or intrahepatic duct  dilation can suggest choledocholithiasis. The ultrasonogra-  pher should evaluate for liver and pancreatic disease as well.   the first two trimesters, but open procedures are often  required in the third trimester.   Routine intraoperative cholangiography is not recom-  mended during pregnancy; however, bile duct exploration  and intraoperative ultrasound are alternatives. Successful  laparoscopic common bile duct exploration during acute  gallstone pancreatitis has been reported in a patient who was  14 weeks pregnant. If needed, cholangiography can be done  with a fetal shield to minimize radiation.   Choledocholithiasis is rare in pregnancy, but endoscopic  retrograde cholangiopancreatography (ERCP) with stone  extraction, sphincterotomy, or stent insertion can all be per-  formed and is indicated for common bile duct stones and  cholangitis.   Bagci S, Tuzun A, Erdil A, et al. Treatment of choledocholithiasis in   239-241. [PMID: 12592428]  Ko CW. Risk factors for gallstone-related hospitalization during   2263-2268. [PMID: 17032191]  Ko CW, Beresford SA, Schulte SJ, et al. Incidence, natural history,   Hepatology. 2005;41:359-365. [PMID:15660385]  Lu EI, Curet MJ, El-Sayed YY, et al. Medical versus surgical man-  agement of biliary tract disease in pregnancy. Am J Surg.   2004;188:755-759. [PMID: 15619495]  Tarnasky PR, Simmons DC, Schwartz AG, et al. Safe delivery of bile   The management of gallstones in the absence of cholecystitis  or choledocholithiasis is medical, including avoidance of  fatty foods and a brief period of bowel rest and pain control  if needed. For patients who do not respond to medical ther-  apy or who develop recurrent symptoms, early operative  management is advocated as there is a high rate of recurrence  and risk of complications during pregnancy.   When cholecystitis is present, intravenous antibiotics  should be started. Intravenous cefazolin and extended-spectrum  penicillin are effective and generally considered safe in preg-  nancy. Because of the risk of fetal loss, teratogenesis, and  preterm labor during the first trimester, and the risk of  preterm labor, premature delivery, and technical difficulties  due to the gravid uterus during the third trimester, surgery is  often delayed until the second trimester or after delivery if  possible. Recent improvements in less-invasive surgical tech-  niques may lead to improved surgical outcomes. One study  showed an overall benefit of medical versus surgical manage-  ment of cholelithiasis during pregnancy, and another showed  no significant increase in major birth defects in patients who  underwent surgery during the first trimester.   Gallstone pancreatitis, choledocholithiasis, or acute  cholecystitis that fails to resolve is an indication for early  surgery. Typically, laparoscopic surgery is performed during   Acute pancreatitis can complicate up to 1% of pregnancies  and is most common during the third trimester and post-  partum. Gallstones are the cause in the vast majority of preg-  nant patients with pancreatitis; however, the typical  differential diagnosis of pregnancy still applies, and alco-  holism, hypercalcemia, hypertriglyceridemia, infections,  trauma, and medication-induced causes should be ruled out.   Clinical presentation and elevated amylase and lipase levels  are typically diagnostic, as pancreatic enzyme levels are not  affected by pregnancy. Ultrasound can diagnose gallstones  and choledocholithiasis (bile duct dilation) and can also  sometimes visualize pancreatic inflammation. CT scan is  reserved for severe, refractory pancreatitis to evaluate for  areas of pancreatitis necrosis, and MRI may be a safer alter-  native during pregnancy.   Medical management includes stopping oral intake, aggres-  sive intravenous fluids, histamine blockers, and PPL  Laboratory values such as calcium, blood urea nitrogen, cre-  atinine, white blood cell count, and hematocrit should be   monitored carefully (see Chapter 25). Meperidine is typically  chosen for pain control and is a category B drug; it appears  to be safe for use in pregnancy. For severe pancreatitis, surgi-  cal debridement or endoscopic or percutaneous drainage of  abscesses or pseudocysts should not be delayed. Severe pan-  creatitis may in rare cases require antibiotics and parenteral  nutrition. Although endoscopic procedures and tests involv-  ing radiation are generally avoided during pregnancy, one  study noted a significant relapse rate in patients with gall-  stone pancreatitis. These findings argue for ERCP, cholecys-  tectomy, or both. Currently, acute gallstone pancreatitis  complicated by evidence of persistent biliary obstruction is  one of the indications for ERCP with sphincterotomy during  all stages of pregnancy. Cholecystectomy is often deferred  until the second trimester or postpartum period.  Pancreatitis is associated with fetal wastage in the first  trimester and premature labor in the third trimester.  Maternal mortality can be as high as 10% in severe, compli-  cated pancreatitis but is low if pancreatitis improves quickly  with medical management.   Kim YW, Zagorski SM, Chung MH. Laparoscopic common bile  duct exploration in pregnancy with acute gallstone pancreatitis.  JSLS. 2006;10:78-82. [PMID: 16709365]   Acute appendicitis is the most common gastrointestinal dis-  order requiring surgery during pregnancy. The key to man-  agement is prompt diagnosis.   Patients typically present with anorexia, nausea, vomiting,  and abdominal pain; however, in pregnancy this presentation  needs to be distinguished from conditions such as nausea  and vomiting of pregnancy, particularly in the first trimester.  Abdominal pain associated with appendicitis can be located  in nontraditional places. During the first trimester, the  appendix has the usual right lower quadrant location, and  patients typically present with periumbilical pain that  migrates to the right lower quadrant. During the second and  third trimesters, however, the appendix gradually moves  upward and laterally until by the third trimester, it is located  in the right upper quadrant (Figure 7-3). This changes the  presentation of appendicitis and can delay diagnosis and  management. Fever, tachycardia, abdominal tenderness, and  peritoneal signs can be clues to an inflamed appendix, but  their absence does not rule out appendicitis.   Although pregnancy can elevate the white blood cell count, a  finding of more than 80% neutrophils on the differential is  suggestive of an acute disorder. Abdominal ultrasound can be   ▲ Figure 7-3. Changes in location and direction of the  appendix during pregnancy in relationship to the  McBurney point and the height of the fundus at various  weeks of gestation. (Adapted, with permission, from  Mahmoodian S. Appendicitis complicating pregnancy. South  Med J. 1992;85:19.)   diagnostic during the first trimester but less helpful when the  appendix migrates. Abdominal CT scan can be used to diag-  nose appendicitis; however, this exposes the fetus to radia-  tion teratogenicity. Diagnostic laparoscopy can also be  performed if there is diagnostic uncertainty. If there is any  suspicion of appendicitis, surgical consultation should be  obtained immediately.   Once appendicitis is diagnosed, either clinically or by imag-  ing, immediate surgery is indicated, as appendiceal perfora-  tion can increase maternal mortality to as high as 4% and  fetal mortality to as high as 20%. The only exception to this   is in the setting of active labor, in which case it is undertaken  after vaginal or cesarean delivery if labor is prolonged. In the  first two trimesters, laparoscopic appendectomy can be done  safely; however, in the third trimester or in the setting of  diffuse peritonitis, laparotomy is generally indicated. Fetal  complications are similar between laparoscopic and open  approaches.   Carver TW, Antevil J, Egan JC, et al. Appendectomy during early  pregnancy: what is the preferred surgical approach? Am Surg.  2005;71:809-812. [PMID: 16468524]   Palanivelu C, Rangarajan M, Parthasarathi R. Laparoscopic appen-  dectomy in pregnancy: a case series of seven patients. JSLS.  2006;10:321-325. [PMID: 17212888]   Although the most common cause of intestinal obstruction  in pregnancy is adhesions, another important cause is volvu-  lus, which accounts for more than 20% of cases. Most cases  of volvulus during pregnancy occur near term, presumably  because the gravid uterus can push a redundant colon out of  the pelvis to twist around a point of fixation. Other causes of  intestinal obstruction include intussusception, hernia, acute  appendicitis, and gastric and colorectal cancer. Incarcerated  diaphragmatic hernias are rare but more common during  pregnancy and have a high rate of complications.   Prompt recognition and treatment of obstruction and  pseudo-obstruction are critical. Sigmoid volvulus during preg-  nancy is associated with high maternal and fetal mortality  even with appropriate intervention. Patients present with con-  stipation, progressive abdominal pain, and abdominal disten-  tion. Later on, bilious vomiting and obstipation can be  present. Abdominal radiographs and CT scans may be  required for evaluation and are typically diagnostic of this  condition. Flexible sigmoidoscopy or colonoscopy may be  required for diagnosis or decompression. Pseudo-obstruction  or colonic distention without obstruction can occur following  delivery; symptoms are similar to those of intestinal obstruc-  tion. Pseudo-obstruction is typically diagnosed with abdomi-  nal radiographs. Colon and gastric cancer are the most  common gastrointestinal malignancies during pregnancy and  can cause bleeding, anemia, abdominal pain, or obstruction.   Conservative management includes nasogastric decompres-  sion, fluid resuscitation, monitoring of electrolytes, bowel  rest, and careful use of analgesia. Prophylactic antibiotics  should be considered. Pseudo-obstruction and some cases of  volvulus or adhesion-induced small bowel obstruction will  resolve with conservative management. Suspected intestinal   ischemia, perforation, persistent tachycardia, fever, abdomi-  nal tenderness, and failure to resolve with conservative man-  agement are indications for surgery.   Patients with postpartum pseudo-obstruction should be  followed radiographically if required. A colonic diameter  greater than 10-12 cm increases the risk of colonic perfora-  tion. Neostigmine or colonic decompression can be per-  formed for pseudo-obstruction if required to avoid surgery.   Volvulus during pregnancy may be treated by decompres-  sion with colonoscopy, flexible sigmoidoscopy, or rectal tube;  however, surgery may be required if the condition is recur-  rent or persistent. Hernias frequently require surgical repair,  and an incidental incarcerated diaphragmatic hernia should  be repaired during surgery due to risk of strangulation.  Mortality can be high for volvulus or intestinal ischemia, and  preterm delivery is common in patients that require surgery.   Patients with gastrointestinal cancer diagnosed during  pregnancy should undergo colonoscopy for biopsy and for  evaluation of synchronous lesions. Resections can be per-  formed during the first half of pregnancy but are often  deferred until after delivery. There is no contraindication to  vaginal delivery as long as the birth canal is not obstructed.  All options should be discussed with the patient. Chemotherapy  is typically delayed until the second trimester, and pelvic  radiation is often delayed until after delivery to protect the  fetus. Maternal outcome in colorectal cancer diagnosed dur-  ing pregnancy is similar to that of the general population;  however, pregnant women with gastric cancer often present  with advanced disease and have a worse survival rate than  nonpregnant women.   Lai SK, Morgenstern R, Vinjirayer EP, et al. Sigmoid volvulus an  update. Gastrointest Endoscopy Clin N Am. 2006;16:175-187.  |PMID: 16546032]   Although endoscopy is routine in the evaluation of many gas-  trointestinal disorders, it is typically only performed when  absolutely needed in pregnancy due to the risk to the fetus of  sedative medications, particularly in the first trimester, and  technical complexity during the third trimester. The risks of  sedative medications include overdosage, allergic reaction,  teratogenesis, and hemodynamic instability of the mother  leading to hypoxia and hypotension of the fetus.   In general, maternal hypotension should be avoided as  much as possible; patients with gastrointestinal bleeding  should be resuscitated with packed erythrocytes and fluid as  needed before the procedure. Antihypertensives prior to the  procedure and colonic overdistension during the procedure  should be avoided. Patients should not be placed or moved to  the supine position (because the gravid uterus compresses  the vena cava and can lead to hypotension), and sedative  medications should be used judiciously but sparingly. If  hypotension occurs during the procedure, intravenous fluids  should be used and the patient's position should be changed   to drain blood from the lower extremities to the vital organs.  Consideration should be given to terminating the procedure.  Premature uterine contractions during endoscopy may  require tocolytics such as magnesium sulfate or terbutaline.  Consultation with an obstetrician is important, and anesthe-  siologic assistance with the procedure should always be con-  sidered, particularly in the first trimester, during a high-risk  pregnancy, in the presence of maternal or fetal instability, or  for a prolonged procedure such as ERCP. The risks of med-  ications used during endoscopy and considerations relating  to specific procedures are outlined below.   Meperidine is generally a category B drug in pregnancy; it has  a rating of D when used in high doses and for a prolonged   period of time at term. Although it is rapidly transferred  across the placenta, it has been used extensively in pregnancy  and, with the exception of one study that noted a higher rate  of congenital inguinal hernias, teratogenicity has not been  observed even with exposure during the first trimester. The  drug can cause diminished fetal beat-to-beat cardiac variabil-  ity that can last 1 hour after administration; however, this is  generally transient and not considered a poor prognostic sign.  It is preferred over benzodiazepines for endoscopic proce-  dures and is approved by the American Academy of Pediatrics  in single dose administration for breast-feeding women.  Dosage should be restricted to 50 or 75 mg intravenously dur-  ing routine endoscopy.   Diazepam is categorized as a class D drug during pregnancy  due to earlier studies suggesting an association between use  during pregnancy and cleft palates in animals and humans,   Reproduced, with permission, from Mahadevan U, Kane S. American Gastroenterological Association Institute technical review on the use of   as well as other congenital malformations and neonatal neu-  robehavioral abnormalities. Recent data suggest, however,  that it may be safer than previously appreciated when admin-  istered at low doses for a brief period of time.   Less is known about the effects of midazolam exposure in  utero. Exposure during parturition suggests transient respi-  ratory depression and abnormal neurobehavioral respon-  siveness, but little is known about the effects of fetal exposure  during the first or second trimester. Because of its similarity  to diazepam, midazolam is classified as category D during  pregnancy; in general, however, it is preferable to diazepam if  one of these agents is required during endoscopy.   Propofol is used by anesthesiologists and some gastroenterol-  ogists for sedation during endoscopy. The advantages include  a greater depth of sedation, quicker onset, and shorter dura-  tion of action than the benzodiazepines. Propofol is also a  pregnancy category B drug; it is considered safe for use during  parturition, but at this time there is inadequate experience to  recommend its use during the first trimester.   Fentanyl is a pregnancy category C drug. Studies in rats showed  injury to embryos, but some human studies of use during labor  found no evidence of neonatal toxicity. It is used in low doses  for endoscopy during pregnancy despite some case reports  describing respiratory depression and muscle rigidity in  neonates. Frequent use has been associated with neonatal with-  drawal in a mother with opiate addiction.   Ketamine is used by anesthesiologists during endoscopy  because of its rapid action of onset, short duration of effects,  and ability to sedate people who experience insufficient seda-  tion from propofol. Ketamine has been used during labor  and delivery and although some neonatal respiratory depres-  sion may occur, it is often less than that of other sedatives. It  has not been associated with teratogenicity and is classified  as pregnancy category B; however, it is relatively unstudied  during the first trimester.   Naloxone is an opioid reversal agent with a pregnancy category  B designation. It is appropriate for administration in pregnant  patients with signs of narcotic toxicity from sedation, such as  respiratory depression, hypotension, or unresponsiveness. It  should not be used in patients who are opiate dependent, how-  ever, due to the risk of maternal and fetal withdrawal. Naloxone  should be used only when necessary and carefully; overdose  can cause maternal myocardial infarction, pulmonary edema,  or severe hypertension.   Flumazenil is a benzodiazepine reversal agent and a preg-  nancy category C drug because little is known about fetal   risk. Overdose can cause maternal seizures and maternal and  neonatal withdrawal, especially in patients who chronically  use benzodiazepines. It should be used only if absolutely  needed for benzodiazepine toxicity. There are no data  regarding either reversal agent during breast feeding.   Lidocaine is classed as a pregnancy category B drug based on  studies showing no harm in rats and safety during parturition  and appears safe for use as a numbing agent for the orophar-  ynx during upper endoscopy. It is recommended that the  patient gargle and spit it out rather than swallow it to mini-  mize systemic absorption.   Simethicone is used to coalesce gastric bubbles during  endoscopy and is a pregnancy category C drug. When used  during endoscopy, however, it is unlikely to be absorbed and  therefore unlikely to be a risk during either pregnancy or  breast feeding.   Glucagon is a pregnancy category B drug. Although there is  no evidence of harm in rats, it is uncharacterized in pregnant  humans. The American Gastroenterological Association sup-  ports its use in decreasing motility in endoscopy with the  goal of decreasing procedure time, particularly during thera-  peutic ERCP.   Diatrizoate contrast is used during ERCP and is classified as  pregnancy category D because of the risk to fetal thyroid  function during amniography. However, it has been used in  diagnostic and therapeutic endoscopy without fetal harm  and in the setting of maternal cholangitis, the benefits likely  outweigh the risks.   Briggs GG, Freeman RY, Yaffe SJ. Drugs in Pregnancy and  Lactation: A Reference Guide to Fetal and Neonatal Risk, 7th ed.  Lippincott Williams & Wilkins, 2005.   Cappell MS. Sedation and analgesia for gastrointestinal endoscopy  during pregnancy. Gastrointest Endosc Clin N Am. 2006;16:1-31.  [PMID: 16546020]   Hawkins JL. Obstetric anesthesia and analgesia. In: Scott JR, Gibbs  RS, Karlan BY, et al (editors). Danforth's Obstetrics and  Gynecology, 9th ed. Lippincott Williams & Wilkins, 2003:57-73.   Mahadevan U, Kane S. American Gastroenterological Association  Institute position statement on the use of gastrointestinal med-  ications in pregnancy. Gastroenterology. 2006;131:278-282.  [PMID: 17261292]   Mahadevan U, Kane S. American Gastroenterological Association  Institute technical review on the use of gastrointestinal med-  ications in pregnancy. Gastroenterology. 2006;131:283-311.  [PMID: 16831610]   Choledocholithiasis occurs in one out of every 1200 deliveries  and is the most common indication for ERCP during preg-  nancy. Other indications for ERCP include severe acute gall-  stone pancreatitis, cholangitis, bile duct injury, and pancreatic  duct disruption. To minimize risk in pregnancy, less-invasive  testing should be considered to confirm the presence of gall-  stones in the bile duct in the setting of choledocholithiasis,  cholangitis, and gallstone pancreatitis. Endoscopic ultrasound  has been used with high diagnostic accuracy to confirm or  exclude choledocholithiasis. There are a few reports of the use  of ultrasound-guided or endoscopic needle-knife papillotomy  for choledocholithiasis without exposure to fluoroscopy. One  group has described the use of magnetic resonance cholan-  giopancreatography (MRCP) in a pregnant patient to demon-  strate a stone in a dilated common bile duct. There were no  adverse outcomes; however, the safety of MRI, especially in the  first trimester has not been rigorously tested.   The predominant concern with ERCP is the effect of radi-  ation, a known teratogen, on the health of the fetus. Nineteen  case and clinical series have been published on use of ERCP  during pregnancy. Fetal and maternal outcome data were  available for a total of 164 ERCP procedures, and the overall  complication rate of 8.5% mainly involved pancreatitis and  post-sphincterotomy bleeding. Most cases involved sphinc-  terotomy or stent placement, or both, to prevent future  recurrence. Eighty- nine percent of these pregnancies resulted  in the birth of healthy term infants. Six percent of births were  premature, and there were three spontaneous abortions. Two  infants had intrauterine growth restriction.   The second trimester is felt to be the safest time to perform  ERCP; however, often the need arises during the first or third  trimester. Although a growing body of data supports the safety  of ERCP during pregnancy, precautions to minimize radiation  risk to the fetus should be taken, particularly during the first  trimester. One group has reported a case series of six pregnant  patients who underwent ERCP and bile duct cannulation  without fluoroscopy. The common bile duct was cannulated  and a guidewire advanced approximately 10-15 cm into the  bile duct under endoscopic view. The catheter was then  advanced over the wire and bile aspirated to confirm place-  ment, after which sphincterotomy with balloon stone extrac-  tion was performed. This method, if technically possible,  minimizes exposure to radiation. Some authors also advocate  using a lead apron to protect the entire abdomen from radia-  tion until cannulation, during which time the apron can be  repositioned to expose the necessary area. The patient should  be in the left lateral recumbent position, facilitating both the  procedure and blood flow to the fetus. The grounding pad  should be placed so that the uterus is not between the pad and  the sphincterotome. If antibiotics are required, penicillins or  cephalosporins are preferred. Clindamycin is generally safe in  patients with allergies to penicillin. Tetracycline, quinolones,  and streptomycin should be avoided. Metronidazole should be   avoided during the first trimester, and sulfonamides and nitro-  furantoin should be avoided in the third trimester.   There are a few case reports of endoscopic cystgastros-  tomy for pseudocysts; if drainage is required, endoscopic  methods may be safer than the alternative surgical or percu-  taneous techniques that expose the patient to risks of surgery  and radiation from imaging studies, respectively.   Kahaleh M, Hartwell GD, Arseneau KO, et al. Safety and efficacy of  ERCP in pregnancy. Gastrointest Endosc. 2004;60:287-292.  [PMID: 15278066]   Menees S, Elta G. Endoscopic retrograde cholangiopancreatogra-  phy during pregnancy. Gastrointest Endosc Clin N Am. 2006;  16:41-57. [PMID: 16546022]   Simmons DC, Tarnasky PR, Rivera- Alsina ME, et al. Endoscopic  retrograde cholangiopancreatography in pregnancy without the  use of radiation. Am ] Obstet Gynecol. 2004;190:1467-1469.  [PMID: 15167871]   Tham TC, Vandervoort J, Wong RC, et al. Safety of ERCP during preg-  nancy. Am J Gastroenterol 2003;98:308-311. [PMID: 12591046]   The most common indications for upper endoscopy during  pregnancy include upper gastrointestinal bleeding, particu-  larly to rule out variceal bleeding or PUD, and severe dyspep-  sia or epigastric comfort to rule out PUD. Severe hyperemesis  that is unresponsive to management and odynophagia or dys-  phagia are other possible indications. Recent studies have not  demonstrated an increase in complications in pregnant  patients who have undergone EGD. Informed consent should  still involve a discussion of possible fetal risks related to seda-  tion and the procedure. An obstetrician should be involved to  determine if fetal monitoring is needed. The American Society  for Gastrointestinal Endoscopy (ASGE) also recommends that  patients not lie in the supine position during recovery due to  the risk of inferior vena cava compression. During the proce-  dure the patient should be placed in the left lateral position  with the head elevated due to an increased risk of regurgita-  tion of gastric contents in pregnant patients. Aspiration  should be avoided by aggressive perioral suctioning, elevation  of the head of the patient, nasogastric aspiration in patients  with upper gastrointestinal bleeding before EGD, and aspira-  tion of the gastric lake during the procedure. For patients with  gastrointestinal bleeding, resuscitation should be performed  before the procedure to the extent possible.   Bruno IM, Kroser J. Efficacy and safety of upper endoscopy proce-  dures during pregnancy. Gastrointest Endosc Clin N Am.  2006;16:33-40. [PMID: 16546021]   Qureshi WA, Rajan E, Adler DG, et al. ASGE guideline: guidelines  for endoscopy in pregnant and lactating women. Gastrointest  Endosc. 2005;61:357-362. [PMID: 17212888]   The most common symptom leading to the use of lower  endoscopy during pregnancy is hematochezia. Severe diarrhea,   abdominal pain, colonoscopic decompression of volvulus,  and evaluation of a mass lesion are other possible indica-  tions. Another indication for lower endoscopy during preg-  nancy is incarceration of the gravid uterus; in this condition,  the uterus becomes lodged beneath the inferior margin of  the sacral promontory. One report has described five patients  who underwent successful colonoscopic release by intubat-  ing the sigmoid colon to apply pressure to the anterior wall  of the rectum after manual reduction had failed. No adverse  fetal outcomes were observed, and the alternative would have  been surgery, which carries a much higher risk.   The safety of flexible sigmoidoscopy has been demon-  strated in multiple case reports and studies. Flexible sigmoi-  doscopy has been performed without adverse outcome in all  three trimesters of pregnancy. Most procedures are done with  minimal bowel preparation (tap-water enemas) and without  sedation to minimize adverse effects. Although hemodynamic  monitoring of the mother should always be a part of the pro-  cedure, most reported cases did not involve any fetal monitor-  ing, though this may be considered, especially in cases of  maternal hemodynamic instability.   Colonoscopy is rarely indicated during pregnancy and less  is known about the safety of this procedure. If required, the  second trimester is generally considered the safest time to per-  form colonoscopy during pregnancy. The theoretical risks of  colonoscopy include premature labor, uterine rupture, placental  abruption, and fetal compression. Most data come from case  reports, case series, and retrospective studies, which have not  shown adverse fetal effects from the procedure performed  during any trimester. The use of colonoscopy should be  restricted to strong indications or life-threatening emergen-  cies. Patients should be placed in the left or right lateral decu-  bitus position, minimal external compression away from the  uterus should be used, and maternal and fetal monitoring  should be utilized. Trauma to the uterus from compression or  colonoscope looping should be avoided.   In regard to bowel preparation, the risk of polyethylene  glycol, a category C drug in pregnancy, is not known,  although one study indicated safety when used to treat con-  stipation. There is one report of repeated use of phosphate  enemas in combination with phosphate solution leading to  neonatal bone demineralization. One-time use of sodium  phosphate enemas has been done safely in pregnancy,  although this has not been studied. In general, phosphate  solutions are associated with electrolyte shifts, and the effect  of these shifts on the fetus is unknown.   for the indication of gastrointestinal bleeding, endoscopic  hemostasis may be required to maintain hemodynamic sta-  bility of the mother and fetus and to avoid the greater risks  of persistent bleeding or surgery. No adverse events related to  the use of thermocoagulation in pregnancy have been  reported in case reports and small studies; however, electric  current can cross the amniotic fluid and the risk of fetal  exposure remains. The ASGE recommends that bipolar  cautery should be used rather than monopolar to reduce the  risk of fetal exposure to stray current. The patient should be  positioned so that the uterus is not between the electrical  catheter and the grounding pad.   Epinephrine is a category C drug during pregnancy  because of the theoretical risk of decreasing placental perfu-  sion. Although no adverse outcomes have been reported in  pregnancy when used during endoscopy, the drug should be  used sparingly, to avoid systemic effects on both the mother  and the fetus. Hemoclips have not been studied but may be  safer than methods that involve injection of substances or  electric current.   In the case of lower endoscopy, lesions such as polyps may  be identified. If there is no urgent need to remove or biopsy  the lesion, many endoscopists will defer intervention until  after delivery to avoid exposure to bleeding risks or risks of  electrocautery. In these situations, tattooing the lesion can be  considered; India ink is generally felt to be safe in nonpreg-  nant patients although there are no existing studies examin-  ing its use in pregnant patients. Methylene blue is labeled as  a teratogen and should be avoided during pregnancy.   Patients with cirrhosis and portal hypertension are at  increased risk for variceal bleeding during pregnancy due to  physiologic rises in portal pressure and increased volume in  the splanchnic vessels during pregnancy. Variceal bleeding is  associated with poor fetal outcomes, and effective hemosta-  sis is critical. Case reports of esophageal banding and scle-  rotherapy have shown effectiveness in controlling variceal  hemorrhage without any reports of fetal harm. Because  there is a theoretical risk of the sclerosant entering the fetal  circulation, many authors recommend banding as the pre-  ferred method and some suggest that it may be more effec-  tive. Somatostatin and octreotide have not been studied in  pregnancy but are thought to be relatively safe. Vasopressin  is not recommended due to the risk of placental ischemia.  Additionally, a reported series of cases has described the  control of gastric varices with cyanoacrylate glue during  pregnancy.   Siddiqui U, Proctor DD. Flexible sigmoidoscopy and colonoscopy  during pregnancy. Gastrointest Endosc Clin N Am. 2006;16:  59-69. [PMID: 16546023]   There are very few data on the risks related to endoscopic  therapy in pregnancy. Because endoscopy is often performed   Upper gastrointestinal series, barium enemas, abdominal  radiographs, angiography, and CT are generally avoided in  pregnancy due to radiation teratogenicity. Bleeding scans are  also contraindicated due to ionizing radiation. MRI, on the  other hand, is believed to be safer in pregnancy than CT  scans; short-term exposure to electromagnetic radiation from   MRI does not appear to produce harmful fetal effects. MRCP  may be an alternative to diagnostic ERCP during pregnancy.  Videocapsule endoscopy may be a useful alternative or  adjunct to endoscopy during pregnancy as it does not require  sedation and does not exert mechanical pressure on the  uterus. Theoretically the gravid uterus and effect of preg-  nancy on motility may retard the passage of the capsule, but  these factors should not predispose to retention in the  absence of strictures or bowel obstruction. On the other   hand, radiographs to confirm passage, and surgery in the  event of retention, would involve risks to the mother and the  fetus. The safety of this method has not been evaluated in  pregnancy, but it is theoretically promising as a less-invasive  diagnostic approach to luminal disease.   Kanal E, Borgstede JP, Barkovich AJ, et al. American College of  Radiology white paper on MR safety. AJR. 2002;178:1 135-1 147.  [PMID: 15100103]   Exceptions are albumin, total protein, and bilirubin  (decreased) and alkaline phosphatase and cholesterol  (increased).   ► Hyperemesis gravidarum, often in the first trimester,  invariably before the 20th week of pregnancy.   ► Intrahepatic cholestasis of pregnancy (IHCP), often in  the third trimester (pruritus and mild liver tests  abnormalities).   ► Acute fatty liver disease of pregnancy (AFLP) in the  third trimester (nausea and vomiting, jaundice, and  oliguria; typically mild increase in transaminases,  hyperbilirubinemia, coagulopathy, thrombocytopenia,  and hypoglycemia).   ► Preeclampsia (classic triad of hypertension, protein-  uria, and edema) and eclampsia (preeclamptic triad  plus seizures and coma), in the second or third  trimester.   ► HELLP syndrome (hemolysis, elevated liver enzymes,  and low platelets), between the start of the third  trimester and the immediate postpartum period,  often manifesting with right upper quadrant pain,  edema, and hypertension.   Various hepatic conditions may occur in pregnancy, and the  interpretation of common liver biochemical tests in women  who are pregnant can sometimes be challenging. Among the  specific conditions unique to pregnancy that may manifest   with altered liver tests are hyperemesis gravidarum, IHCP,  AFLP, preeclampsia/eclampsia, and HELLP syndrome.  Other common hepatic conditions, such as viral hepatitis  and cirrhosis, are not unique to but can manifest during  pregnancy.   Guntupalli SR, Steingrub J. Hepatic disease and pregnancy: An  overview of diagnosis and management. Crit Care Med.  2005;33:S332-S339. [PMID: 16215356]   The pregnant state is accompanied by a 30-50% increase in  blood volume. As a result, several biochemical tests have  reduced values during pregnancy. These include albumin,  total protein, and bilirubin.   The most significant change is noted during the second  trimester. The alkaline phosphatase level is elevated because  of the presence of placental derived alkaline phosphatase.  The biliary-derived alkaline phosphatase stays within the  normal range as illustrated by normal levels of y-glutamyl  transpeptidase (GGT) and 5' nucleotidase (5' NT). Cholesterol  also increases to approximately twice its prepregnancy level.  Lastly, the hepatic markers of inflammation, alanine amino-  transferase (ALT) and aspartate aminotransferase (AST), are  unchanged.   Pathologic conditions that result in abnormal biochemical  tests during pregnancy tend to be divided into three broad cat-  egories: ( 1 ) those that lead to a mild increase in transaminases,   (3) those that result in predominantly cholestatic biochemical  abnormalities. Conditions that lead to mild increase in  transaminases include AFLP, preeclampsia, eclampsia, HELLP  syndrome, Budd-Chiari syndrome, IHCP, drug-induced   ALT, alanine aminotransferase; AST, aspartate aminotransferase;  GGT, y-glutamyl transpeptidase; 5' NT, 5'-nucleotidase.   hepatitis, and chronic liver diseases. Those that result in  marked increase in ALT and AST also include preeclampsia  and eclampsia, especially in the setting of hepatic infarct,  Budd-Chiari syndrome with portal vein thrombosis, hepatic  rupture, acute viral hepatitis, drug-induced hepatitis, and  hepatic shock. Lastly, conditions that result predominantly in  cholestasis include 1HCP, choledocholithiasis, or drug-  induced cholestatic conditions.   This disorder produces occasional severe and intractable nau-  sea and vomiting. It begins characteristically in the first  trimester but can last late into pregnancy. Liver biochemical  abnormalities, specifically, elevations in aminotransferases  and bilirubin, are seen in more than 50% of patients hospital-  ized as a result of hyperemesis gravidarum. The level of  aminotransferase elevation is on average two to three times the  upper limit of normal, but occasional reports of transaminase  elevations of greater than 1000 IU exist in the literature.   The cause of hepatic dysfunction in hyperemesis gravi-  darum is unknown and in the few well-documented instances  results of liver biopsies have been normal. Regardless, the  consequences of hypovolemia, ketosis, and malnutrition  likely contribute to observed biochemical abnormalities.   Treatment is symptom management-based with intra-  venous hydration and antiemetic therapy. In the most severe  cases, parenteral feeding may be necessary.   LHCP is a rare disease in the United States, occurring in less  than 0.1% of all pregnancies. The highest incidence is in   Chile, where approximately 12-22% of all pregnancies are  affected. The disease is very rare among African Americans.  The major risk factors for IHCP include multiparity,  advanced maternal age, family history of IHCP, and pruritus  while on oral contraceptive medicines.   The molecular basis of IHCP remains unclear, but a  mutation in the gene for multidrug resistance protein 3  (MDR3) has been implicated as a potential cause in two fam-  ilies. However, a study of Finnish patients with IHCP did not  reveal linkage with MDR3 or for other cholestatic genes,  specifically the bile salt export pump {BSEP) and familial  intrahepatic cholestasis type 1 (FIC1).   Patients with IHCP present with cholestasis in the third  trimester of pregnancy. Pruritus occurs in 80% of patients;  it usually begins peripherally and then progresses centrally.  In approximately 20% of patients with pruritus, jaundice  may occur. The diagnosis is often made by clinical history,  although laboratory abnormalities, especially mild ALT,  AST, and alkaline phosphate elevations, may occur. Serum  levels of bile acids are elevated 30-100 times the upper limit  of normal.   Control of pruritus is important for maternal comfort,  and ursodiol and cholestyramine are the first agents of  choice. Studies have demonstrated the efficacy of ursodiol in  control of pruritus, improvement of biochemical parame-  ters, and increasing the likelihood of a term birth. Finally,  there have been reports that dexamethasone can be used to  good effect in controlling pruritus and also in enhancing  fetal lung maturity.   There are usually no post-pregnancy sequelae for the  mother, and pruritus usually resolves postpartum. Fetal  complications include prematurity (38%), meconium stain-  ing, fetal distress, and intrauterine fetal demise.   Dixon PH, Weerasekera N, Linton KJ, et at. Heterozygous MDR3  missense mutation associated with intrahepatic cholestasis of  pregnancy: evidence for a defect in protein trafficking. Hum  Mol Gen. 2000;9:1209-1217. [PMID: 10767346]   Savander M, Ropponen A, Avela K, et al. Genetic evidence of het-  erogeneity in intrahepatic cholestasis of pregnancy. Gut.  2003;52:1025-1029. [PMID: 12801961]   Zapata R, Sandoval L, Palma I, et al. Ursodeoxycholic acid in the  treatment of intrahepatic cholestasis of pregnancy. A 12-year  experience. Liver Int. 2005;25:548-554. [PMID: 15910492]   AFLP is a potentially fatal disease that occurs most often in  the third trimester and is reported in 1 in 13,000 pregnan-  cies. Complications include preeclampsia (see later discus-  sion) in 20-40% of cases. Maternal mortality is estimated at  around 18%.   The medical basis of the disease has been identified as a  defect in P-oxidation of long chain fatty acids in the fetus. The  most commonly invoked molecular defect is a mutation in  the long chain- 3 hydroxyacyl CoA dehydrogenase (LCHAD).    ALT/AST 1-5x  Bilirubin > 10x  Hypoglycemia  PT/PTT increased  Platelets decreased  CT/US-fatty infiltration  Liver biopsy —    ALT/AST 1-1 Ox  Bilirubin < 5  PT/PTT increased  Proteinuria  Platelets decreased    ALT/AST 1-1 Ox  Bilirubin: <5 mg/dL  PT/PTT increased  Platelets decreased  Hemolysis   AFLP, acute fatty liver disease of pregnancy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed tomog-  raphy; HELLP, hemolysis, elevated liver enzymes, and low platelets; IHCP, intrahepatic cholestasis of pregnancy; PT, prothrombin  time; PTT, partial thromboplastin time; RUQ, right upper guadrant; US, ultrasound.  Adapted, with permission, from Wolf JL. Liver disease in pregnancy. Med Clin North Am. 1996;80:1167-1187.   Mothers who are heterozygotes for LCHAD are at risk. The  disorder arises from excess unmetabolized long chain fatty  acids, generated by a fetus homozygously defective for  LCHAD. This results in elevated levels of long chain fatty  acids in the serum of the mother heterozygously defective for  LCHAD, leading to subsequent hepatotoxicity. Indeed, muta-  tions in the gene for LCHAD have been identified in affected  women; specifically, G1528C is seen in 60% and E474Q in  19% of cases. Although LCHAD is implicated in the disease,  other disorders of p-oxidation of long chain fatty acid may  produce a similar disease syndrome. There is at least one case  report of a deficiency in palmityl transferase that led to AFLP.  The clinical presentation may be nonspecific, with nausea  and vomiting present in 70% of patients. However, jaun-  dice encephalopathy and oliguria often follow. Laboratory   evaluation may show mild serum transaminase elevation,  hyperbilirubinemia, coagulopathy, thrombocytopenia, and  hypoglycemia. Ultrasound and computed tomography (CT)  scans often show fatty infiltration of the liver. Liver biopsy  examination shows microvesicular steatosis, easily dis-  cernible on oil red O staining.   Early delivery is the recommended therapeutic interven-  tion, although some clinicians argue that mild cases should  be managed expectantly. Regardless, management decisions  should consider the rapidity in which complications develop  and the significant mortality rate in patients with AFLP.  There are no long-term sequelae for the mother as most  recover; however, at least one case report exists of liver trans-  plantation in AFLP. For the child, mortality is estimated at  13-18%, and developmental delay, hypoglycemia, and   striated muscle dysfunction are all potential complications.  Therapy with medium chain fatty acids is often necessary for  infants with homozygous LCHAD deficiency.   Ibdah JA. Acute fatty liver of pregnancy: an update on pathogene-  sis and clinical implications. World J Gastroenterol. 2006;12:  7397-7404. [PMID: 17167825]   Innes AM, Seargeant LE, Balachandra K, et al. Hepatic carnitine  palmitoyltransferase I deficiency presenting as maternal illness  in pregnancy. Pediatr Res. 2000;47:43-45. [PMID: 10625081]   This complication of pregnancy, which occurs during the  second or third trimester, is characterized by a triad of clinical  findings: hypertension (defined as an elevation of at least  30 mm Hg systolic, 15 mm Hg diastolic, or a blood pressure  > 140/90), edema, and proteinuria. It occurs in 5-10% of all  pregnancies. Eclampsia includes the above triad plus seizures  and coma. The risk factors include preexisting hypertension,  family history of preeclampsia, primigravida, multiple gesta-  tions, and early and late ages at the time of childbearing.   Clinically, patients present as a result of symptoms related  to increased blood pressure or edema. The ALT level is  abnormal in approximately 20% of patients with preeclamp-  sia, and in 90% of those with full-blown eclampsia. The diag-  nosis is often made on clinical grounds with elimination of  other potential causes of late pregnancy liver abnormalities.  Hypoglycemia as seen in AFLP is unusual.   Management calls for the delivery of the infant. At expe-  rienced institutions the mortality rate is less than 1%.  Complications include seizure, coma, hepatic rupture, and  fulminant hepatic failure.   This syndrome is a potential complication of preeclampsia,  occurring in 0.1-0.6% of all pregnancies and in 4-12% of all  preeclamptic patients. Seventy percent of patients with  HELLP syndrome develop this problem between the 27th  week of pregnancy and the time of delivery. However,  approximately 30% develop the problem postpartum.   Signs and symptoms are right upper quadrant pain,  occurring in 65-90% of patients; jaundice, in around 5%;  edema, in 60%; and hypertension, in 80%. Laboratory  abnormalities include a mean ALT level of around 150 IU/L;  serum bilirubin is often normal or minimally elevated.  Hypoglycemia as seen in AFLP is unusual.   Delivery remains the mainstay of management, and it is  recommended that if the pregnancy has progressed beyond  34 weeks, the infant should be delivered. Observation for  24-48 hours is recommended, but only if hypertension and  central nervous system abnormalities are not present.   Complications of HELLP include a mortality rate of  1-3%, disseminated intravascular coagulation (DIC) in 20%  of patients, placenta abruptio in 16%, acute renal failure in  7%, and pulmonary edema in 6%. Perinatal mortality is  approximately 35%.   Barton JR, Sibai BM. Diagnosis and management of hemolysis,  elevated liver enzymes, and low platelets syndrome. Clin  Perinatal. 2004;31:807-833. [PMID: 15519429]   This is a severe and devastating complication of pregnancy,  which often occurs in the third trimester and almost always in  the setting of HELLP, preeclampsia, AFLP, cocaine abuse, neo-  plasms, sickle cell disease, polyarteritis nodosa, and rupture of  hepatic adenoma during pregnancy. Intraparenchymal hem-  orrhage always precedes the rupture. This diagnosis should be  suspected in any pregnant woman with right upper quadrant  pain, preeclampsia, and shock. Maternal mortality is esti-  mated at 57-75%, and fetal mortality of approximately  62-77% is seen.   Acute viral hepatitides from hepatitis A, B, C, D, and E can  occur in pregnant women as in nonpregnant patients.  Nonhepatotropic viruses such as cytomegalovirus, Epstein-  Barr virus, and herpes simplex virus (HSV) can also cause  hepatic injury in pregnant women. Considerations in man-  aging pregnant patients with some of these hepatitides are  presented here. For additional information about acute and  chronic hepatitis, see Chapters 39 and 40.   The incidence and management of hepatitis A are the same  in pregnant as in nonpregnant individuals (see Chapter 39).  The management of hepatitis A is conservative. Perinatal  transmission is rare, but there may be horizontal transmis-  sion at the time of delivery. Hepatitis A vaccine and  immunoglobulin are safe during pregnancy.   The risk of vertical transmission to the fetus of acute infec-  tions in the second and third trimesters is 10% and 90%,  respectively. Intrauterine infections are rare. Most infections  occur in intrapartum. In women who are positive for hepatitis B e  antigen (HBeAg), there is a 70-90% chance of vertical trans-  mission. Hepatitis B vaccine is safe during pregnancy and once  infants are administered protective immunoglobulins (hepati-  tis B immunoglobulin [HBIG] ) at the time of birth, there is no  additional risk from breast feeding. All children born to hep-  atitis B surface antigen positive mothers should receive HBIG   at the time of birth and the first of their hepatitis B vaccines  before discharge from the hospital.   Hepatitis C virus (HCV) infection is not a contraindication  to pregnancy, but perinatal transmission is around 5% in  mothers who are positive for HCV RNA. If patients are coin-  fected with HIV, the risk of infection increases to 19%.  Amniocentesis and fetal blood monitoring are contraindi-  cated in HCV-positive mothers because of worries regarding  percutaneous exposure. Breast feeding is permitted.   The hepatitis E virus causes a fulminant hepatitis resem-  bling hepatitis A. The mortality rate in pregnant mothers is  around 30%.   HSV hepatitis is a rare disorder seen in immunocompro-  mised and in pregnant patients. There is usually a short pro-  drome of between 2 days and 2 weeks. Symptoms are mostly  nonspecific, although fever and abdominal pain can occur.  Oropharyngeal or genital lesions, or both, are seen in roughly  50% of infected persons; thus, their absence does not elimi-  nate this as a possible etiology.   Factors associated with possible diagnosis include low  bilirubin in the presence of elevated transaminases (anicteric  hepatitis), AST greater than ALT, third trimester of preg-  nancy, and immunocompromised state. Diagnosis can be  made through HSV- 1 and HSV-2 serologies, viral cultures, or  liver biopsy, which is the gold standard. The biopsy sample  often shows minimal inflammatory infiltrate and is charac-  terized by zonal necrosis of hepatocytes.   In untreated patients the mortality rate exceeds 80%.  In one study of 14 pregnant patients who received acyclovir,  10 patients survived. Because the results of serologic tests,  viral cultures, and biopsy examination often are not available  for several days, clinical decision making in the absence these  findings is important. If suspicion is high, therapy should be  begun immediately while awaiting diagnostic results.   Kang AH, Graves CR. Herpes simplex hepatitis in pregnancy: a  case report and review of the literature. Obstet Gynecol Surv.  1999;54:463-468. [PMID: 10394584]   This syndrome results from an obstruction of the hepatic  vein or the suprahepatic portion of the vena cava. The most  common reason is thrombosis. Because of increased risk of  thrombotic events in pregnancy, this disorder should be con-  sidered in any pregnant with right upper quadrant pain,  rapid weight gain, and ascites.   Evaluation relies heavily on ultrasonographic Doppler  examination. Occasionally CT or venography may be necessary.   If the patient is stable, heparin is the therapy of choice. If  unstable, transjugular intrahepatic portosystemic shunts  should be performed if feasible. Warfarin cannot be used  during pregnancy.   Horton JD, San Miguel FL, Ortiz JA. Budd-Chiari syndrome: illus-  trated review of current management. Liver Int. 2008;28:455-466.  [PMID: 18339072]   Wilson disease is a disorder of copper metabolism that  results in systemic manifestations, with hepatic and neuro-  logic symptoms as the most prominent components (see  Chapter 40). Many patients are diagnosed in their teenage  years; thus issues related to disease management become a  concern during their childbearing years.   In general, patients whose disease is well controlled dur-  ing pregnancy do well. Therapy should continue throughout  pregnancy as fulminant liver failure has been reported in  patients who discontinue therapy. Penicillamine, trientine,  and zinc have been used with success during pregnancy.  Many practitioners decrease the dose of penicillamine to  between 25% and 50% during pregnancy.   Sternlieb I. Wilson's disease and pregnancy. Hepatology. 2000;31:  531-532. [PMID: 10655282]   Although infertility is common in persons with advanced  liver disease, pregnancy does occur in cirrhotic patients.  Maternal mortality in pregnant patients with cirrhosis is esti-  mated at 10-18%. In a large case series of 117 pregnant  women with cirrhosis, portal hypertension, or both, 50% had  uncomplicated term pregnancies but variceal bleeding  occurred in 24 women and was responsible for death in 4%  of the patients. The few case reports available indeed confirm  that variceal bleeding is by far the most common complica-  tion of cirrhosis in pregnancy. This is not surprising given  the 30-50% increase in plasma volume that accompanies the  pregnant state.   Although no uniformed consensus exists on management  in these cases, most agree that endoscopic evaluation for  esophageal varices should be performed and patients with  high-grade varices treated either by nonselective p-blockade  or by esophageal variceal band ligation if (3-blockers are con-  traindicated. There are no reliable data to show superiority of  cesarean delivery over vaginal delivery; thus, decisions  should be made based on the individual clinical information.   Cerqui AJ, Haran M, Brodribb R. Implications of liver cirrhosis in  pregnancy. AustNZ] Obstet Gynaecol. 1998;38:93-95. [PMID:  9521402]   During the last decade, many new tools became part of the  radiologist's armamentarium to image the gastrointestinal (GI)  system. Developments in computerized tomography (CT),  magnetic resonance (MR) technology, and positron emission  tomography (PET) made GI radiologists essential physicians in  the diagnosis and evaluation of a vast array of diseases involv-  ing the abdomen and pelvis. Moreover, these major innovations  mandated the replacement of some classic invasive diagnostic  methods with noninvasive and efficient ones.   Multidetector-row CT (MDCT), initially introduced in  1998, has diffused into clinical imaging practice in a short  time. Rapid volume coverage speed combined with thin  image thickness allows creation of a volume data set. In addi-  tion to technical advances, such as shorter scanning times,  multiplanar imaging, and improved ability to perform true  multiphasic contrast-enhanced studies, advances in postac-  quisition data-processing techniques have made MDCT a  powerful imaging tool in abdominal visceral imaging.   Compared with CT, magnetic resonance imaging (MRI)  still plays a relatively minor role in the diagnosis and imag-  ing workup of patients with abdominal diseases. However,  technical improvements, such as the development of phased  array multicoils and faster sequences, allow excellent contrast  resolution images of the liver, pancreas, biliary tree, and even  GI tract with an acceptable spatial and temporal resolution.  Published results of MRI compared with CT and sonography  have allowed, in a vast array of abdominal diseases, not only  a more accurate delineation of the extent of disease, but also  improvements in disease characterization. Furthermore, the  evaluation of abdominal organs by means of contrast-  enhanced dynamic MRI can be optimized with the use of  MR angiography, which visualizes the vessels, and MR  cholangiopancreatography (MRCP), which depicts the bil-  iopancreatic ductal system. At present, this "all-in-one"  approach is presumably the most cost-effective imaging  technique in the evaluation of a vast array of liver function   abnormalities, exocrine pancreatic diseases, and biliary dis-  orders. Currently, the indications for MRI of the GI tract are  limited to staging of rectal cancer and assessing the extent of  perianal fistulae and anal sphincter tears. However, the value  of MR colonography, MR enterography, and MRI of appen-  dicitis is rapidly emerging.   PET-CT is another rapidly evolving technique with  increasing applications in GI diseases. The majority of  investigations allow staging of cancer and monitoring ther-  apy, using the glucose analog 2-deoxy [18F] fluoro-D-glucose  (FDG). Because tumors cells preferentially utilize glucose  as a metabolic substrate, FDG-PET depicts areas of increased  metabolism as "hot spots"; a CT scan performed in the  same session allows linking these areas to morphologic  abnormalities.   Coupled with these recent innovations in cross-sectional  imaging, there has been a serious decline in the utilization of  more routine diagnostic imaging methods used in the past to  evaluate the GI system. Nowadays, fluoroscopic examina-  tions of the small bowel and colon have very specific but lim-  ited indications. Nevertheless, some contrast examinations,  such as barium swallow and upper GI studies, remain cost-  effective investigations and continue to play an important  role in the evaluation of the upper GI tract.   This chapter details the current imaging algorithms and  key imaging features of various diseases involving the GI sys-  tem, with special emphasis on new imaging techniques cur-  rently available in clinical practice.   Although endoscopy may comprise the initial examination  to evaluate the esophagus in many centers, fluoroscopic  examination of the esophagus after contrast administration   still has a high yield to detect clinically significant pathology,  and can compliment endoscopy in several ways. Using a  biphasic technique (single and double contrast), the esopha-  gogram has proven invaluable in the evaluation of dysphagia,  odynophagia, gastroesophageal reflux disease, and especially  motility disorders; assessment of the integrity of the esopha-  gus following local surgery or invasive procedures is another  useful and common indication. Nowadays, CT and especially  PET-CT are used increasingly in the evaluation of patients  with esophageal neoplasms in order to stage the cancer  locally and more distantly.   Levine MS, Rubesin SE, Laufer I. Barium esophagography: a study  for all seasons. Clin Gastroenterol Hepatol. 2008;6:11-25.  [PMID: 18083069]   Esophageal carcinoma. Double-contrast esophagography has  a sensitivity of greater than 95% in the detection of  esophageal cancer. Approximately 70% of esophageal neo-  plasms are squamous cell carcinomas and the remaining  30% are adenocarcinomas arising in Barrett esophagus. The  appearance of esophageal cancers on barium studies is vari-  able and has been described as infiltrating, polypoid, ulcera-  tive, or varicoid (Figure 9-1). Fistula formation is seen in  approximately 5-10% of cases. Nowadays, PET-CT imaging  is increasingly used to detect non-regional lymphadenopathy  or distant metastases (Plate 4).   Zenker diverticulum (see Chapter 13) is an acquired  mucosal herniation between the horizontal and oblique  fibers of the cricopharyngeus muscle; it is more common in  men and probably associated with GI reflux disease. On bar-  ium studies, a contrast-filled midline sac is seen posterior to  the pharyngoesophageal junction (Figure 9-2). Below the  opening of the sac, a prominent cricopharyngeal muscle is  commonly identified. It is important for a Zenker diverticu-  lum to be diagnosed on barium swallow because of an  increased risk of perforation at endoscopy.   Gastroesophageal reflux disease (GERD). (See Chapter 11.)  Barium studies have proved invaluable in patients with  GERD to document the presence of a hiatal hernia, gastroe-  sophageal reflux, and reflux esophagitis, and to detect com-  plications, such as ulcerations, strictures, Barrett esophagus,  and neoplasms. Early esophagitis in patients with GERD is  manifested by a fine nodular or granular appearance with  small well-defined radiolucencies caused by mucosal edema.  In more advanced disease, contrast-filled ulcers may be pres-  ent near the gastroesophageal junction on the posterior  esophageal wall and peptic strictures may be detected in the  distal esophagus above a hiatal hernia (Figure 9-3). The clas-  sic signs of Barrett esophagus include a high, midesophageal  stricture, ulcer or reticular pattern (see Chapter 12).   Infectious esophagitis is most frequently encountered in  patients who are immunocompromised; among the possible  infectious agents are Candida albicans, herpes simplex virus,    ▲ Figure 9-1. Polypoid esophageal carcinoma. Upright  double-contrast esophagogram shows a thick, polypoid,  and irregular tumor {arrows) in the midesophagus.   cytomegalovirus (CMV), and HIV. Candida esophagitis  (moniliasis) is typically manifested on barium studies as dis-  crete, linear, plaquelike lesions separated by normal interven-  ing mucosa, with a predilection for the upper and  midesophagus. Herpes esophagitis shows the presence of  small barium-filled ulcers on a normal background mucosa  while CMV and HIV esophagitis is manifested by giant, flat  ulcerations that are typically several centimeters in length.   Achalasia can be categorized as primary when it is idiopathic  and as secondary when it is caused by other conditions,  such as tumors or Chagas disease. Patients with idiopathic  achalasia are typically young and demonstrate lack of  esophageal peristalsis and incomplete relaxation of the  lower esophageal sphincter. On barium studies, the esopha-  gus appears dilated, flaccid, and obstructed by a tapered,   ▲ Figure 9-2. Zenker diverticulum. Lateral view from a  single-contrast esophagogram shows a barium-filled  diverticulum (arrows) posterior to the cervical esophagus.   ▲ Figure 9-3. Peptic stricture and ulceration. Upright  double-contrast esophagogram shows a smooth, tapered  stricture in the distal esophagus above a hiatal hernia  (white arrows). Also note a small barium-filled ulcera-  tion (black arrow) on the left lateral wall.   bird beak-like narrowing at the gastroesophageal junction.  In patients with secondary achalasia, due to destruction of  ganglion cells caused by miscellaneous processes, the length  of the narrowed segment is often greater and may appear  nodular or ulcerated.   Diffuse esophageal spasm (DES) is characterized by inter-  mittent, abnormal esophageal peristalsis with presence of  multiple, simultaneous nonperistaltic contractions. In  approximately 15% of patients with DES, lumen-obliterating  nonperistaltic contractions can be seen that compartmental-  ize the esophagus, producing the classic "corkscrew" esopha-  gus on barium studies.   Upper endoscopy has largely replaced fluoroscopic studies as  the primary investigation in patients with suspected gastric  or duodenal pathology. Nevertheless, if endoscopy is con-  traindicated or unsuccessful, a well-performed upper GI  study is the next sensitive diagnostic test. In addition to   displaying the morphology of the stomach in patients fol-  lowing bariatric surgery, with suspected gastric volvulus, or  gastric outlet obstruction, upper GI studies also readily detect  mucosal and submucosal abnormalities that distort the gas-  tric wall with high sensitivity. More recently, MDCT with  neutral contrast material has been proposed as an excellent  imaging test to evaluate the gastric wall, especially in the  evaluation of gastric neoplasms. Other diagnostic methods  utilized to diagnose and stage gastric neoplasms include  ultrasonography, endoscopic ultrasound (EUS), MRI, and  PET (CT) scan.   Rubesin SE, Levine MS, Laufer I. Double-contrast upper gastroin-  testinal radiography: a pattern approach for diseases of the  stomach. Radiology. 2008;246:33-48. [PMID: 18096527]   Adenocarcinoma is by far the most common gastric malig-  nancy and represents approximately 90% of all gastric malig-  nancies. CT is currently the staging modality of choice  because it can identify the primary tumor, assess for local    ▲ Figure 9-4. Gastric adenocarcinoma. Axial T2-  weighted MR image shows a thick hyperintense mass  (arrows) arising from the gastric cardia.   spread, and detect nodal involvement and distant metastases.  On CT, if larger than 5 mm, gastric cancer may present as a  focal enhancing soft tissue mass or as diffuse thickening of  the gastric wall (Figure 9-4). Both CT and PET-CT have a  reported sensitivity of 90% in detecting distant metastases.  Classic features of gastric cancer include the presence of a  lobulated or nodular mass with associated irregular ulcera-  tion (Figure 9-5). In scirrhous adenocarcinoma, the stomach  demonstrates a long segment of circumferential narrowing  and focal areas of mucosal nodularity.   Other gastric malignancies occur much less frequently and  include lymphoma (< 5%), GI stromal tumors (< 2%), and  malignant carcinoid (< 1%). Gastric lymphoma typically  appears as segmental or diffuse gastric wall thickening. In  contrast to gastric cancer, lymphoma typically involves more   ▲ Figure 9-5. Gastric adenocarcinoma. Upright double-  contrast upper GI image shows a large irregular mass  (arrow) arising from the fundus.   ▲ Figure 9-6. Gastrointestinal stromal tumor Axial MDCT  image shows a well-defined hypervascular mass  (arrows) in the gastric body.   than one region of the stomach, is unlikely to cause gastric  outlet obstruction, and may be associated with lym-  phadenopathy below the renal hila. Gastric stromal tumors  can be benign or malignant and 90% of them originate in the  gastric fundus or body. Because of their extramucosal origin,  upper GI series may be negative. Small masses appear as  intramural hypervascular lesions on CT. Larger stromal  tumors tend to necrose, hemorrhage, or ulcerate (Figure 9-6).  They typically are partially exophytic in location. Associated  lymphadenopathy is uncommon, in contrast with gastric  adenocarcinoma or lymphoma.   Peptic ulcer disease (see Chapter 15) is most commonly  caused by infection by Helicobacter pylori or by nonsteroidal  anti-inflammatory drugs (NSAIDs). Most duodenal ulcers  are caused by H pylori, while most gastric ulcers are caused  by NSAIDs. Erosion is an area of focal necrosis confined to  the epithelium or lamina propria, whereas a true ulcer  extends through the muscularis mucosa into the deeper lay-  ers of the gastric wall. On upper GI studies, a depressed  lesion greater than several millimeters in depth is called an  ulcer. When viewed en face, most peptic ulcers are mani-  fested as round or ovoid collections of barium filling the ulcer  crater with smooth, straight folds radiating to the ulcer's  edge (Figure 9-7). The presence of a Hampton line (a thin  radiolucent line traversing the base of the crater due to  undermining of the submucosa) is diagnostic of a benign  gastric ulcer. CT does not detect most peptic ulcers because  they affect only the superficial layers of the gastric wall.  However, deep or perforated ulcers manifest as focal wall  thickening with associated inflammatory changes in the  adjacent soft tissues.    ▲ Figure 9-7. Gastric benign ulcer. Double-contrast  upper Gl study shows a small ulcer (arrow) with  radiating folds surrounding it.   Gastritis, due to H pylori or other causes, typically appears  on barium studies as thickened, scalloped folds that have a  longitudinal or transverse orientation. Similarly, the most  common CT finding in patients with gastritis is thickening of  the gastric folds (Figure 9-8). In severe cases, the gastric wall  appears stratified due to extensive submucosal edema and  mucosal hyperenhancement. This striated appearance helps  to distinguish gastritis from gastric cancers. H pylori gastritis,  the most common infection in humans, is by far the most  likely cause of focally or diffusely thickened folds, especially  involving the antrum. Gastritis by a gas-producing organism  (eg, Escherichia coli) may cause the classic appearance of  emphysematous gastritis, a condition with a high mortality  rate. Menetrier disease typically causes massive enlargement  of the rugal folds predominantly involving the gastric fundus  and body with sparing of the antrum.    ▲ Figure 9-8. Gastritis. Axial MDCT image shows severe  thickening of the gastric folds (arrow).   Traditionally, the small bowel has been studied noninvasively  with fluoroscopic imaging techniques, such as small bowel  follow-through (SBFT) or enteroclysis. The accuracy of SBFT  and enteroclysis for detecting and characterizing small bowel  abnormalities, however, varies widely among radiologists and  institutions. Moreover, the inherent disadvantage of studying  only the mucosa represents another limitation of enteroclysis  and SBFT. CT enteroclysis is a successful alternative imaging  method for a more detailed evaluation of bowel wall disease  and for accurate diagnosis of extraluminal pathologies. With  this technique, a nasogastric tube is fluoroscopically placed  and oral contrast agent is infused subsequently; for most  patients, however, the intubation remains a traumatizing  experience. Today, imaging of the small bowel with noninva-  sive adequate distention of bowel loops is possible without  fluoroscopically guided intubation. Recent studies have  demonstrated that noninvasive, peroral CT enterography is  an accurate and feasible technique for detecting active small  bowel inflammation in patients with Crohn disease. The use  of a neutral oral contrast agent provides a better evaluation of  the bowel wall due to the inherent contrast between the neu-  tral bowel content and the enhancing bowel wall.   MR enteroclysis or enterography is performed with  increasing frequency due to the lack of ionizing radiation,  which allows it to be used in young patients with Crohn dis-  ease who need repeated evaluation. MR enterography is also  performed using oral and intravenous contrast material.   Remaining indications for plain film of the abdomen, SBFT,  and enteroclysis in the evaluation of the small bowel include  the detection and evaluation of adynamic ileus, small bowel  perforation, small bowel obstruction, correct placement of  jejunostomy tubes, and functional small bowel abnormalities.   CT enterography is preferably performed using an MDCT  scanner after the oral administration of barium sulfate 0.1%  w/v suspension. Patients drink 1350 mL of Vo Lumen prior to  the scan. For specific indications, such as obscure GI bleed-  ing, small bowel neoplasms, and chronic ischemia, a biphasic  contrast-enhanced MDCT study is performed: images are  acquired during the late arterial phase (40 seconds) and  parenchymal phase (70 seconds) following intravenous  administration of nonionic contrast material.   Patak MA, Mortele KJ, Ros PR. Multidetector row CT of the small  bowel. Radiol Clin North Am. 2005;43:1063-1077. [PMID:  16253662]   In many institutions, SBFT is still the most common imaging  technique used in the evaluation of suspected small bowel   Crohn disease. Nevertheless, although SBFT can demon-  strate early active mucosal disease, such as ulcers, it has  limitations; most importantly, the radiologist must rely on  secondary signs to evaluate the complete small bowel wall and  mesentery.   Although CT has traditionally been used to assess  extraenteric complications of Crohn disease, including  abscesses, fistulas, or obstruction, it has been shown that CT  features of the small bowel wall itself, such as mural stratifi-  cation, mucosal and mural hyperenhancement, edema in the  mesenteric fat, and engorged ileal vasa recta, correlate with  active inflammation (Figure 9-9). Furthermore, submucosal  fat deposition and mural thickening without hyperenhance-  ment or mural stratification typically correlate with fibrotic  or quiescent disease. Large studies have evaluated the sensi-  tivity and specificity of MDCT for detection of Crohn dis-  ease using SBFT as the gold standard; the sensitivity and  specificity of MDCT for advanced disease were reported as  95% and 98%, respectively. In particular, adding multiplanar  reconstructions to the axial data significantly improves the  diagnostic confidence.   The early diagnosis of bowel obstruction is critical in pre-  venting complications, particularly perforation and ischemia.  The accuracy of conventional radiography in determining the  presence of obstruction is 46-80% (Figure 9-10). Today,  while abdominal radiography is often still the preferred initial  radiologic examination, CT has gained favor because it can be  effectively used to reveal the site, level, and cause of obstruc-  tion and it displays the signs of threatened bowel viability  with high accuracy.   Adhesions are responsible for more than half of all small  bowel obstructions, followed by hernias and extrinsic com-  pression from neoplasms. Improvements in MDCT technol-  ogy allow the transition point to be viewed from a variety of  perspectives, increasing the diagnostic confidence once other  causes have been appropriately excluded. Recently, Jaffe and  colleagues reported a specificity of 87% and a sensitivity of  90% for diagnosing small bowel obstruction. MDCT is also  excellent for detecting external hernias and for characterizing  the bowel and mesentery in the hernia sac in patients with  internal herniation.    Jaffe TA, Martin LC, Thomas J, et al. Small-bowel obstruction:  coronal reformations from isotropic voxels at 16-section multi-  detector row CT. Radiology. 2006;238:135-142. [PMID:  16293807]    ▲ Figure 9-9. Crohn disease. Coronal CT enterography  image shows mucosal hyperenhancement of the wall of  the terminal ileum (arrows).   A Figure 9-10. Small bowel obstruction. Abdominal  radiograph image shows severe dilation of jejunal small  bowel loops with acute transition (arrow).   Dual-phase MDCT can demonstrate changes in ischemic bowel  segments accurately, is often helpful in determining the primary  cause of ischemia, and can demonstrate important concomitant  findings or complications. CT findings in acute bowel ischemia  may consist of various morphologic changes, including homo-  geneous or heterogeneous hypoattenuating or hyperattenuating  wall thickening, dilation, abnormal or absent wall enhance-  ment, mesenteric stranding, vascular engorgement, ascites,  pneumatosis, and portal venous gas (Figure 9-11). Dual-phase  imaging of the abdomen is necessary during the arterial and the  portal phases of enhancement to adequately opacify both the  mesenteric arteries and veins. Three-dimensional (3D) imaging  is crucial to visualize even the more distal branches of mesen-  teric arteries, which sometimes are not easily visualized on axial  images. MDCT 3D imaging also can be used in the follow-up of  patients after surgery, which typically includes bypass with  grafts, whose patency is well documented by 3D imaging.   Diagnosis of small bowel tumors is still challenging because  they are uncommon, usually produce nonspecific symptoms,  and often are small. Therefore, MDCT, because of the thin-  ner collimation, is achieving an even more important role in  the detection and staging of small bowel tumors.   Benign small bowel tumors are uncommon and are typi-  cally detected on SBFT and CT as incidental findings. The  most common of these tumors are lipomas and leiomyomas.  Lipomas are easily recognized by their fat attenuation values  (—90 to -120 Houndsfield units [HU]). Leiomyomas are  typically smooth, homogenous submucosal masses that  enhance up to 1.5 times baseline following injection of  intravenous contrast material.   ▲ Figure 9-11. Mesenteric ischemia. Axial MDCT image  shows lack of enhancement of the small bowel wall  (arrow) and presence of pneumatosis (arrowhead).   A Figure 9-12. Duodenal adenocarcinoma. Upright  double-contrast upper Gl image shows an apple-core  lesion (arrow) at the level of the third portion of the  duodenum.   The most common primary malignant tumor of the  small intestine is adenocarcinoma; it accounts for approxi-  mately 40% of all small bowel neoplasms. Most adenocarci-  nomas are located in the duodenum (Figure 9-12). On  MDCT images, adenocarcinoma is typically visualized as a  focal area of wall thickening that encases the lumen. The sec-  ond most common primary small bowel neoplasm is carci-  noid, representing approximately 25% of all primary small  bowel tumors. Carcinoid tumors usually present as small  enhancing nodules, which when bigger, may cause metastatic  infiltration of the mesentery (Figure 9-13). On CT, this  appears as an infiltrating mesenteric mass that contains cal-  cifications in up to 70% of cases. Non-Hodgkin lymphoma  represents approximately 10-15% of all small bowel neo-  plasms. The primary tumor often can be detected with small  bowel contrast studies and CT; however, CT offers the advan-  tage of simultaneously detecting adenopathy and the extra-  luminal extent of disease. Primary small bowel lymphomas  often appear as a focally thickened, aneurysmally dilated  loop. Celiac disease is a predisposing factor for small bowel  lymphoma (Figure 9-14). Gastrointestinal stromal tumors  (GISTs) are estimated to comprise 9% of all small bowel neo-  plasms. They typically appear as large, bulky masses. Central  necrosis and ulceration are common. MDCT imaging may  be especially helpful in defining the exact site of origin and  helping the surgeon plan for resection, and, more impor-  tantly, improve the capability of CT to detect small lesions.   Sailer J, Zacherl J, Schima W. MDCT of small bowel tumours.  Cancer Imaging. 2007;17:224-233. [PMID: 18083648]   ▲ Figure 9-13. Ileal carcinoid. A: Coronol CT enterogra-  phy image shows a hypervascular mass (arrow) in the  wall of the terminal ileum. B: Selected images from an  octreotide nuclear medicine study show increased  uptake of the tracer in the terminal ileum (arrow).    ▲ Figure 9-14. Small bowel lymphoma in celiac sprue.  SBFT image shows an irregular mass in the distal  jejunum (arrows), mild dilation of small bowel loops,  and jejunization of the ileum (arrowhead).    A Figure 9-15. Inguinal hernia. Axial MDCT image  shows the presence of nonobstructed small bowel loops  (arrow) in a right-sided inguinal hernia.   Several uncommon small bowel abnormalities, such as graft  versus host disease, diverticulitis, radiation enteritis, intussus-  ception, hernia, and volvulus may be better visualized using  multiplanar MDCT images than SBFT. On CT, the key to the  diagnosis of radiation enteritis is the presence of abnormal  findings only in the bowel loops localized to the area corre-  sponding to the radiation port. Inguinal hernias can be either  direct or indirect. Indirect hernias are the most common and  occur predominantly in males. The peritoneal sac enters the  inguinal canal and exits at the external ring. Because of their  long course, indirect hernias can become incarcerated, lead-  ing to bowel obstruction and infarction. Direct hernias are  less common and occur when the hernia enters the inguinal  canal medial to the inferior epigastric vessels. On CT, finding  of abdominal contents (small bowel, sigmoid, rectum, mesen-  teric fat) in the inguinal canal anterior to the femoral vessels  is virtually diagnostic of an inguinal hernia (Figure 9-15).   Although sonography has proven to be a reliable technique to  diagnose acute appendicitis in children and slim patients, it  may be significantly limited in obese patients. Moreover, mild  inflammatory changes of the appendix as well as retrocecal  appendicitis may be missed if the cecum is air filled. In con-  trast, CT has an accuracy of up to 98% in diagnosing appen-  dicitis and allows for diagnosis of even very mild and early  stages of the disease. Furthermore, CT can often diagnose  other pathologies that may clinically mimic appendicitis; CT  is, therefore, able to decrease significantly the rate of negative  appendectomies. Currently, MRI of appendicitis is increas-  ingly used, with excellent accuracy, in pregnant patients pre-  senting with right lower quadrant pain and leukocytosis.    ▲ Figure 9-16. Appendicitis. Axial MDCT image shows  hyperenhancement of the wall of the appendix and  periappendiceal fat stranding (arrows).   Typical CT findings of appendicitis are a thickened appendix  with a diameter of more than 6 mm, an edematous or hyper-  emic wall of the appendix, infiltration of the surrounding  mesenteric fat, and, sometimes, inflammatory changes in the  adjacent cecum (Figure 9-16). If an appendolith is present,  along with pericecal inflammation, the scan is virtually diag-  nostic for appendicitis. The presence of inflammation in the  surrounding mesenteric fat is reported to have a sensitivity of  100% and a specificity of 80%. Perforation is one of the seri-  ous complications that may occur in acute appendicitis, and  CT can confirm this diagnosis. In cases with pronounced  surrounding fluid collections perforation should be consid-  ered. If extraluminal air can be identified in the peritoneal  cavity or in the retroperitoneum or if the fluid collections  have already taken on the appearance of a phlegmon or an  abscess, perforation can be diagnosed with certainty. Lastly,  in complicated cases, CT can be also used to diagnose pyle-  phlebitis or pylephlebitic liver abscesses and for CT-guided  abscess drainage in cases in which surgeons prefer to operate  electively.   Nitta N, Takahashi M, Furukawa A, et al. MR imaging of the nor-  mal appendix and acute appendicitis. / Magn Reson Imaging.  2005;21:156-165. [PMID: 15666398]   CT is almost universally accepted as the primary screening  modality for the evaluation of patients suspected of having  colonic disease. Key advantages of CT over other imaging  modalities include the fact that CT not only allows accurate  demonstration of the colonic wall but also outlines the   pericolonic tissues and adjacent structures. CT can help  assess infectious and inflammatory conditions, as well as  facilitate diagnosis and staging of colonic neoplasms. The lat-  ter is typically performed using a dedicated CT method,  known as CT colonography or virtual colonoscopy.   CT colonography has several advantages over optical  colonoscopy: no sedation is needed, it is only minimally inva-  sive, and the examination is less time consuming. However,  there is still a need for bowel cleansing and insufflation of gas  to expand the colon. Moreover, exposure to radiation is inher-  ent to CT and there is no possibility of biopsy or polypectomy  or treatment. Failed optical colonoscopy or a medical con-  traindication for endoscopy is a good indication for CT  colonography. There is still substantial debate about the use-  fulness of CT colonography as a general screening tool for  colonic polyps and colorectal cancer.   MR colonography is performed using contrast within the  colonic lumen, resulting in increased and decreased signal  intensity accordingly to the contrast used.   Remaining indications for single- and double-contrast  barium enema are rapidly declining and are typically  reserved for the postoperative patient, to detect strictures,  fistula formation, or anastomotic leaks.   Ajaj W, Goyen W. MR imaging of the colon: "technique, indica-  tions, results and limitations." Eur ] Radiol. 2007;61:415-423.  [PMID: 17145153]   Optimal CT colonography technique requires careful cleans-  ing and distention of the colon. Residual stool causes prob-  lems similar to those encountered with barium enema as it  simulates polyps or masses. In theory, any preparation that  results in a clean colon will suffice. Stool markers (mostly  barium, eg, Tagitol) or iodine can be administered orally  24-48 hours before CT to improve differentiation of soft tis-  sue intraluminal lesions and retained stool. This technique is  called fecal tagging.   Three-dimensional endoluminal images are useful to  confirm the presence of a lesion and to improve diagnostic  confidence. Most investigators use a primary 2D interpreta-  tion with so-called lumen tracking, starting from the rectum  and following the course of the bowel from slice to slice to  the caecum. Primary 3D endoluminal assessment of the  colon (endoluminal "fly-through") is less often performed as  it is more time consuming and more susceptible to pitfalls.  It is imperative that the 2D images be reviewed by using  colon window settings (approximately W: 1600, C: -400).  In addition, soft tissue windows must be used for further  characterization of suspected lesions and when searching for  extracolonic abnormalities.   The majority of colorectal cancers are believed to arise  within benign adenomatous polyps and follow the   adenoma-carcinoma sequence. The duration of this  sequence is very long (± 10 years) and the removal of these  precursor adenomatous polyps decreases the risk for lethal  colorectal cancer significantly.   The aim of colorectal imaging and screening is to detect  early malignancies or premalignant lesions (see Chapter 22).  Colorectal polyps appear as round, oval, or lobulated intra-  luminal projections and are homogeneous in attenuation  (Figure 9-17 and Plate 5). Most large colorectal carcinomas  appear as fungating masses, often causing luminal narrowing  (Figure 9-18). Flat colorectal adenomas and carcinomas are  difficult to identify, not only on 3D endoluminal images, but  also on thin 2D images. It is important to remember that the  adenomatous polyp (particularly advanced lesions) is the  primary target of screening. Because the prevalence of malig-  nancy is extremely low in lesions smaller than 10 mm (only  1%) this could be a good target. Patients with polyps larger  than 10 mm should undergo immediate colonoscopy for  excision of the lesion. Diminutive filling defects (< 5 mm)  can represent normal mucosal protrusion, adherent fecal  material, hyperplastic polyps, or small adenomatous polyps.  The clinical significance of missing a diminutive adenoma is  probably minimal, and the question can be asked whether  these very small polyps (< 5 mm) should be reported at all.  What about lesions between 5 and 9 mm? This remains a  dilemma. Most gastroenterologists remove these lesions  when endoscopically visualized.   ▲ Figure 9-17. Colonic polyp. Axial MDCT image  displayed in a "colon" window shows a 1.2-cm polyp  (arrow) in the ascending colon. (For corresponding 3D  endoluminal reconstructed image, see Plate 5.)   ▲ Figure 9-18. Colon cancer. Double-contrast barium  enema image shows an apple-core lesion in the  sigmoid colon with irregularity of the mucosal lining  (arrows).   Both patients with Crohn disease and those with ulcerative  colitis may have isolated colonic disease. Many of the  imaging features used to diagnose inflammatory bowel dis-  ease on CT are derived from the appearance of the colon at  barium enema examinations. Double-contrast enemas and  optical colonoscopy are superior to CT for demonstrating  superficial changes in the mucosa (Figure 9-19). Despite  considerable overlap between the CT features seen in  Crohn disease and ulcerative colitis, some differentiating  findings can be detected. In Crohn disease, the wall thick-  ening is eccentric or asymmetric, typically along the  mesenteric border; the rectum is typically spared; the dis-  tribution of disease is typically discontinuous and involves  mainly the right-sided colon; the wall thickening is usually  greater than 10 mm; and pericolonic phlegmon formation  and presence of sinus tracts and fistulas are common. In  ulcerative colitis, the wall is typically symmetrically thick-  ened; the wall measures less than 10 mm; the rectum is  always involved; the distribution of disease is continuous  and mainly involves the left colon; and pericolonic abnor-  malities are rare (Figure 9-20).    ▲ Figure 9-19. Ulcerative colitis. Double-contrast barium  enema image shows numerous contrast-filled superficial  ulcerations (arrows) with loss of normal colonic haustrations.    ▲ Figure 9-20. Ulcerative colitis. Coronal MDCT image  shows mild symmetric wall thickening (arrows) of the  left colon with associated lymphadenopathy in the  mesocolon.   Pseudomembranous colitis is a toxin-mediated disease with-  out evidence of microbial invasion into the bowel wall. The  causative organism is Clostridium difficile, and disease occurs  typically after antibiotic use. On CT, pseudomembranous  colitis usually manifests as marked bowel wall thickening  (average, 15 mm). The thickening is homogeneously low in  attenuation due to edema. Contrast material insinuating  between the large pseudomembranes of pseudomembranous  colitis, also known as the "accordion" sign, is considered rel-  atively specific.   Typhilitis classically occurs in neutropenic patients receiv-  ing chemotherapy to treat leukemia. Mechanisms probably  related to its occurrence include infection with CMV, neo-  plastic infiltration, ischemia, and mucosal hemorrhage. The  disease usually presents acutely with abdominal right lower  quadrant pain, fever, and bloody diarrhea. Pathologically,  typhilitis is characterized by cecal wall edema and inflamma-  tion, frequently also involving the ascending colon and ter-  minal ileum. In more advanced disease, bowel wall necrosis  and perforation may be present. Because barium enema or  colonoscopy carries a high risk for bowel perforation in these  patients, CT is the imaging modality of choice for the diag-  nosis of neutropenic colitis. Typically, a circumferential  thickening of the cecum is detected along with inflammatory  changes in the adjacent mesenteric fat. Due to extensive  edema, the affected bowel wall is hypoattenuating.  Complications important to recognize include intramural  perforation with pneumatosis, transmural necrosis with  pneumoperitoneum, and pericolic abscesses because they  indicate a need for urgent surgical intervention.   Thoeni RF, Cello JP. CT imaging of colitis. Radiology. 2006;  250:623-638. [PMID: 16926320]   The spectrum of ischemic lesions in the colon ranges from  mild, superficial necrosis and mucosal hemorrhage to total  transmural infarction, with or without perforation. Acute  occlusion of mesenteric vessels due to thromboembolism,  dissection, or arteriosclerosis is a well-known cause that may  lead to severe ischemic damage or even infarction of the large  bowel. Although all these conditions are due to partial or  total extrinsic or intrinsic vascular occlusion, ischemic colitis  is most commonly caused by nonocclusive reduction of the  blood supply. If blood pressure falls in hypovolemic, cardio-  genic or septic shock, systemic and local regulatory mecha-  nisms try to preserve blood supply to the brain, heart, and  muscles by, among other means, reducing intestinal perfu-  sion dramatically. As a result, intestinal ischemia may  develop, especially around the watershed areas at the splenic  flexure or in the rectosigmoid. Rarely and especially in  younger patients, such nonocclusive ischemic colitis may also  appear in the cecum and ascending colon.   On CT, colonic ischemia may be diffuse or localized, seg-  mental, or even focal. Imaging findings may include wall  thickening, fold enlargement or loss of haustra in the affected  bowel segments (due to the submucosal edema, hemorrhage,  or both). If edema is dominating, the affected segment will  present with a more hypodense wall thickening and a shaggy  inner layer. In contrast, the wall thickening will appear  hyperdense if mucosal and submucosal hemorrhage or reac-  tive hyperperfusion are dominating. Following the adminis-  tration of iodinated contrast material, the ischemic bowel  wall may show heterogeneous or even absent wall enhance-  ment with zones of low attenuation. Sometimes, discrete  findings such as pericolic streakiness may be found in the  surrounding mesenteric fat. Although wall thickening is the  most common finding, it seems that decreased or even  absent wall enhancement is the most specific CT finding for  bowel ischemia (Figure 9-21).    A Figure 9-21. Ischemic colitis. A: KUB image shows  wall thickening (arrows) of the transverse colon with  thumbprinting. B: Axial MDCT image shows thickening of  the wall of the left colon (arrows) with lack of wall  enhancement.   Clinical history and physical examination under anesthesia  often are sufficient for the diagnosis of perianal fistula. The  major role of imaging is in establishing the relation of the fistula  to the anal sphincter and related structures. MRI assessment of  perianal fistula provides important anatomic and pathologic  information required to guide surgical management. MRI is the  investigation of choice in accurately classifying perianal fistulas.   MRI was first introduced for staging of anorectal cancer  in 1986. MRI has been used increasingly because it gives  more information for preoperative staging than any other  diagnostic method. It can show a clear relationship between  the rectal cancer and the rectal wall and any adjacent pelvic  organ. It can also show the status of the lateral pelvic lymph  nodes and any involvement of pelvic floor muscles beyond  the reach of transrectal ultrasonography. MRI is also valuable  as it is able to provide surgeons with information regarding  the presence of sphincter invasion and the surrounding  structures in patients with distal rectal cancer, which is  important for making a decision on whether to perform  sphincter preservation surgery or not.   MRI of the anal sphincter muscles using an endoanal coil  has been applied to study the integrity of the anal sphincters  in patients with fecal incontinence. The external anal sphinc-  ter muscle and pelvic floor muscles are clearly visualized, and  muscle atrophy and tears may be detected accurately.   Pelvic floor weakness is characterized by abnormal symp-  tomatic displacement of pelvic organs. It represents a com-  plex clinical problem most commonly seen in middle-aged  and elderly parous women. Fluoroscopic colpocystodefecog-  raphy has been proven to surpass physical examination in the  detection and characterization of functional abnormalities of  the anorectum and surrounding pelvic structures. Similarly,  MR defecography appears to be an accurate imaging tech-  nique to assess clinically relevant pelvic floor abnormalities.  Moreover, MR defecography negates the need to expose the  patient to harmful ionizing radiation and allows excellent  depiction of the surrounding soft tissues of the pelvis.   Perianal disease encompasses a wide range of conditions includ-  ing skin tags, ulceration, fissures, abscesses, and fistulas. Fistulas  associated with Crohn disease tend to be complex, with second-  ary extensions and abscesses; as a result, their diagnosis and  treatment can be particularly challenging. Accurate anatomic  mapping and the identification of abscesses are imperative as  this determines the outcome of both medical and surgical treat-  ment. The preferred investigation for perianal disease depends  in part on local expertise, facilities available, and patient toler-  ance. High soft tissue contrast resolution, multiplanar capabil-  ity, and lack of ionizing radiation all make MRI a well suited  examination for the diagnosis of perianal Crohn disease.  Imaging can be supplemented with dynamic intravenous    ▲ Figure 9-22. Anal fistula. Axial T2-weighted MR image  shows the presence of a fluid-filled hyperintense fistula  (arrow) that transgresses the external anal sphincter.   gadolinium- enhanced sequences and by MR fistulography.  Tl -weighted images provide anatomic information of the  sphincter complex and demonstrate active fistulas as low signal  with enhancement post-gadolinium administration. The active  fistula track is of high signal on T2-weighting (Figure 9-22).  Fistula appearance is accentuated by using fat suppression tech-  niques, which eliminate the high signal from fat in the pelvis  thus maximizing tissue contrast. Inactive fistulas have low signal  on T2 -weighted images. Fistulas can be classified according to  the Parks classification, a surgically based classification, to pro-  vide the surgeon with a road map, which should minimize both  operative trauma to the anal sphincters and subsequent recur-  rence. Fistulas can also be classified according to the St James's  University Hospital classification, which is an MR imaging-  based classification.   Recently, there has been a shift in emphasis in the use of  radiology in perianal Crohn disease. Traditionally, its indi-  cation was confined to the diagnosis and mapping of dis-  ease preoperatively. However, the development of the drug  infliximab has resulted in a role for radiology in monitor-  ing response to therapy.   Sahni VA, Ahmad R, Burling D. Which method is best for imaging  of perianal fistula? Abdom Imaging. 2008;33:26-30. [PMID:  17805919]   Transrectal ultrasound (TRUS) has been applied to the stag-  ing of rectal cancer for many years. Its ability to visualize the  different layers of the rectal wall was its main strength. The  main problem with TRUS is the overstaging of T2 tumors  due to the extensive peritumoral tissue reaction surrounding  the growing tumor. TRUS has some other limitations, such as  operator dependency, limitation to tumors located 8-10 cm  from the anal verge when a rigid probe is used, and inability   to assess stenotic tumors or the mesorectal fascia. This may  explain the more recent widespread use of MR imaging as  these limitations do not apply to MRI.   The optimal imaging sequences for endoluminal MR  imaging are multiplanar T2-weighted and axial Tl-weighted  sequences. The T2-weighted images clearly demonstrate nor-  mal anorectal anatomy and allow differentiation of the rectal  wall layers. Tl-weighted imaging is particularly helpful to  determine the extent of the lesion in the mesorectal fat. The  use of intravenously administered gadolinium may be helpful  to determine tumor extent, especially to differentiate T2 from  T3 tumors. A drawback of the endorectal MRI technique is  that coil insertion can be difficult or impossible in patients  with stenosing rectal tumors. The major limitation of endolu-  minal MR imaging, however, is its limited ability to detect  lymph node metastases. Pelvic MRI for rectal carcinoma uses a  phased array coil. These high-resolution images demonstrate  local tumor stage (Figure 9-23), and scanning the entire pelvis  may be of further help in detecting distant lymphadenopathy.   The preoperative evaluation of a patient with rectal cancer  determines the type of surgical approach and the need for  chemotherapy and radiotherapy. Tumor size, local stage, pres-  ence of distant metastases, and proximity to the anal sphincter  decide which individuals are eligible for local excision and which  require either transanal resection or abdominoperineal or low  anterior resection. Furthermore, an accurate preoperative assess-  ment and staging of the patient is valuable for the centers admin-  istrating neoadjuvant chemoradiotherapy prior to the surgery.   Bipat S, Glas AS, Slors FJ, et al. Rectal cancer: local staging and  assessment of lymph node involvement with endoluminal US,  CT, and MR imaging-a meta-analysis. Radiology. 2004;232:  773-783. [PMID: 15273331]    ▲ Figure 9-23. Rectal cancer. Axial T2-weighted MR  image shows a T2 rectal cancer arising from the right  lateral wall of the rectum with involvement of the  muscularis propria (arrows).   At present, functional pelvic floor abnormalities represent a  common health care problem. These abnormalities result in  more than 300,000 surgeries in the United States annually,  and it is estimated that approximately 15% of older multi-  parous women suffer from some sort of pelvic support  defect. These conditions often have a significant impact on  quality of life and result in a variety of symptoms, including  chronic pelvic pain, urinary or fecal incontinence, and con-  stipation. Because physical examination is not a reliable  method for evaluating these symptoms, an objective assess-  ment of rectal evacuation that is reproducible and allows  quantification is extremely valuable. Fluoroscopic defecogra-  phy is conventionally used to evaluate functional and  anatomic anorectal disorders (Figure 9-24). The develop-  ment of fast MRI sequences provides a new and better alter-  native to study all pelvic visceral movements in a dynamic  fashion. MR defecography has several important advantages  over conventional defecography. First, it avoids exposure of  the patient to harmful ionizing radiation. Second, it provides    ▲ Figure 9-24. Rectal intussusception and enterocele.  Sagittal image from a fluoroscopic defecography study  shows intra-anal rectal intussusception (arrowhead) and  the presence of a large enterocele (arrows).   excellent soft tissue resolution of all pelvic floor compartments  and supporting structures, including pelvic floor muscles  and fascial planes. Therefore, MR defecography is a much  more comprehensive examination that allows assessment of  coexisting bladder and uterocervical prolapse, which is vital  when planning surgical treatment.   Mortele KJ, Fairhurst J. Dynamic MR defecography of the poste-  rior compartment: indications, techniques, and MRI features.  Eur J Radiol. 2007;61:462-472. [PMID: 17145152]   Because the clinical implications and therapeutic strategies  of focal liver lesions vary tremendously depending on their  causes, the ability to differentiate focal hepatic lesions is  extremely important. The development of both dynamic  multiphasic CT and fast MR imaging, and the ability to use  tailored MR techniques (such as fat-suppression sequences  and in/out phase imaging), have facilitated assessment of the  morphologic and hemodynamic features of liver tumors. In  the majority of cases, familiarity with the most relevant CT  and MRI features, in combination with additional clinical  information, provides enough information for adequate  lesion characterization. MRI is typically used as a problem-  solving tool in cases where CT remains inconclusive.   Hepatic cysts are developmental anomalies present in 2.5% of  the population. They can be either solitary or multiple as  part of hepatorenal polycystic disease. Hepatic cysts are well  defined and anechoic on ultrasound, homogeneously hypo-  dense on nonenhanced CT scans, and show no enhancement  following administration of contrast. On MRI, hepatic cysts  reveal very low signal intensity on Tl -weighted and very high  signal intensity on T2-weighted images, especially heavily  T2-weighted images. They are typically round or ovoid  shaped, well delineated, without a capsule, and lack enhance-  ment following gadolinium administration.   Hemangioma is the most common benign hepatic tumor.  Hemangiomas are usually solitary (80%), measure less than 4 cm  in diameter, and are most often peripherally located. A giant  hemangioma is larger than 10 cm in diameter and often con-  tains a central cleftlike area of fibrosis or cystic degeneration.  Typical hemangiomas appear homogeneously hyperechoic on  ultrasound with acoustic enhancement. The classic appearance  on CT is that of a well-defined hypodense lesion showing foci of  peripheral globular enhancement during early phase imaging  after contrast administration. On delayed images, the mass usu-  ally shows a centripetal fill-in with persistent delayed enhance-  ment. MRI findings in hemangiomas reflect their vascular  nature. On Tl- and T2 -weighted images, the lesions show    A Figure 9-25. Hepatic hemangioma. A: T2-weighted  axial MR image shows a well-defined hyperintense mass  (arrows) in the right lobe of the liver. B: Contrast-  enhanced T1-weighted axial MR image shows peripheral  nodular incomplete enhancement (arrow) of the lesion.   ▲ Figure 9-26. Focal nodular hyperplasia. A: Coronal  MDCT image shows a homogeneous, lobulated, hyper-  vascular mass in the liver (arrow). B: Contrast-enhanced  T1-weighted axial MR image shows a homogeneous  hypervascular mass (arrows) with the presence of a  central scar (black arrowhead).   decreased and markedly increased signal intensity, respectively.  Dynamic Tl -weighted imaging obtained following administra-  tion of gadolinium also shows a peripheral nodular centripetal  enhancement pattern progressing to homogeneity. In 94% of  the large hemangiomas, however, a persistent hypointense cen-  ter is present on the delayed images due to variable degree of  fibrosis and cystic degeneration (Figure 9-25).   Focal nodular hyperplasia (FNH) is a rare (3%) benign  tumor predominantly diagnosed in asymptomatic women  during the third to fifth decades of life. The size of FNH  ranges between 0.5 and 15 cm with an average of 5 cm in  greatest dimension. On CT, FNH is classically seen as a soli-  tary hypodense area with immediate intense enhancement  (96%) and homogeneity (85%) after contrast material injec-  tion. The presence of an enhancing central scar has been  reported to occur in 14-43% of cases (Figure 9-26A). Typical  MRI features of FNH are isodensity on Tl- and T2-weighted  images, homogeneity (96%), hypervascularity, and the presence   of a central scar, which is hyperintense on T2-weighted  images due to its vascular and biliary components and pres-  ence of myxoid stroma (Figure 9-26B).   Hepatic adenoma is a rare benign neoplasm associated  with oral contraceptive use and most commonly seen in  women of childbearing age. Adenomas are usually solitary,  and the presence of intratumoral fatty infiltration, necrosis,  hemorrhage, peliotic changes, a capsule, and central scar are  common pathologic features. Unenhanced CT usually reveals  a neoplasm that is slightly more hypodense than surrounding  liver. Hyperdense foci represent intratumoral hemorrhage.  Following contrast administration, they usually enhance  early, and appear heterogeneous and strong due to their  hypervascular nature (Figure 9-27). MRI classically shows a  heterogeneous (93%) mass, with predominantly hyperintense  signal intensity on T2-weighted images (47-75%), and vari-  able signal intensity on Tl -weighted images, according to  fatty changes (25%), hemorrhage (38%), and necrosis (16%).    A Figure 9-27. Hepatic adenoma. Axial MDCT image  shows a large heterogeneously hyperenhancing mass  (arrow) in segment IV of the liver.   On dynamic gadolinium-enhanced Tl -weighted images, 86%  of adenomas show early arterial enhancement. Small lesions  tend to enhance homogeneously during the arterial phase  with early washout of contrast material.   Mortele KJ, Ros PR. Benign liver neoplasms. Clin Liver Dis.  2002;6:119-145. [PMID: 11933585]   Hepatocellular carcinoma is the most common primary epithe-  lial neoplasm of the liver. In classical cases, it presents on unen-  hanced CT, in a patient with underlying cirrhosis, as a  hypodense mass. Following the administration of contrast  material, smaller lesions tend to be hypervascular (with early  hyperdense enhancement) and larger lesions more hypovascular  (revealing a mosaic-like enhancement pattern) (Figure 9-28).  Signs of vascular invasion and arterial-portal shunting are fre-  quently present. On T2 -weighted MRI images, typical cases of  hepatocellular carcinoma demonstrate a mild hyperintensity  relative to normal liver. The variable signal intensity seen on  Tl -weighted images depends on the presence or absence of  glycogen, steatosis, or hemorrhage. High signal intensity on T2-  weighted images is especially meaningful in the setting of  underlying cirrhosis for the differential diagnosis with dysplas-  tic nodules. The latter typically have a low intensity on T2-  weighted images due to accumulation of iron. Following  intravenous administration of gadolinium, enhancement pat-  terns similar to those seen on CT are described (Figure 9-29).   Intrahepatic cholangiocarcinoma (I-CAC) is relatively  uncommon, although it is the second most common pri-  mary hepatic malignant neoplasm. Some underlying liver  diseases, such as Caroli disease, primary sclerosing cholangi-  tis, and clonorchiasis, may favor the development of I-CAC.  The average age of the patients with I-CAC ranges from 50 to  60 years. Because of the peripheral localization relative to the   A Figure 9-28. Hepatocellular carcinoma. Axial MDCT  image shows a round homogeneous and hypervascular  mass in the right lobe of the liver (arrow) in a patient  with underlying cirrhosis.   bile ducts, jaundice is seldom present at presentation. On CT,  I-CAC usually presents as a large hypoattenuating mass  (6-10 cm), irregularly delineated, with satellite nodules  (62%), and sometimes a central scar. Other MRI features of  I-CAC are encasement of the portal vein, usually without  evidence of thrombus (25-75%), focal liver atrophy (43%),  dilation of peripheral intrahepatic bile ducts (29%), capsular  retraction (21%), and small calcifications.   Metastases. Neoplastic infiltration due to metastatic disease  can occur with many primary tumors. CT appearances of  hepatic metastases depend on the vascularity of the lesions  compared with the normal liver parenchyma. Hypovascular  lesions, such as metastases of colorectal adenocarcinoma,  show a lower attenuation compared with normal liver and are    A Figure 9-29. Hepatocellular carcinoma. Contrast-  enhanced T1-weighted axial MR image shows a  homogeneous hypervascular mass (arrow).    ▲ Figure 9-30. Colorectal cancer metastases. Contrast-  enhanced T1-weighted axial MR image shows numerous  hypovascular masses scattered throughout the liver.   best detected on portal venous phase contrast-enhanced  images (Figure 9-30). Hypervascular metastases, including  those from endocrine tumors, melanoma, sarcoma, renal cell  carcinoma, and certain subtypes of breast and lung carcinoma,  enhance more rapidly than normal liver and require arterial  phase imaging for accurate depiction. Infrequently, metastatic  involvement is very discrete and only detectable through indi-  rect features, such as diffuse parenchymal heterogeneity, vas-  cular and architectural distortion, or alterations of the liver  contour. The latter, especially seen in breast cancer patients,  has been reported as the so-called "pseudocirrhosis sign". Other  suggestive features that may be seen with both small and large  metastases include central amorphous calcifications in muci-  nous primary malignancies, "peripheral washout" sign during  the delayed phase, capsular retraction, and presence of biliary  or vascular invasion. On MRI, hepatic metastases are typically  moderately hyperintense on T2-weighted images, hypointense  on Tl -weighted images, and appear hypointense or hyperin-  tense following gadolinium administration, depending on  their vascularity. Hepatospecific contrast agents, such as iron  oxides particles, may be useful in the detection of hepatic  metastatic disease; because Kupffer cells are not present in  metastases, they do not show uptake of contrast medium and  hence appear significantly more conspicuous.   During the last decade, the role of the radiologist in evaluat-  ing patients with diffuse liver diseases has increasingly  expanded. In some cases, such as fatty liver and iron over-  load, imaging (especially MRI) may point directly to the  diagnosis; in many others, such as hepatitis and cirrhosis,  imaging helps in narrowing the differential diagnosis sub-  stantially or is crucial in the follow-up of patients.   Mortele KJ, Ros PR. Imaging of diffuse liver disease. Semin Liver  Dis. 2001;21:195-212. [PMID: 11436572]   Cirrhosis is a diffuse, progressive process of liver fibrosis,  pathologically characterized by architectural distortion and  nodular regenerative change. The presence of intrahepatic  and extrahepatic imaging findings of cirrhosis (eg, surface  nodularity, hepatic morphologic changes, splenomegaly,  ascites, portosystemic collaterals) depends on the severity of  the cirrhosis (Figure 9-31). Enlargement of the hilar peri-  portal space, in the absence of other conventional signs, has  been described as a helpful sign in the diagnosis of early cir-  rhosis. More pronounced lobar or segmental changes of  hepatic morphology such as atrophy of the right hepatic lobe  and left medial segment, enlargement of the caudate lobe  and left lateral segment, and the expanded gallbladder fossa  sign are seen in advanced cirrhosis.   Accurate identification of different types of hepatocellu-  lar nodules arising in the cirrhotic liver is crucial. Nowadays,  MRI is by far the most specific imaging technique for differ-  entiating those nodules based on characteristic features, such  as signal intensity and enhancement pattern. Regenerative  nodules, like normal liver, invariably have a portal venous  blood supply with minimal contribution from the hepatic  artery. As a consequence, they are usually isointense with  background liver on both Tl- and T2-weighted images, and  they show no predominant enhancement following gadolin-  ium administration. Dysplastic nodules are neoplastic prema-  lignant nodules found in approximately 25% of cirrhotic  livers. Similar to regenerative nodules, the main blood supply  to dysplastic nodules is from the portal venous system. A dys-  plastic nodule is typically homogeneously hyperintense on    ▲ Figure 9-31. Cirrhosis. Contrast-enhanced T1-  weighted axial MR image shows a nodular contour of  the liver, splenomegaly, and ascites. Note portal vein  thrombosis (arrow).   Tl-weighted images, hypointense on T2-weighted images,  shows a portal-venous phase enhancement, is smaller than  3 cm, and has no capsule. In cases of dysplastic nodules with  foci of hepatocellular carcinoma, the classic appearance is  that of a "nodule within a nodule," consisting of a high signal  intensity focus of hepatocellular carcinoma within a low sig-  nal intensity dysplastic nodule on T2-weighted images.   Extrahepatic associated signs of cirrhosis include features of  portal hypertension, such as splenomegaly and the formation  of portosystemic collateral vessels, and findings related to hepa-  tocellular dysfunction (ascites, bowel wall edema, gallbladder  wall thickening). MR angiography provides useful information  regarding the presence, location, and flow pattern in portosys-  temic shunts. These findings are useful both for diagnostic pur-  poses (eg, detection of bleeding varices) and for treatment  planning (eg, prior to transjugular intrahepatic portosystemic  shunt placement or shunt surgery).   Hepatic steatosis results from a variety of abnormal metabolic  processes. The distribution of steatosis can be variable, ranging  from focal, to regional, to diffuse (Figure 9-32). Undoubtedly  the most sensitive technique to detect microscopic fatty change  of the liver is the use of gradient echo MR pulse sequences.  With those, by varying the echo time to image water and fat in  and out phase, chemical shift between water and lipid protons  can be demonstrated. On out-of-phase images, areas with a sig-  nificant amount of intracellular fat will show lower signal  intensity than on the corresponding in-phase images, and this  loss of signal intensity between the two types of images allows  the radiologist to establish the diagnosis of fatty change of the  liver (Figure 9-33). On imaging, several features enable correct  identification of focal fatty change or focal spared areas: the   ▲ Figure 9-32. Steatosis. Axial MDCT image shows a  wedge-shaped area of low attenuation (arrows) in the  right lobe of the liver with vessels coursing through it.   ▲ Figure 9-33. Steatosis. A: Axial in-phase unenhanced  T1-weighted MR image shows a normal hyperintense  appearance of the liver parenchyma. B: Axial out-  off-phase unenhanced T1-weighted MR image shows a  significant drop in signal of the liver compatible with  steatosis.   typical periligamentous and periportal location, lack of mass  effect, sharply angulated boundaries of the area, nonspherical  shape, absence of vascular displacement or distortion, and  lobar or segmental distribution.   Hereditary or primary hemochromatosis is characterized  by excessive deposition of iron into the hepatocytes, pancre-  atic acinar cells, myocardium, joints, endocrine glands, and  skin. MRI is far more specific than any other imaging modal-  ity for the characterization of iron overload due to the  unique magnetic susceptibility effect of iron. The superpara-  magnetic effect of accumulated iron in the hepatocytes  results in significant reduction of signal intensity of the liver  parenchyma on T2-weighted images, particularly T2*-  weighted gradient-echo sequences. Comparison of the signal   intensity of liver with that of paraspinal muscles, which are  normally less intense than liver and not prone to excessive  iron accumulation, provides a useful internal control.   In patients with hemosiderosis or siderosis, either due to  transfusional iron overload states or dyserythropoiesis, the  excessive iron is processed and accumulates in organs con-  taining reticuloendothelial cells, including liver, spleen, and  bone marrow. As a result, although the distribution of iron in  patients with siderosis is demonstrated in the liver as diffuse  low signal intensity changes similar to those seen in primary  hemochromatosis, extrahepatic signal intensity changes in  the spleen and bone marrow enable MRI to distinguish pri-  mary hemochromatosis from hemosiderosis.   Budd-Chiari syndrome is defined as obstruction of the large  hepatic venous outflow pathways, typically at the level of the  hepatic veins or inferior vena cava (IVC). Imaging findings  associated with Budd-Chiari syndrome include direct find-  ings of hepatic venous obstruction, secondary morphologic  changes of the liver, and extrahepatic features. Direct diag-  nostic features are the visualization of intraluminal  echogenic or hyperdense material (web, tumor, thrombus)  within the hepatic veins or IVC. The absence of hepatic vein  flow or presence of flow disturbances on Doppler ultrasound  is also diagnostic. Additional features supporting the diagno-  sis include presence of intrahepatic venous collaterals, non-  visualization of the hepatic veins or IVC, and dilation of the  azygos venous system. Indirect morphologic changes in the  liver result from the tremendous venous congestion pro-  duced by the outflow obstruction. In the acute setting, the  peripheral portion of the liver becomes congested and  swollen and appears hypoechoic on sonography, hypodense  on CT, and hyperintense on T2-weighted images. In contrast,  the central portions of the liver, because of the direct  drainage into the IVC, show increased enhancement on con-  trast-enhanced imaging studies. Over time, in the chronic  phase, these central portions of the liver become hyper-  trophic while the periphery of the liver becomes atrophic  (Figure 9-34).   Veno-occlusive disease is another cause of hepatic outflow  obstruction but differs from Budd-Chiari syndrome in that  veno-occlusive disease involves inflammation and obstruc-  tion of the postsinusoidal venules. Hepatic veno-occlusive  disease is usually associated with prior full-body chemoradi-  ation in leukemia patients or certain herbal medications and  tea ("bush tea" disease). On imaging, the liver appears con-  gested and enhances heterogeneously (mosaic-like). The  hepatic veins and IVC, although narrowed due to the hepatic  edema, are patent and no morphologic hepatic changes are  identified.   Passive hepatic congestion is typically caused by right-  sided heart failure. Although the liver also shows a heteroge-  neous mosaic-like enhancement in patients with passive  congestion, it can be easily differentiated from Budd-Chiari    ▲ Figure 9-34. Budd-Chiari syndrome. Axial MDCT  image shows enlargement and hyperenhancement of  the caudate lobe with congestion and atrophy of the  periphery of the liver. Note the presence of ascites.   syndrome and veno-occlusive disease, because in passive  hepatic congestion the IVC and hepatic veins are abnormally  dilated due to reflux of blood from the heart.   Ultrasound is still the modality of choice for the evaluation  of the gallbladder and biliary ductal system. Ultrasound is  fast, readily available, and noninvasive, and does not use ion-  izing radiation. However, ultrasound also has some inherent  limitations; these include the dependence of diagnostic accu-  racy on the skill of the operator, body habitus, bowel gas  interference, and patient cooperation. Because many biliary  stones do not contain a sufficient amount of calcium, CT  performs very poorly in the detection of gallstones and  choledocholithiasis. However, thin-section unenhanced CT  imaging may be useful in detecting partially calcified ductal  stones. CT cholangiography is a relatively novel technique  that provides high-resolution images of the biliary tree based  on thin-section MDCT after the intravenous administration  of a biliary contrast agent.   MRI has an increasing role in the routine workup of  patients with suspected choledocholithiasis when compared  with ultrasound or CT. Today, in the initial diagnostic  workup of choledocholithiasis, especially in patients with low  and intermediate probability of having common bile duct  stones, MRCP has replaced the use of diagnostic endoscopic  retrograde cholangiopancreatography (ERCP) in many insti-  tutions. Compared with ERCR MRCP offers several advan-  tages, such as noninvasiveness and short examination times.   It avoids a variety of possible complications, including pan-  creatitis and hemorrhage, which occur in 5% of ERCP  attempts. Unlike ERCP, MRCP does not expose patients to  ionizing radiation or iodinated contrast material. It can be  performed in patients in whom it is almost impossible to  perform ERCP due to anatomic alterations from previous  surgery. Nevertheless, the major strength of ERCP is the  access it offers for therapeutic interventions; unlike ERCP,  MRCP is a purely diagnostic technique.   Bennett GL, Balthazar EJ. Ultrasound and CT evaluation of emer-  gent gallbladder pathology. Radiol Clin North Am. 2003;41:  1203-1216. [PMID: 14661666]   Levy AD, Murakata LA, Abbott RM, et al. From the archives of the  AFIP. Benign tumors and tumorlike lesions of the gallbladder  and extrahepatic bile ducts: radiologic-pathologic correlation.  Armed Forces Institute of Pathology. Radiographics.  2002;22:387-413. [PMID: 11896229]   Mortele KJ, Wiesner W, Cantisani V, et al. Usual and unusual  causes of extrahepatic cholestasis: assessment with magnetic  resonance cholangiography and fast MRI. Abdom Imaging.  2004;29:87-99. [PMID: 15160760]   Gallstones. In approximately 80% of gallstones, the main  component is cholesterol and 10% of these are pure choles-  terol stones. The term pigment stone is used for gallstones  that contain calcium bilirubinate as the major component  and less than 25% cholesterol. The other constituent, cal-  cium carbonate, is relatively less common. Only approxi-  mately 15-20% of gallstones contain enough calcium to be  demonstrable on plain radiographs. Ultrasound has 95%  sensitivity for the detection of cholelithiasis. A gallstone can  be diagnosed with certainty when a mobile hyperechoic  intraluminal filling defect is identified along with acoustic  shadowing (Figure 9-35). CT detects only approximately  80% of gallstones seen via sonography. In depicting  cholelithiasis, MRCP with conventional MR imaging has  sensitivity comparable to sonography (90-95%). It is espe-  cially useful when sonography results are equivocal or there  is a clinical suspicion of diseases of adjacent organs, such as  pancreatitis. Furthermore, common bile duct stones can be  detected with much greater sensitivity with MRCP than with  ultrasonography.   Choledocholithiasis is the most common cause of biliary  obstruction. Ultrasound is less capable of detecting common  bile duct (CBD) stones than gallstones, with reported sensi-  tivities ranging from 13 to 75%. The major difficulty lies in  detecting distal CBD stones, especially when there is no asso-  ciated acoustic shadowing or ductal dilation (30% of cases).  MRI is highly accurate in the detection and characterization  of CBD stones. CBD stones are usually hypointense on both  Tl- and T2-weighted images and are typically surrounded by  bile (Figure 9-36). On axial images, the stone typically reveals  a dependent position in the duct thus differentiating it from    A Figure 9-35. Gallstones. Sagittal ultrasound image  shows hyperechoic stones in the gallbladder along with  shadowing (short arrows). Also note a nonshadowing  stone in the cystic duct (long arrow).   pneumobilia (air is located in the nondependent position)  and bile flow artifacts (typically central in location).   Ultrasound is the initial imaging modality of choice in cases  of suspected cholecystitis. Hepatobiliary scintigraphy has a  similar diagnostic sensitivity to ultrasound for acalculous  cholecystitis. CT and MRI, imaging modalities with excellent    A Figure 9-36. Choledocholithiasis. Coronal oblique  thick-slab MRCP image shows a round filling defect  (arrow) in the distal common bile duct.   sensitivity and specificity, are typically reserved for cases in  which ultrasound shows equivocal results. Cross-sectional  imaging techniques, especially MRI with MRCP, have proven  to be as sensitive as the more invasive test ERCP in the detec-  tion of cholangitis.   Sonographic findings supportive of the diagnosis of acute  cholecystitis include the presence of gallstones, gallbladder  wall thickening greater than 3 mm, pericholecystic fluid, and  the detection of tenderness directly over the gallbladder  (sonographic Murphy sign). When all these findings are  present, the sensitivity for the diagnosis of acute cholecystitis  with ultrasound is more than 90%. CT features of acute  cholecystitis include the presence of gallstones, gallbladder  wall thickening greater than 3 mm, pericholecystic fluid and  fat stranding, hydrops, and hyperenhancement of segment  IV of the liver due to hyperemia (Figure 9-37). On T2-  weighted unenhanced MR images, inflammatory perichole-  cystic changes are visualized as linear and strandlike  structures of high signal intensity around the gallbladder.  MRI shows the thickened gallbladder wall, which has    increased signal intensity on T2-weighted images.  Gadolinium-enhanced Tl-weighted images are useful in  depicting inflammatory changes of the gallbladder wall, peri-  cholecystic fat, and intrahepatic periportal tissues. Contrast  enhancement of the gallbladder wall is increased and on  dynamic imaging there is a transient enhancement of liver  segments adjacent to the gallbladder on early images. The  role of MRCP in the diagnostic workup of acute cholecysti-  tis is mainly to detect small cystic duct and gallbladder neck  calculi. Impacted cystic duct or gallbladder neck calculi can  be demonstrated with MRCP accurately to a resolution as  low as 2 mm.   Chronic cholecystitis may be asymptomatic or may present as  acute cholecystitis on a background of chronic disease. Other  manifestations of this entity may be biliary colic, fistula for-  mation, and hydrops of the gallbladder or perforation.  Deposition of calcium within the gallbladder wall, a condition  termed porcelain gallbladder, is an uncommon manifestation  of chronic cholecystitis and is associated with an increased  prevalence of gallbladder carcinoma (Figure 9-38).   On imaging studies, chronic cholecystitis may have find-  ings similar to those of acute cholecystitis, such as wall thick-  ening and stones. However the gallbladder is typically  contracted around the stones rather than distended.  Furthermore, on contrast-enhanced images, the degree of  contrast enhancement of the gallbladder wall is significantly  lower in comparison with acute cholecystitis. The transient  pericholecystic liver enhancement on early postcontrast  images, which is described with acute cholecystitis, is also not  evident in chronic cholecystitis. Secondary signs of malig-  nancy, such as local invasion, distant metastases, and bile  duct dilation, are helpful in distinguishing chronic cholecys-  titis from gallbladder carcinoma.   ▲ Figure 9-37. Acute cholecystitis. Coronal MDCT image  shows hydrops of the gallbladder (white arrows), peric-  holecystic fluid, and gallstones. Note a stone in the neck  of the gallbladder (black arrow).    ▲ Figure 9-38. Porcelein gallbladder. KUB image  shows linear calcifications in the wall of the gallbladder  (arrows).   Cholangitis can be categorized as bacterial cholangitis, pri-  mary sclerosing cholangitis, and secondary sclerosing  cholangitis or chronic pyogenic (obstructive) cholangitis.  Primary sclerosing cholangitis is an autoimmune disorder  characterized by obliterative fibrotic inflammation of the bile  ducts and, typically, both intrahepatic and extrahepatic bile  ducts are involved simultaneously. On MR1, the characteris-  tic appearance is marked by the presence of multiple  stenoses, minor dilation of the proximal segments (due to  periductal fibrosis), a beaded appearance of intrahepatic bile  ducts, presence of sacculations resembling diverticula,  enhancing bile duct wall, and intrahepatic lithiasis.   Ultrasound is very valuable in the evaluation of the patient  with jaundice caused by malignant biliary obstruction. The  accuracy of MRCP in assessing the level and the morphology  of the malignant obstruction is comparable to that of ERCP  or percutaneous transhepatic cholangiography. However,  compared with ERCP, MRCP may more accurately depict the  suprahilar tumor extension in cases of severe stenosis of the  confluence (because in such cases the accuracy of ERCP will  be impaired due to insufficient contrast filling). Another  advantage of MRCP is its ability to visualize an undrained  bile duct without injection of contrast material, thus avoid-  ing secondary cholangitis. In addition, portal venous inva-  sion and hepatic metastases in patients can be detected  accurately with dynamic contrast-enhanced MR sequences  coupled to the MRCP protocol. It offers significant advan-  tages in the preoperative staging of hilar cholangiocarci-  noma, because it becomes possible to simultaneously assess  the bile duct, the vascular structures, and the liver  parenchyma. For all these reasons, ERCP should not be per-  formed for diagnostic purposes but be reserved for thera-  peutic interventions.   Gallbladder carcinoma is the most common malignancy of  the biliary tree and the fifth most common GI malignancy.  More than 90% of gallbladder cancers are adenocarcinomas  but other cell types such as squamous cell carcinoma,  anaplastic carcinoma, and sarcomas also have been reported.  Gallstones are detected in more than 70% of the cases. There  are three common radiologic appearances for gallbladder  carcinoma. The most common appearance is that of a mass  replacing the gallbladder fossa (55%) (Figure 9-39). The sec-  ond most common appearance is that of either focal or dif-  fuse gallbladder wall thickening (25%); this pattern is the  most difficult to diagnose because of the small size of early  masses. In addition, diffuse wall thickening is also caused by    ▲ Figure 9-39. Gallbladder carcinoma. Axial MDCT  image shows large mass replacing the gallbladder fossa  with presence of intrahepatic metastases.   a wide variety of other pathologic conditions, such as acute  and chronic cholecystitis, adenomyomatosis, and low protein  states. The third presentation is an intraluminal polypoid  mass. Metastases are present at the time of diagnosis in  approximately 75% of cases.   Extrahepatic cholangiocarcinomas include biliary adenocar-  cinomas located at the bifurcation or proximal hepatic duct  (Klatskin tumors) and the distal duct types. They are usually  seen in older patients presenting with painless jaundice,  weight loss, and cholangitis. Once the diagnosis has been  established, accurate local staging of the tumor is essential  for the planning of patient management, because few  patients are eligible for surgery at time of diagnosis. The stag-  ing system described by Bismuth and Corlette is widely  accepted as a guide for the extension of surgery required.   On MRI, these tumors typically present as a mass located  at the liver hilum and causing biliary dilation. They are usu-  ally hypointense on Tl -weighted images and slightly hyper-  intense on T2-weighted images, with heterogeneous and  variable enhancement following gadolinium administration.  MRCP images typically reveal a stenotic lesion at the bifur-  cation, with proximal biliary dilation; nodular intraductal  tumor components are occasionally seen (Figure 9-40).  Hilar extrahepatic cholangiocarcinomas can involve the dis-  tal common hepatic duct alone (Bismuth type I), the conflu-  ence of the left and right hepatic duct (Bismuth type II), the  confluence and either the right (Bismuth type Ilia) or the left  (Bismuth type Illb) hepatic duct, or both the left and right  secondary confluence (Bismuth type IV).    ▲ Figure 9-40. Klatskin tumor. Maximum intensity projec-  tion (MIP) image of a multislice MRCP data set shows  intrahepatic biliary ductal dilation with the presence of an  obstructing mass (arrows) at the level of the porta hepatis.   Congenital biliary anomalies are commonly encountered on  imaging studies and can be accurately diagnosed, with  increasing level of specificity, by ultrasound, CT, MRI with  MRCP, and ERCR   Choledochal cysts are rare congenital biliary tract anomalies  characterized by biliary ductal dilation. The five subtypes, as  described by Todani, have different pathophysiologies but  are grouped together by the commonality of the cystic  changes present.   The type I choledochal cyst (Figure 9-41) is a choledochal  cyst confined to the extrahepatic bile duct. This cyst results  from an anomalous pancreaticobiliary union characterized  by formation of a long common channel, frequently ectatic.   The type II choledochal cyst represents a true diverticulum  of the extrahepatic bile duct.   The type III choledochal cyst (Figure 9-42), also known as  a choledochocele, is formed by ectasia of the intramural  common bile duct segment. It is not embryologically related  to the other cystic dilations of the choledochal cysts. This  subtype occurs typically as focal dilation of the intraduode-  nal segment of the distal common bile duct.   The type IV choledochal cysts are, by definition, multiple  and can have both intrahepatic and extrahepatic components.   Caroli disease (Todani type V choledochal cyst) is a rare  congenital cystic dilation of the intrahepatic bile ducts. It is an  autosomal-recessive disorder resulting from the arrest of or a  derangement in the normal embryologic remodeling of ducts    A Figure 9-41. Type I choledochal cyst. ERCP image  shows saccular dilation of the extrahepatic bile duct  (arrows) with presence of a long common channel  (arrowhead) and mass cholangiocarcinoma (thick arrow)  arising from the cranial aspect of the cyst.    A Figure 9-42. Type III choledochal cyst. Oblique  coronal MRCP image shows telescoping of the distal  common bile duct (arrow) in the duodenum.   that, in turn, causes varying degrees of destructive inflamma-  tion and segmental dilation. If the large intrahepatic bile ducts  are affected, the result is Caroli disease, whereas abnormal  development of the small interlobular bile ducts results in con-  genital hepatic fibrosis. If all levels of the intrahepatic biliary  tree are involved, features of both congenital hepatic fibrosis  and Caroli disease are present; this condition has been termed  Caroli syndrome. Imaging methods show intrahepatic saccular  or fusiform dilated cystic structures of varying sizes that com-  municate with the biliary tree. The presence of tiny dots with  contrast enhancement within the dilated intrahepatic bile duct  ("central dot sign") is considered very suggestive of Caroli dis-  ease. The "central dot sign" represents the enhancing portal  branches surrounded by cystic alterations of the intrahepatic  biliary ducts.   With the introduction of MDCT, the visualization of the  pancreas has dramatically improved. Therefore, MDCT has  become a superb tool for detection of solid neoplasms, with  an increasing overall diagnostic accuracy (by means of better  differentiating pancreatitis from neoplasm and characteriz-  ing the different neoplasms) and an able method to assess  unresectability. Recent studies have compared the accuracy  of MRI in staging pancreatic carcinoma with CT With  breath-hold imaging and the use of phased array coils,  dynamic MRI was shown superior to CT in determining the  degree of tumor extension, while both modalities performed  equally well in establishing the degree of vascular involve-  ment. Other studies indicate that the two modalities perform  comparably in the global assessment of resectability. PET-CT  may be helpful to stage pancreatic cancer accurately by  detecting distant metastatic disease.   Because MRI is so sensitive to fluid, it is not surprising  that this modality has great potential to accurately assess cys-  tic pancreatic neoplasms. The cyst fluid improves contrast  resolution within the mass, often rendering subtle irregular-  ities of the cyst wall that aid in differential diagnosis between  benign and malignant neoplasms. When combined with MR  pancreatography, the duct system can be visualized and the  relation of these lesions to the main and branch ducts may be  predicted. MRCP has been shown to be more sensitive than  CT and ERCP in the depiction of these lesions.   Mortele KJ, li H, Ros PR. CT and magnetic resonance imaging in  pancreatic and biliary tract malignancies. Gastrointest Endosc.  2002;56(Suppl):S206-S212. [PMID: 12447269]   Shah S, Mortele KJ. Uncommon solid pancreatic neoplasms: ultra-  sound, computed tomography, and magnetic resonance imag-  ing features. Semin Ultrasound CT MR. 2007;28:357-370.  [PMID: 17970552]   Ductal pancreatic adenocarcinoma accounts for nearly 95%  of all malignant pancreatic neoplasms and is the ninth most  common malignancy. Prognosis is poor, with a 5-year sur-  vival rate ranging from 1% to 5%; at the time of clinical pres-  entation, 66% of patients have an advanced tumor stage,  with metastatic disease present in 85% of cases. The major-  ity of tumors are located in the pancreatic head and, because  of the involvement of the common bile duct, they present  earlier than tumors arising in the body or tail of pancreas.   CT is the imaging modality of choice for the detection  and preoperative staging of pancreatic cancer. The new  MDCT scanners provide radiologists enormous capabilities  for fast data acquisition and narrow collimation, resulting  in accuracies of 96% for detecting pancreatic tumors. On  contrast-enhanced MDCT images, adenocarcinomas present  as hypoattenuating lesions with respect to the surrounding  normal pancreatic parenchyma (Figure 9-43). There are also  some indirect signs for the presence of a tumor on CT without  identification of the tumor itself: dilation of the common bile  and pancreatic duct without calculi, dilation of the pancreatic    A Figure 9-43. Pancreatic adenocarcinoma. Curved,  reformatted CT image shows a low-density pancreatic  mass (arrows) with invasion of the superior mesenteric  vein (arrowhead).   duct in the body and tail but not in the head, a homogenous  zone within a heterogeneous atrophic gland, bulging of the  uncinate process, and atrophy of the pancreatic tail. The  detection of hepatic metastases is critical in the preoperative  staging of the patients, because presence of metastatic foci  within the liver makes the tumor unresectable. MDCT scan-  ners have the ability to depict very small lesions (< 5 mm). In  the absence of obvious liver metastases, tumor respectability  depends on the presence of local invasion or vascular  involvement. In a recent prospective study comparing EUS,  CT, MRI, and angiography in preoperative staging and  tumor resectability assessment of pancreatic cancer, Soriano  and colleagues reported that CT is the mainstay for pancre-  atic cancer staging, with the best figures in the evaluation of  extent of primary tumor, locoregional extension, vascular  invasion, and metastatic spread (with accuracies 73%, 74%,  83%, and 88%, respectively). In this study, EUS was evalu-  ated as essential in assessing tumor size and lymph node  involvement. Nevertheless, it can be assumed that the initial  enthusiasm for EUS staging of pancreatic cancer has today  diminished as a result of studies reporting that EUS is not as  accurate as it was earlier suggested in locoregional staging,  especially in the diagnosis of vascular involvement.  Furthermore, detection of distant metastases, including non-  regional lymph node groups, is far beyond the capability of  EUS, thus favoring MDCT as a single imaging technique for  staging pancreatic cancer.   Detection of pancreatic adenocarcinoma is based on non-  contrast Tl -weighted fat-suppressed images and immediate  postgadolinium Tl-weighted images. On Tl-weighted fat-  suppressed images, pancreatic cancer appears as a low signal  intensity mass, and is clearly separated from normal pancreatic  tissue, which is high in signal intensity (Figure 9-44). MRCP  has proven an accurate means of evaluating the level and causes  of pancreatic ductal obstruction. A major advantage of MRCP    ▲ Figure 9-44. Pancreatic adenocarcinoma. Tl-  weighted axial MR image shows a hypointense pancre-  atic mass (arrows). Note the normal hyperintense  residual pancreas (arrowhead).   is that the visualization of the duct is based on the signal fea-  tures in the pancreatic secretions. Thus, one can visualize the  duct before and after an obstructing lesion.   PET with F-18 fluorodeoxyglucose (F-18 FDG PET) is a  relatively novel modality in pancreatic imaging. In a com-  parison between CT and F-18 PET, F-18 PET was more sen-  sitive than CT for detecting malignancy (92% vs 65%), as  well as more specific (85% vs 61%). Whereas for pancreatic  tumors less than 2 cm in diameter, the sensitivity of F-18  FDG PET is markedly superior to that achieved with CT, CT  is superior to F-18 FDG PET when pancreatic lesions are  large (> 4 cm in diameter).   Soriano A, Castells A, Ayuso C, et al. Preoperative staging and  tumor resectability assessment of pancreatic cancer: prospective  study comparing endoscopic ultrasonography, helical computed  tomography, magnetic resonance imaging, and angiography. Am f  Gastroenterol. 2004;99:492-501. [PMID: 15156091]   Serous cystadenoma is a benign neoplasm that occurs most  frequently in the pancreatic head of elderly female patients.  This well-circumscribed tumor is often lobulated and con-  tains a central, stellate, calcified scar in addition to multiple  small cysts divided by thin septations. Imaging studies may  show this tumor as either homogeneously solid, or, more  commonly, a predominantly cystic mass with multiple small  cysts. It has been stated that the presence of six or more small  cysts within the mass is suggestive of serous rather than  mucinous cystic neoplasm. On unenhanced MDCT scans,  serous cystic tumors are low-density, solid or, more com-  monly, multiple cyst-containing lesions with Hounsfield  values similar to water. If present, the characteristic central  stellate scar with dystrophic calcifications is demonstrated.  The amount of fibrous stroma determines the appearance of  the tumor on contrast-enhanced CT images. An innumer-  able cyst-containing tumor appears as an irregular heteroge-  neously enhancing mass whereas a tumor with microscopic  cysts and a dominant fibrous stroma presents as a homoge-  nous mass on postcontrast images. Serous cystic tumors are  usually markedly hyperintense on T2-weighted MR images,  although some central areas of low signal intensity may occa-  sionally be seen related to the presence of a fibrous scar  (Figure 9-45). On Tl-weighted MR images, the tumor is of  low signal intensity, except in cases in which hemorrhage is  present. The tumor is hypervascular secondary to its rich  subepithelial capillary network.   Mucinous cystic tumors range from tumors with malignant  potential to frankly malignant mucinous cystadenocarcinomas.  In 95% of cases, they occur in women during their fourth to  sixth decades. Most tumors are located in the tail or body of  the pancreas. These encapsulated hypovascular tumors are  most frequently multilocular. They may contain internal sep-  tations, solid papillary excretions, and occasionally peripheral  calcifications and septations. Unenhanced MDCT studies    ▲ Figure 9-45. Serous cystadenoma. Coronal T2-  weighted image shows a tabulated cystic mass (arrows)  composed of numerous small cysts.   show a round mass, which is well delineated and has smooth  external margins. Attenuation values are usually similar to that  of water. MDCT scans obtained after the intravenous admin-  istration of contrast material may demonstrate enhancement  of the wall and the presence of thin septations; on the internal  surface of the tumor, nodularities representing papillary  projections may be demonstrated. MRI studies show the  unilocular or multilocular fluid nature of this mass. If a muci-  nous cystic neoplasm appears unilocular and without septa-  tions on imaging, differentiation from a pseudocyst may not  be possible. MR is advantageous to show internal septations,  mural nodules, and solid excrescences in the tumor wall.   Intraductal papillary mucinous neoplasm (IPMN) is a rel-  atively new and increasingly reported entity typically pre-  senting either as a dilated main pancreatic duct or a  unilocular or multilocular cystic lesion. IPMN are cystic pan-  creatic neoplasms characterized by proliferation of pancre-  atic ductal epithelium and excess mucin production. They  are classified into main and branch duct types. The branch  duct type mostly presents in the uncinate process or pancre-  atic head, but it can also involve the body or tail. On unen-  hanced MDCT, branch-duct tumor appears as clusters of  multiple small cysts or as a single cystic lesion with irregular,  lobulated margins and septations (Figure 9-46). Diffuse or  segmental dilation of the main pancreatic duct is typical for  main-duct type tumors. Contrast-enhanced thin section  MDCT images may demonstrate communications between  dilated cystic segments and the main pancreatic duct. MDCT  may also depict the papilla bulging into the duodenal lumen  and hyperdense filling defects secondary to mucin in the  dilated duct. On MRI and MRCP, a dilated main pancreatic  duct with a unilocular or multilocular cystic lesion is typical  (Figure 9-47); communication between the main pancreatic  duct and the cystic lesion may be depicted. Biliary obstruction,    A Figure 9-46. Intraductal papillary mucinous neo-  plasm. Axial CT image shows a dilated pancreatic side-  branch duct (arrow) in the uncinate process.   a bulging papilla, large size (> 3 cm) of a side-branch lesion,  and large caliber of the main pancreatic duct (> 1 cm) are  more common in patients with malignant IPMN.   Sidden CR, Mortele KJ. Cystic tumors of the pancreas: ultrasound,  computed tomography, and magnetic resonance imaging features.  Semin Ultrasound CTMR. 2007;28:339-356. [PMID: 17970551]   Islet cell tumors are benign or malignant neoplasms with  endocrine cell differentiation. Insulinoma is the most common  and, at the time of diagnosis, is usually smaller than 1.5 cm; only  5-10% are malignant. Gastrinoma (see Chapter 16) is the second  most common endocrine tumor of the pancreas. Glucagonomas  and vipomas represent less than 10% of endocrine pancreatic  tumors, and the majority of them are malignant. The tumors are    ▲ Figure 9-47. Intraductal papillary mucinous neoplasm.  Oblique coronal MRCP image shows irregular segmental  dilation of the main pancreatic duct.    ▲ Figure 9-48. Islet cell tumor. Coronal MDCT image  shows a heterogeneously enhancing hypervascular mass  in the pancreatic head (arrows). Note trie presence of a  biliary stent (arrowhead).   found predominantly in the pancreatic body and tail and tend to  be larger than insulinomas or gastrinomas. Somatostatinoma is  the rarest endocrine pancreatic tumor (< 1%) and at the time of  diagnosis the majority are malignant (75%).   On multiphasic contrast-enhanced MDCT, islet cell  tumors present as hypervascular lesions, best seen in the  early phases of pancreatic enhancement (Figure 9-48). Using  optimized thin-slice CT scans, even small tumors can be  visualized. The most striking evidence of malignancy is evi-  dence of metastatic disease to the liver or local lymph nodes.   On MRI, insulinomas and gastrinomas appear as lesions  with low signal intensity on Tl -weighted and high signal  intensity on T2-weighted imaging. The use of intravenous  gadolinium is helpful as they are hypervascular. Ringlike  enhancement in the periphery of the tumor is typically seen,  while the center may remain hypointense secondary to fibro-  sis. The more uncommon but generally larger hyperfunc-  tioning and nonhyperfunctioning tumors present with  slightly low signal intensity on T 1 -weighted and bright signal  intensity on T2-weighted MRI.   The role of radiologic imaging in patients with suspected  pancreatitis is to help diagnose pancreatitis, try to establish  the cause of the disease, assess disease severity, and detect  complications. In assessment of acute pancreatitis, MRI, as  well as CT, can depict the presence and extent of necrosis and  peripancreatic fluid collections. MRI is used instead of rou-  tine CT in some cases because mild pancreatitis cannot be  well visualized by CT, MRI is better in defining the internal  composition of peripancreatic fluid collections, and MRI   is capable of detecting underlying causes of pancreatitis  (eg, pancreas divisum, choledocholithiasis).   Of all the imaging modalities, CT is the most commonly used  to evaluate acute pancreatitis. Contrast-enhanced CT plays a  critical role in establishing necrosis in acute pancreatitis. CT  features in mild acute pancreatitis consist of normal findings  or focal or diffuse enlargement of the pancreas, a normal  pancreatic enhancement (50-60 HU above baseline) with or  without peripancreatic fat stranding. In more severe cases,  pancreatic parenchymal necrosis develops with acute fluid  collections that occur mostly around the pancreas, in the  anterior or posterior pararenal spaces and in the lesser sac  (Figure 9-49). CT is also used for staging of severity; for diag-  nosis, follow up, and monitoring of established local pancreatic  complications; for demonstrating other nonpancreatic seque-  lae, such as renal, splenic, vascular, and GI complications; and  for guidance of interventional procedures.   In assessment of acute pancreatitis, MRI can depict the  presence and extent of necrosis and peripancreatic fluid collec-  tions. Gadolinium-enhanced MRI is particularly useful for the  assessment of pancreatic parenchymal perfusion and presence  of necrosis. T2-weighted sequences are the most sensitive in  demonstrating fluid collections. Furthermore, by using addi-  tional MRCP or MR angiography sequences, MRI enables  underlying etiologies, such as choledocholithiasis or pancreas  divisum, or vascular complications to be accurately diagnosed.   Mortele KJ, Wiesner W, Intriere L, et al. A modified CT severity  index for evaluating acute pancreatitis: improved correlation  with patient outcome. AJR Am J Roentgenol. 2004;183:  1261-1265. [PMID: 15505289]    A Figure 9-49. Acute pancreatitis. Axial MDCT image  shows a diffusely enlarged pancreatic gland (arrows).  Note the lack of normal enhancement and presence of  acute fluid collections in the retroperitoneum.    A Figure 9-50. Chronic pancreatitis. Curved, reformatted  CT image shows an atrophic pancreas with numerous  calcifications and irregular ductal dilation (arrow).   Chronic pancreatitis is a progressive, irreversible inflamma-  tory and fibrosing disease of the pancreas. CT findings of  chronic pancreatitis include dilation of the main pancreatic  duct, parenchymal atrophy, pancreatic calcifications, and  pseudocysts (Figure 9-50). In chronic pancreatitis, optimal  MRI examination should include Tl- and T2- weigh ted images  and MRCP sequences. The role of MRCP in chronic pancre-  atitis is still controversial but evolving. Comparisons between  MRCP and ERCP in cases of chronic pancreatitis have revealed  agreement of 83-100% for identification of ductal dilation,  70-92% for identification of narrowing, and 92-100% for  identification of filling defects, respectively. Several centers have  investigated functional MR pancreatic evaluation by obtaining  MRCP images before and after intravenous secretin adminis-  tration, and it showed improved visualization of the pancre-  atic duct and its side branches. Furthermore, the volume of  effluent into the duodenal lumen can be graded, allowing a  relative estimation of the exocrine function.   De Backer AI, Mortele KJ, Ros PR, et al. Chronic pancreatitis: diag-  nostic role of computed tomography and magnetic resonance  imaging. JBR-BTR. 2002;85:304-310. [PMID: 12553661]   The definitive diagnosis of the two most important pancre-  atic developmental disorders, pancreas divisum and annular  pancreas, is made with ERCP. MDCT and MRI, however,   may depict both pancreas divisum and annular pancreas.  MR pancreatography has been shown to be highly sensitive  and specific for depicting pancreas divisum.   Pancreas divisum is the most common congenital anomaly of  the pancreatic ductal system, being reported in up to 10% of  the population. The ventral duct (duct the Wirsung) drains  only the ventral pancreatic anlage through the major papilla  while the majority of the gland empties into the minor  papilla through the dorsal duct or duct of Santorini. Pancreas  divisum usually causes no symptoms but it is found more  frequently in patients with chronic abdominal pain, elevated  pancreatic function tests, and idiopathic pancreatitis than in  the general population. MRCP demonstrates the noncom-  municating dorsal and ventral ducts with their independent  drainage sites.   Annular pancreas is a rare congenital anomaly in which  incomplete rotation of the ventral anlage leads to a segment  of the pancreas encircling the second part of the duodenum.  The incidence of annular pancreas is 1 in 2000. Annular pan-  creas can be diagnosed on the basis of CT, MRI, and ERCP  findings that reveal pancreatic tissue and an annular duct  encircling the descending duodenum.   Mortele KJ, Rocha TC, Streeter JL, et al. Multimodality imaging of  pancreatic and biliary congenital anomalies. Radiographics.  2006;26:715-731. [PMID: 16702450]   Mortele KJ, Wiesner W, Zou K, et al. Asymptomatic nonspecific  serum hyperamylasemia and hyperlipasemia: spectrum of  MRCP findings and clinical implications. Abdom Imaging.  2004;29:109-114. [PMID: 15160763]   Developments in imaging technology in recent years have led  to many improvements in the field of diagnostic GI radiol-  ogy. Many semi-invasive diagnostic methods are being  replaced by noninvasive imaging technologies. MRCP has  widely replaced ERCP in the diagnosis and staging of pan-  creatobiliary disorders; virtual colonoscopy proved itself as  an efficient screening method for colon cancer; and MDCT  enterography is becoming the standard imaging technique  for many small bowel disorders. As a result, there is a signif-  icant decline in the use of fluoroscopic imaging techniques.  CT continues to be the most effective modality for the initial  evaluation of patients with diseases involving the GI system.  Additional imaging procedures, such as MRI and MRCP and  PET-CT scanning are best reserved for patient who cannot  undergo a contrast-enhanced CT, or for patients in whom  ultrasound or CT show equivocal findings. Nevertheless, in  many centers, MRI has been adopted as the primary imaging  technique in the diagnosis and staging of a variety of hepa-  tobiliary, pancreatic, and GI tract diseases.   Recurrent infections and diarrhea are the most common  gastrointestinal manifestations of immunodeficiency.   Some pathogens (eg, Mycobacterium avium complex),  are unigue to immunocompromised hosts; others (eg,  Cryptosporidium) cause self-limited diarrhea in healthy  hosts but chronic diarrhea in immunosuppressed  patients.   In patients without a specific diagnosis after routine  study, endoscopic evaluation with biopsy is important in  establishing the diagnosis.   Candida species, herpes simplex virus, cytomegalovirus,  and Mycobacterium species are the most frequent  causative agents of infectious esophagitis in an immuno-  compromised host.   In immunocompromised patients, opportunistic infections  are a major cause of abdominal pain and can evolve   The impaired host immune system results from either  primary congenital defects or secondary lesions acquired  during adulthood through a variety of pathologic insults,  including nutritional deficiencies or the iatrogenic effects of  medical interventions (eg, immunosuppressive therapies).  In addition, the chronic disease burden associated with  advanced age and, to a lesser degree, the poorly understood  physiologic decline of host defense systems associated with  aging play an important role in the development of GI symp-  toms in geriatric populations. A detailed description of the  nature and mechanisms of the GI manifestations of each  individual primary and acquired (secondary) immuno-  deficiency is beyond the scope of this chapter. However, a  comprehensive understanding of the composition and devel-  opment of the immune defense systems of the GI tract and  their alterations in pathologic conditions is essential for the  clinical management of GI problems associated with  immunodeficiency patients.   Castle SC, Uyemura K, Fulop T, et al. Host resistance and immune  responses in advanced age. Clin Geriatr Med. 2007;23:463-479.  [PMID: 17631228]   The gastrointestinal (GI) tract is the largest lymphoid organ,  and dysfunction of the GI tract is one of the most common  manifestations of immunodeficiency. Some studies have sug-  gested that 50-90% of patients with secondary (acquired)  immunodeficiency syndromes, such as full-blown AIDS,  develop significant GI symptoms. The most common GI man-  ifestations of immunodeficiency are infection and malignancy,  which correlate with the progressive deterioration of host  defense systems. Patients often develop diarrhea, abdominal  pain, dysphagia, and odynophagia, as well as nausea, vomiting,  weight loss, and GI bleeding. The overall goal of evaluation is,  therefore, to identify treatable causes of the symptoms and to  preserve the function of the GI tract.   The intestinal epithelium serves as the major frontier of self-  protection from exogenous injurious events. To defend  against the vast quantity of infectious agents and toxins, and  ensure homeostasis of the gut epithelium for nutritional  absorption, the body relies on the proper development and  maintenance of the immunologic defense systems associated  with the intestinal epithelium, which employs both innate  and adaptive immune systems. Abnormalities occurring dur-  ing normal development of the GI defense systems or inability   to maintain the function of these systems, stemming from  congenital abnormalities, nutritional defects, or insults from  toxins (eg, immunosuppressives) or infections, can lead to  disturbances of mucosal homeostasis and defense. These dis-  turbances, in turn, can produce a variety of GI symptoms,  including chronic diarrhea, abdominal pain, and bleeding.   Innate immunity is characterized by a rapid response to  specific general structures associated with microbes of all  classes (bacteria, mycobacteria, viruses, and fungi). Innate  immunity is initiated by specific so-called pattern recogni-  tion receptors such as toll-like receptors (TLRs). TLR4, for  example, recognizes bacterial lipopolysaccharides. Pattern  recognition receptors are expressed on a wide variety of cell  types, including natural killer (NK) cells, a subclass of T cells  called NK-T cells and, most importantly phagocytes, mast  cells, dendritic cells, and epithelial cells. Innate immunity  functions as part of a first line of defense to ward off patho-  genic invasions and to recruit other components of the  defense system to protect the host. For example, in response  to pathogenic bacteria as induced by pattern recognition  receptor interactions with microbes, phagocytes engulf  microorganisms (by phagocytosis), NK cells remove dam-  aged cells (from either pathogen or malignant transforma-  tion) by secretion of lytic enzymes such as granzymes and  perforins, and NK and NK-T cells alarm other immune  defense cells against the microbial invasion by secreting  cytokines, such as interferon-y.   The molecular mechanisms that underlie host interac-  tions with microbes reflect the nature of the innate immune  response which is, as noted, mediated by specific pattern  recognition receptors that recognize the commonly conserved  features of microbes. These pathogen-associated molecular  patterns, such as the lipopolysaccharides recognized by TLR4,  peptidoglycans recognized by TLR2 and double-stranded  RNA recognized by TLR3, are not expressed by host cells.  Recognition of these microbial products by the host immune  cell receptors triggers signal transduction pathways that initi-  ate acute phase inflammatory reactions, which typically occur  within a few hours of exposure. For example, the recognition  of a common pathogen-associated molecule, lipopolysaccha-  ride, by the TLR4 leads to activation of nuclear factor- KB (by  destroying the inhibitory factor IKKa) which initiates an  acute phase inflammatory response. In addition to the cellu-  lar components of innate immunity, noncellular components  of innate immunity — such as normal peristalsis, gastric acid,  bile secretion, pancreatic enzymes, mucus, epithelial cellular  tight junctions, and the indigenous microbial flora — also play  an important role in protecting the host from adverse reac-  tions associated with pathogenic infection.   In comparison to innate immunity, the adaptive (specific  or acquired) immune response is characterized by the large  number of clonally expanded and distinct B cells and T cells  that have been selected to respond to specific foreign anti-  gens and are, at the same time, trained by the host to be tol-  erant to self-antigens in order to avoid autoimmunity. The   selective expansion of the B-cell or T-cell clones is a complex  process that involves bone marrow (for B cells) and thymus  (for T cells), and requires specific receptors on the lympho-  cyte cell surface. Moreover, peripheral tissues and organs,  such as the intestine, are also involved in the development of  adaptive immunity and lymphocyte maturation and, espe-  cially, the Peyer patches and mesenteric lymph nodes. The  involvement of the intestine in the development and matu-  ration of the immune system characterizes the GI tract as  both a site of immune regulation (eg, for the induction of  oral tolerance) and a target of immunologic alterations asso-  ciated with dysregulated immune responses.   As a result of clonal selection, the selected B cells secrete  specific classes of immunoglobulins, such as immunoglobulin  (Ig) A, IgG, and IgM. Decreased or dysregulated production of  immunoglobulins constitutes one of the most common symp-  tomatic forms of immunodeficiency, termed common vari-  able immunodeficiency (CVID). CVID frequently manifests  during early adulthood with recurrent respiratory and GI  infections, and lymphoid hyperplasia, which is presumably a  compensatory response to the immunodeficiency associated  with inadequate immunoglobulin production. The patho-  genesis of CVID is unclear but given the deficiency in  immunoglobulin production, this syndrome is amenable to  infusions with intravenous immunoglobulin (IVIG). Defects  in immunoglobulin class switching or secretion (or trans-  cytosis) can also be associated with immunodeficiency. One  such example is selective IgA deficiency, which is perhaps the  most common primary immune deficiency. Patients with  selective IgA deficiency are often asymptomatic and require no  treatment (partially due to compensation by secreted IgM and  IgG). Recognition of selective IgA deficiency is important  because it can obscure the diagnosis of celiac disease and may  be associated with unusual chronic infections such as Giardia  lamblia.   The other major class of lymphocytes associated with  adaptive immunity is the T cell. T cells originate in the bone  marrow, like B cells, but receive their final maturation and  education within the thymus before being exported into the  systemic circulation and mucosal tissues. Once these so-called  naive T cells leave the thymus, they are instructed by den-  dritic cells to specific differentiated fates that are either regu-  latory and inhibit immune responses (so-called T regulatory  cells) or effector cells (such as T helper [Th] 1, Th2, or Thl7  cells). T cells express an enormous array of specific receptors  that are selected within the thymus for recognition of the  multitude of antigens to which the host may be exposed  within a lifetime. Many rare primary immunodeficiency syn-  dromes are associated with defects in T-cell development that  result in susceptibility to infection, malignancy, autoimmu-  nity, or a combination of all three. For example, mutations of  the transcription factor FoxP3 lead to a disease called  immune-mediated polyendocrinopathy, eczema X-linked  (IPEX), in which there is poor formation of T regulatory cells.  In addition, mutations of the cell surface molecule CTLA4,   which normally inhibits T cells, are associated with autoim-  mune diseases.   External factors also play an important role in maintain-  ing the normal function of the GI immune system and may  form the basis for the development of acquired (secondary)  types of immunodeficiency. Nutritional defects, either from  malnourishment or protein-loosing enteropathy, or selective  nutrient deficiency (eg, vitamin A and zinc deficiency) often  lead to impaired host responses to pathogens and the devel-  opment of recurrent infections. Extensive use of cytotoxic  agents in a variety of clinical settings often causes depletion  of neutrophils, leading to acute infections that may be asso-  ciated with inflammation, such as neutropenic enterocolitis  or typhlitis. In comparison with the primary immunodefi-  ciencies, the acquired immunodeficiencies are much more  common and may be involved in diseases as diverse as severe  trauma, burns, cancer, myeloproliferative diseases, and  immune-depleting infections such as those associated with  HIV and AIDS.   Medzhitov R, laneway C Jr. Innate immunity. N Engl } Med.   2000;343:338-344. [PMID: 10922424]  Takahashi I, Kiyono H. Gut as the largest immunologic tissue.   10483885]  Viswanathan VK, Hecht G. Innate immunity and the gut. Curr   syndromes result from congenitally derived abnormalities in  the structure or function of immune components within the  GI immune system, as outlined earlier. This category therefore  includes abnormalities of T cells, B cells, and other cellular  components, such as macrophages. Primary GI immunodefi-  ciencies are often characterized by abnormalities in antibody  production (either synthesis or release). These diseases include  X-linked hypogammaglobulinemia, selective IgA deficiency,  and selective IgM deficiency. In addition to abnormalities of  B-cell development, primary GI immunodeficiency may be a  consequence of T-cell developmental defects, such as congeni-  tal thymic aplasia (DiGeorge syndrome) or abnormalities of  phagocyte dysfunction, such as chronic granulomatous disease.   2. Acquired (secondary) GI immunodeficiency syn-  dromes — These immunodeficiency syndromes may result  from a variety of insults, such as physical (eg, radiation), chem-  ical (eg, chemotherapeutic agents, steroids, immunosuppressive  drugs such as methotrexate), or infectious agents (eg, HIV),  as well as decreased immunity due to severe malnutrition,  old age, protein-losing enteropathy, and selective nutrient  deficiency (Table 10-1).   A detailed history and physical examination provide the initial  clues to the possible presence of immunodeficiency. However,  the establishment of a definitive diagnosis of immunodefi-  ciency often requires laboratory tests that quantify specific ele-  ments of the immune system such as quantitative T-cell subset  analysis (eg, CD4-positive T cell numbers) or immunoglobu-  lin isotype evaluation, or both.   A history of prolonged and severe GI symptoms (diarrhea,  dysphagia, odynophagia, nausea, vomiting, abdominal pain,  anorectal disease, GI bleeding, or jaundice), relapse of symp-  toms after proper treatment, recurrent respiratory tract or GI  tract infection since childhood, or being a recipient of  immunosuppressive treatments are supportive of an under-  lying state of immunodeficiency.   On physical examination, patients may demonstrate facial  abnormalities (DiGeorge syndrome), oral thrush, oral ulcers,  a paucity of lymphoid tissues (X-linked agammaglobuline-  mia), focal or diffused lymphadenopathy, edema (protein-  losing enteropathy), or eczema (Wiskott-Aldrich syndrome,  IgA deficiency, hyper IgE, or Job syndrome).   Unlike the GI symptoms observed in immunocompetent  hosts (eg, diarrhea and abdominal pain), which are often a  self-limited process, GI symptoms in immunocompromised  patients are commonly associated with chronicity and signif-  icantly higher rates of morbidity and mortality. The impaired   Adapted, with permission, from Yamada T (editor). Textbook of Gastroenterology, Vol 1, 4th ed. Lippincott Williams & Wilkins, 2003:1021.   immune function of immunocompromised patients leads to  both uncommon presentations of common infections and  the development of uncommon opportunistic infections. For  example, in immunocompromised hosts, cytomegalovirus  (CMV) infection may lead to necrotizing colitis or perfora-  tion of the gut. Therefore, the prompt recognition and man-  agement of GI symptoms in an immunocompromised host is  crucial for the rapid relief of symptoms and, consequently,  reduction of morbidity and mortality.   Routine laboratory evaluation may reveal neutropenia, lym-  phopenia, or altered albumin and globulin levels. These stud-  ies are often supplemented by microscopic examination of  the stool. More specific laboratory tests of the cellular and  humoral components of the immune system are often  required to establish a definitive diagnosis of the specific  cause of the immunodeficiency. Because the most common  GI manifestations of immunodeficiency are recurrent infec-  tions and diarrhea, the discussion that follows focuses on the  evaluation and management of these common symptoms.   Diarrhea is typically defined as the passage of three or more  loose or watery stools per day for more than 2 days. Chronic  diarrhea is defined as diarrhea lasting for more than 30 days  in adults and 14 days in children. In immunocompetent  hosts, chronic diarrhea is caused predominately by noninfec-  tious conditions, such as inflammatory bowel disease, celiac   sprue, endocrinopathies, eating disorders, laxative abuse,  malignancies, short bowel syndrome, and bacterial over-  growth. In comparison, in immunocompromised hosts, infec-  tions resulting from a variety of pathogens are the most  common causes of diarrheal disease (Table 10-2).   Some pathogens are unique to immunocompromised  hosts; for example, Mycobacterium avium complex (MAC)  infections are unique to HIV infection and AIDS, occurring  when the CD4 T-cell count declines below 100/mm 3 . Other  pathogens, such as Cryptosporidium, cause self-limited diar-  rhea in healthy hosts but chronic diarrhea in immunosup-  pressed patients.   Small bowel bacterial overgrowth is defined as more than  10 4 bacteria per milliliter in the small intestine, comprising  gram-negative anaerobes of colonic origin rather than gram-  positive aerobes of the stomach and oral microflora. It occurs  more often in immunocompromised hosts with both pri-  mary immunodeficiency (eg, hypogammaglobulinemia) and  acquired immunodeficiency from HIV infection or aging.   To evaluate diarrhea in a patient with an immunocom-  promised condition, a detailed history is necessary to rule out  the common causes of diarrhea, which include medications  (use of multiple medications is common in immunocompro-  mised patients), diet (lactose, food, or fatty acid intolerance),  or inadvertent use of cathartics. Although symptoms alone  are unlikely to identify the cause of the diarrhea, it may facil-  itate the evaluation. For example, diarrhea with cramps,  bloating, and nausea suggests the involvement of the stomach  and small bowel or both (eg, infection with Cryptosporidium,  Microsporidia, Isospora belli, or Giardia). Diarrhea associated  with hematochezia and tenesmus implies large bowel involve-  ment (and therefore the possible involvement of CMV,  Shigella, or Campylobacter infection).   Stool examination is very important for making the diag-  nosis of a pathogenic cause of diarrhea in immunocompro-  mised patients. The stool examination should include stool  culture for enteric bacteria, three samples for Clostridium  difficile toxin analysis (when patients are on antibiotics), and  at least three stool specimens for ova and parasite examina-  tion to increase the sensitivity of the examination.   In cases refractory to routine study, endoscopic evalua-  tion with biopsy is of particular importance in helping to  establish the diagnosis. Colonoscopy or sigmoidoscopy is  helpful in identifying CMV infection, and upper endoscopic  examination can help to uncover small bowel infection with  Cryptosporidium, Microsporidia, or M avium.   Once the cause of diarrhea is identified, specific therapy  should be administrated. Unlike patients with an intact  immune system, in whom supportive care is usually suffi-  cient for self-recovery, immunocompromised patients may  require chronic administration of antibiotics for recurrent  Salmonella, Shigella, Campylobacter, or Isospora infection. An  empiric trial of oral antibiotics or antiparasite therapy for  possible small bowel bacterial overgrowth or undetected  infection should also be considered in the immunocompro-  mised patient who has persistent symptoms and in whom a  specific diagnosis is not made, even after extensive evalua-  tion. Some of the reasonable regimens that might be consid-  ered are the use of sulfonamides, ciprofloxacin, tetracyclines,  or metronidazole.   Symptom relief with antidiarrheal agents, such as lop-  eramide (Imodium) and Lomotil (diphenoxylate with  atropine), may also be considered, using careful clinical judg-  ment. In patients with debilitating conditions, nutritional  support may carry a direct benefit for patient well-being and  contribute to the restoration of immune function. In some  patients with chronic diarrhea, in whom the specific cause  cannot be established, a trial of the somatostatin analog  octreotide may be effective, presumably by inhibition of  secretion of a broad array of GI hormones. However, this  potential benefit must be counterbalanced by the possible  risk of gallbladder ileus and gallstone formation.   Hepatol. 2004;2:198-206. [PMID: 15017602]  Kearney DJ, Steuerwald M, Koch J, et al. A prospective study of   As in the case of diarrhea, the symptoms of dysphagia and  odynophagia in immunocompetent and immunocompro-  mised patients usually have different causes. In immuno-  competent patients, the most frequent causes of dysphagia  and odynophagia are usually acid reflux damage, malig-  nancy, or neuromuscular diseases. In immunocompromised   patients, by comparison, infections are the most frequent  cause or these symptoms. In fact, because symptomatic  infectious esophagitis is extremely rare in the immunocom-  petent host, the development of infectious esophagitis serves  as a strong clinical indicator in and of itself of an underlying  state of immunodeficiency that requires further immuno-  logic evaluation.   Candida species, herpes simplex virus (HSV), CMV, and  Mycobacterium species are the most frequent causative  agents of infectious esophagitis in an immunocompromised  host (see Table 10-2). Although each pathogen is associated  with characteristic clinical manifestations (eg, Candida  infection with oral thrush, HSV with gingivostomatitis,  CMV with abdominal pain and diarrhea, and Mycobacterium  with fever, cough, and weight loss), it is impossible to iden-  tify the particular pathogen causing dysphagia or odynopha-  gia, or both, on the basis of clinical symptoms alone.  Endoscopic evaluation with biopsies is therefore extremely  valuable in establishing the cause of the esophageal symp-  toms in order to commence specific treatment. It has been  suggested that multiple biopsies (more than three) are neces-  sary to establish the diagnosis of a single infection, and addi-  tional biopsies may be necessary to establish causative agents  in complex infections, which may be polymicrobial.   One exception to this general approach to the evaluation  of esophageal symptoms is that of immunocompromised  patients who develop oral thrush. In these patients, empiric  treatment of possible esophageal candidiasis is warranted. In  a large clinical study of 110 HIV-infected patients, the pres-  ence of oral thrush had a positive predictive value of 77% for  Candida esophagitis.   The most frequently used regimen for esophageal candidi-  asis is either fluconazole, 100-200 mg/day, or itraconazole,  200 mg/day orally. Amphotericin B can be effective in patients  with refractory Candida esophagitis. Most HSV esophagitis  responds well to acyclovir, 200 mg orally every 4 hours. In the  rare case of acyclovir resistance, patients may require foscarnet,  which is associated with possible adverse effects of nephro-  toxicity and hypocalcemia. CMV esophagitis usually responds  well to a 2- to 3-week course of ganciclovir. However, a main-  tenance regimen or an additional course of treatment is often  required to suppress CMV infection.   Unlike diarrhea and esophageal symptoms, the common  causes of abdominal pain in immunocompetent persons are  also the common causes of abdominal pain in immuno-  compromised patients (Table 10-3). Nevertheless, in  immunocompromised patients, opportunistic infection  presents a major cause of abdominal pain which, in the set-  ting of immunodeficiency, can proceed more rapidly and  lead to a medical catastrophe. Therefore, to evaluate abdom-  inal pain in immunocompromised patients, the early use of  computed tomographic scanning and abdominal sonogra-  phy is warranted to identify the origin of abdominal pain   capsulatum, lymphoma  Typhilitis  Cholecystitis caused by CMV, Cryptosporidium parvum, Isospora belli,   Microsporidia, Pneumocystis carinii  Pancreatitis caused by CMV, immunosuppressive and antiviral drugs  Graft-versus-host disease  Hepatosplenic candidiasis  Veno-occlusive liver diseases  Tissue infiltration by tumor or lymphoma  Bleeding secondary to drug-induced thrombocytopenia   and uncommon diseases that manifest by bowel wall thicken-  ing. In such cases, patients should be further evaluated with  endoscopic studies and biopsies, which often reveal CMV  infection, lymphoma, and MAC infection.   CMV infection is a frequent cause of abdominal pain in  immunocompromised patients, such as HIV-infected  patients and transplant recipients. Different from biliary  pain and intestinal obstruction, which often fluctuate in  intensity, enteric pain caused by CMV often presents as con-  stant cramping in the lower abdomen. CMV may also cause  severe epigastric pain by inducing pancreatitis, cholecystitis,  or cholangitis. Perforation should be considered in an  immunocompromised patient with an acute exacerbation of  abdominal pain.   The location of abdominal pain can be indicative of the  underlying cause, although further imaging or invasive stud-  ies are usually required to establish the diagnosis. For exam-  ple, in patients with severe neutropenia, right lower quadrant  abdominal pain is suggestive of typhlitis or necrotizing ente-  rocolitis, whereas right upper quadrant abdominal pain and  tenderness associated with nausea and fever may be a typical  presentation of hepatosplenic candidiasis encountered during  the treatment of acute leukemia or lymphoma. Another  common right upper quadrant pain syndrome is veno-  occlusive disease of the liver in a recent bone marrow trans-  plant recipient (within 20 days), which often manifests with  right upper quadrant pain and tenderness, hepatomegaly,  hyperbilirubinemia, and ascites.   Similar to the management of the general population, the  initial question to be answered in immunocompromised  patients with abdominal pain is whether or not surgical  intervention is required. In general, intestinal perforation  and obstruction almost always require surgical management.  Once the cause of the pain has been identified, treatable  infections should be managed promptly. Symptoms resulting  from lymphoma or Kaposi sarcoma may require chemother-  apy or radiation therapy.   1. Gastrointestinal bleeding— GI bleeding is a rare pres-  entation in patients with immunodeficiency. The evaluation  and management of GI bleeding in these patients is the same  as that in the immunocompetent population. The location  and severity of the bleeding should be determined. Upper  endoscopy is usually necessary to define the source of any  severe upper GI bleeding, whereas nuclear red blood cell scan  is more useful to define the approximate site of lower GI  bleeding. During the acute phase, endoscopic mucosal  biopsy is generally not advisable to avoid the risk of precipi-  tating more severe bleeding. A follow-up examination with  mucosal biopsy can be performed when the acute bleeding  subsides.   In addition to the common causes of GI bleeding in the  general population, immunocompromised patients may also  exhibit bleeding as a result of infection. The most common  infectious cause of esophageal bleeding in immunocompro-  mised patients is HSV, which induces shallow ulcers in the  esophagus. In the case of HSV, the bleeding is typically slow  and self-limited. CMV is the more common cause of intestinal  bleeding, which again tends to be slow and self-limited. Both  HSV and CMV are, however, rare causes of bleeding among  immunocompromised patients. The possibility that CMV  infection is the cause of intestinal bleeding is increased with  concurrent symptoms of fever, abdominal pain, and diarrhea.   2. Anorectal and perianal disease— Anorectal disease is one  of the most important GI complications of immunodeficiency  and occurs in 5-7% of neutropenic patients with leukemia or  lymphoma. If not managed properly, devastating morbidity  and high mortality is ensured. The various manifestations of  anorectal disease in neutropenic patients include abscess for-  mation, fissure, fistula, ulceration, and infected hemorrhoids.  Extensive tissue necrosis and breakdown can occur. Surgical  intervention with incision and drainage is usually needed to  reduce the high recurrence (12%) and high mortality (18%)  rate associated with nonoperative management in neutropenic  patients. Early treatment with antibiotics, which should include  aminoglycosides and agents with anaerobic coverage, is advis-  able. HSV infection, which often begins with perianal vesicular  lesions, should be treated promptly with acyclovir to prevent  the devastating progression to perianal ulcers.   3. Neutropenia — A decline in the absolute number of cir-  culating neutrophils below 10007mm 3 is associated with an  increased susceptibility to infections. When the number of  neutrophils decreases below 500/mm 3 , the host's ability to  manage the endogenous GI flora is also significantly  impaired, and patients often develop fever and sepsis due to  passage of commensal bacteria across the epithelial barrier  into the circulation. It must also be remembered that in the  context of an abnormal immune system, symptoms may be  subtle due to the inability of the host to respond properly.   Three GI syndromes are often associated with neutropenia:  oral infection (gingivitis, periodontitis and oral ulcers), anorec-  tal infection, and typhlitis (typically in the area of the cecum).  Early recognition of these complications and commencement  of medical and surgical treatment is mandatory to prevent  severe morbidity and mortality, as previously discussed.   In neutropenic patients who present with fever, right lower  quadrant abdominal pain, diarrhea (which may be bloody), or  a combination of these findings, computed tomography scan  is critical for establishing the diagnosis of typhlitis. For local-  ized disease, bowel rest with broad-spectrum antibiotics can  be effective in preventing disease progression. Diffuse disease  or evidence of perforation warrants consideration of surgical  intervention.   4. Transplant-associated GI illness— GI disease is an  important cause of morbidity and mortality in bone marrow  and solid organ transplant recipients. In general, bone mar-  row transplant recipients experience more frequent and  severe GI disease. Acute graft-versus-host disease (GVHD)   usually occurs during the first 3-4 weeks post- transplantation.  Patients often present with diarrhea and a variety of other GI  symptoms, including anorexia, nausea, vomiting, and  abdominal pain. GVHD occurs in as many as 40% of bone  marrow transplant recipients. Acute GVHD is often accom-  panied by symptoms of skin rash and jaundice. Establishment  of the diagnosis, however, requires histologic examination  demonstrating single-cell apoptosis of the epithelium, crypt  distortion, abscesses, and periglandular infiltrates. CMV  infection has been shown to be a significant cause of GI  bleeding in patients with acute GVHD.   Chronic GVHD typically occurs between 3 and 12 months  after bone marrow transplantation and presents as mucositis  of the oral cavity, dysphagia, and small bowel dysmotility  associated with bacterial overgrowth. GI symptoms in recipi-  ents of solid organ transplants usually are infectious in nature  and less severe than those observed in bone marrow trans-  plant recipients, due presumably to less severe immune sup-  pression in the latter patient group.   ► "Alarm signs'-dysphagia, odynophagia, weight loss, family  history of upper gastrointestinal (Gl) tract cancers, per-  sistent nausea and emesis, long duration symptoms  (>10 years), and incomplete response to treatment.   Gastroesophageal reflux disease (GERD) is the most common  and costly digestive disease. It accounts for at least 9 million  physician office visits in the United States each year, and  annual direct costs for managing GERD are estimated to  exceed $9 billion dollars. GERD is a chronic disorder  resulting from the retrograde flow of gastroduodenal contents  into the esophagus or adjacent organs, and producing a vari-  able spectrum of symptoms, with or without tissue damage.  Transient inappropriate relaxation of the lower esophageal  sphincter (LES) is the predominant pathophysiologic mecha-  nism in the majority of GERD patients. Gastroparesis and a  reduced LES pressure play a significant role in patients with  moderate to severe disease.   Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected  digestive diseases in the United States. Gastroenterology.  2002;122:1500-1511. [PMID: 1984534]   The prevalence of GERD in the United States appears to be  increasing. In Western populations, 25% of people report  having heartburn at least once a month, 12% at least once  per week, and 5% describe having symptoms on a daily  basis. There appears to be no gender predominance of  heartburn symptoms; men and women are affected equally.   The relationship of age and reflux is unclear. One study has  suggested an association between advancing age and fewer  reflux symptoms but the presence of more severe esophagitis.  There is an unequivocal positive association between body  mass index and reflux symptoms. Inappropriate relaxation of  the LES can be exacerbated by obesity. Even moderate weight  gain among persons of normal weight is thought to cause or  exacerbate reflux symptoms. These epidemiologic characteris-  tics should be considered when evaluating a patient with typ-  ical and atypical GERD.   lohnson DA, Fennerty MB. Heartburn severity underestimates  erosive esophagitis severity in elderly patients with gastro-  esophageal reflux disease. Gastroenterology. 2004;126:660-664.  [PMID: 14988819]   Moayyedi P, Axon AT. Review article: gastro-esophageal reflux dis-  ease: the extent of the problem. Aliment Pharmacol Ther.  2005;22(Suppl 1):11-19. [PMID: 16042655]   Pathologic reflux of gastric contents occurs when the reflux-  ate overcomes the antireflux barriers of the gastroesophageal  junction, typically in a post-prandial state. The antireflux  barrier of the gastroesophageal junction is anatomically and  physiologically complex and vulnerable to a number of  potential mechanisms of reflux. The primary antireflux  mechanism is the LES, a segment of smooth muscle in the  lower esophagus that is chronically contracted to maintain  a pressure that is approximately 15 mm Hg above intragas-  tric pressure. The two main patterns of LES dysfunction  are (1) a hypotensive LES and (2) pathologic transient  LES relaxations. Anatomic disruption of the gastroe-  sophageal junction, commonly associated with a hiatal her-  nia, contributes to the pathogenesis of reflux disease by  impairing LES function. A large hiatal hernia predisposes to  transient LES relaxations and increases the risk of develop-  ing esophagitis. Transient LES relaxations account for the  majority of reflux events in individuals with normal LES   pressure and clinically mild reflux disease. Chronically low LES  pressure is the predominant GERD mechanism in patients  with severe reflux disease, such as in patients with scleroderma.   Gastric factors can play a significant role in producing  GERD. Gastric factors that promote GERD include increased  gastric volume after meals, increased gastric pressure due to  obesity, recumbency after meals, and delayed gastric empty-  ing or gastroparesis, which can be idiopathic or drug induced.  Increased gastric distention can cause an increase in transient  LES relaxations and the volume of refluxate, particularly in  GERD patients with large hiatal hernias. Delayed gastric emp-  tying, or gastroparesis, may be present in approximately 15%  of patients with GERD and is frequently underdiagnosed.   Other factors that decrease LES pressure and contribute to  GERD are medications, lifestyle behaviors, and the ingestion  of certain foods. Certain medicines can exacerbate GERD by  lowering LES pressure; others can cause esophagitis by direct  mucosal injury (Table 11-1). Certain foods, beverages, and  behaviors will cause heartburn by reducing LES pressure  (Table 11-2). Fatty foods, peppermint, chocolate, caffeinated  beverages, alcohol and smoking can all decrease LES pressure.   Horowitz M, Su YG, Rayner CK, et al. Gastroparesis: prevalence,  clinical significance and treatment. Can ] Gastroenterol.  2001;15:805-813. [PMID: 11773947]   Tones MP, Sloan SS, Rabine JC, et al. Hiatal hernia size is the dom-  inant determinant of esophagitis presence and severity in gas-  troesophageal reflux disease. Am ] Gastroenterol. 2001;96:  1711-1717. [PMID: 11419819]   Kahrilas PJ. GERD pathogenesis, pathophysiology and clinical  manifestations. Cleve Clin J Med. 2003;70(Suppl 5):S4-19.  [PMID: 14705378]   Kahrilas P J, Shi G, Manka M, et al. Increased frequency of transient  lower esophageal sphincter relaxation induced by gastric disten-  tion in reflux patients with hiatal hernias. Gastroenterology.  2000;118:688-695. [PMID: 10734020]   The typical manifestations of GERD are heartburn, regurgi-  tation, and dysphagia. Heartburn (pyrosis) is defined as a  retrosternal burning discomfort located in the epigastric  area that may radiate up toward the neck and typically  occurs in the post-prandial period, especially after a high-  fat or a large-volume meal. Postural changes such as bend-  ing over often exacerbate patients' symptoms. Symptoms  can also be aggravated by ingestion of certain foods or bev-  erages, such as tomato sauce, peppermint, chocolate, coffee,  tea, and alcohol. When assessing a patient with heartburn  symptoms, the duration and severity of symptoms  should be investigated. Patients who present with typical  symptoms with a minimum frequency of twice a week  for 4-8 weeks of more should be considered as having  GERD. At initial presentation it is important to consider a  patient's age and the presence of "alarm signs" (Table 1 1-3).  The presence of any alarm signs necessitates the evalua-  tion of GERD symptoms with an upper endoscopy or imaging  modality.   Atypical manifestations of GERD refer to symptoms that  are extraesophageal, particularly pulmonary or ear, nose,  and throat manifestations, as well as noncardiac chest pain   (Table 1 1-4). According to published studies in the literature,  pathologic GERD can be found in 30-80% of adults patients  with asthma. Microaspiration of gastric acid and subsequent  airway irritation are considered the possible triggers for  asthma. Any adult with new-onset asthma should be evalu-  ated for GERD as a possible etiology. A new, more frequently  recognized atypical manifestation of GERD is otitis media in  children. Otitis media with effusion is the most common  cause of childhood hearing loss. Recently, high concentra-  tions of pepsin/pepsinogen were found in greater than 90%  of middle ear effusion samples from children with otitis  media with effusion. Reflux of gastric juice into the middle  ear may be the primary factor in precipitating this disease in  children.   Patients with gastroparesis and GERD often present with  concomitant nausea, vomiting, or early satiety. These patients  may not respond to antisecretory agents alone, as the refluxate  contains bile and other digestive enzymes in addition to gastric  acid. Gastroparesis should be suspected in patients with an  acute or subacute onset of GERD, particularly after an episode  of viral upper respiratory infection or gastroenteritis. The natu-  ral history of GERD with acute gastroparesis is that the major-  ity of patients will achieve symptomatic resolution, although  some will need treatment with prokinetic agents. Antisecretory  agents may offer some symptomatic relief and reduce gastric  volume. Dietary changes such as low-fat, frequent, small meals  may also be helpful in controlling symptoms.   ed. Lippincott Williams & Wilkins, 2004:530-545.  Horowitz M, Su YG, Rayner CK, et al. Gastroparesis: prevalence,   2001;15:805-813. [PMID: 11773947]  Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and   2006;354:2340-2348. [PMID: 16738270]  Tasker A, Dettmar PW, Panetti M, et al. Is gastric reflux a cause of   Classic GERD can be diagnosed by taking a thorough symp-  tom history and confirmed by a complete response to medical  therapy (a "PPI [proton pump inhibitor] test"). In general,  diagnostic testing is reserved for patients who fail to respond  to a trial of adequate medical therapy or for patients who have  alarm symptoms with GERD (Figure 11-1). Available tests  include upper endoscopy, upper GI series, gastric emptying  study, 24-hour esophageal pH study, and Bravo pH study.   PPI therapy is very effective in healing esophagitis.  Patients who have no symptom response to PPI therapy are  unlikely to have GERD. A meta-analysis that assessed the  accuracy of normal or high-dose PPI for 1-4 weeks in the  diagnosis of GERD found a pooled sensitivity of 78% (95%  confidence interval [CI] 66-86%) and a specificity of 54%  (44-65%) when ambulatory pH was used as a gold standard.  The current diagnostic tests for GERD in patients who fail a  PPI test or have alarm signs include radiographic studies,  upper endoscopy, and pH studies.   Radiologic studies can detect moderate to severe  esophagitis, strictures, hiatal hernias, and tumors. The stud-  ies that are most commonly used are the barium swallow,  which only examines the esophagus, and the upper GI series,  which examines the esophagus, stomach, and upper small  intestine. The primary utility of radiographic studies in  GERD is to rule out other diseases in patients in whom there  is a low clinical suspicion that significant disease is present.  These studies can help exclude peptic ulcer disease and  tumors as a cause of a patient's symptoms. In addition,  radiographic studies can be helpful in the evaluation of a  patient with dysphagia to rule out peptic rings, which can  sometimes be difficult to visualize on upper endoscopy.  Compared with endoscopy, radiologic studies are noninva-  sive, widely available, and relatively inexpensive. However,  they are less sensitive and specific than upper endoscopy and  require an operator skill that may be becoming scarcer in the  era of cross-sectional imaging.   Upper endoscopy, in addition to excluding the presence of  other diseases such as tumors and peptic ulcers, can detect and  grade the severity of GERD-induced esophagitis (Plate 6).  Upper endoscopy is highly specific (90-95%) for GERD but  has limited sensitivity (-50%). The extent and severity of  mucosal injury can be assessed endoscopically. The Los  Angeles classification of esophagitis quantifies the length and  circumference of mucosal breaks. Upper endoscopy also  allows the evaluation of any complications of the disease, such  as strictures or Barrett esophagus. It is therefore the test of  choice in patients with alarm signs. If a patient has dysphagia  and a stricture is detected, dilation of the stricture can be per-  formed during the same procedure. Esophageal biopsy is also  the best test for patients in whom eosinophilic esophagitis is  suspected, namely younger patients with a history of intermit-  tent dysphagia and atopy. Newer technologies such as ultra-  thin, transnasal endoscopes and video capsules may replace  traditional upper endoscopy in evaluating uncomplicated  GERD patients. However, at present, upper endoscopy is the   Continue therapy,  decreasing to least potent  acid suppression  necessary to keep patient  symptom free   ▲ Figure 11-1. Algorithm for the diagnosis and treatment of gastroesophageal reflux (GERD). bid, twice daily; EGD, esophagogastroduodenoscopy;  H 2 RA, H 2 -receptor antagonist; OTC, over-the-counter; prn, as needed; qd, daily.   test of choice in evaluating complicated GERD patients despite  its invasiveness and expense compared with other studies.   Intraesophageal ambulatory pH monitoring utilizes a  probe that can record the distal esophageal pH continuously  for 24 hours. The test is done with a pH probe that is passed  transnasally to 5 cm above the manometrically determined  LES. The data are collected by a battery-powered device car-  ried by the patient, who also records when meals are eaten  and symptoms experienced. This technique allows for corre-  lation of symptoms with reflux episodes. Ambulatory  esophageal pH monitoring records the timing, length, and  number of reflux episodes. Acid reflux episodes are defined  as an esophageal pH below 4. Normally the total amount of  time during which the esophagus has a pH of 4 or less is 4%  or less. Intraesophageal pH probe monitoring is the most  sensitive test to detect the presence of intraesophageal acid.   Despite its sensitivity, esophageal pH testing should only  be used in a select minority of GERD patients. Twenty-four  hour pH monitoring is useful in patients who have typical  GERD symptoms but are unresponsive to therapy. When  performed in this patient population, ambulatory pH moni-  toring can determine if the diagnosis is correct or if addi-  tional medical or surgical therapy is required. It is also  helpful in patients with atypical GERD symptoms, such as  asthma and chronic cough, when these symptoms are not  responsive to acid suppression therapy. Ambulatory  esophageal pH monitoring is also important in the postoper-  ative evaluation of a patient who has had antireflux surgery,  in order to determine whether GERD is still present.   Although extremely useful in selected patients, esophageal  pH testing is not widely available, can be uncomfortable, and  is expensive. The discomfort associated with nasal probe  placement has prompted the development of a wireless pH  monitoring system. The Bravo pH monitoring system  (Medtronic, Inc) allows for a wireless, pill-sized capsule to be  attached to the distal esophageal mucosa during an upper  endoscopy. The pH monitoring lasts for 48 hours (vs 24 hours  with a conventional pH probe). The capsule detaches and is  spontaneously passed within 2 weeks. The main disadvantage  of this system is that up to 10% of patients experience dis-  comfort due to the presence of the pH capsule or may feel  that the capsule is present (mild foreign body sensation). In  some patients, the capsule may dislodge prematurely, not  allowing for the full 48-hour period of pH monitoring. There  have also been isolated reports of esophageal bleeding requir-  ing transfusion and esophageal perforation.   DeVault KR, Castell DO. American College of Gastroenterology.  Updated guidelines for the diagnosis and treatment of gastroe-  sophageal reflux disease. Am ] Gastroenterol. 2005;100:190-200.  [PMID: 15654800]   Numans ME, Lau J, de Wit NJ, et al. Short-term treatment with  proton pump inhibitors as a test for gastroesophageal reflux dis-  ease: a meta-analysis of diagnostic test characteristics. Ann  Intern Med. 2004;140:518-527. [PMID: 15068979]   Am J Med Sci. 2003;326:300-308. [PMID: 14615671]  U.S. Food and Drug Administration. Center for Devices and   Complications from chronic GERD include bleeding from  esophageal erosions or ulceration, stricture formation, and  Barrett esophagus.   Although somewhat counterintuitive, the severity and dura-  tion of GERD symptoms poorly correlates with the presence  or severity of esophagitis. Esophageal ulcers due to esophagi-  tis account for approximately 2% of all upper GI bleeding.  The vast majority of esophageal peptic ulcers heal completely  with acid-suppression therapy using PPIs.   Peptic esophageal strictures have been described in 10% of  patients who seek medical attention for GERD symptoms. When  questioned, most patients with esophageal strictures report dys-  phagia for an average of 4-6 years and up to 25% deny any prior  GERD. Weight loss, a cardinal symptom of esophageal cancer, is  uncommon with peptic strictures because patients gradually  learn to change their dietary habits to avoid foods that cause  dysphagia.   Although the severity and duration of GERD symptoms  appears to have little correlation with the presence of  esophagitis, there is increasing evidence that frequent, severe  GERD, particularly nocturnal, is a major risk factor for the  development of esophageal adenocarcinoma. The incidence  of esophageal adenocarcinoma is increasing in the United  States and Europe at a very rapid rate. Esophageal adenocar-  cinoma and its predisposing risk factor, Barrett esophagus, are  discussed in Chapter 12.   The goals of treatment for GERD are to resolve symptoms,  heal esophagitis, and prevent complications of GERD. Once  a patient is in remission, the goal is to maintain remission  from symptoms and prevent further tissue injury.   A cornerstone of the treatment of GERD is lifestyle modifica-  tions. Patients are instructed to avoid foods and acid-containing  beverages that can exacerbate their symptoms of GERD (see  Table 11-2). Patients should avoid lying down for 3 hours   after eating as ingested food may remain in the stomach and  contribute to reflux. This practice is a frequent trigger of  GERD symptoms and one of the most effective lifestyle  changes a patient can institute to control symptoms. Smaller  and frequent meals are also recommended for GERD patients.  Elevation of the head of the bed by 6 in. (by placing blocks  underneath the front feet of the bed) can also reduce symp-  toms by using gravity to prevent reflux. Patients should be  instructed to stop smoking and lose weight, which can be  critical to reducing or eliminating symptoms. The current  epidemic of obesity is a major contributing factor to increasing  prevalence of GERD.   Medical treatment is characterized by antacid and antise-  cretory agents. Over-the-counter antacids are taken at least  twice a month by more than one fourth of the U.S. popula-  tion. Antacids provide symptom relief by neutralizing  refluxed gastric acid thereby increasing esophageal pH and  inactivating pepsin. Antacids are inexpensive, readily avail-  able, convenient, and effective. Short-term use of antacids for  occasional symptoms is safe.   Histamine-2 (H 2 ) -receptor antagonists inhibit the secre-  tion of gastric acid by competitively blocking the H 2 -receptors  located on gastric parietal cells. H 2 -blockers have an excellent  safety record and have been approved by the U.S. Food and  Drug Administration (FDA) for over-the-counter sales. Low  dose H 2 -receptor antagonists not only prevent heartburn  symptoms when taken before meals but also relieve meal-  induced heartburn symptoms in 15-40 minutes when taken  after meals. H 2 -receptor antagonists should be given twice  daily to be most effective in patients with frequent GERD.  These drugs are approximately 75% effective in patients with  mild to moderate degrees of esophagitis; however, in patients  with moderate to severe esophagitis, they are only 50% effec-  tive in healing esophagitis. H 2 -receptor antagonists are  appropriate for patients with mild to moderate GERD and  remain a major treatment modality for GERD.   PPIs act by blocking the hydrogen-potassium ATPase  on the apical surface of the parietal cell. PPIs are more   effective than H 2 -receptor antagonists because they act on  the final common pathway of acid secretion rather than one  of its three receptors (histamine, acetylcholine, and gastrin).  Side effects can occur in up to 3% of patients and can include  headaches and diarrhea. Rare side effects include hepatitis  and interstitial nephritis. PPIs induce the cytochrome P450  system, necessitating dosage adjustments of warfarin, pheny-  toin, and diazepam. The timing of PPI use is important as  these drugs are most effective when taken in a fasting state  30 minutes before meals when parietal cells have large num-  bers of active proton pumps.   PPIs are indicated as initial therapy in patients with mod-  erate to severe GERD and in patients with complications of  GERD such as bleeding and strictures. A recent study  reviewed 26 trials involving 4064 patients that compared  PPIs with H 2 -receptor antagonists. PPI therapy was signifi-  cantly better than H,-receptor antagonist therapy in treat-  ment of esophagitis at 4-8 weeks.   Independent comparisons of the currently available  PPIs have consistently shown first-generation PPIs (all  except esomeprazole) to be essentially equal in esophagitis  healing rates and intragastric profiles. There have been sev-  eral reports that rabeprazole has a faster onset of action  that the others; however, the clinical significance of this is  debatable. A comparison of all five available PPIs in con-  trolling 24-hour intragastric pH showed a statistically sig-  nificant advantage for esomeprazole on day 5 of therapy  (Table 11-5).   The safety of long-term PPI therapy has been demon-  strated by the treatment of millions of patients over the past  20 years. During the initial testing of these medicines, gastric  carcinoids were seen in animal models. This complication  has not been demonstrated to occur in humans. There is also  a theoretical concern about interference with nutrient  absorption (especially calcium, iron, and protein) due to a  significant decrease in gastric acid production; however,  there has not been a demonstrable reduction of absorption  of these nutrients. A modest reduction of vitamin B ]2 levels   Table 11-5. Efficacy of proton pump inhibitors in decreasing intragastric pH.   b Mean 24-h intragastric pH on day 5 by treatment group (n = 34).   Adapted, with permission, from Miner PJr, Katz PO, Chen Y, et al. Gastric acid control with esomeprazole,   lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol.   has been seen with long-term PPI use, which may be due to  a decrease in protein-bound vitamin B 12 absorption.  Therefore, vitamin B ]2 levels should be periodically monitored  in patients who are on continuous PPI therapy for more  than 5 years. Clinically insignificant bacterial overgrowth of  the small bowel has been noted to occur in patients on  chronic PPIs. However, the bacterial overgrowth can  become significant if there is an underlying motility disor-  der of the small intestine or surgically altered anatomy.  Recently the use of PPIs has been associated with increased  rates of community-acquired pneumonias, Clostridium difficile  infection, and hip fractures.   Although most patients with GERD are successfully man-  aged with lifestyle modifications and medical therapy, some  patients may have persistent symptoms despite treatment.  Mechanical antireflux therapies, either surgical or endo-  scopic, can be employed in patients with a good clinical  response to medical treatments who wish to discontinue  medications or in patients who have failed medical therapy.   Gastroesophageal reflux surgery has been performed since  the early 1950s. The goal of antireflux surgery is to narrow  the lower esophageal luminal diameter to prevent the reflux  of gastroduodenal contents. The most widely performed  procedure is the Nissen fundoplication. Several studies have  reported a symptomatic response of 80-90% in patients  undergoing this fundoplication procedure. A review of six  randomized controlled trials comparing open and laparo-  scopic fundoplications found no difference in the GERD  recurrence rate between the two procedures but demon-  strated a lower operative morbidity and shorter postopera-  tive hospital stay with the laparoscopic approach. However, it  has been noted that 62% of patients again require medica-  tions 10 years after antireflux surgery.   Complications of fundoplication include dysphagia, chest  pain, gas-bloat syndrome, postoperative flatulence, and vagal  nerve injuries leading to gastroparesis and diarrhea. The preva-  lence of these complications ranges between 5% and 20%.  Postoperative dysphagia ranges from 0% to 18%, with early  dysphagia occurring in approximately 20% of patients and late  dysphagia occurring in 6% of patients at 2 years. The benefit of  antireflux surgery must also be balanced against the 0.5-1%  risk of operative mortality. The risk of mortality is reduced by  the laparoscopic approach and the experience of the surgeon.   Various endoscopic techniques have been developed for the  treatment of GERD. Most studies of endoscopic therapy have  reported limited follow-up information for a relatively small  number of patients. Each endoscopic antireflux technique is  designed to alter the anatomy of the gastroesophageal junc-  tion to prevent GERD. For endoscopic antireflux treatments,  there are two available types of therapy: radiofrequency   energy and suturing of the gastroesophageal junction. An  injectable treatment designed to decrease the lumen of the  gastroesophageal junction was approved by the FDA in 2003  but was withdrawn from the market due to safety concerns.   Although some studies demonstrate improvement in 24-  hour intraesophageal acid exposure, normalization of acid expo-  sure is the exception rather than the rule for these techniques.  The patient population that may benefit most from these proce-  dures remains to be determined; however, preliminary data sug-  gest that patients with atypical GERD may benefit most.  Complications associated with these endoscopic antireflux pro-  cedures include bleeding, aspiration pneumonia, perforation,  mediastinitis, and rarely, death. At present the indications for  endoscopic therapy of GERD are unclear. Future studies are  needed to better understand the mechanism of these treatments  and improve the efficacy and durability of these procedures.   Mechanical treatment of GERD can be curative for  patients provided the antireflux effects are achieved. Surgical  or endoscopic approaches can be offered to patients on long-  term medical therapy; however, the optimal approach needs  to be individualized for each case.   Fewer than half of patients with typical reflux symptoms  have evidence of esophagitis on upper endoscopy, giving rise  to the term nonerosive reflux disease (NERD). NERD patients  have typical GERD symptoms but only half have evidence of  abnormal acid exposure. The causes of symptoms in such  patients include nonacid reflux, visceral hypersensitivity, and  abnormal esophageal motor function. The treatment of  NERD patients is similar to that of patients with erosive  esophagitis; however, several studies have shown that these  patients are less likely to respond to PPI therapy. Low-dose  tricyclic antidepressants can be used in NERD patients who  do not respond to conventional therapy.   Bytzer P, Morocutti A, Kennerly P, et al. ROSE Trial investigators.  Effect of rabeprazole and omeprazole on the onset of gastro-  esophageal reflux disease symptom relief during the first seven  days of treatment. Scand J Gastroenterol. 2006;(10):1132-1140.  [PMID: 15990197]   Catarci M, Gentileschi P, Papi C, et al. Evidence-based appraisal of  antireflux fundoplication. Ann Surg. 2004;239:325-337. [PMID:  15075649]   Dial S, Delaney IA, Barkun AN, et al. Use of gastric acid-suppressive  agents and the risk of community-acquired Clostridium difficile-  associated disease. JAMA. 2005;294:2989-2995. [PMID:  16414946]   Falk GW, Fennerty MB, Rothstein RI. AGA Institute technical  review on the use of endoscopic therapy for gastroesophageal  reflux disease. Gastroenterology. 2006;131:1315-1336. [PMID:  17030199]   Finlayson SR, Laycock WS, Birkmeyer JD. National trends in  utilization and outcomes of antireflux surgery. Surg Endosc.  2003;17: 864-867. [PMID: 12632134]   Flum DR, Koepsell T, Heagerty P, et al. The nationwide frequency  of major adverse outcomes in antireflux surgery and the role of  surgeon experience, 1992-1997. J Am Coll Surg. 2002;195:61 1-618.  [PMID: 12437246]   Klinkenberg-Knol EC, Nelis F, Dent J. Long-term omeprazole  treatment in resistant gastroesophageal reflux disease: efficacy,  safety, and influence on gastric mucosa. Gastroenterology.  2000;118:661-669. [PMID: 10734017]   Klok RM, Postma MJ, van Hout BA, et al. Meta-analysis: compar-  ing the efficacy of proton pump inhibitors in short-term use.  Aliment Pharmacol Therapeut. 2003;(10):1237-1245. [PMID:  12755827]   Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-  acquired pneumonia and use of gastric acid-suppressive drugs.  JAMA. 2004;292:1955-1960. [PMID: 15507580]   Liu JJ, Carr-Locke DL, Osterman MT, et al. Endoscopic treatment  for atypical manifestations of gastroesophageal reflux disease.  Am J Gastroenterol. 2006;101:440-445. [PMID: 16542278]   Moayyedi P, Soo S, Deeks J, et al. Pharmacologic interventions for  non-ulcer dyspepsia. Cochrane Database System Rev. 2006;(4):  CD001960. [PMID: 17054151]   Spechler SI, Lee E, Ahnen D, et al. Long-term outcome of medical  and surgical therapies for gastroesophageal reflux disease: follow-  up of a randomized controlled trial. JAMA. 2001;285: 2331-2338.  [PMID: 11343480]   Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump  inhibitor therapy and risk of hip fracture. JAMA. 2006;296(24):  2947-2953. [PMID: 17190895]   The degree of dilation within an endoscopic session should  be based on the severity of the luminal narrowing (Plates 7  and 8). A "rule of three" has been described for esophageal dila-  tion using bougie dilators. After moderate resistance is encoun-  tered, no more than three consecutive dilators in increments  of 1 mm should be passed in a single session. This rule does  not appear to apply to balloon dilators in simple esophageal  strictures, which may be incrementally dilated greater than 3 mm.  No data exist on the optimal time the balloon should remain  inflated. Dilation therapy for a symptomatic Schatzki ring  should be directed toward achieving rupture of the ring.   No clear advantage has been demonstrated between bougie  and TTS dilators. In patients with benign peptic strictures, the  long-term benefits of dilation appear greatest when a luminal  diameter of more than 12 mm in achieved. For peptic stric-  tures, smaller lumen diameter, presence of a hiatal hernia  greater than 5 cm, persistence of heartburn after dilation, and  number of dilations needed for initial dysphagia relief were  significant predictors of early symptomatic recurrence.   2. Proton pump inhibitors — Patients with peptic strictures  should be treated with PPI therapy. Patients with peptic stric-  tures complicated by food impactions should undergo treat-  ment with PPIs prior to dilation of the peptic stricture. PPI  use decreases stricture recurrence and the need for repeat  stricture dilation.   1. Esophageal dilation — Peptic strictures of the esophagus  due to GERD account for nearly 80% of esophageal strictures  although this may be decreasing due to the use of PPIs. The pri-  mary indication for esophageal dilation is to relieve dysphagia;  empiric dilatation with large-bore dilators cannot be recom-  mended if no structural abnormalities are seen endoscopically.   Three general types of dilators are currently in use. These  are (1) mercury or tungsten-filled bougies (Maloney or  Hurst), (2) wire-guided polyvinyl dilators (Savary-Gilliard or  American), and (3) TTS ("through the scope") balloon dila-  tors. Maloney bougies have a tapered tip and can be passed  blindly or under fluoroscopic control. Savary and American  dilators are passed over a guidewire that has been positioned  in the antrum, with or without fluoroscopic guidance. TTS  dilating balloons are available in either single or multiple  diameters that may be passed with or without wire guidance.   In preparation for endoscopic dilation anticoagulants  should be discontinued. Routine antibiotic coverage is not  recommended; however, endocarditis prophylaxis should be  followed. Patients should be informed of the risks associated  with esophageal dilation; the principal complications are  perforation, bleeding, and aspiration. The perforation rate  for esophageal strictures after dilation has been reported to  be 0.1-0.4%. Perforation is more common in radiation-  induced strictures, malignant strictures, complex strictures  due to lye ingestion, and in patients with achalasia.   [PMID: 10744819]  Said A, Brust D J, Gaumnitz EA, et al. Predictors of early recurrence   1252-1256. [PMID: 12818265]  Standards of Practice Committee, Egan IV, Baron TH, Adler DG,   Once patients without esophagitis have responded to lifestyle  changes and medical therapy and achieved remission from  clinical symptoms, most should have a trial of medication  withdrawal. Symptom relief should be sustained for 2-3  months before attempting to withdraw medications. PPI ther-  apy can be tapered to an every-other-day regimen or to a  reduced dose (if possible), or switched to a H 2 -blocker. Most  patients who are treated with H,-blockers are on twice-daily  medications, and the initial tapering should be to a once-a-day  regimen. If a patient tolerates a taper for 2-4 weeks without an  increase in symptoms, the dosage can be further decreased or  the medication discontinued. The goal of long-term treatment  is to step down management to the lowest level of medical ther-  apy that controls symptoms, or consider surgery. However, if a  patient experiences recurrent symptoms, the medication regi-  men should be increased until symptom resolution is achieved.   If GERD patients on long-term PPI therapy are not  tapered from their medicine, many will experience symp-  toms that are worse than their initial presenting complaints.  This phenomenon of "rebound hypersecretion" occurs when  parietal cells secrete elevated amounts of acid after a pro-  longed blockade. A prolonged tapering of PPI therapy helps  improve these symptoms. Helicobacter pylori eradication has  been found to worsen rebound gastric hypersecretion.   Therapy for GERD is frequently chronic and long-term in  most patients as the underlying disorder is dysfunction of the  LES, which is not directiy affected by medical therapy. Among  patients with erosive esophagitis, more than 80% will relapse if  their therapy is stopped. The same medication that induces  remission is usually required in the same dosage to maintain  remission. In those with nonerosive GERD, on-demand therapy  is a cost-effective alternative to maintenance treatment.   Long-term GERD treatment can be challenging, but  empowering patients to recognize the dietary and lifestyle  choices that produce symptoms enables the majority of moti-  vated patients to wean themselves off medical therapy. For  those patients who are unable to discontinue acid suppression  therapy due to symptom recurrence, the medical therapies  available are fortunately very effective and generally safe.   Inadomi IM, Jamal R, Murata GH, et al. Step-down management  of gastroesophageal reflux disease. Gastroenterology. 2001;121:  1095-1100. [PMID: 11677201]   Inadomi IM, Mclntyre L, Bernard L, et al. Step-down from multiple-  to single-dose proton pump inhibitors (PPIs): a prospective study  of patients with heartburn or acid regurgitation completely relieved  with PPIs. Am } Gastroenterol. 2003;98: 1940-1944. [PMID:  14499769]   ► Replacement of normal squamous epithelium of the  distal esophagus with specialized intestinal metaplasia.   ► Presence of high-grade dysplasia should be con-  firmed by two gastrointestinal pathologists skilled in  this area.   ► Risk factors for progression to adenocarcinoma include  a large hiatal hernia, long segment of Barrett esopha-  gus, and mucosal abnormalities (nodules, ulcerations or  strictures).   Barrett esophagus is named after a London thoracic surgeon  who published a paper in 1950 entitled "Chronic Peptic  Ulcer of the Esophagus and 'Oesophagitis'." In this article,  Norman Barrett described cases of esophageal ulcers sur-  rounded by columnar mucosa found at autopsy. Barrett  esophagus, the clinical entity first described in the 1950 arti-  cle, is the replacement of the normal squamous epithelium of  the distal esophagus with specialized intestinal metaplasia  (SIM). It is caused by chronic gastroesophageal reflux disease  (GERD), which leads to esophagitis and subsequent meta-  plastic change of the esophageal lining. SIM may be protec-  tive against further injury by gastric acid; however, this  metaplastic epithelium is also associated with an increased  risk for esophageal adenocarcinoma. There is considerable  ongoing debate regarding various aspects of Barrett esopha-  gus, such as the exact neoplastic risk it confers as well as its  management once it has become dysplastic.   Barrett NR. Chronic peptic ulcer of the oesophagus and  "oesophagitis." Br J Surg. 1950;38:175-182. [PMID: 14791960]   The overall prevalence of Barrett esophagus in the general  population is thought to be 1.6-1.7%. As of the 2000 U.S.  Census, this would translate to approximately 3.3 million indi-  viduals with the condition. In GERD patients, the prevalence  of Barrett esophagus is higher, approximately 5-10%. In patients  with severe GERD, such as those with erosive esophagitis, the  prevalence is approximately 10%; in patients with peptic stric-  tures of the esophagus, the prevalence is almost 30%. Barrett  esophagus affects males more than females by a ratio of  approximately 3:1. The typical patient is a Caucasian, middle-  aged male. In certain studies alcohol and smoking have been  found to be risk factors for the presence of Barrett esophagus.  The conclusion that Barrett esophagus is a complication of  chronic GERD is supported by the fact that Barrett esophagus is  exceedingly rare in children with competent lower esophageal  sphincters (LES).   El-Serag HB, Gilger MA, Shub MD, et al. The prevalence of sus-  pected Barrett's esophagus in children and adolescents: a multi-  center endoscopic study. Gastrointest Enclose. 2006;64:671-675.  [PMID: 17055854]   Evans DE, Barron WG. 2000 Census of Population and Housing. US  Department of Commerce Economics and Statistics, 2005.   Fitzgerald RC. Barrett's oesophagus and oesophageal adenocarci-  noma: how does acid interfere with cell proliferation and differ-  entiation? Gut. 2005;54(SupplI):i21-i26. [PMID: 15711004]   Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett's  esophagus in the general population: an endoscopic study.  Gastroenterology. 2005;129:1825-1831. [PMID: 16344051]   The components of the refluxate in GERD (both gastric acid  and bile salts) are important etiologic factors in the develop-  ment of Barrett esophagus. Esophageal pH monitoring stud-  ies have shown that patients with Barrett esophagus have  more esophageal acid exposure than healthy controls or even  patients with mild heartburn. The greater acid exposure in   Barrett esophagus results from longer periods of acid reflux  (ie, > 5 minutes), rather than from a greater number of reflux  episodes. Patients with Barrett esophagus may be predis-  posed to more severe acid reflux episodes due to mechanical  dysfunction of the LES as well as the decreased amplitude of  distal esophageal contractions. The role of bile salts in refluxed  gastric acid in the development of Barrett esophagus contin-  ues to be debated and investigated. Increased levels of refluxed  bile acid concentrations have been found in patients with  Barrett esophagus. Some clinicians argue that the increased  reflux of bile salts in these patients necessitates a mechanical  treatment for their GERD, such as a fundoplication. Finally,  the genetic and environmental factors that also play a role in  the development of Barrett esophagus are only beginning to  be understood.   Stein HJ, Hoeft S, Demeester TR. Functional foregut abnormalities  in Barrett's esophagus. / Thorac Cardiovasc Surg. 1993;105:  107-111. [PMID: 8419690]   Barrett esophagus cannot be detected on clinical grounds as  there are no specific symptoms that distinguish this condi-  tion from GERD without Barrett esophagus. In addition  Barrett esophagus cannot be reliably detected radiologically.  The gold standard for the diagnosis of Barrett esophagus is  upper endoscopy with biopsy of the distal esophagus.   Barrett esophagus is diagnosed when excisional biopsies con-  firm the presence of SIM in a columnar-lined distal esophagus.  In normal individuals the squamocolumnar junction (SCJ)  coincides with the gastroesophageal junction (GEJ). The SCJ is  the transition from the white squamous mucosa of the esoph-  agus to the salmon-colored gastric mucosa. Endoscopically, the  GEJ is best defined as the top of the gastric folds. If there is  proximal displacement of the SCJ above the top of the gastric  folds into the tubular esophagus, a columnar-lined esophagus  is present and biopsies should be taken (Plate 9).   Early studies defined the diagnosis of Barrett esophagus as  the presence of 3 cm of columnar-lined distal esophagus with  SIM (Plate 10). Subsequent work deemed the presence of less  than 3 cm of SIM as "short-segment" Barrett esophagus.  Finally, a study in which investigators biopsied the normal-  appearing SCJ of consecutive patients undergoing upper  endoscopy found a SIM prevalence of 18%. The significance of  intestinal metaplasia at the SCJ is debatable and, at present, it is  not recommended that a normal-appearing SCJ be biopsied.   It is important to note that intestinal metaplasia of the  cardia cannot be distinguished from intestinal metaplasia of  the esophagus. Therefore, the proximal migration of the SCJ  into the tubular esophagus must be demonstrated in order to  diagnose a patient with Barrett esophagus.   The clinical significance of Barrett esophagus length is  important as studies have confirmed that longer segments  have higher risks of progression to adenocarcinoma. However,  in a recent workshop Barrett esophagus concluded that the  division of Barrett esophagus into short and long segments  should not be used to guide decisions about surveillance  endoscopy intervals.   Biopsy specimens of Barrett esophagus are classified as  negative for dysplasia (or nondysplastic), indefinite for dys-  plasia (or indefinite-grade dysplasia), low-grade dysplasia, or  high-grade dysplasia. The diagnosis of dysplasia is typically  reserved for lesions in which nuclear atypism is present on  the mucosal surface.   Avidan B, Sonnenberg A, Schnell T, et al. Hiatal hernia size,  Barrett's length and severity of acid reflux are all risk factors for  esophageal adenocarcinoma. Am J Gastroenterol. 2002;97:  1930-1936. [PMID: 12190156]   Sharma P, McQuaid K, Dent J, et al. A critical review of the  diagnosis and management of Barrett's esophagus: the AGA  Chicago workshop. Gastroenterology. 2004;127:310-330. [PMID:  15236196]   Wang KE, Sampliner RE. Practice Parameters Committee of the  American College of Gastroenterology. Updated guidelines for  the diagnosis, surveillance and therapy of Barrett's esophagus.  Am J Gastroenterol 2008;103:788-797. [PMID: 18341497]   Screening refers to performing a test on a large asympto-  matic sample of the population to identify a disease. The role  of screening upper endoscopy for Barrett esophagus is  unclear, and the major gastroenterologic societies are not  unanimous in their recommendations. Patients with chronic  GERD are at increased risk for Barrett esophagus, and the  prevalence of Barrett esophagus is higher in middle-aged  white males, suggesting that screening should be reserved for  this higher risk subgroup. The American College of  Gastroenterology suggests that patients with chronic GERD  symptoms should undergo an endoscopy for the detection of  Barrett esophagus. If the only criteria for Barrett esophagus  screening were the presence of GERD symptoms, however,  the population to be screened would be enormous as it is  estimated that 20% of the U.S. adult population experiences  reflux symptoms. Decision analysis studies that have looked  at the cost-effectiveness of screening for Barrett esophagus  have shown conflicting results. In addition, a significant  proportion of patients with esophageal adenocarcinoma  report no prior symptoms of reflux. What cannot be  debated, however, is that most patients newly diagnosed with  esophageal cancer have not had a previous diagnosis of  Barrett esophagus, emphasizing a need for more effective  screening strategies. As the cost of upper gastrointestinal  tract visualization decreases with newer techniques, such as  transnasal and video capsule endoscopy, these issues will  need to be readdressed.   Dulai GS, Guha S, Kahn KL, et al. Preoperative prevalence of  Barrett's esophagus in esophageal adenocarcinoma: a systematic  review. Gastroenterology. 2002;122:26-33. [PMID: 11781277]   Gerson LB, Groeneveld PW, Triadafilopoulos G. Cost-effectiveness  of endoscopic screening and surveillance in patients with gas-  troesophageal reflux disease. Clin Gastroenterol Hepatol.  2004;2:868-879. [PMID: 15476150]   Inadomi JM, Sampliner R, Lagergren J, et al. Screening and  surveillance for Barrett's esophagus in high-risk groups: a cost  utility analysis. Ann Intern Med. 2003;138:176-186. [PMID:  12558356]   Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a  large multicenter cohort of patients with Barrett's esophagus.  Clin Gastroenterol Hepatol. 2006;4:566-572. [PMID: 16630761]   Surveillance in patients with Barrett esophagus refers to the  performance of serial endoscopies at regular intervals with  the goal of detecting dysplasia and early cancer at a curable  stage. If the incidence of cancer in patients with Barrett  esophagus were high, surveillance would be cost-effective;  however, if the incidence were low, an extremely small pro-  portion of the at-risk population would benefit. The overall  risk of cancer in Barrett esophagus patients is estimated to be  approximately 0.5% per year. Stated another way, the risk of  any given patient with Barrett esophagus developing cancer  is approximately 1 in 200 per year.   As with screening, the cost-effectiveness of surveillance in  Barrett esophagus is debated. Retrospective data have shown  that cancers detected during Barrett esophagus surveillance  are more likely to be found at an early stage and are asso-  ciated with better survival compared with those not  detected during surveillance. Such retrospective studies are  subject to both lead time and length time bias. A few stud-  ies have demonstrated no difference in overall survival  between patients with Barrett esophagus and the general  population, calling into question the utility of Barrett esoph-  agus endoscopic surveillance. Barrett esophagus patients  more frequently die from other causes other than esophageal  adenocarcinoma, suggesting that surveillance is of no benefit  to the vast majority of these patients.   At present, until better markers of risk stratification are  found, the surveillance interval of upper endoscopy is deter-  mined by the degree of dysplasia found in a Barrett esopha-  gus segment. Until better biomarkers are validated, dysplasia  remains the best indicator of risk of cancer development.  Barrett esophagus biomarkers are being actively investigated  because the diagnosis and detection of dysplasia have signif-  icant limitations. There is a high inter-observer variability in  the reading of dysplasia, particularly among community  pathologists. Many pathologists have difficulty distinguish-  ing between inflammatory changes and dysplasia. In addi-  tion, random biopsy surveillance introduces the possibility  of sampling error given that the distribution of dysplasia  throughout a Barrett esophagus segment can be patchy. At  present, however, the presence of dysplasia in a Barrett   esophagus segment remains the best method of cancer risk  stratification. It is strongly recommended that when a diag-  nosis of dysplastic Barrett esophagus is being considered, the  histopathologic slides be reviewed by two senior pathologists  with expertise in this area.   Currendy upper endoscopy with four-quadrant "jumbo"  biopsies at 2-cm intervals remains the best method for obtain-  ing surveillance biopsies once esophageal inflammation related  to GERD has been well controlled with antisecretory therapy.  Biopsy specimens should be obtained in four quadrants at  2-cm intervals beginning at the end of the tubular esophagus  (top of the gastric folds) and continuing proximally to the SCJ.  Any mucosal abnormalities such as ulcerations, strictures, or  nodules should be extensively sampled. At present, chromoen-  doscopy and other "optical biopsy" techniques have not been  validated on a large scale and are not recommended for stan-  dard use.   The recommendations of the major gastroenterologic  societies differ slightly regarding the time interval between  surveillance endoscopies in Barrett esophagus (Table 12-1). If  a patient is found to have nondysplastic Barrett esophagus on  incident endoscopy, it is generally recommended that a repeat  EGD be performed in 1 year for repeat biopsies. If no dyspla-  sia is found on the second surveillance endoscopy performed  1 year later, it is reasonable to repeat surveillance endoscopies  every 2-3 years. Some investigators advocate that this interval  be extended to every 3-5 years given that Barrett esophagus  surveillance has not been proven cost-effective. It is impor-  tant to note that in a recent retrospective study of patients  with Barrett esophagus, 53% of patients who developed high-  grade dysplasia or cancer had two consecutive initial endo-  scopies with biopsies that revealed nondysplastic mucosa.   Corley DA, Levin TR, Habel LA, et al. Surveillance and survival  in Barrett's adenocarcinomas: a population-based study.  Gastroenterology. 2002;122:633-640. [PMID: 11874995]   Macdonald CE, Wicks AC, Playford RJ. Final results from 10 year  cohort of patients undergoing surveillance for Barrett's esopha-  gus: observational study. BMJ. 2000;321:1252-1255. [PMID:  11082084]   Many studies have assessed risk factors for the development  of adenocarcinoma in patients with Barrett esophagus  (Table 12-2). Dysplasia is a risk factor for progression to  adenocarcinoma, as well as a risk for having an occult, coin-  cident carcinoma present in the Barrett esophagus segment.  Dysplastic transformation of Barrett esophagus epithelium is  thought to precede the development of adenocarcinoma,  although whether this progression occurs without interrup-  tion from nondysplastic Barrett esophagus to low-grade dys-  plasia to high-grade dysplasia is unclear. Biomarkers for the  development of adenocarcinoma in Barrett esophagus  patients, such as flow cytometry and fluorescence in situ  hybridization (FISH), are still experimental.   Table 12-1. Summary of recommendations for surveillance endoscopies in Barrett esophagus.    If 2 pathologists agree, then yearly; if  disagreement, then every 3 y   Repeat EGD to exclude cancer  Consider ablative therapy, surgery,  or surveillance every 3 mo   ACG, American College of Gastroenterology; AGA, American Gastroenterological Association; ASGE, American Society for Gastrointestinal  Endoscopy; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease.   Adapted with permission from Wang KK: Surveillance and Screening for Barrett's Esophagus. Clinical Update, Vol.13 (2), 2005. American  Society for Gastrointestinal Endoscopy.   Cooper BT, Chapman W, Neumann CS, et al. Continuous treatment  of Barrett's oesophagus patients with proton pump inhibitors up  to 13 years: observations on regression and cancer incidence.  Aliment Pharm Ther. 2006;23:727-733. [PMID: 16556174]   De Jonge PJ, Steyerberg EW, Kuipers EJ, et al. Risk factors for the  development of esophageal adenocarcinoma in Barrett's esopha-  gus. Am J Gastroenterol. 2006;101:1421-1429. [PMID: 16863542]   Wongsurawat VJ, Finley JC, Galipeau PC, et al. Genetic mecha-  nisms of TP53 loss of heterozygosity in Barrett's esophagus:  implications for biomarker validation. Cancer Epidemiol  Biomarkers Prev. 2006;15:509-516. [PMID: 16537709]   Table 12-2. Risk factors for esophageal adenocarcinoma  in patients with Barrett esophagus.    Diet low in fruits and vegetables  High body mass index  Male gender  Older age  Tobacco smoking  Heavy alcohol use  Working in a stooped posture  Less use of proton pump inhibitors  Fewer heartburn symptoms  Use of medicines that relax the  lower esophageal sphincter   Every patient with Barrett esophagus should be on proton  pump inhibitor (PPI) therapy indefinitely. There are data  demonstrating that patients on PPIs have a lower rate of  progression to dysplasia and adenocarcinoma than patients  not taking PPIs. In one study, the cumulative incidence of  dysplasia was significantly lower among patients who  received PPI after Barrett esophagus diagnosis than in those  who received no therapy or histamine receptor antagonists.  Furthermore, among those on PPIs, a longer duration of  use was associated with a less frequent occurrence of dyspla-  sia. Every patient diagnosed with Barrett esophagus should  be started on a PPI whether or not symptomatic GERD is  present.   At present there are not enough data to support ablative  therapies for nondysplastic Barrett esophagus. In the future  biomarkers may provide better risk stratification justifying  endoscopic ablation of nondysplastic Barrett esophagus in  high-risk patients. However, given that the vast majority of  patients with Barrett esophagus do not progress to adenocar-  cinoma, the use of these methods for this indication cannot  currently be recommended.   Data suggest that, despite long-term antisecretory ther-  apy, long segments of Barrett esophagus do not regress.  Normalization of SIM has been described in cases of "ultra-  short" Barrett esophagus and short-segment Barrett esopha-  gus. Patients with long segments of Barrett esophagus should  be informed that their Barrett esophagus will not regress and  that they should remain on PPI therapy indefinitely and  undergo surveillance endoscopies.   Cyclooxygenase (COX)-2 inhibitors are being studied as  chemoprevention of Barrett esophagus progression. A  study of esophagectomy specimens correlating COX-2   immunopositivity and clinical course demonstrated that  tumors expressing higher levels of COX-2 were more likely to  be associated with distant metastases, local recurrence, and  reduced survival. In vivo studies on Barrett esophagus have  also shown decreased levels of cellular proliferation markers  in patients taking COX-2 inhibitors. In the future chemopre-  vention of Barrett esophagus progression may become the  standard of care if further human clinical studies can sub-  stantiate these findings.   Buskens CJ, Van Rees BP, Sivula A, et al. Prognostic significance of  elevated cyclooxygenase 2 expression in patients with adenocar-  cinoma of the esophagus. Gastroenterology. 2002;122:1800-1807.  [PMID: 12055587]   El-Serag HB, Aguirre TV, Davis S, et al. Proton pump inhibitors  are associated with reduced incidence of dysplasia in Barrett's  esophagus. Am } Gastroenterol. 2004;99:1877-1883. [PMID:  15447744]   Hayashi GM, Haggitt RC. The histology of Barrett's esophagus:  metaplasia and dysplasia. In: Sharma P, Sampliner RE (editors).  Barrett's Esophagus and Esophageal Adenocarcinoma. Blackwell  Publishing, 2001:80-88.   Horwhat ID, Baroni D, Maydonovitch C, et al. Normalization of  intestinal metaplasia in the esophagus and esophagogastric junc-  tion: incidence and clinical data. Am J Gastroenterol. 2007;102:  497-506. [PMID: 17156135]   Kaur BS, Khamnehei N, Iravani M, et al. Rofecoxib inhibits  cyclooxygenase 2 expression and activity and reduces cell prolif-  eration in Barrett's esophagus. Gastroenterology. 2002;123:60-67.  [PMID: 12105834]   In indefinite-grade dysplasia nuclear enlargement, crowding,  hyperchromatism, prominence of the nucleoli, and mild  stratification can be seen but are confined to the lower por-  tion of the glands whereas the upper portion of the glands  and surface epithelium show less abnormality or are normal.  The diagnosis of dysplasia should be made with caution  when atypical changes do not involve the mucosal surface.   Active inflammation due to GERD may cause nuclear  changes that mimic both low-grade and high-grade dysplasia.  If a biopsy specimen is obtained adjacent to an ulcer and  numerous neutrophils infiltrate the epithelium, the diagnosis  of dysplasia may not be possible and the diagnosis of "indef-  inite for dysplasia" may be assigned.   If Barrett esophagus surveillance biopsy specimens are  obtained and indefinite-grade dysplasia is the highest grade  lesion found, aggressive antisecretory therapy should be insti-  tuted and repeat surveillance biopsies should be performed in  3 months.   Low-grade dysplasia is characterized by mucosal cells with  nuclei that are larger and hyperchromatic, with irregular   contours that are basally located in the cell with minimal or  no stratification (Plate 1 1 ) . As with other grades of dysplasia,  the interpretations of low-grade dysplasia biopsy specimens  should be considered for review by experts in esophageal  pathology. Extensive surveillance biopsies should be done to  confirm that low-grade dysplasia is the highest grade lesion  in a Barrett esophagus segment.   Several clinical studies have not demonstrated a signifi-  cantly increased malignant potential of Barrett esophagus with  low-grade dysplasia. In these studies the risk of progression to  esophageal adenocarcinoma was not significantly higher in  patients with low-grade dysplasia than in those without dys-  plasia. In addition, some case series have demonstrated a tran-  sient nature to low-grade dysplasia, which can regress and  revert to nondysplastic Barrett esophagus on subsequent biop-  sies. More recent data suggest that the extent of low-grade dys-  plasia measured as the mean proportion of low-grade dysplastic  crypts may be a more significant predictor of esophageal adeno-  carcinoma outcome than the presence of low-grade dysplasia  alone.   The natural history of low-grade dysplasia is variable; it  can persist for long periods of time or even revert to nondys-  plastic Barrett esophagus. A repeat esophagogastroduo-  denoscopy (EGD) with surveillance biopsies should be  performed within 3-6 months after low-grade dysplasia is  detected to confirm it is the highest grade lesion present and  then annually as long as low-grade dysplasia persists. Given  the emerging data regarding the implications of a large dys-  plastic burden, a shorter interval may be considered if multi-  ple biopsies reveal a large numbers of low-grade crypts.   2004;127:1233-1238. [PMID: 15481000]  Srivastava A, Hornick JL, Li X, et al. Extent of low-grade dysplasia is   The accurate pathologic diagnosis of high-grade dysplasia is  critically important because therapeutic intervention may be  initiated based on its diagnosis. Histopathologically, at low  magnification power, distortion of the glandular architecture  is usually present and may be marked. The glands are com-  posed of branching and lateral budding of crypts and a villi-  form configuration of the mucosal surface. Most importantly,  the diagnosis of high-grade dysplasia requires that the dys-  plastic epithelium on the mucosal surface demonstrate loss  of nuclear polarity and the absence of a consistent relationship  of nuclei to each other (Plate 12).   The clinical implications of the presence of high-grade  dysplasia in Barrett esophagus remain somewhat controver-  sial. Owing to the risk of occult, coincident malignancy in a  Barrett esophagus segment as well as the higher risk of pro-  gression to malignancy, the previous standard recommendation   was that all patients diagnosed with high-grade dysplasia  undergo esophagectomy once the diagnosis was confirmed by  two senior GI pathologists. Esophagectomy is a very invasive  surgery and is associated with 3-10% mortality and up to  45% morbidity. Subsequent studies found that the rate of  progression to esophageal adenocarcinoma in patients with  high-grade dysplasia can vary widely from 15-60% and, in a  subset of patients, may not occur at all. Therefore, the recom-  mendations regarding the management of high-grade dys-  plasia have become more patient specific and tailored to each  clinical scenario.   It is imperative that the diagnosis of high-grade dysplasia  be confirmed by two senior GI pathologists prior to formu-  lating a treatment plan. Extensive surveillance biopsies must  be performed every 1 cm in all four quadrants of the Barrett  esophagus segment in order to rule out the presence of any  occult malignancy. Any suspicious nodules or ulcerations  must be extensively sampled. An assessment of the patient's  operative risk should be performed. After the preceding  information has been obtained a treatment plan can be for-  mulated with the patient's input regarding the risks and ben-  efits of each course of action.   The extent of high-grade dysplasia present in a patient's  Barrett esophagus segment has been shown to correlate with  the patient's likelihood of progression to cancer. These find-  ings suggest that patients with "focal" high-grade dysplasia  (ie, involving five or fewer crypts) on a single biopsy may be  aggressively surveyed endoscopically, and more invasive  treatment may be deferred only for patients who progress to  frank adenocarcinoma.   If a patient is found to have high-grade dysplasia in a  nodule or a focal, discrete lesion, endoscopic mucosal resec-  tion (EMR) may be considered. This is a method of endo-  scopically resecting the mucosal layer of the esophagus after  separating it from the muscular layer with a submucosal  injection of saline (Plates 13 and 14). The main risks of EMR  include bleeding and perforation. An endoscopic ultrasound  should be performed prior to considering EMR to confirm  that the stage of the lesion is superficial and appropriate for  endoscopic resection. If the resected specimen is removed en  bloc, the completeness of cancer resection may be assessed  pathologically. Frequently EMR is combined with an endo-  scopic ablative technique, photodynamic therapy, to treat  high-grade dysplasia and intramucosal carcinoma.   Photodynamic therapy is a mucosal ablation technique  whereby a patient is given a photosensitizer intravenously  which is preferentially taken up by dysplastic cells. After a  time delay, laser light of a certain wavelength is used to illu-  minate the tissue and activate the photosensitizer which then  interacts with oxygen to mediate cell injury (Plates 15, 16,  and 17). The lining of the esophagus is ablated with a trans-  mural burn, which can cause odynophagia and chest pain  immediately following illumination. The risks of photody-  namic therapy include post-treatment strictures, atrial fibril-  lation, and pleural effusions. This therapy is typically used  alone in patients who are not operative candidates with   extensive, diffuse high-grade dysplasia or intramucosal carci-  noma. The overall mortality and long-term survival in  patients with high-grade dysplasia who are treated with pho-  todynamic therapy appears to be comparable to that of those  treated with esophagectomy.   Various other endoscopic ablative techniques have been  developed to treat dysplastic Barrett esophagus epithelium,  including radiofrequency ablation, focal thermal, and  cryoablation methods. Long-term comparative studies are  needed to determine which method is the safest and most  effective; however, it appears that radiofrequency ablation  holds significant promise, with a recent study demonstrating  a 90% eradication rate for high-grade dysplasia.   The treatment of high-grade dysplasia has evolved over  time from a standard recommendation of esophagectomy for  all patients to a more case-specific, less-invasive approach.  Once the diagnosis has been confirmed by two senior GI  pathologists, the patient's operative risk, the focality of the  dysplasia, and the local surgical and endoscopic expertise  should be considered before deciding on intensive surveil-  lance, endoscopic ablation, or a surgical approach.   Buttar NS, Wang KK, Lutzke LS, et al. Combined endoscopic  mucosal resection and photodynamic therapy for esophageal  neoplasia within Barrett's esophagus. Gastrointest Endosc.  2001:54;682-688. [PMID: 11726842]   Buttar NS, Wang KK, Sebo TJ, et al. Extent of high-grade dysplasia  in Barrett's esophagus correlated with risk of adenocarcinoma.  Gastroenterology. 2001;120:1630-1639. [PMID: 11375945]   Ganz RA, Overholt BF, Sharma VK, et al. Circumferential ablation  of Barrett's esophagus that contains high-grade dysplasia: a U.S.  Multicenter Registry. Gastrointest Endosc. 2008;68:35-40.  [PMID: 18355819]   Prasad GA, Wang KK, Buttar NS, et al. Long-term survival follow-  ing endoscopic and surgical treatment of high-grade dysplasia  in Barrett's esophagus. Gastroenterology. 2007:132;1226-1233.  [PMID: 17408660]   Reid BI, Levine DS, Longton G, et al. Predictors of progression to  cancer in Barrett's esophagus: baseline histology and flow  cytometry identify low and high-risk patient subset. Am J  Gastroenterol. 2000;95:1669-1676. [PMID: 10925966]   Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical  management of Barrett's esophagus with high-grade dysplasia.  Gastroenterology. 2001;120:1608-1619. |PMID: 11375943]   Spechler SI, Lee A, Ahnen D, et al. Long-term outcome of medical  and surgical therapies for gastro-esophageal reflux disease: a  follow-up of a randomized controlled trial. JAMA. 2001:285;  2331-2338. [PMID: 11343480]   Weston AP, Sharma P, Topalovski M, et al. Long-term follow-up of  Barrett's high-grade dysplasia. Am J Gastroenterol. 2000;95:  1888-1893. [PMID: 10950031]   The vast majority of patients with Barrett esophagus have no  long-term sequelae from the presence of their metaplastic  esophageal epithelium other the inconvenience of undergo-  ing surveillance endoscopy. Patients should be reassured that   despite the increased risk of progression to adenocarcinoma,  the number of patients who progress is very small, and  patients can be cured provided they adhere to a surveillance  protocol. The goal of treatment of patients with Barrett esoph-  agus is to adequately control their GERD, which empiric evi-  dence suggests may prevent progression to malignancy. If  patients require antireflux surgery to control their GERD, the  risk of adenocarcinoma is not reduced and continued sur-  veillance is required, even if the patient is asymptomatic.   As mentioned previously, there have been attempts to jus-  tify treating nondysplastic Barrett esophagus by endoscopic  ablative therapies. Currently there are no long-term studies  regarding the cost-effectiveness, safety, and efficacy of this  practice. A decrease in the incidence esophageal cancer in  patients who have undergone ablative therapies of nondys-  plastic Barrett esophagus has not been demonstrated.   Therefore, at present, ablating nondysplastic Barrett esopha-  gus cannot be recommended.   The course and prognosis for the majority of patients  with Barrett esophagus is benign and, despite the anxiety that  this diagnosis can provoke in patients, the disease can be  managed effectively by appropriate surveillance, acid sup-  pression therapy, and patient reassurance.   Corey KE, Schmitz SM, Shaheen NJ. Does a surgical antireflux pro-  cedure decrease the incidence of esophageal adenocarcinoma in  Barrett's esophagus? A meta-analysis. Am J Gastroenterol. 2003;98:  2390-2394. [PMID: 14638338]   Ye W, Chow WH, Lagergren J, et al. Risk of adenocarcinoma of the  esophagus and cardia in patients with gastroesophageal reflux  disease after antireflux surgery. Gastroenterology. 2001;121:  1286-1293. [PMID: 11729107]   Oropharyngeal and esophageal motility disorders have a signif-  icant impact on patients' quality of life. Mechanical and func-  tional problems can interact to cause patients' symptoms; thus,  diagnosis of these disorders can sometimes be challenging.   Dysphagia must be distinguished from other symptoms  such as odynophagia (pain on swallowing, suggestive of a  defect in mucosal integrity, eg, from trauma, irradiation,  inflammation, or infection), and aphagia (inability to swal-  low, generally suggestive of obstruction in patients present-  ing acutely). Symptoms that do not necessarily correlate with  the immediate process of swallowing, such as rumination  and globus sensation, should also be discerned. Acute dys-  phagia most often results from mechanical obstruction, such  as food impaction.   Dysphagia can be differentiated into two categories:  (1) oropharyngeal (also called transfer dysphagia), arising  from disorders affecting the oropharynx, larynx, and upper  esophageal sphincter (UES); and (2) esophageal, arising from  the esophagus, lower esophageal sphincter (LES), or gastroe-  sophageal junction. The causes of dysphagia are many, and  specific entities are considered here.   Massey BT, Shaker R. Oral pharyngeal and upper esophageal  sphincter motility disorders. GI Motility Online. Available at:  http://www.nature.com/gimo/index.html; doi:10.1038/ gimol9,  2006.   Paterson WG, et al. Esophageal motility disorders. GI Motility  Online. Available at: http://www.nature.com/gimo/index.html;  doi: 10.1038/gimo20,2006.   Wise JL, Murray IA. Oral, pharyngeal and esophageal motility dis-  orders in systemic diseases. GI Motility Online. Available at: http://  www.nature.com/gimo/index.html; doi: 10.1038/ gimo40, 2006.   ► History of poor oral bolus preparation and control, diffi-  culty in initiating a swallow, nasal and oral regurgitation,  aspiration and coughing with swallowing, food sticking  at the level of the throat.   Many neuromuscular disorders can cause dysphagia  (Table 13-1). Among these are various disorders causing  cortical lesions; supranuclear, nuclear, and cranial nerve  lesions; defects of neurotransmission at the motor end plates;  and muscular diseases.   Many patients with dysphagia are elderly and hence  develop this symptom secondary to other disorders (eg,  stroke). History of strokes or other neurologic illnesses, nasal  regurgitation and frequent coughing immediately upon  swallowing, and poor oral coordination of bolus formation  or dysphonia may help suggest the greater likelihood of  oropharyngeal dysphagia over esophageal dysmotility, but  diagnosis, assessment of severity, and therapeutic interven-  tion are generally guided by VFSS.   • Altered consciousness, metabolic encephalopathy, encephalitis,  meningitis, cerebrovascular accident, brain injury   c. Neuropathy (Guillain-Barre syndrome, familial dysautonomia, sarcoid,  diabetic, and other causes)   Adapted, with permission, from Goyal RK. Dysphagia. In: Fauci AS,  et al (editors). Harrison's Principles of Internal Medicine,^ 7th ed.  McGraw-Hill, 2008:237-240.   transport and may aggravate the symptoms of pharyngeal  stasis. On the other hand, a hypotonic UES may lead to  esophagopharyngeal reflux and aspiration not related to  swallowing.   Because many neuromuscular structures involved in  swallowing are also involved in speech, dysarthria and dys-  phonia are common in these patients. Moreover, patients  usually have evidence of neuromuscular defects in other  parts of the body. Many patients with oropharyngeal dyspha-  gia have impaired consciousness and cognitive functions that  may make evaluation difficult.   VFSS is the study of choice for the evaluation of oropharyn-  geal dysphagia (Figure 13-1). VFSS allows slow-motion  replay of oropharyngeal swallowing. This aids in identifying  defects of the oropharyngeal phase of swallowing, which  normally takes less than a second to complete. Barium swal-  low or an upper gastrointestinal series is not useful in evalu-  ation of oropharyngeal dysphagia. Plain radiographs and  computed tomography (CT) scan of the neck are useful in  evaluating structural lesions such as tumors and cysts.  Imaging studies should be obtained prior to upper  endoscopy, because pharyngeal and upper esophageal abnor-  malities such as diverticula and malignant strictures can per-  forate in this poorly visualized region.   Gramigna GD. How to perform videofluoroscopic swallowing stud-  ies. GI Motility Online. Available at: http://www.nature.com/  gimo/index.html; doi: 10.1038/gimo95, 2006.   History and physical examination provide the most valuable  information in making the diagnosis. Defects in different  phases of oropharyngeal swallowing should be identified by  careful analysis of symptoms and signs.   Defects in the oral preparatory phase of swallowing mani-  fest as chewing problems, oral stasis of food, inability to form  a bolus, and coughing, choking, or aspiration pneumonia  from regurgitation and aspiration. These symptoms occur  during or immediately after the onset of swallowing. Liquids  are usually more problematic than solids in causing symptoms  of misdirection.   Generally, problems in the pharyngeal phase result in dys-  phagia, which the patient localizes to the throat. Often the  patient makes repeated attempts to clear the throat of food  or saliva.   Abnormalities of the UES phase have no distinctive symp-  toms, but impaired UES opening further impairs pharyngeal   Because of the complex anatomy of the oral and pharyngeal  passages, intraluminal manometry is not usually helpful.  However, it may be useful in the evaluation of upper  esophageal function and resistance to flow across the UES.   Regular upper endoscopy is not helpful in the evaluation of  oropharyngeal dysphagia; however, videoendoscopy, avail-  able at some specialized centers, can provide information  about oropharyngeal dysfunction.   Figure 13-2 is an algorithm outlining an approach to the  patient with oropharyngeal dysphagia.   The major complications of oropharyngeal dysphagia are  fatal pulmonary aspiration and pneumonia, malnutrition,  and weight loss.    ▲ Figure 13-1. Radiologic appearance of oropharyngeal motility disorders. A: Frontal view of the pharynx demon-  strates aspiration of retained bolus. Note that there is retention of contrast in the valleculae (v) and piriform sinuses  (ps). No swallow is taking place, yet there is entry of contrast into the laryngeal vestibule (ve) and between the vocal  folds and in the ventricle (arrows). B: A stop-frame print from a cinepharyngogram in the lateral position shows  incomplete laryngeal closure during swallowing with laryngeal penetration (arrows) and aspiration (arrowheads)  down into the trachea. The bolus is passing through the open cricopharyngeus into the cervical esophagus.  Degenerative change is noted in the cervical spine. C: Cricopharyngeal bar. D: Zenker diverticulum. (Reproduced, with  permission, from (A) Jones B (editor): Normal and Abnormal Swallowing: Imaging in Diagnosis and Therapy, 2nd edition.  Springer-Verlag, 2003; (B) Jones B, Donner MW (editors): Normal and Abnormal Swallowing: Imaging in Diagnosis and  Therapy. Springer-Verlag, 1991.)   Evaluation and management by a deglutition team consisting  of a deglutitionist (speech and swallow therapist), radiologist,  gastroenterologist, otolaryngologist, and neurologist provides  the best outcome in the care of these patients. Deglutitionists  assess the risk of aspiration, type of food, and patient posture  that is most likely to prevent aspiration and facilitate safe swal-  lowing. Certain rehabilitative exercises to strengthen swallow-  ing muscles may be helpful. Investigations are performed to  find the underlying cause of the disorder and appropriate  therapy, if available, is initiated. If safe oral feeding cannot be  undertaken, a percutaneous endoscopic gastrostomy (PEG)  tube is placed by a gastroenterologist. The overall management  of the patient, rather than focused treatment of the swallow-  ing difficulty, is essential for effective management.   Prognosis depends on the underlying cause, compliance  with therapy, and prevention of acute pulmonary compli-  cations. Patients with cerebrovascular accidents usually  regain their swallowing function with time. Those with dis-  eases such as myasthenia gravis, metabolic myopathies such  as thyroid disorders, polymyositis, and Parkinson disease  usually respond to appropriate treatment. Other patients,  such as those with muscular dystrophy and multiple sclerosis,   2005;39:357-371. [PMID: 15815202]  Cook IJ. Clinical disorders of the upper esophageal sphincter. GI   index.html; doi: 10.1038/gimo37, 2006.  Curtis IL. Pulmonary complications of oral-pharyngeal motility   nature.com/gimo/index.html; doi: 10.1038/gimo33, 2006.  Ford CN. Evaluation and management of laryngopharyngeal   reflux. JAMA. 2005;28:1534-1540. [PMID: 16189367]  Goyal RK. Dysphagia. In: Fauci AS, et al (editors). Harrison's   2008:237-240.  Logemann JA. Medical and rehabilitative therapy of oral, pharyn-  geal motor disorders. GI Motility Online. Available at: http://   Cricopharyngeal achalasia involves persistent spasm or fail-  ure of relaxation of the UES. It is classified as primary if the  abnormality is confined to the cricopharyngeus muscle with-  out neurologic or systemic cause, and secondary if produced  by another disease process. Primary cricopharyngeal achalasia,   Difficulty in initiating a swallow, misdirectional food  causing coughing, choking, or nasal regurgitation   ▲ Figure 13-2. Algorithm outlining an approach to the patient with dysphagia. ENT, ear, nose, throat; VFSS, videofluroscopic swallowing study.   in turn, is subdivided into idiopathic and intrinsic myopathies  (eg, polymyositis, inclusion body myositis, muscular dystro-  phy, and hypothyroidism). Secondary causes include amy-  otrophic lateral sclerosis, polio, oculopharyngeal dysphagia,  stroke, and peripheral nerve disorders such as myasthenia  gravis and diabetic neuropathy. Gastroesophageal reflux has  also been suggested to cause cricopharyngeal spasm.   The diagnostic criteria for this entity are subject to much  controversy. The plain radiographic appearance is not reliable  in making this diagnosis, and some experts advocate highly  specialized radiologic (VFSS) and solid-state manometric  probe studies. However, many clinicians base their diagnosis  simply on symptoms. Thus, the true incidence is unknown but  may involve 5-25% of patients being evaluated for dysphagia.   The classic finding is a cricopharyngeal bar, which results  from failure of the cricopharyngeus to relax but normal for-  ward movement of the larynx on swallowing. Barium swal-  low shows a characteristic prominent projection on the  posterior wall of the pharynx at the level of the lower part of  the cricoid cartilage (see Figure 13-1C). A transient cricopha-  ryngeal bar is seen in up to 5% of individuals without dyspha-  gia undergoing upper gastrointestinal studies; it can be  produced in normal individuals during a Valsalva maneuver. A  persistent cricopharyngeal bar may be caused by fibrosis in the  cricopharyngeus.   Cricopharyngeal myotomy is usually not helpful unless  obstruction at the cricopharyngeus is demonstrated by vide-  ofluoroscopy in a severely symptomatic patient. Similarly,  local injection of botulinum toxin for cricopharyngeal acha-  lasia is falling out of favor with recognition that the injection  is rarely well localized to the affected muscles and effects  appear to be short lived. However, a trial injection may be  considered to aid in making the diagnosis, or for patients  who are poor surgical candidates. These procedures are con-  traindicated in patients with cervical tumors, and relatively  contraindicated in those who have a fibrotic lesion after neck  irradiation, or who have a progressive neurologic disorder  such as bulbar palsy. One exception appears to be patients  with oculopharyngeal dysphagia, who appear to do well with  surgical myotomy or with repeated dilations. Myotomy is  also contraindicated in the presence of severe gastroe-  sophageal reflux because it may lead to pharyngeal and pul-  monary aspiration. In patients with gastroesophageal reflux,  aggressive therapy with proton pump inhibitors is warranted  in addition to management of the underlying disorder.   Zenker diverticulum arises in the posterior wall of the  hypopharynx, just above the cricopharyngeus muscle. The  pathogenesis of Zenker diverticulum is not fully understood.  It may form due to natural weakness of the pharynx (Killian  triangle) associated with impaired opening of the cricopha-  ryngeus muscle. Barium swallow or VFSS shows characteristic  findings that allow easy diagnosis (see Figure 13-1D). With  time, the diverticulum may become very large. Zenker   diverticulum may retain food and secretions and classically  leads to halitosis, delayed regurgitation, recurrent aspiration,  and pneumonia. Dysphagia is usually due to compression of  a food-filled diverticulum of the esophagus. Treatment is  diverticulectomy with cricopharyngeal myotomy.   Globus pharyngeus is a common functional disorder charac-  terized by the sensation of a lump in the throat but without  any difficulty in swallowing. This disorder is more common  in women than in men, and is often associated with an  underlying psychiatric disorder. Many of these patients also  have gastroesophageal reflux disease (GERD). Findings on  barium swallow are normal. Results of upper endoscopy and  esophageal motility studies, when performed, also are nor-  mal. Treatment of associated GERD is sometimes helpful in  alleviating the symptom of globus pharyngeus. In most  cases, treatment consists of reassurance.   Three esophageal motility disorders commonly seen in clin-  ical practice are esophageal motor dysphagia, GERD, and  esophageal chest pain. In these disorders, symptoms result  from dysfunction of one or more of the mechanisms neces-  sary for normal esophageal function.   Esophageal motility disorders are classified, depending on  the involvement of one or more of the three components of  esophageal peristalsis, as disorders of inhibitory innervation,  excitatory innervation, or smooth muscles (Figure 13-3).   The inhibitory innervation to the esophagus consists of  vagal preganglionic neurons and the postganglionic neurons  in the myenteric plexus, which release vasoactive intestinal  peptide (VIP) and nitric oxide. The inhibitory pathway is  responsible for relaxation of the LES and the gradient of  peristaltic contraction in the esophageal body. Deficiency of  inhibitory innervation results in achalasia and diffuse  esophageal spasm. In achalasia, both the LES and esophageal  body are affected, whereas in diffuse esophageal spasm, the  esophageal body is primarily affected. Increased inhibitory  nerve activity is responsible for so-called transient LES relax-  ation (TLESR).   The excitatory innervation consists of vagal preganglionic  neurons and postganglionic neurons that release acetylcholine  and substance P. The excitatory nerves contribute to basal LES  hypertension, hypertensive contraction, and the force of peri-  staltic contraction. Deficiency of the excitatory nerves causes  hypotensive LES and hypotensive peristaltic contractions. The  esophageal body and LES consist of phasic and tonic muscles,  respectively. Phasic muscles of the esophageal body contract  during peristalsis, and tonic muscles of LES are responsible for  tonic contraction. Muscle disorders may lead to hypotensive  LES and hypotensive peristalsis.   ▲ Figure 13-3. Pathophysiologic classification of motor disorders of the smooth muscle portion of the esophagus. DES,  diffuse esophageal spasm; GERD, gastroesophageal reflux disease; LES, lower esophageal sphincter; LM, longitudinal  muscle; TLESR, transient lower esophageal sphincter relaxation.   Goyal RK, Sivarao DV. Functional anatomy and physiology of swal-  lowing and esophageal motility. In: Castell DO, Richter JE  (editors). The Esophagus, 4th ed. Lippincott Williams & Wilkins,  2003:1-31.   Goyal RK. Diseases of the esophagus. In: Fauci AS, et al (editors).  Harrison's Principles of Internal Medicine, 1 7th ed. McGraw-Hill,  2008:1847-1855.   ► Dysphagia to solids and liquids, localized to the chest or  throat.   ► Coughing and choking spells at night and unrelated to  swallowing.   ► Confirmation of abnormal motility by barium study and  esophageal manometry.   Dysphagia must be distinguished from odynophagia (pain  on swallowing); the latter suggests a breach in mucosal  integrity by trauma, infection, and inflammation. The role of  upper endoscopy is to rule out mucosal abnormalities such  as strictures, webs, malignancies, infections, and eosinophilic   esophagitis. Full-column barium swallow may reveal muscu-  lar rings, which are often missed on endoscopy. Manometric  studies differentiate specific motility disorders.   Motor dysphagia in the thoracic esophagus occurs when deg-  lutitive inhibition is lacking, due to loss of inhibitory nitrergic  nerves, and peristaltic contractions become nonperistaltic;  when the LES does not relax properly; or when the peristaltic  contractions are weakened due to muscle weakness. Causes of  esophageal motor dysphagia are listed in Table 13-2.   Dysphagia resulting from dysfunction of the esophageal  body is described as a feeling that the bolus becomes "stuck"  or "hung up" on the way down. This may be accompanied by  pain or discomfort. The patient typically describes difficulty  in swallowing both solids and liquids. Although most  patients feel as though the bolus stops at the level of the  suprasternal notch, the area of obstruction may be well below  this. Many patients have associated symptoms of regurgitation  and chest pain.   Chest radiographs may show mediastinal widening and air-  fluid level when a food-filled dilated esophagus is present as  in long-standing achalasia. Barium swallow may show the   Adapted, with permission, from Goyal RK. Dysphagia. In: Fauci AS,  et al (editors). Harrison's Principles of Internal Medicine, 17th ed.  McGraw-Hill, 2008:237-240.   characteristic appearance of achalasia or diffuse esophageal  spasm (Figure 13-4). Radiographic studies also help in  excluding mechanical causes of dysphagia. Videofluoroscopic  examination of the esophagus may identify abnormalities in  peristaltic sequence and in the force of peristaltic contractions.   Esophageal manometry can be used to measure the strength  (amplitude), duration, and sequential nature of the con-  tractions of the esophageal body, as well as the resting pres-  sure and relaxation of the LES. This technique involves  passage, through the nose and into the esophagus and stom-  ach, of a small, flexible catheter with an array of pressure  sensors. Figure 13-5 summarizes patterns of esophageal  motility in normal subjects and in a variety of esophageal  motility disorders.   Endoscopy is required in most patients with esophageal  motility disorders that cause dysphagia. This step is necessary  to exclude mechanical causes of dysphagia, mechanical  lesions such as peptic stricture and other complications of an  erosive esophagitis, and lesions such as gastroesophageal  junction adenocarcinoma that may produce secondary acha-  lasia. Biopsies at multiple levels of the esophageal body are  also often obtained to rule out eosinophilic esophagitis.    ▲ Figure 13-4. Radiologic appearance of motor disorders  of the smooth muscle portion of the esophagus. A: Note  the sigmoid-shaped esophagus and "bird-beaking" of the  lower end in achalasia. B: Corkscrew appearance in diffuse  esophageal spasm. (B: Courtesy of Dr. Harvey Goldstein)   Refer to Figure 13-2, which outlines an approach to the patient  with dysphagia.   Management of esophageal motility disorders depends on the  type of the disorder and its clinical consequences. (For details,  see "Disorders of Inhibitory Innervation" and "Disorders of  Excitatory Nerves and Smooth Muscles" later in this chapter.)   2005;39:357-371. [PMID: 15815202]  Goyal RK. Dysphagia. In: Fauci AS, et al (editors). Harrison's   GERD is the most common manifestation of impaired  esophageal motility and one of the most common disorders  seen in clinical practice. The basic cause of GERD is incom-  petent antireflux barriers at the gastroesophageal junction,  which normally prevents backflow of gastric acid into the  stomach. Competence of the gastroesophageal barrier is the  result of the intra-abdominal location of the LES, mucosal  folds at the gastroesophageal junction, LES closure, reflex   ▲ Figure 13-5. Motility patterns in esophageal smooth muscle disorders. LES, lower esophageal sphincter; UES, upper  esophageal sphincter. (Adapted, with permission, from Goyal RK: Diseases of the Esophagus. In: Fauci AS, et al (editors):  Harrison's Principles of Internal Medicine, 17th ed. McGraw-Hill, 2008.)   LES contraction, and the diaphragmatic crura. Factors such  as increased intra-abdominal pressure and gastric stasis  increase the likelihood of developing GERD.   The pathogenesis of gastroesophageal reflux is complicated  and multifactorial. Important esophageal motor abnormali-  ties underlying GERD are hypotensive LES, TLESR, or both.  Hypotensive esophageal contractions are commonly associ-  ated with hypotensive LES and contribute to reflux-associated  esophageal mucosal damage.   Although the main clinical manifestations of GERD are  heartburn and regurgitation, other manifestations may  occur. Moreover, the majority of patients with GERD do not  have symptoms. Manifestations and complications of GERD  are discussed in detail in Chapter 11,   gimo/index.html; doi: 10.1038/gimo21, 2006.  Harding SM. Gastroesophageal reflux and chronic cough. GI Motility   ► Rule out panic disorder, related psychiatric disorders,  and musculoskeletal disorders.   ► Well-accepted causes are reflux esophagitis, achalasia,  and diffuse esophageal spasm.   ► Probable causes are hypertensive esophageal motor dis-  orders, sustained longitudinal muscle contraction, and  esophageal hypersensitivity.   Heartburn and odynophagia are classical symptoms of  esophageal disease. However, some patients with esophageal  disorders present with chest pain that is neither typical  heartburn nor odynophagia. Esophageal chest pain may  resemble cardiac chest pain. This overlap is due to the spinal  primary sensory afferent that carries cardiac and esophageal  nociceptive information and also innervates common cuta-  neous segments.   For practical purposes, causes of chronic esophageal chest  pain can be divided into well-accepted and possible causes.   Well-established causes of chest pain are reflux esophagitis  and motility disorders such as achalasia and diffuse  esophageal spasm. Overall, reflux esophagitis is the most  common cause of noncardiac chest pain.   Esophageal disorders that have been proposed as causes of  chest pain are hypertensive esophageal motility disorders,  sustained longitudinal muscle contraction, esophageal  hypersensitivity, and esophageal sensory neuropathy.   esophageal motility disorders, particularly those associated  with hypertensive esophageal peristaltic contractions (so-  called nutcracker esophagus), hypertensive LES, and hyper-  contracting LES, have been identified during manometric  evaluation of patients with unexplained chest pain. Therefore,  these manometric diagnoses were proposed as causing chest  pain. However, a causal relationship has not been established.  Moreover, a temporal association between these conditions  and chest pain has not been documented, and treatment of the  hypercontractile states with smooth muscle relaxants has not  proved to be effective in the relief of chest pain.   high-resolution endoscopic ultrasound has shown that  episodes of chest pain are associated with sustained contrac-  tion of the esophageal longitudinal muscle. The longitudinal  muscle contraction remains undetected by intraluminal  manometry. Therefore, sustained esophageal longitudinal  muscle contraction has been proposed as a cause of chest  pain in patients with normal esophageal manometry. Further  studies are needed to fully establish this sustained contrac-  tion as the cause of unexplained chest pain.   recent studies have suggested that the esophagus may develop  sensory hypersensitivity, in which stimuli that do not nor-  mally produce pain are perceived as painful. Esophageal  hypersensitivity may be a part of generalized visceral hyper-  sensitivity. The pathophysiology of visceral hypersensitivity is  not fully understood but may occur peripherally in the  esophageal afferent nerves or centrally in the central nervous  system. Esophageal hypersensitivity is demonstrated by show-  ing a reduced threshold to esophageal balloon distention.  Esophageal mucosal hypersensitivity can also be tested by the  esophageal acid perfusion test (Bernstein test), discussed later.   Chest pain is a common and alarming symptom. Acute chest  pain syndromes are due to life-threatening conditions such  as myocardial infarction, aortic dissection, esophageal perfo-  ration, acute bolus obstruction, or penetrating esophageal  ulcer. Patients with these conditions require emergent care.   Patients presenting with chronic chest pain should  undergo careful clinical evaluation to classify them into the  following broad groups: cardiac chest pain, musculoskeletal  chest pain, psychosomatic chest pain, esophageal chest pain,  and miscellaneous causes of chest pain. In the majority of  patients, the origin of chest pain is easily identified and   treated. However, in some patients, the origin of chest pain  remains obscure.   Lee R, Mittal R. Heartburn and esophageal pain. GI Motility  Online. Available at: http://www.nature.com/gimo/index.html;  doi: 10.1038/gimo75, 2006.   An algorithm outlining an approach to the patient with chest  pain of unknown origin (CPUO) is presented in Figure 13-6.  A working definition of CPUO has not been developed.  However, it is clear that this diagnosis should be used only  after careful initial evaluation. For example, cardiac evalua-  tion and treatment should be performed for patients with  ischemic heart disease and typical symptoms of cardiac  ischemia; a trial of a proton pump inhibitor should be initi-  ated for patients suspected of having heartburn and GERD; a  trial of nonsteroidal anti-inflammatory drugs (NSAIDs) and  possibly skeletal muscle relaxants should be used for those  with musculoskeletal disorders; and a therapeutic trial  should be started for those with panic disorder.   Patients in whom the initial evaluation does not yield a cause  are identified as having CPUO. The first step in the evalua-  tion of a patient with CPUO is to carefully exclude coronary  artery disease because of the life-threatening nature of cardiac  chest pain. This may require coronary angiography, which  remains the gold standard, apart from careful consideration  of cardiac causes of chest pain. The speculative cardiac causes  of chest pain include microvascular angina or syndrome X.  This diagnosis is sometimes considered in patients with atyp-  ical anginal symptoms and normal coronary arteries, espe-  cially when abnormalities are present on noninvasive tests of  cardiac function such as exercise radionuclide angiography or  exercise thallium scintigraphy. Similarly, mitral valve prolapse  is frequently present in patients with chest pain of undeter-  mined etiology; however, most investigators agree that it does  not cause chest pain. CPUO patients in whom cardiac causes  of chest pain have been excluded are identified as having non-  cardiac chest pain. These patients require careful screening for  esophageal, musculoskeletal, psychosomatic, and miscella-  neous causes of chest pain.   Reflux esophagitis is one of the most common causes of  esophageal chest pain. Among patients with reflux, 10-20%  will have chest pain alone, and reflux esophagitis remains the  most common cause of unexplained chest pain. Therefore, the  first step is to prescribe a therapeutic trial of a proton pump  inhibitor if this therapy has not already been initiated. If there  is no satisfactory response, the patient should undergo endo-  scopic examination. Esophageal erosions, ulcers, and peptic stric-  tures provide evidence of GERD, which should be treated   ▲ Figure 13-6. Algorithm outlining an approach to the patient with unexplained chest pain. CPUO, chest pain of  unknown origin; DES, diffuse esophageal spasm; Dx, diagnosis; EGD, esophagogastroduodenoscopy; ECG, electrocardio-  gram; EUS, esophageal ultrasound; Rx, prescription; PPI, proton pump inhibitor; TCA, tricyclic antidepressant. (Reproduced,  with permission, from Fang J, Bjorkman D: A critical approach to noncardiac chest pain: pathophysiology, diagnosis, and  treatment. Am J Gastroenterol. 2001;96:958.)   with a proton pump inhibitor, including high-dose therapy if  needed. If no or minimal mucosal abnormalities are found,  high-magnification endoscopy or narrow band image  endoscopy may be performed to look for microerosions.  Mucosal biopsies should be obtained in patients with nega-  tive endoscopic results. These patients should undergo pH  monitoring by placement of a pH capsule in the distal esoph-  agus. If capsule monitoring is not available, 24-hour ambu-  latory esophageal pH testing should be performed. Mucosal  biopsy specimens may show enlarged intercellular spaces,  which are thought to represent very early mucosal damage  in reflux esophagitis. Patients having abnormal mucosal  biopsy and esophageal pH findings are diagnosed as having   nonerosive reflux disease and treated aggressively with pro-  ton pump inhibitor therapy.   Fass R, Dickman R. Nonerosive reflux disease. GI Motility Online.  Available at: http://www.nature.com/gimo/index.html; doi:  10.1038/gimo42, 2006.   In patients showing no evidence of esophagitis, intraluminal  manometry should be performed to evaluate for the pres-  ence of motility disorders such as early achalasia, diffuse   esophageal spasm, and hypertensive esophageal motility.  These disorders comprise only a small number of cases of  unexplained chest pain. Patients who have normal esophageal  motility should be evaluated for esophageal hypersensitivity  by determining the threshold to esophageal distention by  intraesophageal balloon inflation. Mucosal sensitivity may be  determined by the acid perfusion test (also called the Bernstein  test), in which 0.1% hydrochloric acid is perfused by catheter  into the distal esophagus.   The antidepressant trazodone (100-150 mg/day), which  has no direct effect on esophageal motility, has been effective  in decreasing the distress of esophageal symptoms in patients  with motility disorders. This suggests that underlying psychi-  atric problems may play a role in patients with esophageal  motility abnormalities. Use of trazodone in men is limited by  the side effect of priapism. Surgical myotomy has no role in  the management of patients with chest pain and motility dis-  orders other than achalasia.   The diagnosis of musculoskeletal chest pain may be over-  looked in the initial evaluation of the patient with CPUO.  Careful history and physical examination is required. Several  musculoskeletal disorders may cause chest pain. Localized  myofascial pain, ankylosing spondylitis, fibromyalgia, Tietze  syndrome, rheumatoid arthritis, thoracic outlet syndrome,  and "slipping rib" syndrome should be considered in the dif-  ferential diagnosis. The diagnosis of fibromyalgia is based on  at least a 3-month history of widespread pain, with more  than 10-18 trigger points of tenderness on digital palpation.  Patients with musculoskeletal chest pain are treated with  reassurance, application of local heat, NSAIDs, and corticos-  teroid-lidocaine injection when appropriate. Patients with  fibromyalgia may benefit from cyclobenzaprine (2.5-10 mg  four times daily) or amitriptyline (10-50 mg at bedtime).   Psychiatric disorders, including depression, anxiety, and panic  disorder, may not be recognized initially as a cause of chest  pain, in part because these disorders are very common in clin-  ical practice, affecting approximately 5% of the U.S. popula-  tion. Patients with symptoms of panic and anxiety should be  referred to a psychiatric specialist for diagnostic evaluation and  treatment. Treatment of these disorders includes antidepres-  sants, anxiolytics, and cognitive-behavioral therapy. Many  patients with these disorders require education about their dis-  ease, and gentle persuasion and reassurance that effective treat-  ment exists, before they will accept these recommendations.   It is important to recognize the various disorders that cause  chest pain as they are very common and more than one cause  may be present concurrently. For example, the incidence of  GERD is markedly increased in patients with ischemic heart   disease because of the overlapping risk factors for the two  diseases and also because smooth muscle relaxants that are  used in the treatment of coronary angina aggravate GERD.  Similarly, patients with unexplained chest pain may be diag-  nosed with esophageal motility disorder, panic disorder, and  microvascular angina. Moreover, many of these patients  complain of characteristic chest pain during catheterization  with right ventricular stimulation, suggesting a heightened vis-  ceral nociception.   Patients with CPUO have a normal survival rate. However,  their quality of life and functional status are markedly  impaired. Most patients continue to experience chest pain  and functional impairment even after a diagnosis of CPUO  has been made, resulting in high utilization of health care  resources and associated medical costs.   Fang J, Bjorkman D. A critical approach to noncardiac chest pain:  pathophysiology, diagnosis, and treatment. Am J Gastroenterol  2001;96:958-968. [PMID: 11316212]   ► Regurgitation of undigested food without acid or bile;  episodes of pneumonia.   ► Chest radiograph may show a mediastinal mass with  air-fluid levels.   ► Barium esophagogram shows a dilated esophagus with-  out peristalsis and a "bird beak" in the distal esophagus.   ► Esophageal manometry shows nonperistalsis esophageal  contractions and failure of LES relaxation on swallowing.   Achalasia is a disorder of the thoracic esophagus character-  ized by nonperistaltic esophageal contractions and impaired  relaxation of the LES in response to swallowing. It results  primarily from degeneration of nitrergic inhibitory neu-  rons in the myenteric plexus. Achalasia is an important  but uncommon clinical disorder with an incidence of 1 in  100,000 persons. It most often manifests between the ages of  25 and 50 years but affects patients of all ages, and both sexes.   Diagnosis is generally established on the basis of radiologic  findings and manometric studies, and by ruling out second-  ary causes such as cancer. Definitive therapy is surgical  myotomy, but various medical and endoscopic treatments  have been employed for symptomatic relief.   Achalasia is associated with degeneration of postganglionic  inhibitory neurons, which release nitric oxide and VIP.  Postganglionic excitatory neurons may also be affected in  advanced disease. Preganglionic vagal fibers and vagal nuclei  may also be involved.   Most cases in the United States are of no known cause and  are classified as idiopathic achalasia. A viral etiology for the  inflammation has also been proposed, and elevated antibody  titers to measles and varicella zoster have been described in a  high proportion of patients with idiopathic achalasia.  Autoimmunity has been proposed as contributing to the etiol-  ogy based on observation of T-lymphocyte infiltration in the  myenteric plexus, and there is a higher prevalence of the disor-  der in patients with certain HLA types. Autoantibodies to neu-  rons are also found in many patients with achalasia.   Familial achalasia comprises about 2-5% of all cases and  generally involves an autosomal-recessive mode of inheri-  tance, particularly in children younger than 4 years of age. In  children, this may be part of the AAA syndrome (achalasia,  alacrima, achlorhydria), which may also be associated with  adrenocorticotropic hormone insensitivity, microcephaly,  and nerve deafness. Additionally, a small percentage of  patients have associated neurodegenerative diseases such as  Parkinson disease and hereditary cerebellar ataxia.   Secondary achalasia refers to inhibitory neuronal degenera-  tion caused by a known etiologic agent such as Trypanosoma  cruzi (the causative organism in Chagas disease) and carcinoma.   Although the cause of primary achalasia is largely  unknown, degenerative changes have been noted in the dorsal  motor nucleus (Lewy bodies), along with degeneration of  vagal fibers and loss of ganglion cells in the esophageal body  and LES. In particular, there may be an inflammatory  response, predominantly of T-cell lymphocytes. However,  these changes are not consistent and may be secondary to an  enteric nervous system disease involving loss of nitrergic and  VIP-containing neurons (the main relaxatory mediators of the  esophageal smooth muscle) and a decrease in the number of  interstitial cells of Cajal. Muscular hypertrophy, possibly sec-  ondary to the denervation, and variable extent of muscle  degeneration have also been described. However, these muscu-  lar and neuronal changes cannot be assessed by evaluation of  mucosal biopsies obtained during endoscopy.   Hirano I, Pathophysiology of achalasia and diffuse esophageal  spasm. GI Motility Online. Available at: http://www.nature.com/  gimo/index.html; doi: 10.1038/gimo22, 2006.   Dysphagia is the most common presenting symptom of  achalasia and is present in nearly all patients. Dysphagia to  both liquids and solids is characteristic of this disease; how-  ever, symptoms may initially involve primarily solids, followed  by liquids. Dysphagia is mainly localized to the lower chest,  although it may be localized to the neck. Generally, it is wors-  ened by emotional stress or hurried eating. Patients often  complain of taking longer to eat a meal, or of drinking a large  amount of liquid to clear the food from the esophagus. They  may even describe having to stand up, perform the Valsalva  maneuver, or arch their backs to help clear food from the  esophagus.   The second most frequent presenting symptom is regurgi-  tation of food, which is generally undigested, nonbilious, and  nonacidic. Patients may wake in the middle of the night as a  result of coughing or choking after regurgitation, the content  of which is often described as white and foamy, arising from  an inability to clear saliva from the esophagus. Chest pain and  heartburn occur in approximately 40% of patients and can be  misdiagnosed as GERD. However, the heartburn is generally  not post-prandial or responsive to antacids.   Mild weight loss is noted in approximately 85% of patients  and may even mimic cancer when profound. However, the  interval from the presenting symptom to the point at which the  patient seeks medical attention is quite variable, sometimes  extending beyond a decade.   Some patients with idiopathic achalasia have increased anti-  neuronal antibodies, including anti-Hu-1 antineuronal anti-  bodies. Enzyme-linked immunosorbent assay (ELISA) tests,  agglutination tests, and confirmatory assays, including  immunofluorescence, immunoblot, Western blot, and  radioimmunoprecipitation tests, may aid in identifying T cruzi  in patients with achalasia caused by Chagas disease.   Barium esophagogram, the preferred initial method of evalua-  tion in patients with dysphagia, may reveal characteristically  smooth, symmetric narrowing or "bird-beaking" of the distal  esophagus, and often a dilated esophagus with no peristaltic  activity and poor esophageal emptying. In severe achalasia,  chest radiographs may reveal a dilated esophagus containing  food, possibly air-fluid level within the esophagus in the upright  position, absence of gastric air bubble, and sometimes a tubular  mediastinal mass beside the aorta. Administration of a smooth  muscle relaxant such as sublingual nitroglycerin or inhaled amyl  nitrate may cause relaxation of the LES and distinguish achala-  sia from pseudoachalasia arising from mechanical causes. Severe   cases may reveal a markedly dilated and tortuous esophagus,  called a sigmoid esophagus (see Figure 13-4).   Esophagogastroduodenoscopy is not sensitive in the diagnosis  of esophageal motility disorders. However, it is very useful in  excluding mechanical disorders, particularly those that may be  the cause of the motility disorder (eg, infiltration by gastroe-  sophageal junction cancer, causing secondary achalasia).   The diagnosis is confirmed by esophageal manometry, which  typically reveals complete absence of peristalsis, incomplete LES  relaxation (< 50% of baseline pressure), and often but not nec-  essarily increased lower esophageal basal tone (> 30 mm Hg).  Weak contractions may be noted in the esophageal body, which  are simultaneous or appear simultaneous but identical if the  esophageal body becomes a single lumen (common cavity  effect) (see Figure 13-5). Esophageal pressures may also exceed  gastric pressures when the esophagus is filled with food or fluid.   The differential diagnosis of achalasia begins with the broad  differential diagnosis of dysphagia and exclusion of mechan-  ical causes of dysphagia. Strictures, benign neoplasms, vascu-  lar rings, webs, foreign bodies, and severe esophagitis (peptic,  infectious, chemical, drug induced) are among the frequently  encountered entities.   Achalasia must be distinguished from other motility disor-  ders such as diffuse esophageal spasm and scleroderma that has  been complicated by a peptic stricture. The next step is to deter-  mine whether it is due to an identifiable cause. These cases,  termed secondary achalasia, may be due to infection with T cruzi  (Chagas disease) or neural degeneration as a paraneoplastic syn-  drome associated with many malignancies. Gastroesophageal  junction carcinoma may produce myenteric plexus degeneration  by local tumor invasion, resulting in achalasia. The term  pseudoachalasia is used when there is no functional cause of  achalasia but the gastroesophageal junction is narrowed due to  outside compression or fibrosis and the esophageal body is  dilated due to obstruction. Patients with secondary achalasia due  to tumor at the gastroesophageal junction present with more  recent and progressive onset of dysphagia or with progressive  weight loss. Careful retroflexed inspection of the cardia and gas-  troesophageal junction by upper endoscopy is necessary.   Current options for treatment of achalasia are directed at  removing the functional obstruction caused by the nonrelax-  ing LES. However, these therapeutic modalities do not  restore peristalsis. Treatment includes pharmacologic ther-  apy, pneumatic dilation of the LES, surgical myotomy, and  botulinum toxin injection therapy.   Sublingual nitroglycerin, calcium channel blockers, phos-  phodiesterase inhibitors, and anticholinergics are used to  relieve the symptoms in the subset of patients who have mild  symptoms without esophageal dilation, or are unable to  undergo dilations or surgery.   The disruption of muscle requires far larger diameters com-  pared with disruption of mucosal lesions such as strictures. A  3-cm diameter balloon is used initially. Based on patient's  response, successive dilations of up to 4 cm can be applied. At  each session, a balloon is placed under fluoroscopic guidance  to stretch the area of the gastroesophageal junction. In less  than 4% of dilations, perforations occur that may require sur-  gical repair. In experienced hands, the efficacy of pneumatic  dilation and laparoscopic surgery are nearly equal, and dila-  tion appears to be the more cost-effective initial approach.   A modified Heller cardiomyotomy of the LES and cardia  results in good to excellent symptomatic relief in over 85% of  patients. GERD is expected to ensue in up to 20% of patients.  Myotomy can also be performed using a laparoscopic  approach; this is less invasive, reduces postoperative compli-  cations, and allows a shorter hospital stay. The success of sur-  gery does not appear to be compromised by prior botulinum  or pneumatic dilation treatments.   Botulinum toxin A is injected directly into the LES using an  endoscope. Approximately 20-25 units of the toxin are used  per injection into four quadrants in the LES. This results in  reduction of lower esophageal pressures in 85% of patients.  However, approximately 50% of patients relapse with symp-  toms over the next 6-9 months. Approximately 25% have a  sustained response lasting more than 1 year. Approximately  75% of initial responders who relapse have improvement  with repeat injection therapy. Because of the lower efficacy  and sustained response compared with surgical myotomy,  this method is often reserved for elderly patients or those  with multiple medical problems.   Untreated, achalasia can lead to severe weight loss mimicking  cancer, and respiratory complications such as stridor. Patients  may develop distal esophageal diverticulum and bezoars. After  surgery, patients may develop GERD, strictures, and Barrett  esophagus.   Pehlivanov N, Pasricha PJ. Medical and endoscopic treatment of  achalasia. GI Motility Online. Available at: http://www.nature.com/  gimo/index-html; doi: 10.1038/gimo52, 2006.   ► Dysphagia to solids and liquids and chest pain are com-  mon presenting symptoms.   The reported incidence of diffuse esophageal spasm depends  on the diagnostic criteria used. When large amplitude of con-  tractions is considered in the diagnosis, only 3-5% of patients  undergoing manometry for suspected esophageal motility  disorders fit the diagnostic criteria. Diffuse esophageal spasm  is a disorder of the thoracic esophagus resulting from impair-  ment of inhibitory innervation. It involves the esophagus but  spares the LES, leading to nonperistaltic contractions but nor-  mal LES relaxation, as evidenced on manometry. The ampli-  tude of the contractions may be normal, increased, or  decreased. Acid suppression and other medical and endo-  scopic treatments may alleviate symptoms. A subset of  patients may progress to achalasia.   Nonperistaltic contractions are due to loss of deglutitive inhi-  bition associated with impaired inhibitory nerve function in  the esophageal body. The amplitude of contractions involves  many components, including the rebound contraction, which  is dependant on the inhibitory nerves, cholinergic excitatory  nerves, and myogenic factors. Loss of inhibitory nerves alone  would be expected to reduce the force of contraction whereas  compensatory cholinergic and myogenic factors may lead to  increased force of contraction. However, little is known about  the pathology of diffuse esophageal spasm. There appears to  be patchy neural degeneration localized to nerve processes  rather than degeneration of nerve cell bodies, as evidenced in  achalasia. Hypertrophy of the muscularis propria and associ-  ated development of distal esophageal diverticula also occur.   Chest pain, dysphagia, and regurgitation are the main pre-  senting symptoms. Chest pain may be particularly promi-  nent in patients with high-amplitude and protracted  contractions and can occur at rest, with swallowing, or with  emotional stress. The pain is generally retrosternal but can  radiate to the back, sides of the chest, both arms, or the jaw.  Pain can last from seconds to several minutes and can mimic   that of cardiac angina. Dysphagia for solids and liquids can  be present. Regurgitation of food that fails to move into the  stomach may occur.   Findings on barium swallow may be normal or show non-  propagated contractions (called tertiary contractions), par-  ticularly below the aortic arch, with the appearance of curling  or multiple ripples in the wall, sacculations, and pseudodiver-  ticula, leading to the appearance of a "corkscrew" esophagus  in severe cases.   The diagnosis is generally made by esophageal manometry,  which reveals more than 20% of wet swallows as simultane-  ous contractions. However, because the disorder is episodic,  manometric findings can be entirely normal at the time of  study. Simultaneous contractions must be distinguished  from identical contraction patterns suggestive of a common  cavity effect from functional or mechanical obstruction in  the esophagus during the study. Moreover, occasional non-  peristaltic contractions can occur normally. The amplitude  of the nonperistaltic contractions can be increased, normal,  or even decreased, and sometimes the contractions are mul-  tipeaked. However, LES relaxation is normal, and normally  conducted peristaltic contraction must be evidenced in at  least one swallow.   Methods to provoke esophageal spasm, including cold  swallows and edrophonium, can induce chest pain but may  not necessarily correlate with motility changes. Thus, provo-  cation tests have limited utility.   Diffuse esophageal spasm must be distinguished from other  causes of chest pain, especially cardiac ischemia. Esophageal  motility disorders are an uncommon cause of noncardiac chest  pain, which is more commonly caused by reflux esophagitis or  visceral hypersensitivity.   The mainstay of therapy is reassurance, control of esophageal  acidification by proton pump inhibitors or histamine recep-  tor antagonists, and use of smooth muscle relaxants such as  nitrates and calcium channel blockers. There are no con-  trolled studies to substantiate any particular treatment  modality, although smooth muscle relaxants or anticholiner-  gic agents used for achalasia may be helpful for improving  symptoms. Some studies suggest that low-dose tricyclic anti-  depressant therapy may be a better option for treating chest  pain. Empiric bougienage has been advocated, but studies  comparing large versus small caliber bougies showed no dif-  ferences in response rate, suggestive of a placebo effect.  Similarly, there have been no controlled studies to validate   the use of botulinum toxin either into the LES or at intervals  along the esophageal body. Long esophageal myotomy is  rarely used to treat intractable dysphagia and chest pain, par-  ticularly when associated with pulsion diverticula.   Patients may have intermittent dysphagia and chest pain for  many years without progression. A small subset of these  patients (~5%) develops vigorous or classic achalasia, which  should be suspected if patients develop regurgitation with  worsening dysphagia.   Transient LES relaxation normally occurs on swallowing,  belching or vomiting reflexes. When it occurs in the absence of  such activities, it has been called inappropriate transient LES  relaxation or simply transient LES relaxation (TLESR).  Transient LES relaxation is vagovagal inhibitory reflex that is  mediated via the nitrergic inhibitory nerves to the LES. The fre-  quency of TLESR is increased by gastric distention. Increased  frequency of TLESR has been shown to be an important cause  of GERD. Diagnosis of TLESR can only be made by long-term  manometric recordings, which are employed mainly in  research but not in common clinical practice.   Basal LES pressure is dependent on the myogenic tone of  the sphincter muscle, and superimposed, counterbalancing  influence of inhibitory and excitatory nerves. The force of  peristaltic contraction is dependent on the contractile ability  of the smooth muscle and influence of the excitatory as well  as the inhibitory nerves. The inhibitory nerves are responsi-  ble not only for inhibition but also for the rebound contrac-  tion that follows the inhibition. Therefore, loss of rebound  contraction can only occur if the preceding deglutitive inhi-  bition is also lost. Disorders of TLESR that involve normal  deglutitive inhibition and peristaltic sequence can be classi-  fied into hypotensive and hypertensive esophageal motility  disorders and are described in the following sections.   Hypotensive esophageal disorders include hypotensive LES,  hypotensive peristaltic contraction, or both. Hypotensive  LES may lead to GERD, and hypotensive peristaltic contrac-  tions lead to dysphagia, impaired esophageal clearing of  refluxed material, and accentuation of GERD.   Hypotensive esophageal disorders are due to either impaired  excitatory innervation or impaired muscle contractility. Most  cases are idiopathic, but a few are secondary to known causes.  Secondary causes include anticholinergic agents, smooth  muscle relaxants, estrogens, progesterone, and pregnancy.  Other important causes are connective tissue disorders, par-  ticularly scleroderma and intestinal pseudo-obstruction syn-  drome. The latter may be caused by muscular atrophy, disease  or impairment of the cholinergic neurons, or both. Most  cases of hypotensive LES are idiopathic in nature.   ► Hypertensive LES, hypercontracting LES, and hyperten-  sive peristalsis identified on intraluminal manometry.   ► Usually noted in patients being evaluated for noncar-  diac chest pain or dysphagia.   Hypercontractile syndromes include entities such as hyper-  tensive LES, hypercontracting LES, hypertensive peristalsis  (nutcracker esophagus), and sustained contraction of the  esophageal longitudinal muscle.   These hypercontractile states may result from overactive  excitatory nerves or stress. The cause is unknown, but  patients may have esophageal hypersensitivity.   When hypertensive peristalsis or nutcracker esophagus was ini-  tially described, it was a common manometric abnormality  found in patients with noncardiac chest pain. However, it is now  appreciated that these episodes of high-amplitude contraction  coincide poorly with chest pain and may be an epiphenomenon  or perhaps a marker for hypersensitivity or a hyper-reactive  esophagus. Dysphagia has been reported by some patients with  manometric findings of hypercontractile esophagus.   Hypertensive peristalsis is the most common manometric  finding in patients referred for evaluation of noncardiac  angina-like chest pain. Generally, barium studies show nor-  mal peristalsis, normal esophageal transit, and no structural  esophageal disease. Esophagoscopy is also normal.   Prolonged ambulatory manometric studies reveal that  some patients with hypertensive peristalsis have nonperi-  staltic contractions during mealtime, but not during stan-  dard wet swallows of a standard manometric study.   A subset of these patients may have inappropriate con-  tractions of the esophageal longitudinal muscles that are  poorly transduced on standard manometric evaluations but  may be revealed on esophageal ultrasonography.   Specimens are rarely available for pathologic examination  of these hypercontractile states, although a single report has  described loss of intramural neurons in the LES of patients  with isolated hypertensive LES.   As the names imply, hypertensive peristalsis, hypertensive  LES, and hypercontracting LES are diagnosed manometri-  cally. In hypertensive peristalsis, the amplitude of the peri-  staltic contractions exceeds 180 mm Hg or the duration of  contraction exceeds 7.5 seconds. In hypertensive LES, the  basal pressure of the LES exceeds 40 mm Hg. Similarly,  hypercontracting LES shows prolonged and high-amplitude  postrelaxation (rebound) contraction.   As with achalasia, ischemic heart disease must be excluded in  patients presenting with chest pain. GERD is the most com-  mon cause of atypical noncardiac chest pain and should be  excluded, either with an empiric trial of proton pump  inhibitor therapy or through ambulatory pH testing. Other  causes of chest pain include chest wall origin, pericarditis,  atelectasis, and panic attacks.   Anticholinergic drugs and smooth muscle relaxants (nitrates  and calcium channel blockers) are often used but have   unproven value. Low-dose tricyclic antidepressants may  improve chest pain in some patients, perhaps because of their  modulation of visceral hypersensitivity. Cognitive-behavioral  therapy has also been employed with benefit to some patients.   Esophageal scleroderma occurs as part of a connective tissue  disorder and leads to atrophy of esophageal smooth muscle  with consequent loss of LES tone and force of esophageal  peristalsis. The condition occurs in 75-85% of patients with  scleroderma and affects particularly woman in the 30- to 50-  year age group. Patients with Raynaud phenomenon fre-  quently have esophageal motor abnormalities.   The cause of scleroderma is unknown, but it is thought to  involve an autoimmune response. Progressive atrophy and  sclerosis of the esophageal smooth muscles lead to poor peri-  staltic contractions in the distal esophagus and to LES  incompetence. Microvessel disease in scleroderma may lead  to intramural neuronal dysfunction early in the disease.  Subsequently, fibrosis and atrophy of esophageal smooth  muscle develop, leading to a markedly hypotensive LES and  loss of peristaltic contractions in the smooth muscle segment  of the esophagus.   Diagnosis is confirmed by the presence of Raynaud phenom-  enon and cutaneous manifestations of scleroderma along  with symptoms of dysphagia and GERD. Physiologic changes  in the esophagus contribute to poor esophageal clearance  and marked gastroesophageal reflux. This can result in reflux  esophagitis and strictures in advanced cases. Pulmonary  interstitial fibrosis can result from either direct involvement  of the disease, or from aspiration of refluxate.   Owing to LES incompetence and lack of esophageal acid  clearance from lack of esophageal peristalsis, patients often  have severe GERD, leading to heartburn, regurgitation,   dysphagia, and chest pain. However, symptoms can be rela-  tively mild despite severe mucosal disease. Dysphagia may  occur even in the absence of obvious skin and joint involve-  ment, although Raynaud phenomenon is usually present.   Certain autoimmune markers such as the antiendonuclear  antigens and anti-ScL-70 and anticentromere antibodies may  be present.   In advanced disease, barium swallow reveals a dilated esoph-  agus with poor esophageal clearance and weak contractions.   Manometry shows a hypotensive LES and low- amplitude  peristaltic contractions in the thoracic esophagus. Sometimes,  swallow-induced contractions are nonperistaltic, suggesting  additional impairment of the nitrergic inhibitory nerves.   In the absence of other features of a connective tissue disorder,  scleroderma can be confused with primary GERD. Cutaneous   manifestations of scleroderma may be absent in up to 5% of  patients. History of Raynaud phenomenon may be very useful  in the diagnosis. Pulmonary fibrosis may even be attributed to  repeated aspiration from GERD. In patients presenting with  dysphagia, eosinophilic esophagitis should by excluded by  multiple mucosal biopsies obtained at different levels of the  esophagus. Scleroderma esophagus may sometimes be con-  fused with achalasia, particularly in patients with a dilated  esophagus on barium swallow and poor peristaltic contractions  in the thoracic esophagus on barium swallow or esophageal  manometry. However, patulous and hypotensive LES on  endoscopic and manometric findings can distinguish the two.  In scleroderma, LES is usually patulous unless complicating  peptic stricture is present.   There is no specific treatment for esophageal scleroderma.  Severe reflux, which is generally the source of the patient's pre-  dominant symptoms, is treated with proton pump inhibitors,  often requiring doubledose, twice daily administration.  Esophageal bougienage may be required for strictures.  Generally, antireflux surgery should be avoided because of the  risk of severe postoperative dysphagia. Otherwise, a partial fun-  doplication, generally with a Collis procedure and esophageal  lengthening, is performed.   ► In adults a major symptom is recurrent dysphagia, often  with food impaction; mean duration of symptoms before  treatment is 4-6 years.   ► Esophageal biopsy shows dense eosinophilic infiltration  (> 20 eosinophils per high power field [HPF]).   ► Full diagnostic criteria are (1) clinical symptoms of  esophageal dysfunction; (2) increased eosinophils in  esophageal mucosal biopsies; (3) lack of response to  high-dose proton pump inhibition treatment or normal  pH monitoring of the distal esophagus.   Eosinophilic esophagitis is a chronic and increasingly recog-  nized inflammatory disorder of the esophagitis characterized by  abnormal infiltration of eosinophils of the esophageal mucosa,  often resulting in dysphagia and food impaction. The disorder  is being diagnosed with much greater frequency and increased  recognition alone may not be responsible for this trend. Studies  have indicated that the incidence has increased more than four-  fold in the last 5-10 years. More than 80% of patients diagnosed  with eosinophilic esophagitis complain of dysphagia, and  between 5% and 16% of patients undergoing endoscopic eval-  uation for dysphagia are found to have eosinophilic esophagitis.  Further, more than 50% of patients presenting with frank food  impaction are diagnosed with eosinophilic esophagitis. By con-  trast, in children and adolescents, gastroesophageal reflux dis-  ease (GERD) and esophageal reflux symptoms are as common  as food impaction and dysphagia.   The pathogenesis of eosinophilic esophagitis is incompletely  defined. The recruitment of eosinophils occurs in several  inflammatory or infectious conditions and after exposure to   inhaled or ingested allergens. Eosinophilis also release  chemoattractants, such as interleukins, which can perpetuate  an inflammatory response. The latter phenomenon has led to  trials of leukotriene inhibitors in the treatment of eosinophilic  esophagitis.   The leading symptom in adults is recurrent attacks of dys-  phagia. Mean duration of symptoms before diagnosis and  initiation of treatment in one large series was 4.6 years.  Recurrent dysphagia is present in the majority of patients as  is the history of food impaction. A personal history of aller-  gic diseases (ie, airway allergies, food allergies, or skin aller-  gies) is frequently present. Serum immunoglobulin E (IgE)  elevations have been documented in one series in two thirds  of the patients. However, it should be emphasized that there  is no difference in symptoms, endoscopic findings, or histol-  ogy in patients with increased serum IgE levels versus those  with normal IgE levels. Symptoms appear to be more pro-  nounced in patients with peripheral blood eosinophilia.  Another clinical feature is the presence of symptoms of  GERD, dyspepsia, and xiphisternal and retrosternal discom-  fort that are seemingly refractory to medical management. In  children and adolescents, symptoms include vomiting,  regurgitation, GERD symptoms not responding to medical  management, upper abdominal pain, and food impaction in  the esophagus.   Endoscopic features associated with eosinophilic esophagitis  are highly variable. The esophageal mucosa may actually  appear to be normal. Other more frequent findings include  trachea-like circular rings that can be transient or fixed,  white exudates, white nodules with granularity, linear furring,  and vertical lines on the esophageal mucosa. In addition, the   passage of the endoscope may lead to trauma. Finally, stric-  tures in the proximal, middle, or distal esophagitis are some-  times encountered. Examples of typical endoscopic findings  in eosinophilic eosinophils are shown in Plates 18 and 19.   Other disorders also may be associated with increased  eosinophilic infiltration of the esophagus (see below).  Accordingly, biopsies should be taken in both the distal and  mid-esophagus in patients with suspected eosinophilic  esophagitis. Characteristic histologic findings in eosinophilic  esophagitis are shown in Plate 20.   Dellon ES, Aderju A, Woosley JT, et al. Variability in diagnostic  criteria for eosinophilic esophagitis: a systematic review. Am J  Gastroenterol 2007;102:2300-2313. [PMID: 17617209]   Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagi-  tis in children and adults: a systematic review and consensus rec-  ommendations for diagnosis and treatment. Gastroenterology.  2007;133:1342-1363. [PMID: 17919504]   The usual criteria for the diagnosis of eosinophilic esophagi-  tis are as follows:   1. Clinical symptoms of esophageal dysfunction, especially  dysphagia and a history of food impaction.   2. Biopsies of the esophageal mucosa reveal a dense  eosinophilic infiltration (ie, > 20 eosinophils/HPF).   3. Lack of responsiveness or an incomplete response to  treatment of high doses of proton pump inhibitors, or  normal pH monitoring of the distal esophagus, or both.   Although increased eosinophilic infiltration in the esopha-  gus is characteristic of eosinophilic esophagitis, it is not  exclusively found in that disorder. Other disorders that may  be associated with increased eosinophilic infiltration of the  esophagitis include GERD, Crohn disease, hypereosinophilic  syndrome, cardiovascular disease, drug-induced esophagitis,  and infectious esophagitis (ie, herpes or Candida). Increased  eosinophils can be found in the distal esophagus in reflux  esophagitis but not in the mid-esophagus.   Rodrigo S, Abboud G, Oh D, et al. High intraepithelial eosinophil  counts in esophageal squamous epithelium are not specific for  eosinophilic esophagitis in adults. Am J Gastroenterol.  2008;103:435-442. [PMID: 18289205]   Several studies that have employed topical fluticasone in  doses ranging from 220-440 meg two to four times daily have   demonstrated symptom improvement and complete resolu-  tion of symptoms in up to 75% of cases. Patients are generally  instructed to swallow rather than inhale the fluticasone and  not use a spacer. Twice-daily fluticasone is usually adminis-  tered for 6-12 weeks, and during this interval clinical and  histologic symptoms are improved in the vast majority of  patients. Patients receiving the higher dose of fluticasone are  more likely to develop esophageal candidiasis. Furthermore,  higher doses of fluticasone (ie, > 440 meg/day) have been  associated with systemic side effects, including cataracts and  adrenal suppression. Although the use of swallowed cortico-  steroids is effective in relieving symptoms for a short period  of time (4 months or less), long-term efficacy remains con-  troversial. It should be emphasized that symptoms are more  likely to recur in a period of 4-18 months after therapy has  been discontinued in approximately half the patients.   An alternative to swallowed fluticasone is the use of a sus-  pension of budesonide. It has been reported that a prepara-  tion of 1-2 mL of Pulmicort Respules mixed with five 1.0-g  packets of sucralose to create a volume of 8-12 mL was well  tolerated in 20 children and led to a histologic response in  80% of these patients. Pulmicort Respules is a liquid-based  formulation of budesonide containing 0.5 mg of budesonide,  and 2 mL mixed with sucralose will make a dose of 8-12 mL  that can be taken twice daily. Although data are limited, this  preparation may well be a viable alternative to using swal-  lowed fluticasone.   Systemic corticosteroids are effective in eosinophilic  esophagitis but side effects limit their use, especially for peri-  ods longer than 4 weeks. They may be indicated when urgent  symptom relief is required as with patients experiencing  severe dysphagia, dehydration, and significant weight loss or  esophageal strictures.   Esophageal dilation may be necessary in patients with stric-  tures, but it must be done carefully as it has been associated  with deep mucosal tears, esophageal perforation, increased  postendoscopic analgesia, and difficulty in inserting the  endoscope. Approximately half the patients treated with  esophageal dilation will become asymptomatic.   The leukotriene receptor antagonist montelukast has been  studied in a small number of patients with eosinophilic  esophagitis; eight patients showed a complete resolution of  symptoms with a dosage of 20-40 mg/day and maintained  this response for a median of 14 months. However, once the  medication was discontinued, six of the eight patients had a  recurrence of their symptoms. Data are insufficient to rec-  ommend leukotriene receptor antagonists for the treatment  of eosinophilic esophagitis.   Cromolyn sodium, a mast cell stabilizer, has not shown any  apparent benefit for patients with eosinophilic esophagitis  although it has no significant adverse effects.   Efficacy of specific food elimination diets remains controver-  sial. Although several studies have demonstrated a poor cor-  relation of diagnostic skin testing, radioallergosorbent  testing, and IgE skin prick tests with improvement in either  symptoms or tissue inflammation, one center did report a  significant improvement in patients on a specific food elim-  ination diet. Kagalwalla and colleagues demonstrated that  eliminating the six most common allergenic foods (dairy,  eggs, wheat, soy, peanuts, and fish/shellfish) resulted in sig-  nificant improvement in 74% of the 35 patients who received  the six-food elimination diet.   Konikoff MR, Noel RJ, Blanchard C, et al. Randomized, double-blind,  placebo-controlled trial of fluticasone propionate for pediatric  eosinophilic esophagitis. Gastroenterology. 2006;131:1381-1391.  [PMID: 17101314]   Straumann and coworkers described 30 patients followed for  a mean of 7.2 years (range, 1.4-11.5 years); 23% of the  patients reported increased dysphagia and 36.7% reported  stable symptoms. Mean duration of symptoms before treat-  ment was 4.6 years. Recurrent episodes of dysphagia were  documented in 29 of 30 patients, and the symptoms were  more pronounced in patients with peripheral eosinophilia.  Eosinophilic esophagitis does not seem to be associated with  esophageal metaplasia (ie, Barrett esophagus or cardiac meta-  plasia or esophageal neoplasms).   Antireflux therapy with proton pump inhibitors is usually  not successful or achieves only a partial response in patients  with GERD. However, some patients may have both GERD  and eosinophilic esophagitis and in this setting, treatment  with a proton pump inhibitor may be appropriate.   Aceves SS, Bastian IF, Newbury RO, et al. Oral viscous budesonide:  a potential new therapy for eosinophilic esophagitis in children.  Am J Gastroenterol. 2007;102:2271-2275. [PMID: 17581266]   Bohm M, Richter JE, Treatment of eosinophilic esophagitis: overview,  current limitations, and future directions. Am J Gastroenterol.  2008;103:2635-2644.   Furuta GT, Liacouras CA. Collins MH, et al. Eosinophilic  esophagitis in children and adults: a systematic review and con-  sensus recommendations for diagnosis and treatment.  Gastroenterology. 2007;133:1342-1363. [PMID: 17919504]   Kagalwalla AF, Sentongo TA, Ritz S, et al. Effects of six-food elimi-  nation diet on clinical and histologic outcomes in eosinophilic  esophagitis. Clin Gastroenterology. 2006;4:1097-1102. |PMID:  16860614]   Straumann A, Spichtin HP, Grize L, et al. Natural history of primary  eosinophilic esophagitis: a follow-up of 30 adult patients for 11.5  years. Gastroenterology. 2003;125:1660-1669. [PMID: 14724818]   There are several unresolved issues with regard to the natural  history and treatment of eosinophilic esophagitis. Treatment  end points and maintenance medical management remain  incompletely denned. Treatment initiatives are aimed at reliev-  ing symptoms, which may or may not be accompanied by reso-  lution of eosinophilic esophagitis. In this regard, after treatment  esophageal eosinophilia can persist and in some patients may be  asymptomatic or only have minimal symptoms. It may well be  necessary to continue treatment in patients with documented  eosinophihc esophagitis and persistent esophageal symptoms  in the absence of esophageal abnormalities.   Peptic ulcers are mucosal defects in the stomach or small  intestine.   Helicobacter pylori infection, NSAIDs, and aspirin use  are the most common causes.   Patients may have epigastric pain or complications such  as gastrointestinal bleeding, perforation, and obstruction.   Peptic ulcers are defects or breaks in the gastric or small  intestinal mucosa that have depth and extend through the  muscularis mucosa. In contrast to erosions, which are small  and superficial mucosal lesions, peptic ulcers can vary in size  from 5 mm to several centimeters and may lead to complica-  tions such as gastrointestinal (GI) bleeding, obstruction,  penetration, and perforation.   The pathogenesis of ulcers is multifactorial and arises  from an imbalance of protective and aggressive factors such  as when GI mucosal defense mechanisms are impaired in  the presence of gastric acid and pepsin. Peptic ulcer disease  was long considered an idiopathic and lifelong disorder.  This paradigm changed dramatically in 1984 when  Marshall and Warren reported that a curved bacillus, ini-  tially named Campylobacter pyloridis and subsequently  classified as Helicobacter pylori, was linked to ulcers.  Multiple studies have since shown that eradication of H pylori  significantly reduces the rate of ulcer recurrence. Another  major risk factor for peptic ulcers is the use of nonsteroidal  anti-inflammatory drugs (NSAIDs) and aspirin. These  medications generally exert their therapeutic and toxic  effects by inhibiting the enzymes cyclooxygenase-1 (COX-1)  and cyclooxygenase-2 (COX-2), which, in turn, impair   mucosal protection and promote ulcers. The treatment of  ulcer patients has been revolutionized since the development  of the acid suppressive medications such as the histamine-2  (H 2 )-receptor blockers and proton pump inhibitors, the syn-  thetic prostaglandin misoprostol, and the selective COX-2  inhibitors. To date, H pylori and the use of NSAIDs and  aspirin account for most cases of peptic ulcers. Only a small  fraction of ulcers are associated with neoplasia or caused by  acid hypersecretory states such as Zollinger-Ellison syn-  drome and other rare disorders.   The incidence of both gastric and duodenal ulcers in  developed countries rapidly increased throughout the 19th  century and peaked during the first half of the 20th century.  Since the 1950s, however, the incidence and prevalence of  both ulcers has steadily declined. There has also been a  decrease in the prevalence of H pylori in the general popu-  lation over recent decades, attributed to improved hygiene  and widespread use of antibiotics in developed countries.   In the United States, over 4 million individuals are  affected by peptic ulcers and approximately 15,000 die from  ulcer complication each year. Over two thirds of ulcer  patients develop the disease between the ages of 25 and 64 years.  The lifetime prevalence of peptic ulcers is 12% in men and  10% in women. The impact of peptic ulcer disease on U.S.  health care costs is substantial, with direct and indirect costs  totaling over an estimated $10 billion per year. In addition,  peptic ulcer complications adversely affect functional status  and quality of life. Over 30% of patients with peptic ulcers  have a marked decline in their functional levels or frank dis-  ability, whereas 30% also have somatic and psychological  symptoms.   Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected  digestive diseases in the United States. Gastroenterology.  2002;122:1500-1511. [PMID: 11984534]   Sonnenberg A. Time trends of ulcer mortality in Europe. Gas-  troenterology. 2007;132:2320-2327. [PMID: 17570207]   Helicobacter pylori infection as well as the use of NSAIDs and  aspirin have numerous effects on the GI tract and are the  most common causes of peptic ulcers (Table 15-1). In gen-  eral, both factors disrupt normal mucosal defenses and  repair, making the mucosa more susceptible to acid.  Suppression of gastric acid secretion using pharmacologic  agents heals ulcers and reduces future complications. Only a  few patients have an underlying acid hypersecretory state  causing ulcers. For example, less that 1% of patients with  duodenal ulcers have a gastrin-secreting tumor causing pro-  found acid secretion as part of the Zollinger-Ellison syn-  drome. Approximately 3-5% of gastric ulcers represent  malignancy, including adenocarcinoma, lymphoma, or  metastatic lesions. Other infections and conditions that  increase ulcer formation include cytomegalovirus or herpes  simplex (especially among immunosuppressed patients),  tuberculosis, Crohn disease, the use of other non-NSAID  medications, hyperparathyroidism, sarcoidosis, myeloprolif-  erative disorder, and systemic mastocytosis.   Cigarette smoking also promotes the development of  ulcers and may interact with H pylori and NSAIDs to  increase mucosal injury. Smoking also impairs ulcer healing  and increases ulcer recurrence. Several studies suggest that  alcohol use and diet do not appear to increase ulcer forma-  tion, whereas emotional stress may predispose some individ-  uals to ulcers. Critically ill patients with severe burns,  physical trauma, or multiple organ failure also have an  increased risk of developing gastroduodenal ulcers and asso-  ciated complications. There is also an association of peptic  ulcers with medical conditions such as chronic obstructive  lung disease and chronic renal failure, but the mechanisms  are unclear. A genetic susceptibility has been reported but   Other rare infections (eg, cytomegalovirus, herpes simplex, tuberculosis)  Critically ill patients with severe burns, head injury, physical trauma,   now is thought to stem mainly from intrafamilial infection  with H pylori. Recent studies have also suggested that an  increasing proportion of ulcers are idiopathic, as they are not  related to H pylori, NSAIDs, aspirin, acid hypersecretion, or  any other known cause.   Chan FK, Leung WK. Peptic-ulcer disease. Lancet. 2002;360:  933-941. [PMID: 12354485]   Helicobacter pylori is a spiral gram-negative urease-producing  bacterium that can be found in the mucus coating the gastric  mucosa or between the mucous layer and gastric epithelium.  Multiple factors enable the bacterium to live in the hostile  stomach acid environment, including its ability to produce  urease, which helps alkalinize the surrounding pH.  Helicobacter pylori infection is most commonly acquired in  childhood and results in a chronic active gastritis that is usu-  ally lifelong without specific treatment. Risk factors for  acquiring H pylori include low socioeconomic status, house-  hold crowding, as well as country of origin. The prevalence of  H pylori varies among different countries and is significantly  higher in developing than in industrialized countries. The  majority of infected persons remain asymptomatic, but  approximately 10-15% develop peptic ulcer disease during  their lifetime. In addition to causing chronic gastritis and  peptic ulcers, H pylori has been associated with the devel-  opment of gastric adenocarcinoma and gastric mucosa-  associated lymphoid tissue (MALT) lymphoma. In 1994, the  International Agency for Research on Cancer classified H pylori  as a group 1 carcinogen and a definite cause of gastric cancer  in humans.   Infection with H pylori increases the risk of peptic ulcers  and GI bleeding from threefold to sevenfold. Depending on  the population, H pylori is present in up to 70-90% of  patients with duodenal ulcers and up to 30-60% of gastric  ulcers. Multiple clinical studies show that H pylori eradica-  tion reduces ulcer recurrence to less than 10% as compared  with recurrences of 70% with acid suppression alone.  Helicobacter pylori generally causes mucosal injury and ulcer  complications through inflammation and cytokines. Despite  a vigorous systemic and mucosal humoral response, antibody  production does not lead to eradication of the infection.   A combination of microbial and host factors determines  the outcome of H pylori infection. These include the viru-  lence of the organism, host genetics, as well as environmen-  tal factors that affect the distribution and severity of gastric  inflammation and level of acid secretion. Helicobacter pylori  that express the cytotoxin-associated gene A (Cag A-positive  strains) reportedly represents virulent strains having greater  interactions with humans. Several genes in a genomic frag-  ment that make up a Cag pathogenicity island encode com-  ponents of a type IV secretion island that translocates Cag A  in host cells and affects cell growth and cytokine production.   Cag A is a highly antigenic protein that is associated with a  prominent inflammatory response by eliciting interleukin-8  production. Helicobacter pylori strains that also express the  vacuolating cytotoxin or the outer membrane protein OipA  are similarly associated with a higher risk of diseases, includ-  ing gastric cancer.   Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and  disease. J Clin Invest. 2004;113:321-333. [PMID: 14755326]   Go MF. Review article: natural history and epidemiology of  Helicobacter pylori infection. Aliment Pharmacol Ther. 2002; 16:  3-15. [PMID: 11849122]   Aspirin and NSAIDs are among the most frequently used  drugs worldwide. These drugs treat pain and inflammation,  but they have substantial GI toxicity and are associated with  the development of peptic ulcers and life-threatening GI  bleeding. Endoscopic studies have shown that up to 15-30%  of patients using NSAIDs develop gastric and duodenal  ulcers. Epidemiologic studies also suggest that the risks of  ulcer complications and death among regular NSAID users  are 3-10 times higher as compared with those not taking  these drugs. More than 107,000 hospitalizations in the  United States are attributed to NSAIDs each year. The elderly  are at particularly increased risk, and one study found that  the adjusted hospitalization rate for ulcer complications was  16.7 per 1000 person-years among elderly Medicaid patients  on NSAIDs, in contrast to a rate of 4.2 among nonusers, with  an attributable rate of 12.5 excess hospitalizations for ulcer  disease per 1000 person-years among users.   Aspirin and nonselective NSAIDs inhibit both COX-1 and  COX-2 isoenzymes, which, in turn, decrease prostaglandin  synthesis. Inhibition of COX-1 impairs mucosal protection  and leads to ulcers. The risks of peptic ulcers and GI bleeding  are dependent on the dose, duration, and type of NSAID.  Several other factors have also been shown to increase the  development of peptic ulcers among NSAID users. They  include increasing age, a previous history of GI bleeding or  ulcers, and concomitant use of steroids. In a meta-analysis,  the pooled relative risks for ulcer complications ranged from  1.6-9.2, according to the individual NSAID, with a pooled rel-  ative risk of 1.6 for aspirin. Even very low doses of aspirin  have been associated with ulcers and GI bleeding suggesting  that there are no true safe doses of aspirin. A case-control  study, for example, found that low-dose aspirin as well as  nonaspirin NSAIDs both significantly increased the risk of  ulcer bleeding with odds ratios of 2.4 and 7.4, respectively.   Dore MP, Graham DY. Ulcers and gastritis. Endoscopy. 2004;36:  42-47. [PMID: 14722854]   Laine L. Review article: the effect of Helicobacter pylori infection on  nonsteroidal anti-inflammatory drug-induced upper gastroin-  testinal tract injury. Aliment Pharmacol Ther. 2002;16(Suppl 1):  34-39. [PMID: 11849126]   Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of  nonsteroidal anti-inflammatory drugs. N Engl J Med. 1999;17:  1888-1899. [PMID: 10369853]   Epigastric pain is the classic symptom associated with peptic  ulcer disease. The pain is often described as a gnawing, dull,  aching, "empty," or "hunger-like" sensation. The classic pain  associated with duodenal ulcer is sometimes relieved with  ingestion of milk, food, or antacids but recurs 2-4 hours after  eating and may also awaken the patient at night. In contrast,  most patients with gastric ulcers report that eating exacer-  bates the pain. During fasting they may have relief of their  symptoms, which then recur shortly after eating. As a result,  some gastric ulcer patients experience nausea, avoidance of  food/anorexia, and even weight loss.   Peptic ulcer symptoms tend to recur at intervals of weeks  or months. An acute worsening or change in the pain char-  acteristic such as generalized pain may arise from ulcer pen-  etration or perforation. Alarm symptoms such as melena,  hematemesis, guaiac positive stools and unexplained anemia  suggest possible ulcer bleeding, while persistent vomiting  may represent obstruction. Early satiety, anorexia and unex-  plained weight loss may arise from a cancer. Patients with  upper abdominal pain with radiation to the back may have  penetration while those with severe or worsening abdominal  pain may have perforation. However, many ulcer patients  present with few or no symptoms until the development of  complications such as GI bleeding, perforation, penetration,  and obstruction. In one study, abdominal pain was absent in  over 30% of older patients with peptic ulcers seen on upper  endoscopy. Less common symptoms such as nausea and  vomiting may arise from a gastric outlet obstruction with  ulcer edema or scarring.   The physical examination is unreliable and often normal,  although some ulcer patients have epigastric tenderness to  deep palpation. Occult or gross blood may be detected in the  setting of bleeding ulcers. Tachycardia and orthostasis may be  found in patients with significant bleeding or dehydration,  while a rigid abdomen with diffuse rebound tenderness may  reflect ulcer perforation with peritonitis. Rarely, a distended  abdomen or a succession splash can be noted in patients with  an ulcer that is complicated by outlet obstruction.   The majority of duodenal ulcers develop in the bulb or  pylori channel. Patients with duodenal ulcers tend to have a  younger age of onset, often between 30 and 55 years of age on  average. These duodenal ulcer patients also have an increased  parietal cell mass and acid secretion (with increased average  basal and nocturnal gastric acid secretion). Bicarbonate  secretion has been reported to be impaired among patients  with active duodenal ulcers. It is thought that the imbalance  between duodenal acid load and buffering capacity leads to   the development of small islands of gastric metaplasia in the  duodenal bulb. Colonization of these islands by H pylori sub-  sequently leads to duodenitis and duodenal ulcer.   In the stomach, most benign ulcers are found in the  antrum and lesser curvature of the stomach at the junction  of the body and antrum. Gastric ulcers often occur later in  life, usually among patients between the ages of 55 and 70 years  with a peak incidence in the sixth decade. Patients with gastric  ulcers often have normal or decreased acid secretion. A few  patients present with both gastric and duodenal ulcers and  are found to have increased acid secretion. The gastric ulcers  in these patients tend to be located in the distal antrum or  pyloric channel.   Definitive diagnosis of peptic ulcers can be made with upper  endoscopy. Endoscopy has a much higher diagnostic yield  than barium contrast radiology and enables biopsy speci-  mens to be obtained for evaluation of H pylori infection and  underlying malignancy. Because up to 5% of gastric ulcers  are malignant, it is generally recommended that biopsy sam-  ples be taken from the ulcer margin or that a follow-up  endoscopy be scheduled 12 weeks after starting acid suppres-  sive medications to document complete healing. Ulcers  greater than 3 cm in size and those that are associated with a  mass are more likely to be malignant. In contrast, the inci-  dence of malignant duodenal ulcers is extremely low; thus,  they do not routinely require biopsy. Actively bleeding ulcers  or ulcers at high risk for rebleeding can also be treated dur-  ing endoscopy with hemostasis therapy.   Patients suspected of having an ulcer who present with  alarm symptoms such as GI bleeding, early satiety, and unex-  plained weight loss, and those who are elderly should undergo  prompt evaluation with endoscopy.   In contrast, there is some controversy as to the best  approach in initially treating young patients under the  age of 55 years without alarm symptoms who present with  ulcer-like symptoms or dyspepsia. Possible options include  (1) testing and treating for H pylori, (2) treating with acid  suppressive medications and monitoring response, or (3) mak-  ing a direct referral for evaluation with upper endoscopy.  Several studies, for example, recommend that young patients  with undifferentiated dyspepsia initially undergo noninva-  sive testing for H pylori followed by treatment if this infec-  tion is present. Successful cure of H pylori potentially reduces  the need for endoscopy as well as ulcer recurrence, and clin-  ical studies suggest that this strategy does not adversely affect  outcomes. Further evaluation with endoscopy is recom-  mended for patients with persistent symptoms despite ther-  apy. Alternatively, young patients with a presentation  suggestive of uncomplicated ulcers may first be given empiric  treatment with acid-suppressive medications. Further evalu-  ation is recommended if these patients continue to have per-  sistent or recurrent symptoms 2-4 weeks later. All patients  should discontinue aspirin and NSAIDs if possible, as well as   stop alcohol, smoking, and use of illicit drugs. Patients who  are found to have multiple ulcers, or refractory ulcers, or  those in unusual locations such as postbulbar or jejunum, or  who have diarrhea and weight loss should also be considered  for evaluation of Zollinger-Ellison syndrome.   Barium upper GI studies are widely available and are safer  and cheaper than endoscopy, but they have limited accuracy  for detecting ulcers and other mucosal lesions. In contrast to  endoscopy, barium upper GI studies do not permit biopsy  and other specimens to be obtained for histologic evaluation  nor immediate treatment of bleeding ulcers.   Several methods are available to detect H pylori infection  (Table 15-2). The noninvasive tests include serologic test-  ing, urea breath test, and stool antigen test. Infection can  also be detected during endoscopy in which a biopsy sam-  ple is obtained for a rapid urease testing, histologic study, or  even culture. Serum immunoassays for immunoglobulin G  (IgG) antibodies to H pylori are inexpensive but have a  reported sensitivity of 85% and specificity of 79%. As a  result, the positive predictive value of serologic testing is  limited in populations with a low pretest probability of  having the infection. Moreover, serologic testing should not  be used to determine the success of H pylori cure after treat-  ment since antibody titers do not always become negative.  The urea breath test or the stool antigen test can be used for  both the initial diagnosis and follow up of eradication ther-  apy because they have sensitivities and specificities of over  90%. Urea breath testing is based on detecting H pylori-derived  urease activity in the stomach, whereas the stool antigen test  uses polyclonal anti-ff pylori capture antibody adsorbed  to microwells. It is generally recommended to wait at least  4 weeks or more after completing eradication therapy to con-  firm successful cure. To help minimize false-negative results,  proton pump inhibitors should be withheld for 1-2 weeks  and antibiotics and bismuth compounds for 4 weeks prior  to testing.   In patients who undergo endoscopy, an antral biopsy can  be obtained for rapid urease testing, which has a sensitivity of  89-100% and specificity of 92-100%. Biopsies can also be per-  formed and specimens sent for histologic examination using  routine hematoxylin and eosin staining. The presence of poly-  morphonuclear leukocytes in inflamed gastric tissue is sugges-  tive of H pylori gastritis. In biopsy specimens in which H pylori  cannot be found, the use of modified Giemsa, Warthin- Starry,  Genta, and other stains may be helpful. Culture of H pylori  from biopsy samples has a specificity of 100% if results are  positive, but it is not routinely performed. Because culture is  difficult to perform and expensive, it is usually reserved to  determine antibiotic susceptibilities for patients who fail to  respond to second-line eradication therapy.    Detects exposure to H pylori but cannot be used to confirm  successful cure after treatment    Recommended for both screening and confirming cure; recent use  of antibiotics and PPIs can increase false-negative results    Can be used for initial diagnosis and to confirm successful cure    Widely used method of diagnosis during endoscopy; sensitivity is  improved by taking at least 2 biopsies from antrum and 1 from  body of stomach   CtO, Campylobacter-^ organism; ELISA, enzyme-linked immunosorbent assay; Gl, gastrointestinal; PPI, proton pump inhibitor.   In some studies, only half of patients with peptic ulcer pres-  ent with classic symptoms. Unfortunately, the history and  physical examination are neither sensitive nor specific enough  to accurately diagnose peptic ulcers or distinguish between  duodenal and gastric ulcers. A diagnosis of a peptic ulcer may  be suspected in selected patients presenting with epigastric  pain but the differential is broad and includes gastroe-  sophageal reflux disease, biliary tract disease, hepatitis, pan-  creatitis, abdominal aortic aneurysm, gastroparesis, functional  dyspepsia, neoplasia, mesenteric ischemia, and myocardial  ischemic pain, among others.   Although peptic ulcers can be diagnosed during upper  endoscopy, laboratory and radiologic tests may help narrow the  differential diagnosis. Some ulcer patients are anemic due to  acute bleeding or chronic blood loss from benign or malignant  ulcers. Liver function tests and levels of amylase and lipase  should be checked to help evaluate for hepatitis and pancre-  atitis. An abdominal ultrasound may show gallstone disease  or an abdominal aortic aneurysm. An electrocardiogram and  measurement of cardiac enzymes helps evaluate myocardial  causes of pain. Finally, an acute abdominal series with upright  and lateral decubitus views showing free air suggests perforation.   The most common complication associated with peptic  ulcers is the development of Gl hemorrhage. Up to 15% of  peptic ulcers bleed, and affected patients have an overall  mortality rate of 10%. Patients older than 60 years of age   have a higher incidence of bleeding ulcers and mortality.  Those who also have a large initial bleed, continued or recur-  rent bleeding, or severe comorbid illnesses have the greatest  risk of death. Patients with bleeding ulcers can present with  hematemesis or coffee ground emesis, passage of black tarry  stool, and rarely, hematochezia.   Up to 7% of ulcer patients have perforation with severe  abdominal pain and a rigid abdomen from peritonitis.  Owing to the widespread use of NSAIDs among the elderly,  they are at increased risk and many do not present with  antecedent ulcer pain or peritoneal findings. Penetration  occurs when the ulcer crater erodes into an adjacent organ  as, for example, when a duodenal ulcer penetrates into the  pancreas leading to pancreatitis or a gastric ulcer penetrates  into the left hepatic lobe.   Gastric outlet obstruction occurs in less than 2% of ulcer  patients and may arise from ulcer inflammation and edema  in the prepyloric area. Chronic ulcer scarring in the prepy-  loric area can also lead to a fixed mechanical obstruction that  may require endoscopic balloon dilation or surgical therapy.  This diagnosis should be suspected in patients who complain  of nausea, vomiting, early satiety, and weight loss, especially  if they also have dehydration and electrolyte imbalances.   Treatment of peptic ulcers consists of healing the ulcer and  preventing ulcer recurrences and future complications. All  ulcer patients should be tested and treated for H pylori even   if they have a clear history of NSAID use. It is not clinically  possible to determine whether ulcers arise directly from H pylori,  NSAID use, or a combination of the two. Although H pylori  and NSAID use cause most ulcers, the level of acid secretion  still plays a role in pathogenesis and healing. Multiple studies  show that the administration of acid-suppressive medications  promotes active ulcer healing. Intravenous acid-suppressive  therapy should be promptly started in ulcer patients with  signs of upper GI bleeding, followed by early endoscopy to  improve outcomes. In some studies, the use of an intra-  venous proton pump inhibitor decreased transfusion  requirements, the need for surgery, and even duration of  hospitalization but did not reduce mortality. Hemostasis  therapy is recommended for ulcers that are actively bleeding  during endoscopy, or those that have a visible vessel or an  adherent clot, as these lesions have a significant risk of  rebleeding. Hemostasis can be performed through coagula-  tion of bleeding sites; placement of hemoclips; injection of  epinephrine, alcohol, or a sclerosant; or a combination of  these methods. Nonhealing gastric ulcers should be biopsied  to exclude underlying neoplasia.   Patients who develop peptic ulcers while on NSAIDs should  be tested and treated for H pylori and the NSAID should be  discontinued if possible. Acid-suppressive medication, usu-  ally with a proton pump inhibitor, should also be adminis-  tered. Proton pump inhibitors block acid secretion by  irreversibly binding and inhibiting the hydrogen-potassium  ATPase that resides on the luminal surface of the parietal cell.  The proton pump inhibitors include omeprazole, lansopra-  zole, pantoprazole, rabeprazole, and esomeprazole. The use  of a proton pump inhibitor or a prostaglandin analog, miso-  prostol, reduces the recurrences of ulcers especially if the  patient needs to continue to take NSAIDs. Unfortunately,  misoprostol at 200 meg four times daily is often associated  with cramps, diarrhea, and poor patient compliance.   Drugs that selectively inhibit COX-2 were developed to  have similar analgesic and anti- inflammatory effects as tradi-  tional NSAIDs but with a reduced risk of GI complications.  Several studies have suggested that COX-2 inhibitors help  treat musculoskeletal as well as arthritic conditions with  fewer ulcer complications because they do not inhibit the  gastric mucosal prostaglandins. However, they are also asso-  ciated with an increased risk of cardiovascular and throm-  botic events. The exact mechanisms for this are not clear but may  be related to the fact that thromboxane A2 is COX-1-  mediated product that causes irreversible platelet aggrega-  tion, vasoconstriction, and smooth muscle proliferation. In  contrast, prostacyclin is synthesized from COX-2 and is an  inhibitor of platelet aggregation while causing vasodilation  and inhibition of smooth muscle proliferation. Selective  inhibition of COX-2 may lead to an imbalance in these prod-  ucts that promotes thrombosis. The addition of low-dose  aspirin to a COX-2 inhibitor increases the ulcer rate to that  seen with nonselective NSAIDs.   The use of enteric-coated or buffered aspirin does not  substantially reduce the risk of ulcer complications com-  pared with uncoated aspirin due to the systemic effects of  these drugs. A recent study of patients with ulcer bleeding  from aspirin has shown that administration of a proton  pump inhibitor with aspirin significantly reduces recurrent  ulcer bleeding as compared with substituting the aspirin for  another antiplatelet agent, clopidogrel. Also, as expected, the  use of both aspirin and clopidogrel significantly increase the  bleeding risk compared with use of aspirin alone. Although  recent studies suggest that the use of nitric oxide-releasing  NSAIDs may help reduce ulcer complications, they are not  yet available for clinical use. In small trials, for example,  adding a nitric oxide-donating moiety to aspirin was associ-  ated with less GI mucosal damage and yet provided similar  inhibition of platelet aggregation and thromboxane B2 pro-  duction as traditional aspirin. Long-term studies are needed  to determine whether nitric oxide-releasing aspirin is truly  safer and provides the same benefits as traditional aspirin.   Bombardier C, Laine L, Reicin A, et al. Comparison of upper gas-  trointestinal toxicity of rofecoxib and naproxen in patients with  rheumatoid arthritis. N Engl J Med. 2000;343:1520-1528.  [PMID: 11087881]   Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and  esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med.  2005;352:238-144. [PMID: 15659723]   Chan FK, To KF, Wu JC, et al. Eradication of Helicobacter pylori  and risk of peptic ulcers in patients starting long-term treat-  ment with non-steroidal anti-inflammatory drugs: a ran-  domised trial. Lancet. 2002;359:9-13. [PMID: 11809180]   Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper  gastrointestinal bleeding in patients with Helicobacter pylori  infection who are taking low-dose aspirin or naproxen. N Engl J  Med. 2001;344:967-973. [PMID: 11274623]   Fiorucci S, Santucci L, Gresele P, et al. Gastrointestinal safety of  NO-aspirin (NCX-4016) in healthy human volunteers: a proof  of concept endoscopic study. Gastroenterology. 2003;124:  600-607. [PMID: 12612897]   Hawkey CJ, Karrash JA, Szczepafiski L, et al. Omeprazole com-  pared with misoprostol for ulcers associated with nonsteroidal  anti-inflammatory drugs. Omeprazole versus Misoprostol for  NSAID-induced Ulcer Management (OMNIUM) Study Group.  N Engl J Med. 1998;338:727-734. [PMID: 9494149]   Lanas A, Bajador E, Serrano P, et al. Nitrovasodilators, low-dose  aspirin, other nonsteroidal anti-inflammatory drugs, and the  risk of upper gastrointestinal bleeding. N Engl } Med. 2000;343:  834-839. [PMID: 10995862]   Patients with active duodenal or gastric ulcers and those with  a prior ulcer history should be tested for H pylori. Appropriate  therapy should be given for eradication. Patients with MALT  lymphoma should also be tested and treated for H pylori since  eradication of this infection can induce remission in many  patients when the tumor is limited to the stomach. Several  consensus conferences, including the Maastricht Consensus  Report, recommend testing and treating several other groups   of patients but there is limited evidence of benefit. This  includes patients diagnosed with gastric adenocarcinoma  (especially those with early-stage disease), patients found to  have atrophic gastritis or intestinal metaplasia, as well as  first-degree relatives of patients with gastric adenocarcinoma  since the relatives themselves are at increased risk of gastric  cancer partly due to the intrafamilial transmission of H pylori.  To date, it remains controversial whether to test and treat all  patients with functional dyspepsia, gastroesophageal reflux   The success of H pylori cure depends on the type and  duration of therapy, patient compliance, and bacterial factors  such as antibiotic resistance. There are multiple treatment  regimens for H pylori eradication and most include the use of  a proton pump inhibitor combined with two antibiotics for  7-14 days (Table 15-3). Some commonly used antibiotics are  amoxicillin, clarithromycin, metronidazole, and tetracycline;    Often used as first-line therapy; in U.S., recommendation  is to treat for at least 10 days    Usually used as second-line therapy in patients who  fail to respond to triple therapy   Amoxicillin, 1 g twice daily for the first 5 days followed by    Overall eradication rate > 90%; recommended for  second-line or rescue therapy but may also be considered  for initial therapy   studies often report cure rates of over 80-90% with these  agents. European studies report that 7-day regimens are ade-  quate, but a meta-analysis suggested that a 14-day treatment  regimen had a higher eradication rate and was cost-saving  compared with 7 days therapy (81% vs 72%). In the United  States, the overall resistance to clarithromycin is 10.1%, to  metronidazole is 36.9%, and to amoxicillin is only 1.4%.  Owing to regional antibiotic resistance differences, a 14-day  regimen appears to be more effective in the United States  and is recommended by the U.S. Food and Drug Admini-  stration. A commonly prescribed regimen, for example, is  triple therapy using a proton pump inhibitor (given twice  daily) along with clarithromycin (500 mg twice daily) and  amoxicillin (1 g twice daily) or metronidazole (500 g twice  daily, for penicillin allergic patients) for 14 days. Ranitidine  bismuth citrate (400 mg twice daily) may be substituted for  the proton pump inhibitor. Quadruple therapy uses a pro-  ton pump inhibitor twice daily and four-times-daily dosing  of antibiotics with tetracycline (500 mg) and metronidazole  (500 mg), along with bismuth subsalicylate or subcitrate  (525 mg four times daily).   Patients most often fail to respond to initial H pylori erad-  ication therapy because of noncompliance or antibiotic  resistance. Patients should be queried about any side effects,  missed doses, and completion of therapy. As culture with  antibiotic sensitivities is not routinely performed when  H pylori infection is diagnosed, it is generally recommended  that different antibiotics be given at higher doses for 14 days.  Quadruple therapy has been widely used in the past, with  cure rates of 70-80%, but more recent studies also suggest  the use of either levofloxacin-based triple therapy or sequen-  tial therapy (see Table 15-3). These latter two regimens can  also be used as primary therapy. Sequential therapy, for  example, consists of a proton pump inhibitor (twice daily),  amoxicillin (1 g twice daily for the first 5 days), followed by  clarithromycin (500 mg twice daily) and tinidazole (500 mg  twice daily) for the next 5 days. Sequential therapy is rela-  tively well tolerated and effective as either first- or second-  line therapy even among patients who harbor  clarithromycin-resistant strains. Patients who fail to respond  to second-line eradication may undergo culture for H pylori  and a determination of antibiotic sensitivities to help direct  further therapy.   Malfertheiner P, Megraud F, O'Moran C, et al. Current concepts  in the management of Helicobacter pylori infection: the  Maastricht III Consensus Report. Gut. 2007;56:772-781.  [PMID: 17170018]   Vakil N, Megraud F. Eradication therapy for Helicobacter pylori.  Gastroenterology. 2007;133:985-2327. [PMID: 17570207]   Up to 5% of gastric ulcers represent underlying neoplasia.  Although the incidence of gastric cancer has steadily  declined over the past few decades, it still remains a major   cause of cancer death worldwide. There is wide regional vari-  ation in the incidence of gastric cancer. High incidence rates  have been reported in Japan, eastern Asia, Eastern Europe, and  parts of Latin America, while low incidence rates have been  reported in the United States and Western Europe. Gastric car-  cinogenesis is a multistep process, starting from chronic gas-  tritis and progressing over many years to atrophy, intestinal  metaplasia, dysplasia, and eventually adenocarcinoma. Three  meta-analyses of case-control and cohort studies report sum-  mary odds ratios for H pylori and gastric adenocarcinoma of  1.92 (95% confidence interval [CI], 1.32-2.78), 2.5 (95% CI,  1.90-3.40), and 2.04 (95% CI, 1.69-2.45). In an animal study,  long-term infection with H pylori in Mongolian gerbils has  been shown to induce gastric adenocarcinoma.   The strongest evidence for an association between H pylori  and gastric cancer in humans comes from a long-term  prospective cohort study from Japan by Uemura and col-  leagues. In this study, 1526 patients with various GI disorders,  including duodenal ulcers, gastric ulcers, gastric hyperplasia,  and nonulcer dyspepsia, underwent endoscopy with biopsy at  enrollment and then 1-3 years after enrollment. Helicobacter  pylori infection was assessed using histology, serologic testing,  or rapid urease testing, and subjects were considered to  have H pylori if they had a positive result on any of these tests.  There were 1246 infected and 280 uninfected patients fol-  lowed for a mean duration of 7.8 years. Among the infected  patients, 253 received eradication therapy at an early stage of  follow-up. Gastric cancer developed in approximately 3% of  the infected but in none of the uninfected patients. In addi-  tion, gastric cancer did not develop in any of the 253 infected  patients who received eradication therapy. Infected patients  with severe gastric atrophy, corpus-predominant gastritis,  and intestinal metaplasia were at significantly higher risk for  gastric cancer. The risk was also increased in almost all sub-  groups of H pylori-infected patients (those with gastric  ulcers, gastric hyperplastic polyps, or nonulcer dyspepsia) but  not in those with duodenal ulcers.   It is noteworthy that infected patients who received erad-  ication therapy did not develop gastric cancer. These results  support the notion that eradication of H pylori may poten-  tially prevent or delay the development of cancer. A few stud-  ies, including a randomized chemoprevention trial, suggest  that eradicating H pylori among patients with gastric atrophy  and intestinal metaplasia may increase the regression rate of  these precancerous lesions, as compared with placebo.  Controlled clinical trials are ongoing to determine whether  H pylori eradication prevents gastric cancer, but a recent  large study from China did not show a benefit.   It is known that the risk of gastric cancer is greater in  patients with low gastric acidity, such as those with severe  atrophic gastritis associated with intestinal metaplasia and  pernicious anemia. Patients who have had a partial gastrec-  tomy are also at risk for gastric cancer after a long latency  period, but their risk appears greater after an additional acid-  reducing procedure such as vagotomy. Low acid secretion has  been hypothesized to predispose to gastric cancer by affecting   vitamin C absorption and overgrowth of salivary and intes-  tinal bacteria in the stomach, which potentially promote the  formation of carcinogenic nitrosamines.   Chronic inflammation with alterations to DNA or changes  in expression of cytokines and chemokines may also affect early  progression. In addition, host genetics play a key role, and  recent studies have shown how human genetic polymorphisms  profoundly affect gastric carcinogenesis. For example, inter-  leukin-l|3 is an important proinflammatory cytokine and a  powerful inhibitor of acid secretion. Levels of interleukin-lp  within the gastric mucosa are increased by H pylori infection.  Genetic polymorphisms that promote high expression of inter -  leukin-l|3 help explain why some H pylori-infected patients  develop gastric cancer while others do not.   El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 poly-  morphisms associated with increased risk of gastric cancer.  Nature. 2000;404:398-402. [PMID: 10756728]   Peek RM Jr, Blaser MJ. Helicobacter pylori and gastrointestinal tract  adenocarcinomas. Nat Rev Cancer. 2002;2:28-37. [PMID:  11902583]   Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori  infection and the development of gastric cancer. N Engl J Med.  2001;345:784-789. [PMID: 11556297]   There is strong evidence supporting the role of H pylori  infection in the development of primary MALT lymphoma  of the stomach. Epidemiologic studies have shown that  patients with gastric MALT lymphomas are significantly  more likely than matched control subjects to have had previ-  ous H pylori infection. There is also direct evidence that  MALT lymphomas arise in the presence of H pylori gastritis.  Some investigators have even been able to detect the lym-  phoma B-cell clone in the chronic gastritis that preceded the  lymphoma. Nevertheless, the strongest evidence of a causal  association is that H pylori eradication can induce remission  in patients with low-grade lymphoma in 41-100% of  patients when the disease is limited to the stomach. Many of  these patients remain in remission for years.   Malfertheiner P, Megraud F, O'Moran C, et al. Current concepts in  the management of Helicobacter pylori infection: the Maastricht  III Consensus Report. Gut. 2007;56:772-781. [PMID: 17170018]   ► Peptic ulcer disease, abdominal pain, and diarrhea are  common presentations.   ► Patients have marked gastric acid secretion arising from  a gastrin-secreting non-p islet cell tumor.   ► Multiple endocrine neoplasia syndrome type 1 (MEN 1)  is present in -25-30% of patients.   ► Serum gastrin concentration > 1000 pg/mL in combina-  tion with acidic stomach pH < 2.0 is diagnostic.   ► Up to 40% of patients have elevated serum gastrin lev-  els that are < 500 pg/ml_ and warrant a secretin test.   ► Significant hypergastrinemia can occur with proton  pump inhibitor use, Helicobacter pylori infection, or  chronic atrophic gastritis and hypochlorhydria.   Zollinger-Ellison syndrome (ZES) is characterized by peptic  ulcers, diarrhea, and marked gastric acid hypersecretion in  association with a gastrin-secreting non-(3 islet cell  endocrine tumor (gastrinoma). The reported incidence of  gastrinomas ranges from 0.5 to 4 cases per million of the  population per year. ZES is a rare cause of peptic ulcer dis-  ease and accounts for only 0.1-1% of ulcers. The mean age of  onset of symptoms is 41 years and slightly more men than  women are affected, with a ratio of 3:2. The diagnosis of ZES  is typically delayed by at least 5-7 years. Although the major-  ity of gastrinomas develop as a sporadic tumor, approxi-  mately 25-30% of ZES patients have gastrinomas as part of  the inherited multiple endocrine neoplasia syndrome type 1  (MEN 1). MEN 1 is an autosomal-dominant inherited syn-  drome characterized by pancreatic neuroendocrine tumors,  pituitary tumors, and hyperparathyroidism, and is caused by  mutations of the MEN 1 tumor suppressor gene on chromo-  some llql3.   Patients with ZES most often present with symptoms arising  from excessive gastric acid secretion. The unregulated gas-  trin production from the gastrinoma stimulates parietal cells  to secrete acid mainly by causing histamine release from  enterochromaffin-like cells and also in part by activation of  cholecystokinin B and gastrin receptors expressed on parietal  cells. In addition, gastrin also has trophic effects on gastric  epithelial and enterochromaffin-like cells. Chronic hypergas-  trinemia increases parietal cell mass, which further augments  acid hypersecretion. The enteroendocrine cells that make up  the gastrinoma are well differentiated and round, with small  nuclei and prominent nucleolus. They often contain neu-  roendocrine tumor markers, including chromogranin A,  neurospecific enolase, and synaptophysin.   Peghini PL, Annibale B, Azzoni C, et al. Effect of chronic hyper-  gastrinemia on human enterochromaffin4tke cells: insights  from patients with sporadic gastrinomas. Gastroenterology.  2002;123:68-85. [PMID: 12105835]   Abdominal pain and diarrhea are the most common symp-  toms experienced by ZES patients. Gastroesophageal reflux,  nausea, and bleeding are other typical symptoms. The wide-  spread use of acid suppressive medications such as proton  pump inhibitors (PPIs) may mask symptoms and delay diag-  nosis. Table 16-1 shows the frequency of these presenting  symptoms in ZES patients. Diarrhea arises from the hyper-  secretion of acid, which inactivates pancreatic enzymes  (leading to malabsorption and steatorrhea), damages entero-  cytes, and causes primary bile acids to become insoluble.  Nasogastric suctioning can alleviate the diarrhea. In patients  with advanced disease, symptoms are related directly to the  growth of the gastrinoma. Patients with ZES and MEN 1   MEN, multiple endocrine neoplasia; NIH, National Institutes of Health.  Data from Roy PK, Venzon DJ, Shojamanesh H, et al. Zollinger-Ellison  syndrome. Clinical presentation in 261 patients. Medicine  (Baltimore). 2000,-79:379; and Jensen RT. Gastrinomas: advances in  diagnosis and management. Neuroendocrinology. 2004;80:23.   syndrome may also present with primary hyperparathy-  roidism as well as anterior pituitary tumors, and up to 37%  develop gastric carcinoids.   Over 70% of ZES patients develop peptic ulcers, which  can appear similar to ulcers associated with H pylori and  nonsteroidal anti-inflammatory drug (NSAID) use. ZES  patients often also have prominent gastric folds that can be  seen on upper endoscopy. Only a small fraction present with  a perforated ulcer or esophageal stricture. ZES should be sus-  pected in patients who have had peptic ulcers in unusual  locations (eg, second part of the duodenum and jejunum),  patients with severe ulcers refractory to acid- suppressive  medications, ulcer patients with hypercalcemia, and those  with a personal history or family history of MEN 1 syndrome.  ZES may also be considered as a rare cause of ulcers in  patients without H pylori infection who have not taken any  aspirin or NSAIDs.   Roy PK, Venzon DJ, Shojamanesh H, et al. Zollinger-Ellison  syndrome. Clinical presentation in 261 patients. Medicine  (Baltimore). 2000;79:379-411. [PMID: 11144036]   The diagnosis of ZES is based on finding an elevated fasting  serum gastrin level associated with gastric acid hypersecre-  tion. The upper limit of normal for gastrin is 110 pg/mL.  Figure 16-1 is an algorithm outlining an approach to the   evaluation of ZES. Patients suspected of having ZES should  have a measurement of a fasting serum gastrin level, ideally  while they are off all acid-suppressive medications. PPIs  should be stopped at least 1 week before testing. Patients who  develop significant abdominal symptoms after temporarily  stopping their PPIs may require histamine-2 (H 2 )-receptor  blockers (which should then be stopped at least 2 days before  testing) as well as high doses of antacids during this time.   A serum gastrin concentration above 1000 pg/mL in a  patient with an acidic stomach pH below 2.0 is considered  diagnostic of ZES (in patients who do not have a retained  gastric antrum), and no other diagnostic studies are neces-  sary. Unfortunately, this occurs in only 5-9% of ZES  patients. Up to 40% of ZES patients actually have elevated  serum gastrin levels of less than 500 pg/mL. This range of  hypergastrinemia can overlap with non-ZES patients having  low acid secretion. Many of these patients without ZES  develop a secondary hypergastrinemia in response to high  gastric pH and decreased acid feedback inhibition of gastrin  release. Patients taking PPIs as well as those with H pylori  infection or chronic atrophic gastritis and hypochlorhydria  can develop significant hypergastrinemia. Other disorders  causing hypergastrinemia include G-cell hyperplasia,  retained gastric antrum, gastric outlet obstruction, short  bowel syndrome, and renal insufficiency.   The secretin stimulation test can establish the diagnosis of  ZES and is the provocative test of choice because of its high  sensitivity, ease of administration, and minimal side effects.  Some studies suggest that secretin can stimulate gastrin  release by direct interaction with receptors on gastrinoma  cells. Intravenous administration of secretin stimulates an  exaggerated serum gastrin increase in ZES patients, while  the serum gastrin level falls or remains unchanged in other  disorders.   During secretin stimulation testing, a baseline serum gas-  trin is measured and then 2 units/kg of body weight of  secretin (Secretin-Kabi) are administered intravenously over  1 minute. Repeated measurements of gastrin are subse-  quently made 2, 5, 10, 15, and 20 minutes later. A widely used  criterion for a positive secretin stimulation test is an absolute  increase in serum gastrin by 200 pg/mL or greater after  secretin injection. This result has a sensitivity and specificity  of over 83% for detecting gastrinomas. However, a new cri-  terion for the diagnosis of ZES has been recommended by  Jensen and colleagues as part of a large study involving 293  ZES patients from the National Institutes of Health who were  compared with 537 patients in the literature. An absolute  increase in gastrin of more than 120 pg/mL was found to  have the highest sensitivity (94%) and a specificity of 100%.  It is important to note that another preparation of secretin is  now also available that is made by the Repligen Corporation  (Waltham, MA) and is given at a dose of 0.4 mcg/kg of body  weight.   ▲ Figure 16-1. Algorithm for evaluation of suspected Zollinger-Ellison syndrome (ZES). chemotx, chemotherapy; CT,  computed tomography; EUS, endoscopic ultrasound; INF, alfa-interferon; MEN 1, multiple endocrine neoplasia syndrome  type 1; PPIs, proton pump inhibitors; MRI, magnetic resonance imaging; somatostatin, somatostatin analog therapy;  SRS, somatostatin receptor scintigraphy.   The calcium infusion study has less diagnostic accuracy  (with a sensitivity of 62%) and is difficult to perform. It is also  associated with a higher rate of adverse side effects but may be  positive in the few gastrinoma patients with a negative secre-  tion stimulation test. During meal provocative testing, the  gastrin response unfortunately overlaps with those seen in  patients with antral syndromes and is thus generally not use-  ful. Gastric acid secretion studies have previously aided in the  diagnosis of ZES through a determination of the basal acid  output (BAO) and pentagastrin-stimulated acid output  (MAO) but are not widely available. Hypergastrinemia with a  BAO greater than 15 mEq/h or greater than 5 mEq/h in  patients with a prior vagotomy and partial gastrectomy is sug-  gestive of ZES. Recent reports suggest that serum levels of  chromogranin A may also be helpful, because this value is fre-  quently elevated in patients with neuroendocrine tumors,  including those with gastrinomas.   Berna MJ, Hoffman KM, Long SH, et al. Serum gastrin in  Zollinger-Ellison syndrome: II. Prospective study of gastrin  provocative testing in 293 patients from the National Institutes  of Health and comparison with 537 cases from the literature,  evaluation of diagnostic criteria, proposal of new criteria, and  correlations with clinical and tumoral features. Medicine  (Baltimore). 2006;85:331-364. [PMID: 17108779]   More than 80% of gastrinomas are localized in a gastrinoma  triangle area that is defined by the convergence of the cystic  duct and common bile duct, the junction of the second and  third portion of the head and body of the duodenum, and the  junction of the head and body of the pancreas. Over 80% of  duodenal gastrinomas are located in the first and second por-  tion of the duodenum. Duodenal gastrinomas tend to be  small and multiple whereas pancreatic gastrinomas are often  larger than 1 cm. The gastrinomas associated with MEN 1  syndrome are also multiple and localized in the duodenum.  Rare extrapancreatic sites include the gastric antrum-pyloric  area, ovaries, bones, mesentery, liver, bile duct, heart, and  lymph nodes.   Gastrinomas express somatostatin receptors that bind  octreotide, and this can be used for tumor imaging. Most gas-  trinomas can now be localized through the use of somato-  statin receptor scintigraphy (SRS) with Ill-Indium  pentetreotide (OctreoScan) and single photon emission com-  puted tomography. Although computed tomography scanning  and magnetic resonance imaging are widely available, SRS is  more sensitive than all conventional imaging studies com-  bined and should be considered as the first imaging method  used because of its sensitivity and cost-effectiveness. SRS is  extremely sensitive for diagnosing primary and metastatic  liver lesions as well as bone metastasis in affected patients.  Endoscopic ultrasound is also useful for preoperative tumor  localization and staging in ZES patients, especially for tumors  in the head and body of the pancreas. The combined use of   SRS and endoscopic ultrasound has an overall sensitivity of  93% for detecting gastrinomas.   The more invasive localization methods such as portal  venous sampling and selective intra-arterial injection of  secretin combined with venous sampling may also be helpful  but only provide for a regionalization and not an exact local-  ization of the tumor. During exploratory surgery, duodeno-  tomy is the method of choice to find duodenal gastrinomas.  The addition of endoscopic transillumination of the duode-  nal wall or intraoperative ultrasonography may increase  detection of small duodenal tumors not seen on other imag-  ing studies.   The principal goals of treating ZES patients are to control  gastric acid hypersecretion (which reduces symptoms and  complications) and attempt surgical cure (ie, removal) in  selected patients or control tumor growth. The acid hyper-  secretion can be effectively treated both acutely and long  term through the use of high doses of oral PPIs such as  omeprazole, 60-120 mg/day. Due to the development of  these powerful acid-suppressive medications, the survival of  patients with gastrinomas primarily depends on tumor  growth and the extent of disease involvement.   Surgical exploration with possible curative resection is  currently recommended for all ZES patients without MEN 1  syndrome who are also free of liver and distant metastases.  This includes sporadic ZES patients with localized resectable  tumor in addition to those with no tumor found on imaging  studies. Intraoperative methods such as duodenotomy, pal-  pation, transillumination of the duodenal wall, ultrasonog-  raphy, or a combination of these techniques, greatly helps to  localize the gastrinoma. A recent large study of 195 ZES  patients followed for 12 years after diagnosis demonstrated  that surgical exploration for gastrinoma removal or cure sig-  nificantly increased patient survival. Patients undergoing  surgery had greater disease-related survival than nonsurgery  patients, which was attributed to significant reductions in  (the remaining) tumor growth and progression as well as  liver metastases.   The role of surgery in patients with ZES as part of the  MEN 1 syndrome remains controversial because these gastri-  nomas are multifocal and surgery is rarely curative.  Moreover, previous studies also show that MEN 1 patients  with small gastrinomas (<2 cm) usually have an indolent  clinical course and excellent long-term prognosis. However,  because primary tumor size does affect the subsequent devel-  opment of liver metastases, many authorities recommend  surgical exploration in ZES patients with MEN 1 for tumors  greater than 2-2.5 cm in an attempt to decrease the risk of  malignant spread.   As previously indicated, ZES patients with diffuse liver  metastases and especially those that are rapidly increasing in  size have substantially reduced survival. Aggressive surgical  resection or cytoreductive surgery in patients with advanced  disease may be considered to improve outcomes.  Embolization, chemoembolization, and cryoablation of liver  lesions are alterative approaches for palliation. Somatostatin  analogs are often used alone or with alfa-interferon as the  initial antitumor therapy. This includes the long-acting  somatostatin analogs such as octreotide-LAR or lanreotide-  SR or the auto-gel preparations that not only help control  acid secretion but may also decrease tumor size or slow its  growth. Systemic chemotherapy with streptozotocin, dox-  orubicin, or 5-fluorouracil potentially decreases the tumor  size in a small proportion of patients but does not appear to  improve survival. These agents also have substantial toxicity  and are reserved for patients with diffuse metastatic disease.  The role of liver transplantation is still under investigation  but may be considered for younger patients with metastases  limited to the liver.   Fendrich V, Langer P, Waldmann J, et al. Management of sporadic  and multiple endocrine neoplasia type 1 gastrinomas. Br ] Surg.  2007;94:1331-1341. [PMID: 17939142]   Jensen RT. Gastrinomas: advances in diagnosis and management.  Neuroendocrinology. 2004;80:23-27. [PMID: 15477712]   Norton JA, Fraker DL, Alexander HR, et al. Surgery increases sur-  vival in patients with gastrinoma. Ann Surg. 2006;244:410-419.  [PMID: 16926567]   Norton JA, Jensen RT. Role of surgery in Zollinger-Ellison syn-  drome. J Am Coll Surg. 2007;205:S34-37. [PMID: 17916516]   Tomassetti P, Campana D, Piscitelli L, et al. Treatment of Zollinger-  Ellison syndrome. World J Gastroenterol. 2005;11:5423-5432.  [PMID: 16222731]   Several reports suggest that 60-90% of gastrinomas are  malignant. The single most important determinant of  decreased survival is the presence of liver metastases. Patients  with a gastrinoma and diffuse liver metastases have a 10-year  survival rate of 15% whereas gastrinoma patients without  liver metastases have a much better prognosis with a 20-year  survival of 95%. In part due to a larger tumor size and hence  a greater propensity for liver metastases, the survival rate of  patients with pancreatic gastrinomas tends to be lower than  that of patients with duodenal gastrinomas. The 10-year sur-  vival rate was 57% in patients with sporadic pancreatic gas-  trinomas and 84% in patients with duodenal gastrinomas.  An aggressive form of gastrinoma develops more commonly  among female ZES patients without the MEN 1 syndrome  who have shorter disease duration but large pancreatic  tumors with liver metastases.   Yu F, Venzon DJ, Serrano J, et al. Prospective study of the clinical  course, prognostic factors and survival in patients with long-  standing Zollinger-Ellison syndrome. / Clin Oncol 1999;17:  615-630. |PMID: 10080607]   Dyspepsia is a common symptom having either an organic  or a functional cause; distinguishing between the two can  be a challenge.   Clinical features of functional dyspepsia, gastroesophageal  reflux disease, and gastrointestinal motility disorders over-  lap, making diagnosis difficult.   Endoscopy is indicated for patients with new-onset symp-  toms who are > 55 years of age or have alarm features.   This chapter outlines the evaluation and management of  dyspepsia, with a primary focus on functional dyspepsia, also  interchangeably called nonulcer dyspepsia. The term  dyspepsia derives from the Greek "dys," meaning bad, and  "pepsis," meaning digestion. Dyspepsia is a symptom, not a  diagnosis. The term encompasses a broad spectrum of symp-  toms that include upper abdominal pain or discomfort,  bloating, early satiety, post-prandial fullness, nausea with or  without vomiting, anorexia, symptoms of gastroesophageal  reflux disease (GERD), regurgitation, and belching.   The multiple causes of dyspepsia can be classified as organic  or functional. Among the organic causes are esophagitis,  peptic ulcer disease, benign esophageal strictures, upper gas-  trointestinal malignancies, chronic intestinal ischemia, and  pancreaticobiliary disease. In addition, several medications  can cause dyspeptic symptoms (Table 17-1). Most notable   are nonsteroidal anti-inflammatory drugs (NSAIDs), which  can cause mucosal injury leading to gastritis. Functional dys-  pepsia excludes all organic causes.   Functional dyspepsia was previously defined by the Rome II  criteria as pain centered in the upper abdomen in the setting  of a normal endoscopy. The Rome Foundation established  symptom-based diagnostic criteria with three subtypes of  functional dyspepsia: ulcer-like dyspepsia, dysmotility-like  dyspepsia, and unspecified (nonspecific) dyspepsia. These cri-  teria most recently have been revised in Rome III (Table 17-2)  to address the fact that the prior subtypes were of questionable  clinical value and that patients with functional dyspepsia do  not necessarily have pain as their only symptom, but rather  have a wide range of symptoms with great variability. The  most current definition of functional dyspepsia, derived from  the revised criteria, is "the presence of one or more dyspeptic  symptoms that originate from the gastroduodenal region, in  the absence of any organic, systemic, or metabolic disease that  could explain the symptoms."   Drossman DA. The functional gastrointestinal disorders and the  Rome III process. Gastroenterology. 2006;130:1377-1390. [PMID:  16678553]   The approximate prevalence of dyspepsia is 25%, with the  range being 3-15% if GERD symptoms are excluded.  However, the prevalence of uninvestigated dyspepsia may  range as high as 40%. Of patients who have not been worked  up, 40% may have an organic cause for their dyspepsia. The  prevalence of functional dyspepsia is about 12-15%.   The incidence of dyspepsia is estimated to be 10%, with  new cases accounting for 5-7% of primary care office visits.  Dyspeptic symptoms can account for up to 40-70% of gas-  trointestinal complaints in a general gastroenterology practice.  The cost of treatment is substantial.   Functional Dyspepsia— at least 3 months with onset at least 6 months  previously of 1 or more of the following:   • No evidence of structural disease (including at upper endoscopy)  that is likely to explain the symptoms   a. Post-prandial Distress Syndrome— at least 3 months, with onset  at least 5 months previously of 1 or more of the following:   b. Epigastric Pain Syndrome— at least 3 months, with onset  at least 6 months previously, with all of the following:   2. tocalized to the epigastrium of at least moderate severity,  at least once per week   El-Serag HB, Talley NT. Systematic review: the prevalence and clin-  ical course of functional dyspepsia. Aliment Pharmacol Ther.  2004;19:643-654. [PMID: 15023166]   Fraser A, Delaney B, Moayyedi P. Symptom-based outcome meas-  ures for dyspepsia GERD Trials: A systematic review. Am J  Gastroenterol. 2005;100:442-452. [PMID: 15667506]   Organic dyspepsia can develop as a consequence of the var-  ied disease processes mentioned in this chapter and  described elsewhere in this text. The pathogenesis of func-  tional dyspepsia is unclear. Factors that play a role in causa-  tion include altered visceral sensitivity, disturbances in  motility, alterations in gastric accommodation, dietary factors,  and psychosomatic factors. The role of Helicobacter pylori in  the genesis of symptoms is controversial.   Increased visceral sensitivity, or hyperalgesia, involves increased  sensory input to and from the stomach. Hypersensitivity to  stimulation can occur in response to mechanical, chemical, or  nutrient stimuli; to gastric and intestinal secretions of acid, or  to hormones, such as cholecystokinin and glucagon-like pep-  tide 1. In response, there maybe altered central nervous system  processing of these stimuli. Studies have demonstrated hyper-  sensitivity to balloon distention in the stomach in as many as  50% of patients with functional dyspepsia. Compared with  controls, patients with functional dyspepsia had a significantly  lower threshold to both initial sensation of balloon distention  and to sensation of pain.   Another hypothesis is that disturbances in gastrointestinal  motility represent the underlying causative factor in func-  tional dyspepsia. Motor disorders such as gastroesophageal  reflux, gastroparesis, small bowel dysmotility, and biliary  dyskinesia may cause dyspeptic symptoms. Disturbances in  gastric emptying and gastrointestinal motor function occur  in subgroups of patients with functional dyspepsia, and stud-  ies of these patients show female sex predominance. The  prevalence of motility disorders has varied markedly  between studies, likely due to subject selection criteria and  study methodology. A meta-analysis of studies investigating  functional dyspepsia and disturbed solid phase gastric emp-  tying found 40% of patients with functional dyspepsia had  slower emptying, and the pooled estimate of slowing was  1.5 times that of normal patients. However, the decrease in  gastric emptying was modest.   As mentioned, symptoms of GERD often overlap with  dyspepsia symptoms. Poor visceral localization of symptoms  can often cause a reflux event to be confused with other upper  gastrointestinal sources of discomfort. Both acid and nonacid   reflux can cause symptoms. A recent report noted that patients  with functional dyspepsia swallow air more frequently than  controls; this finding was associated with an increase in  nonacid reflux, which can also cause epigastric symptoms.   Conchillo JM, Selimah M, Bredenoord AJ, et al. Air swallowing,  belching, acid and non-acid reflux in patients with functional dys-  pepsia. Aliment Pharm Ther. 2007;25:965-971. [PMID: 17403001]   Talley NJ, Locke GR, Lahr BD, et al. Functional dyspepsia, delayed  gastric emptying, and impaired quality of life. Gut. 2006;55:  933-939. [PMID: 16322108]   Alterations in gastric accommodation have been hypothe-  sized to be a cause of functional dyspepsia. During normal  ingestion of food, the gastric fundus relaxes to "accommo-  date" the food particles. This accommodation is mediated by  serotonin (5-HTj ) and nitric oxide via vagal inhibitory neu-  rons of the enteric nervous system. The accommodation  reflex may be impaired in as many as 40% of patients with  functional dyspepsia, as demonstrated by gastric scintigra-  phy and ultrasound. Measurement of gastric pressure by a  barostat, or a polyethylene balloon inflated in the stomach,  connected to a pressure monitor has shown impaired meal-  induced accommodation as well.   Kindt S, Tack J. Impaired gastric accommodation and its role in  dyspepsia. Gut. 2006;55:1685-1691. [PMID: 16854999]   true for both the symptom profile and pathophysiology of  functional dyspepsia. Although some epidemiologic studies  have suggested an association between H pylori infection and  functional dyspepsia, others have not. The discrepancy may  stem in part from differences in methodology and lack of  adequate consideration of confounding factors such as past  history of peptic ulcer disease and socioeconomic status.  Controlled trials disagree about whether or not H pylori  eradication is beneficial in functional dyspepsia, with  roughly half of the trials showing improvement and the  other half no improvement. In a recent multicenter U.S. trial  that randomized 240 patients to treatment or placebo, and  followed patients for 12 months, 28% of treated patients  versus 23% of those receiving placebo reported relief of symp-  toms at the 12-month follow-up. Similarly, recent European  trials have not shown significant differences in symptoms after  H pylori eradication as compared with controls. Systematic  reviews of eradication have been conducted, with varying  results. A systematic review in the Annals of Internal Medicine  suggested no statistically significant effect, with an odds ratio  (OR) for treatment success versus control of 1.29 (95% CI,  0.89-1.89; P= 0.18). Still, no effect was seen after adjusting for  heterogeneity and for cure of H pylori. In contrast, the most  recent update of a Cochrane Database review showed a small  but statistically significant effect in curing symptoms (H pylori  cure vs placebo, 36% vs 30%, respectively; relative risk  reduction [RRR] , 8% [95% CI, 3-1 8%] , number needed to treat  [NNT] = 18]).   Dietary factors may be a potential cause of symptoms in  functional dyspepsia. Patients with functional dyspepsia  appear to have altered eating patterns as well as food intoler-  ances. They frequently report being able to tolerate only  small quantities of food, with a high prevalence of snacking,  and low prevalence of eating large meals. Food intolerances  are also high in prevalence among these patients. Fatty foods,  in particular, have been linked to dyspepsia. Other intoler-  ances with a reported prevalence greater than 40% include  spices, alcohol, spicy foods, chocolate, peppers, citrus fruits,  and fish. Food allergy has been cited as a possible mechanism  but has not been explored in functional dyspepsia. Of note,  food-specific immunoglobulin E and immunoglobulin G 4  antibodies have been found to mediate food sensitivity in a  subgroup of patients with irritable bowel syndrome.   Feinle-Bisset C, Horowitz M. Review article: dietary factors in func-  tional dyspepsia. Neurogastroenterol Motil. 2006;18:608-618.  [PMID: 16918725]   The role of H pylori in functional dyspepsia is controversial,  and no clear causal relationship has been established. This is   Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter  pylori in patients with nonuker dyspepsia. A meta-analysis of  randomized, controlled trials. Ann Intern Med. 2001;134:  361-369. [PMID: 11242496]   Moayyedi P, Deeks J, Talley NJ, et al. An update of the Cochrane  systematic review of Helicobacter pylori eradication therapy in  nonuker dyspepsia: resolving the discrepancy between system-  atic reviews. Am J Gastroenterol. 2003;98:2621-2626. [PMID:  14687807]   Talley NJ, Quan C. Review article: Helicobacter pylori and nonuker  dyspepsia. Aliment Pharmacol Ther. 2002;16(Suppl l):58-65.  [PMID: 11849130]   More recently, it has been hypothesized that duodenal  eosinophilia may play a role in a subset of patients with func-  tional dyspepsia. In a case-control study, patients fulfilling  Rome II criteria for functional dyspepsia were compared  with controls and found to be more likely to have eosinophil  counts equal to or greater than 22 per 5 high-power fields on  duodenal biopsies (OR 11.7 for the duodenal bulb [95% CI  3.9-34.9] and 7.3 for the second portion of the duodenum  [95% CI 2.9-18.1]). This suggests that duodenal eosinophils  may play a role in functional dyspepsia. No difference was  seen on gastric biopsies.   Talley NJ, Walker MM, Aro P, et al. Non-ulcer dyspepsia and duo-  denal eosinophilia: an adult endoscopic population-based case-  control study. Clin Gastroenterol Hepatol. 2007;5:1175-1183.  [PMID: 17686660]   Psychosomatic and cognitive factors are important in the  evaluation of patients with chronic dyspepsia. The psychi-  atric hypothesis holds that the symptoms of dyspepsia maybe  due to depression, increased anxiety, or a somatization disor-  der. Epidemiologic studies suggest there is an association  between functional dyspepsia and psychological disorders.  Symptoms of neurosis, anxiety, hypochondriasis, and  depression are more common in patients being evaluated for  unexplained gastrointestinal complaints than in healthy con-  trols. Comparisons of functional and organic dyspepsia have  demonstrated that patients with functional dyspepsia are less  likely to have decreased stress or anxiety at 1-year follow-up  after being reassured of having no serious disease. This sug-  gests that functional dyspepsia symptoms are long-lasting,  compared with those of organic dyspepsia, and that the emo-  tional ties are strong.   Pajala M, Heikkinen M, Hintikka J. A prospective 1-year follow-up  study in patients with functional or organic dyspepsia: changes  in gastrointestinal symptoms, mental distress and fear of serious  illness. Aliment Pharmacol Ther. 2006;24:1241-1246. [PMID:  17014583]   The initial clinical evaluation should focus on symptom  characteristics, onset, and chronicity. The clinician should  try to interpret the symptoms in order to identify possible  etiologies such as GERD, gallstones, medications side effects  (particularly NSAIDs), chronic pancreatitis, diabetic gastro-  paresis, or obstruction. The patient should be asked about  comorbidities, surgical history, family history of upper gas-  trointestinal malignancy, alcohol and tobacco use, stressful  life events, and psychological factors.   In most cases, however, the clinical history is of limited  use in distinguishing organic causes from functional dyspep-  sia. A large systematic review of the literature was recently  performed to evaluate the effectiveness of diagnosing organic  dyspepsia by clinical opinion versus computer models in  patients referred for upper endoscopy. The computer models  were based on patient demographics, risk factors, historical  items, and symptoms. The study showed that neither clinical  impression nor computer models were able to adequately  distinguish organic from functional disease.   In a recent study, patients with peptic ulcer disease were  compared with patients with functional dyspepsia in an age-  and sex-matched study. Although the functional dyspepsia   Table 17-3. "Alarm" features suggestive of the presence  of upper gastrointestinal malignancy.   group reported more upper abdominal fullness, nausea, and  overall greater distress and anxiety, almost all the same  symptoms were seen in both groups.   Therefore, it is the clinician's challenging task to separate  patients who may have an organic disorder, and thus warrant  further diagnostic testing, from patients who have functional  dyspepsia, who are given empiric symptomatic treatment. The  workup should be targeted to identify or rule out specific  causes. Traditionally, high-risk patients have been identified by  "alarm" features, which are listed in Table 17-3. However, the  utility of these features in identifying the presence of upper  gastrointestinal malignancy has been debated. A recent meta-  analysis looking at the sensitivity and specificity of alarm fea-  tures found a range of 0-80% and 40-98%, respectively.  However, there was high heterogeneity between studies.   The physical examination may elicit abdominal tender-  ness, but this finding is nonspecific. A positive Carnett sign,  or focal tenderness that increases with abdominal wall con-  traction and palpation, suggests an etiology involving the  abdominal wall musculature. Cutaneous dermatomal distri-  bution of pain may suggest a thoracic polyradiculopathy.  Thump tenderness over the right upper quadrant may sug-  gest chronic cholecystitis.   Flier SN, Rose S. Is functional dyspepsia of particular concern in  women? A review of gender differences in epidemiology, patho-  physiologic mechanism, clinical presentation and management.  Am } Gastroenterol. 2006;101:S644-S653. [PMID: 17177870]   Moayyedi P, Talley NJ, Fennerty MB, et al. Can the clinical history  distinguish between organic and functional dyspepsia? JAMA.  2006;295:1566-1576. [PMID: 1659759]   If a careful history and physical examination, along with  judicious use of screening laboratory tests, does not lead to  the diagnosis, then other studies with specific management   Hpyfori-negative functional dyspepsia (normal endoscopy)  and failed an adequate PPI trial   A Figure 17-1. Management of dyspepsia based on  age and alarm features. EGD, esophagogastroduo-  denoscopy; GERD, gastroesophageal reflux disease;  NSAIDs, nonsteroidal anti-inflammatory drugs; PPI,  proton pump inhibitor. (Adapted, with permission, from  Talley NJ; American Gastroenterological Association.  American Gastroenterological Association medical position  statement: evaluation of dyspepsia. Gastroenterology.  2005;129:1753-1755.)   strategies are recommended. Strategic algorithms have been  suggested by the American Gastroenterology Association  (Figures 17-1 and 17-2) and the American College of  Gastroenterology.   There are several main strategies for new-onset dyspep-  sia, which include (1) empirical histamine-2 (H 2 )-receptor  blocker therapy; (2) empirical proton pump inhibitor (PPI)  therapy; (3) H pylori testing and treatment of positive cases,  followed by acid suppression if the patient remains symp-  tomatic; (4) early endoscopy; (5) early endoscopy with  biopsy for H pylori and treatment, if positive; (6) acid sup-  pression, followed by endoscopy and biopsy if the patient  remains symptomatic; or (7) H pylori testing and treatment,  if positive, followed by endoscopy if the patient remains  symptomatic.   Several considerations, outlined below, should guide the  selection of a strategy.   1. Esophagogastroduodenoscopy (EGD)— Patients who  have not been previously worked up for dyspepsia should be  scheduled for EGD if they demonstrate alarm features or are  older than 55 years of age. Special consideration also should  be given to patients whose country of origin is a region  where stomach cancer is more prevalent (eg, Japan, China,   2. Consider other sources of abdominal pain (pancreas,  colon, biliary tract)   ▲ Figure 17-2. Management of functional dyspepsia.  IBS, irritable bowel syndrome; PPI, proton pump  inhibitor. (Adapted, with permission, from Talley NJ;  American Gastroenterological Association. American  Gastroenterological Association medical position statement:  evaluation of dyspepsia. Gastroenterology.  2005;129:1753-1755.)   and Chile). EGD is the gold standard for evaluating the  upper gastrointestinal tract, as it can provide direct visualiza-  tion and allows the endoscopist to obtain a biopsy specimen  of the mucosa if needed. Thus, EGD has essentially replaced  the upper gastrointestinal radiologic series as the diagnostic  test of choice. Cost-effectiveness of early endoscopy in  patients older than 50 years of age has been studied in the  United Kingdom, with findings of improvement in symptom  scores, quality of life, and 48% reduction in use of PPIs.  Cost-effectiveness has yet to be studied in older patients in  the United States.   Patient age is an important consideration with regard to  endoscopy. The timing of upper endoscopy in younger  patients (< 55 years) is debatable. Patients who respond to  the H pylori testing and treatment strategy, outlined below,  can be managed without further investigation. In younger  patients with continued symptoms despite this strategy,  endoscopy usually adds little more to the diagnostic workup.  Furthermore, the utility of endoscopy in reassuring patients  with functional dyspepsia has been studied and has been  deemed questionable as measured by anxiety and depression,  which did not change before and after the procedure in these  patients.   Van Kerkhoven LA, van Rossum LG, van Oijen MG, et al. Upper gas-  trointestinal endoscopy does not reassure patients with functional  dyspepsia. Endoscopy. 2006;38:879-885. [PMID: 16981103]   2. Helicobacter pylori testing— For patients younger than  55 years of age and those without alarm features, the clinician  should consider first testing for H pylori and treating, if posi-  tive. The optimal test for H pylori is a 13 C-urea breath test or  stool antigen test. Helicobacter pylori is the main cause of pep-  tic ulcer disease not associated with NSAID use, and it may  cause functional dyspepsia in a small fraction of patients.  Thus, if the patient tests positive for H pylori, treatment is  suggested based on data from randomized controlled trials  and as a preventive measure against future gastric adenocar-  cinoma. Treatment usually consists of two antibiotics of dif-  ferent classes (eg, amoxicillin and clarithromycin), with a  double dose of a PPI (eg, omeprazole, 40 mg twice daily).  Many other regimens are available for use if the patient has a  history of allergic reactions to a particular class or has previ-  ously failed one of the standard regimens (Table 17-4). If the  patient is H py/ori-negative, a trial of acid suppression is sug-  gested; the most optimal approach to acid suppression in use  of a PPI. Empirical therapy should be tried for 4-8 weeks as  this has been shown to be cost effective in patients with a low  prevalence of H pylori (< 10%).   3. Other Studies — If a patient's symptoms are suggestive of  biliary pain, an ultrasound of the abdomen should be  obtained to evaluate the gallbladder for cholelithiasis or  cholecystitis. Classic biliary colic is characterized by sudden  onset of right upper quadrant pain that is constant, lasting  2-6 hours, associated with nausea, and worsened post-prandially.  Because of the visceral nature of the pain, it is poorly localiz-  able. Patients with biliary-type pain with findings of gallstones  should be considered for cholecystectomy. A quantitative  cholescintigraphy scan with cholecystokinin challenge may  suggest chronic cholecystitis as the diagnosis if the ejection  fraction is less than 50%.   Abdominal computed tomography (CT) can also provide  diagnostic clues in patients with chronic unexplained  abdominal pain to the presence of chronic pancreatitis, pan-  creatic cystic lesions, or abdominal tumors such as carcinoid  or gastrointestinal stromal tumors (GIST). CT enterography  can visualize the small bowel to aid in looking for undiag-  nosed Crohn disease or rare small bowel polyps or tumors.   A 24-hour pH test, using a catheter with multichannel  intraluminal impedance, can demonstrate acid or nonacid    Amoxicillin, 1 g twice daily  Clarithromycin, 500 mg twice daily  PPI twice daily    Metronidazole, 500 mg twice daily  Clarithromycin, 500 mg twice daily  PPI twice daily    First line in macrolide-allergic patients or those  who have failed traditional first-line therapy    Amoxicillin, 1 g twice daily  Metronidazole, 500 mg twice daily  PPI twice daily    Amoxicillin, 1 g twice daily  tevofloxacin, 250-500 mg twice daily  PPI twice daily    Bismuth, 525 mg 4 times daily  Metronidazole, 500 mg 4 times daily  Tetracycline, 500 mg 4 times daily  PPI twice daily    Rifabutin, 150 mg twice daily  Amoxicillin, 1 g twice daily  PPI twice daily   reflux in patients with symptoms likely attributable to  GERD. However, in most cases empiric treatment with PPI  therapy is more cost-effective and practical. Gastric scintig-  raphy usually does not add much more information to the  diagnostic picture. Although scintigraphy findings may be  abnormal in up to 40-50% of cases, they do not help estab-  lish the diagnosis or provide therapeutic guidance.   Talley NJ; American Gastroenterological Association. American  Gastroenterological Association medical position statement:  Evaluation of dyspepsia. Gastroenterology. 2005;129:1753-1755.  [PMID: 16285970]   Talley NJ, Vakil N; Practice Parameter Committee of the American  College of Gastroenterology. Guidelines for the management of  dyspepsia. Am } Gastroenterol. 2005;100:2324-2337. [PMID:  16181387]   Vakil N, Moayyedi P, Fennerty MB, et al. Limited value of alarm  features in the diagnosis of upper gastrointestinal malignancy:  systematic review and metaanalysis. Gastroenterology. 2006;131:  390-401. [PMID: 15890692]   The differential diagnosis of dyspepsia is broad. The findings  from the clinical examination and judicious use of the diag-  nostic studies outlined in the preceding section can aid in  distinguishing the various organic causes of dyspepsia from  functional dyspepsia.   GERD and dyspepsia overlap frequently, often coexisting in  the same patient. Thus, GERD should always be considered  in the dyspeptic patient. If the symptoms are predominantly  regurgitation, substernal burning, and acid taste rather than  dyspepsia, then GERD is more likely to be the cause than  other etiologies. Formal reflux testing with a 24-hour pH  study with the patient off medications can clarify whether  reflux is present. The existence of nonacid reflux in nonero-  sive reflux disease may be investigated by using 24-hour pH  studies with esophageal impedance.   Peptic ulcer disease is often one of the first diseases that  comes to mind when evaluating patients with dyspepsia.  About 15% of patients with dyspeptic symptoms have gastric  or duodenal ulcers. Other causes to consider in these patients  are the use of NSAIDs and the presence of H pylori infection.   Less than 2% of dyspeptic patients have gastric cancer. Older  patients are more likely to have gastric cancer, with 98% of   cancers occurring in patients older than 50 years of age.  Other risks for gastric cancer include H pylori infection,  country of origin in an area endemic for gastric malignancy  (Eastern Asia, the Andean regions of South America, and  Eastern Europe), excessive salt and nitrate consumption,  tobacco use, and family history of gastric cancer.   Chronic intestinal ischemia (so-called intestinal angina) is  characterized by chronic post-prandial pain with marked  weight loss due to mesenteric blood flow that is inadequate  to the demands required by digestion. Typically the patient  has a history of tobacco use or underlying atherosclerotic  disease. A diagnosis may be made by magnetic resonance  angiography or CT angiography.   The pain associated with chronic pancreatitis may be epigas-  tric or localized to the central abdomen, classically with radi-  ation to the mid back. Weight loss may occur. Pancreatic  endocrine or exocrine insufficiency (eg, diabetes, steator-  rhea) may or may not be present. Cholelithiasis usually is dis-  tinguishable from dyspepsia in being more localizable to the  right upper quadrant.   Upper gastrointestinal motility disorders also overlap with  dyspepsia. Many patients with functional dyspepsia have  gastroparetic-type symptoms, which led to the Rome II clas-  sification of "dysmotility-like dyspepsia." This classification  was of debatable clinical value, and has now been dropped  from the Rome III criteria. Nonetheless, there is a prepon-  derance of symptoms of bloating, early satiety, and nausea  with vomiting in patients with functional dyspepsia. Causes  of motility disturbance may include diabetic gastroparesis,  chronic intestinal pseudo-obstruction, scleroderma, or post-  vagotomy syndromes.   Dyspepsia may exist in a number of systemic disorders such  as diabetes mellitus, coronary artery disease, thyroid disease,  hyperparathyroidism, adrenal insufficiency, and collagen  vascular diseases.   Gastric infections other than H pylori can cause dyspepsia.  These include cytomegalovirus, tuberculosis, or fungal infec-  tions. Parasites to consider include Giardia lamblia and  Strongyloides stercoralis.   Other conditions to consider in the differential diagnosis are  chronic gastric volvulus, infiltrative diseases (sarcoidosis,  amyloidosis, eosinophilic gastroenteritis, Menetrier disease),  undiagnosed inflammatory bowel disease, celiac sprue, and idio-  pathic cause.   The treatment of organic dyspepsia is targeted to the cause.  The reader is referred to other chapters in this text that  describe specific treatment regimens for GERD, peptic ulcer  disease, and other disorders that may cause dyspepsia, as out-  lined earlier.   The treatment of functional dyspepsia is for the most part  symptom targeted. Studies have shown high placebo effect  rates, and moderate success in response to PPIs, motility  agents, and antidepressants. An effective physician-patient  relationship is vital to treatment success.   McNally MA, Talley NJ. Current treatments in functional dyspep-  sia. Curr Treat Options Gastroenterol. 2007;10:157-168. [PMID:  17391631]   Panganamamula KV, Fisher RS, Parkman HP. Functional (nonulcer)  dyspepsia. Curr Treat Options Gastroenterol. 2002;5:153-160.  [PMID: 11879596]   The physician-patient relationship is crucial to the treatment  of functional dyspepsia. Earnest efforts to accurately assess  the extent and chronicity of the patient's symptoms will  engender trust and reassurance. Fears of having cancer or a  life-threatening condition, anxiety levels, and stressful factors  in the patient's life should be assessed and addressed early in  the evaluation.   Reassuring patients that the cause of their symptoms is  non-life threatening, and that it is not cancer, is therapeutic  in itself. That being said, reviewing the workup and the dif-  ferential diagnosis is also important, so that patients have an  understanding of where they are in the treatment process.  The diagnosis of functional dyspepsia should also be  explained as a recognized clinical entity with the emphasis on  the understood pathophysiology of the problem and per-  haps, more importantly, what is not known about it.   Because of the chronicity of the problem, many patients  have already tried different remedies to alleviate their symp-  toms. Often patients understand what works for them and  what does not prior to the office visit. Dietary factors such as  meal content and quantity, positional factors, and home  remedies may be among them. It is important to recognize  the variability of symptoms, exacerbators, and alleviators, and  response to treatment in patients with dyspeptic symptoms.   No trials have been done to formally evaluate the efficacy of  dietary or lifestyle modifications in functional dyspepsia.  The current understanding of dietary contributors stems  from observation in clinical settings. Foods generally  reported to cause symptoms include onions, peppers, citrus  fruit, coffee, carbonated beverages, and spices. General  dietary recommendations are to avoid fatty or heavily spiced  foods and excessively large meals. Smaller, more frequent  meals are beneficial in patients with GERD, impaired gastric  accommodation, and delayed gastric emptying. Food aller-  gies should be noted and avoided. A food diary can help  identify triggers. A trial of dairy product avoidance may be  helpful in identifying lactose intolerance, with a hydrogen  breath test performed to formally make the diagnosis.  Caffeine intake and alcohol should be minimized. Regular  exercise and adequate restful sleep is also important and can  be helpful in alleviating stress.   If reassurance and lifestyle changes do not alleviate symp-  toms, medications can be tried. However, drug therapy trials  in functional dyspepsia have yielded conflicting results and  conclusions, owing to several factors. Placebo response rates  are known to be high in functional dyspepsia, ranging from  32% to 85%. Studies are often limited by insufficient sample  size, single-center trials, and variability in the definition of  functional dyspepsia. Furthermore, enrollment of patients  from tertiary referral centers into drug trials may not repre-  sent the general population in primary care. Patients with  GERD may inadvertently be included in trials, which would  bias response rates in antisecretory trials.   In addition to H pylori eradication therapy, the pharma-  cologic therapy includes antisecretory agents, promotility  agents, antidepressants and anxiolytics, and other classes of  drugs.   1. Antisecretory agents— Proton pump inhibitors (PPIs)  have been extensively studied in several large, carefully  designed, randomized controlled trials. A systematic review  of eight studies with a total of 3293 patients who received PPI  therapy for 2-8 weeks found a significant effect over placebo.  PPI therapy relieved or eliminated symptoms in 33%  patients compared with 23% of those receiving placebo. The  relative risk of remaining symptomatic on PPI versus  placebo was significantly protective (RR = 0.86; 95% CI,  0.78-0.95; P = 0.003; NNT = 9).   Analysis of the subtypes of functional dyspepsia showed  that patients with reflux-like and epigastric pain had a signif-  icant favorable response with PPI therapy, but those with  dysmotility-type dyspepsia did not. Similarly, another recent  systematic review of seven randomized controlled trials of  PPIs versus placebo, enrolling a total of 3725 patients, found  PPIs were more effective for patients with ulcer-like dyspepsia  (RRR = 12.8%; 95% CI, 7.2-18.1) and reflux-like dyspepsia   (RRR = 19.7; 95% CI, 1.8-34.3%) as compared with dysmotility-  like dyspepsia and unspecified dyspepsia. The latter two sub-  types showed no significant RRRs with PPI therapy over  placebo. As for H^-receptor blockers, the evidence supporting  their use is generally modestly beneficial. Systematic reviews  on H 2 -blockers versus placebo have shown improvement in  epigastric pain, but not global symptoms.   Peura DA, Gudmundson J, Siepman N, et al. Proton pump  inhibitors: effective first-line treatment for management of dys-  pepsia, DigDis Sd 2007;52:983-987. [PMID: 17342402]   2. Promotility agents — Promotility agents are drugs that  accelerate peristalsis by interacting with receptors for sero-  tonin, acetylcholine, dopamine, and motilin (Table 17-5).  The focus of drug development is now on serotonergic and  dopaminergic drugs. Among the prokinetic agents available  in the United States are metoclopramide and macrolide  antibiotics, namely, erythromycin.   The use of these drugs has shown no clear relationship  between pharmacologic enhancement of motility and improve-  ment in symptoms of functional dyspepsia. Therefore, the  benefit of prokinetics cannot be attributed solely to acceler-  ated peristalsis. In fact, some drugs may actually worsen  symptoms. An example is the negative influence that many  drugs (eg, erythromycin and metoclopramide) have on post-  prandial fundic relaxation, or accommodation.   A systematic review of 14 randomized controlled trials  reported prokinetics to be more effective than placebo in  functional dyspepsia. However, the majority of the studies  looked at cisapride, a serotonin 5-HT 4 agonist and 5-HT 3  antagonist that was taken off the market in the United States  because of its association with adverse cardiac arrhythmia  events. Another systematic review of 17 studies looked at cis-  apride and domperidone (also not available in the United  States, again due to cardiac arrhythmia risk) and found both  agents were superior to placebo but only by a global assess-  ment of improvement by the investigator. Both agents are  available through compassionate use protocols. A more   recent systematic analysis of prokinetics showed the effect  over placebo was lost when only high-quality studies were  included in the meta-analysis.   Metoclopramide was found to be more effective than  placebo in two older studies. However, there are medicolegal  concerns about long-term use of metoclopramide because  of potential neurologic side effects, particularly movement  disorders.   Among the more recently tested agents are tegaserod, a  5-HT 4 agonist, and itopride, a dopaminergic antagonist.  Neither drug is currently available in the United States.  Tegaserod was previously approved for treatment of women  with irritable bowel syndrome-predominant constipation  and for men and women younger than 65 years with chronic  constipation but was removed from the market in early 2007  in response to adverse events related to cardiac ischemia and  stroke. Tegaserod was shown to increase gastric emptying of  solids in functional dyspepsia in phase II randomized con-  trolled trials. Phase III trials were nearing completion prior  to the U.S. Food and Drug Administration (FDA) advisory.  Itopride, which is available in Japan, is a dopaminergic antag-  onist that also acts as a weak muscarinic agonist. A recent  phase II randomized controlled study of itopride versus  placebo showed a dose-dependant improvement in the  global assessment of patients with functional dyspepsia with-  out significant differences in adverse events between treat-  ment and placebo groups. The most frequent adverse events  were abdominal pain, diarrhea, nausea, and constipation. A  study of itopride in healthy subjects found that it reduces  total post-prandial volume without significantly accelerating  gastric emptying or altering gastric motor or sensory func-  tion. This suggests that itopride, if efficacious in functional  dyspepsia, is therapeutic in other ways instead of by altering  gastrointestinal motility. More recently, two phase III multi-  center randomized, double-blind, placebo-controlled studies  have shown no benefit over placebo in a global patient  assessment. Safety was comparable to placebo in these stud-  ies, with the rare occurrence of prolactin elevation in the  patients receiving itopride (3.1% vs 0.2%).   Choung RS, Talley NJ, Peterson J, et al. A double-blind, random-  ized, placebo-controlled trial of itopride (100 and 200 mg three  times daily) on gastric motor and sensory function in healthy  volunteers. Neurogastroenterol Motil. 2007;19:180-187. [PMID:  17300287]   Hiyama T, Yoshihara M, Matsuo K, et al. Meta-analysis of the  effects of prokinetic agents in patients with functional dyspepsia.  J Gastroenterol Hepatol. 2007;22:304-310. [PMID: 17295768]   Holtmann G, Talley NJ, Liebregts T, et al. A placebo-controlled  trial of itopride in functional dyspepsia. N Engl J Med.  2006;254:832-840. [PMID: 16495395]   Talley NJ, Tack J, Ptak T et al. Itopride in functional dyspepsia:  Results of two phase III multicenter, randomized, double-  blind, placebo-controlled trials. Gut. 2007;57:740-746. [PMID:  17965059]   Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, et al. Efficacy of  cisapride and domperidone in functional (nonulcer) dyspepsia:  a meta-analysis. Am J Gastroenterol. 2001;96:689-696. [PMID:  11280535]   3. Antidepressants and anxiolytic agents— The efficacy  of antidepressants and anxiolytics is based largely on clinical  observation and anecdotal data. Low-dose tricyclic antide-  pressants (TCAs), such as amitriptyline or desipramine, have  been used in patients with various functional disorders,  including functional dyspepsia and irritable bowel syn-  drome. Typically much lower doses (10-100 mg/day) are given  for functional dyspepsia than for depression. Because TCAs  can slow gastric emptying due to their anticholinergic  effect, they should be avoided in patients with gastroparesis-  functional dyspepsia overlap syndrome. A high-quality ran-  domized trial investigating use of TCAs in the treatment of  functional gastrointestinal disorders (including irritable  bowel syndrome and functional dyspepsia) showed that  patients who could tolerate the therapy might show a benefit  with desipramine over placebo (73% vs 49%, P = 0.0005,  NNT = 4). However, 28% of patients dropped out because of  adverse reactions, the most commonly reported effects being  dry mouth, sleep disturbance, constipation, and confusion. The  side effects are related to the anticholinergic activity of TCAs.  Patients should be warned about the possible occurrence of dry  eyes, dry mouth, constipation, and weight gain prior to use.   Use of selective serotonin reuptake inhibitors in func-  tional dyspepsia has not been studied in randomized con-  trolled trials. These drugs may be helpful in patients with  concurrent depression.   4. Other drugs — Antacids and bismuth have each been eval-  uated in a few trials for functional dyspepsia and have been  consistently found to be no better than placebo. Sucralfate  has been studied in several limited trials and found to be no  more effective than placebo. Consequently all of these agents  play no major role in the treatment of functional dyspepsia.   5. Recommendations for pharmacotherapy— To sum-  marize, if, after providing reassurance and basic dietary and  lifestyle interventions, symptoms persist, the clinician can   consider a trial of pharmacologic agents. If H pylori testing  yields a positive result, treatment is recommended with the  understanding that eradication may or may not improve  symptoms. Antisecretory medications can then be added,  such as H 2 -blockers (ranitidine, 150 mg twice daily; cimeti-  dine, 400 mg twice daily; or famotidine, 20 mg twice daily) or  PPIs (omeprazole, 20 mg daily; esomeprazole, 40 mg daily;  pantoprazole, 40 mg daily; lansoprazole, 30 mg daily; or  rabeprazole, 20 mg daily). Antisecretory medications are  most likely to benefit those with GERD symptoms or ulcer-  like dyspepsia. If there is a response, a course of 2-6 weeks  can be tried, with assessment of resolution of symptoms. If  prokinetics are used, short courses of metoclopramide can be  considered (5-10 mg prior to meals). Metoclopramide elixir  is preferable to pill form. If symptoms are refractory and per-  sist, low-dose TCAs (amitriptyline, imipramine, nortripty-  line, or desipramine at 10-25 mg at bedtime) can be tried  even in those without depression.   Van Zanten SV, Armstrong D, Chiba N, et al. Esomeprazole 40 mg  once a day in patients with functional dyspepsia: the random-  ized placebo-controlled "ENTER" trial. Am } Gastroenterol.  2006;101:2096-2106. [PMID: 16817845]   Psychological therapy addresses the cognitive aspects of the  pathophysiology of functional dyspepsia. Several modalities  have been used, including cognitive-behavioral therapy,  biofeedback, hypnotherapy, relaxation therapy, and insight-  oriented psychotherapy. A systematic review of randomized  controlled trials of psychological therapies found four eligi-  ble trials on applied relaxation therapy, psychodynamic psy-  chotherapy, cognitive therapy, and hypnotherapy that all  reported symptomatic improvement at 1 year. However, the  studies were of small sample size and had other technical  limitations to provide adequate evidence for efficacy.   Nonprescription therapies have been tried in functional dys-  pepsia, often being self-prescribed. These therapies are not  regulated by the FDA; therefore, standardization of purity and  potency is not enforced. Safety and efficacy is also not regu-  lated. That being said, studies have been conducted with sev-  eral of these agents. A systematic review of herbal remedies  was published examining 17 studies that evaluated agents  such as Angelica, artichoke, boldo, gentian, ginger, lemon  balm, milk thistle, peppermint, and turmeric. Although the  definitions of functional dyspepsia and study methodologies  had significant heterogeneity, the symptom improvement  scores ranged from 60% to 90% favoring treatment over  placebo. Few adverse reactions were associated with the reme-  dies, but formal safety reporting was not routinely available.  Short-term use is likely safe.   Thompson Coon J, Ernst E. Systematic review: herbal medicinal  products for non-ulcer dyspepsia. Aliment Pharmacol They.  2002;16:1689-1699. [PMID: 12269960]   The clinical course of functional dyspepsia has been evalu-  ated in retrospective and prospective studies, with follow-up  of 1.5-10 years for prospective studies and 5-27 years for ret-  rospective studies. In general, a significant number of   patients with functional dyspepsia were reported to  become asymptomatic or improve overall after one to sev-  eral years. History of GERD treatment during follow-up,  prior history of peptic ulcer disease, use of aspirin, longer  clinical history (> 2 years), lower education, and psycholog-  ical vulnerability were found to be associated with poorer  prognosis in these studies. One study in Taiwan reported  that patients with H pylori infection and functional dyspep-  sia were less likely to be symptom free at 2 years than those  without H pylori (49% vs 58%).   The three most common causes of gastroparesis are  idiopathic, diabetic, and postsurgical.   Chronic intestinal pseudo-obstruction (CIPO) involves  intermittent failure of intestinal peristalsis in the small  or large intestine, or both.   Noninvasive imaging or endoscopy, or both, should be  used to rule out mechanical obstruction in patients  being worked up for gastroparesis or CIPO.   The 4-hour gastric emptying scintigraphy scan is the best  test for gastroparesis, despite lack of test standardization.   Accelerated gastric emptying and dumping syndrome  are often related to postgastric surgery.   Altered gastric and small bowel motility result in either  delayed gastric emptying or rapid transit. Among the disor-  ders of gastric and small bowel motility discussed in this  chapter are gastroparesis, chronic intestinal pseudo-obstruction  (CIPO), dumping syndrome, and rapid transit dysmotility of  the small bowel.   Gastroparesis and CIPO are chronic long-term problems  that have a variety of causes and can be neuropathic or myo-  pathic. Treatment of these conditions includes dietary, med-  ical, and, rarely, surgical therapies. Research in gastroparesis  is ongoing with a focus on improving diagnostics and on gas-  tric electric stimulation (GES). Clinical trials are ongoing for  newer therapeutic agents. Dumping syndrome is a postsurgi-  cal iatrogenic problem that is occurring less often in relation  to gastric ulcer surgery, but may be increasing among  bariatric surgery patients in tandem with the increase in sur-  gical treatment of weight reduction. Patient education and  dietary change are important factors in the overall manage-  ment of these motility disorders.   Normal gastric emptying requires coordinated efforts by the  muscles that control the four regions of the stomach, nerves  that modulate the actions of these muscles, and chemical  mediators. Important events that occur during gastric filling  and emptying include fundic relaxation (accommodation)  in response to food ingestion, antral contractions and  churning (trituration) of large food particles, and finally  pyloric relaxation.   The neurogenic network of the stomach includes ele-  ments of both the central nervous system (CNS) and the  enteric nervous system (ENS). The CNS elements involve  both sympathetic fibers and parasympathetic fibers.  Sympathetic fibers arise from the thoracic spinal nerves and  extend to postganglionic nerves that run along the celiac  plexus and the vascular supply to the stomach. The sympa-  thetic innervation includes afferent pain fibers that arise  from the stomach, as well as motor fibers that innervate the  pyloric sphincter. The parasympathetic innervation stems  from the right and left vagal trunks, which eventually divide  into multiple branches that course throughout the stomach  wall, and synapse with the ENS.   The ENS is an independent branch of the peripheral  nervous system that is divided into two plexuses, the submu-  cosal (Meissner) and the myenteric (Auerbach) plexuses. The  Auerbach plexus is situated between the middle circular and  the outer longitudinal muscle layers. These plexuses directly  innervate the smooth muscle and are responsible for motil-  ity and secretory functions of the mucosal layer.   The interstitial cells of Cajal (ICCs) are the "pacemaker  cells" of the stomach. They are located in the myenteric  plexus and are responsible for basal slow-wave activity, which  occurs at 3 cycles per minute. This slow-wave activity is also  called the electronic control activity or the pacesetter poten-  tial. The ICCs are also responsible for bridging the myogenic  and neurogenic control mechanisms.   The migrating motor complex (MMC) is the pattern of  motility activity that occurs in the fasted stomach. This is   divided into three phases. Phase I is a quiescent period.  Phase II is a period of random intermittent contractions.  Lastly, phase III, also called the activity front, is a period in  which bursts of uninterrupted contractions occur. Each  cycle lasts 1-2 hours, begins in the small intestine, and  migrates proximally.   Upon ingesting a meal, the MMC is abolished. Gastric  accommodation occurs with distention of the fundus to  make room for the incoming ingested contents. This  response is mediated by the parasympathetic activity from  the vagal nerve through cholinergic neurotransmitters, and  inhibitory input by neurotransmitters such as nitric oxide,  vasointestinal peptide, and serotonin.   The ingested contents upon entering the stomach are dis-  tributed, triturated, and then emptied into the duodenum.  Liquids usually are dispersed and emptied immediately. The  rate of liquid emptying is slowed by high osmolarity, high  nutrient content, and carbonation. Solids, on the other hand,  are stored in the fundus, churned in the antrum, and are  emptied in two phases, a lag period and a linear emptying  period. The two periods occur over 3-4 hours, with the lag  period lasting 1-3 hours. During the lag period, food parti-  cles move proximally to distally and undergo trituration and  redistribution. Trituration occurs in the antrum with high-  amplitude contraction waves that propagate proximally to  distally, while pyloric and duodenal contractions are inhib-  ited. The food particles are reduced to a size of approximately  1-2 mm in diameter prior to emptying. The pylorus ulti-  mately regulates how much content is emptied into the duo-  denal bulb by coordinated contractions and maintenance of  the lumen with fixed tone.   Besides mechanical factors, neurohormonal factors con-  trol the rate of emptying. Glucagon and incretins (eg, amylin  and glucagon-like peptide 1) slow gastric emptying. The  vagus provides both excitatory and inhibitory innervation.  The duodenum provides negative feedback on the rate of  emptying as mediated by duodenal distention, acidification,  or perfusion with fats and protein. The regulation of duode-  nal intake controls the level of post-prandial hyperglycemia  from nutrient absorption.   Camilleri M, Integrated upper gastrointestinal response to food  intake. Gastroenterology. 2006;131:640-658. [PMID: 16890616]   Kindt S, Tack J. Impaired gastric accommodation and its role in  dyspepsia. Gut. 2006;55:1685-1691. [PMID: 16854999]   Gastroparesis is characterized by delayed gastric emptying  that is not associated with the presence of an obstructing  structural lesion in the stomach or distally in the gastroin-  testinal tract. Many disorders that interfere with the normal   neuromuscular coordination of the stomach can lead to  gastroparesis (Table 18-1). The three most common causes  are idiopathic, diabetic, and postsurgical. A tertiary referral  series of 146 patients showed the causes of gastroparesis to  be 36% idiopathic, 29% diabetic, 14% postgastric surgery,  7.5% Parkinson disease, 4.8% collagen vascular disorders,  4.1% intestinal pseudo-obstruction, and 6% miscellaneous  causes (eg, paraneoplastic syndrome, superior mesenteric  artery syndrome, and median arcuate ligament syndrome).  The idiopathic causes included acute viral-like gastroen-  teritis (23%), GERD and nonulcer dyspepsia (19%), and  cholecystectomy.   CIPO is characterized by obstructive symptoms generated  from the small or large bowel occurring in the absence of  anatomic obstruction. It is a severe form of dysmotility that is  considered a failure or insufficiency of the "intestinal  pump." Like gastroparesis, CIPO has a wide variety of causes  (Table 18-2). These can generally be separated into congeni-  tal versus acquired causes, and myopathic versus neuropathic  processes. Because gastroparesis and CIPO have very similar   clinical approaches, this section discusses the assessment and  treatment of these conditions together.   The true prevalence of gastroparesis is unknown, owing  to underdiagnosis and the lack of inexpensive diagnostic  testing that is also widely available. Population studies have  shown gastroparesis to be present in 11-18% of diabetic  patients with nausea and vomiting. The mean age of gastro-  paretic patients in one study was 45 years old, with a mean  age of onset at age 33.7 years. The same study showed a   female preponderance of 82%, and 62% of female patients  with gastroparesis reported a history of physical or sexual  abuse. It is unclear whether gender may influence the patho-  physiology of gastroparesis in other ways, as well. An overlap  syndrome of gastroparesis and functional dyspepsia has been  noted, and 25-42% of patients with functional dyspepsia  have concomitant gastroparesis.   Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal  symptoms associated with diabetes mellitus: a population-  based survey of 15000 adults. Arch Intern Med. 2001;10:  1989-1096. [PMID: 11525701]   Maleki D, Locke GR 3rd, Camilleri M, et al. Gastrointestinal tract  symptoms among persons with diabetes mellitus in the com-  munity. Arch Intern Med. 2000;9:2808-2816. [PMID: 11025791]   Typical complaints of gastroparesis include post-prandial  nausea, vomiting, belching, early satiety, bloating, discomfort,  or pain. Reflux symptoms are also common. Chronic symp-  toms include weight loss or electrolyte disturbances, or both.  Signs and symptoms of nutritional and vitamin deficiencies  that may be noted include temporal wasting and loss of sub-  cutaneous fat (malnutrition), gum bleeding (vitamin C),  visual changes with night blindness (vitamin A), neuropathy,  or impaired memory and confusion (folate, vitamin B 12 ).  Dysphagia or odynophagia may occur as a result of reflux  esophagitis. Diarrhea and malabsorption may be a conse-  quence of bacterial overgrowth caused by altered peristalsis.  Symptoms to look for include dry mouth, eyes, or vagina; dif-  ficulties with visual accommodation in bright light; anhidrosis  (absence of sweating); impotence; dizziness on standing; scle-  roderma symptoms such as Raynaud phenomenon, skin tight-  ening, and peripheral paresthesia, numbness or focal  weaknesses. A medication history can elicit drugs that may  contribute to altered gastric motility (Table 18-3).   The examination should include assessment of volume  status for dehydration (eg, orthostasis, pallor, and poor skin  turgor) and signs of metabolic alkalosis, such as decreased  respirations. Abdominal examination may reveal distention  or surgical scars. The examiner should auscultate for  obstructive high-pitched or absent bowel sounds, and pal-  pate for focal tenderness or mass. A succusion splash may be  heard when auscultating over the stomach while shaking the  abdomen from side to side 1 hour or more post-prandially.  The examiner should also test for abdominal wall-related  pain by observing for Carnett sign (positive when tenderness  is increased upon tensing of the abdominal muscles).  Findings suggesting diabetic microvascular complications  should be noted (eg, retinopathy and sensory or autonomic  neuropathy). Signs of recurrent vomiting may include worn  tooth enamel. Nutritional deficiencies may manifest as brit-  tle hair and nails, cheilosis, glossitis, and tetany.   Symptoms can also be assessed by a validated instrument,  the Gastroparesis Cardinal Symptom Index (GCSI), which was  developed for measurement of three subsets of symptoms,  including postprandial fullness/early satiety, nausea/vomiting,  and bloating. The GCSI has been validated for measuring  symptom severity.   Radiologic studies include plain film abdominal radiographs  and computed tomography of the abdomen. Oral contrast  should be water soluble to prevent formation of barium con-  cretions in the gastrointestinal tract with dysmotility.  Gastroparesis may be demonstrated by retained contrast in  the stomach or its slow gastric transit into the small bowel. In  CIPO, abdominal films may show dilated loops of small  bowel and air-fluid levels (Figure 18-1).   Upper endoscopy is useful for ruling out a mechanical  obstruction of the upper gastrointestinal tract (eg, from  masses, peptic ulcer disease [PUD], complications of pyloric  stenosis, or acute PUD with antral edema). However, the best  clinical test for delayed gastric emptying is gastric emptying  scintigraphy using radionuclide technetium 99-labeled food.  The test involves ingestion of a radiolabeled meal in which the  radioisotope has been cooked into the solid portion of the  meal, usually a soft- textured food such as eggs. Scintigraphy is  then performed 1-4 hours after ingestion (Figures 18-2A  and 18-2B). Retention is abnormal when more than 90% of  the tracer remains in the stomach at 1 hour, more than 60%  at 2 hours, or more than 10% at 4 hours.   Tests shorter than 4 hours are less accurate for several rea-  sons, including reduced sensitivity. Furthermore, the lag  period is variable; some patients with prolonged lag phases  have apparently normal 4-hour tests due to a "catch-up" in  gastric emptying.   There are some concerns about lack of standardization of  the procedure, and several proposed protocols have been    ▲ Figure 18-1. Chronic intestinal pseudo-obstruction  seen on plain upright abdominal film. The stomach and  small bowel are distended with intestinal gas.   suggested. The current protocol based on expert consensus is  a 4-hour test using a standard low- fat meal consisting of toast,  jam, water, and eggs made with a low-fat and low-cholesterol  egg substitute (Egg Beaters). Scintigraphy measurements are  then taken at 0, 1, 2, and 4 hours after ingestion. Other uses of  scintigraphy include assessing gastric accommodation. This is  done by measuring gastric volumes by dividing the area of  interest into a distal and proximal segment, and subsequently  assessing regional changes in radiographic counts over time.  A normal stomach with normal accommodation usually  shows redistribution of the meal to the distal segment after  accumulation in the proximal segment. Impaired gastric  accommodation can be seen in diabetic vagal neuropathy,  postvagotomy surgery, postfundoplication dyspepsia, and  functional dyspepsia.   Guo IP, Maurer AH, Fisher RS, et al. Extending gastric emptying  scintigraphy from 2 to 4 hours detects more patients with gas-  troparesis. DigDis Sri. 2001;46:24-29. [PMID: 11270790]   Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying  using a low fat meal: establishment of international control val-  ues. Am J Gastroenterol 2000;95:1456-1462. [PMID: 10894578]   Ziessman HA, Bonta DV, Goetze S, et al. Experience with a simpli-  fied, standardized 4-hour gastric-emptying protocol. J Nucl  Med. 2007;48:568-572. [PMID: 17401093]   Another tool to measure gastric emptying, which is com-  monly used in research and industry, is the breath test using   ▲ Figure 18-2A. A normal 99m Tc-labeled solid-phase gastric emptying scan showing 74.4% clearance at 90 minutes.   a solid meal with nonradioactive isotope 13 C-labeled medium-  chain triglycerides, octanoate. The 13 C-labeled octanoate,  when ingested, is rapidly absorbed in the small intestine and  metabolized into 13 C0 2 , which then can be measured in breath  samples to estimate indirectly the rate of gastric emptying.  This test has been shown to be correlated strongly to scintig-  raphy by some studies, and weakly by others.   Ingestion of and counting of radiopaque markers at 6 hours  has also been used to identify the location of the functional  dysmotility but may be difficult to use due to lack of stan-  dardization and possible confusion if markers are located in  the stomach or within a segment of small bowel that overlaps  the stomach.   For small bowel motility assessment, upper gastrointesti-  nal and small bowel film series provide rough assessments at  best. Quantification can be done by scintigraphy.   Antroduodenal manometry, which is not widely avail-  able, can provide information about the coordination of gas-  tric and duodenal motility, and can help differentiate  between a neuropathic and a myopathic motility problem in  CIPO. It involves inserting a large catheter with multiple  manometric sensors down to the antrum and the proximal  small bowel, usually with the aid of fluoroscopy. The test  then is performed over several hours in the fasting state, with  a test meal, and sometimes with motility agent stimulus,  such as erythromycin. A neuropathic process that is intrinsic  or visceral is usually characterized by uncoordinated con-  tractions of normal amplitude and abnormal or even absent  phase III contractions of the MMC. The presence of phase III   06-54 MIN 55-53 MIN 64-72 UN 73-81 MIN 90 MIN ANT   ▲ Figure 18-2B. An abnormal 99m Tc-labeled solid phase gastric emptying scan showing 1.4% clearance (or 98.6%  retention) at 90 minutes.   of the MMC is associated with a favorable prognosis, and  with better tolerance of enteral feedings and response to pro-  kinetic drugs. In contrast, in a myopathic process, contrac-  tion amplitudes are reduced, and spatial and temporal  organization preserved. Other antroduodenal manometric  findings in CIPO may include simultaneous waveforms, ret-  rograde propagation of phase III of the MMC, high-amplitude  and high-frequency bursts during both fasting and fed peri-  ods, and sustained high-pressure zones in limited small  bowel segments, or inability of a meal to initiate the fed period  activity pattern, or both.   Electrogastrography can record gastric muscular activity  waveforms via cutaneously placed pads, similar to an   electrocardiogram for the myocardium. Abnormal electrogas-  trograms are defined as observed dysrhythmia more than 30%  of the recording time or failure of an ingested meal to elicit  increased amplitude in gastric signals. However, the electro-  gastrogram has not been widely used clinically. Furthermore,  there has been little evidence that electrogastrography aids in  the management of patients with gastroparesis.   A recent device, the SmartPill GI Monitoring System, is an  ingested capsule that can deliver information on pressure,  pH, and temperature wirelessly to a data recorder worn by  the patient. The pill is swallowed after ingesting a standard  220-kcal meal. The data permit estimates of gastric emptying  time, combined small and large bowel transit time, and total   transit time, as well as study pressure patterns from the gas-  trointestinal tract in the stomach, small bowel, and colon.  The capsule has been approved by the U.S. Food and Drug  Administration (FDA) for use in studying gastroparesis. The  device has been compared with gastric scintigraphy at a  2-hour emptying time (r = 0.63) and at a 4-hour emptying  time (r = 0.73). The better correlation with 4-hour emptying  time is likely due to the capsule, a nondigestible solid, being  emptied from the stomach after the emptying of most of the  test meal in the subject. The device is a reasonable alternative  to conventional scintigraphy.   Vomiting must be distinguished from regurgitation, rumina-  tion syndrome, and the eating disorders of anorexia nervosa  and bulimia. Rumination syndrome is daily, early post-prandial  regurgitation of food that occurs effortlessly without nausea,  likely as a learned behavior. Daily vomiting is seen only in  severe gastroparesis.   Treatment should be tailored for each individual. In most  patients treatment involves correction of dehydration, mal-  nutrition, and nutritional deficiencies; dietary modifications;  use of pharmacologic motility agents, including prokinetics  and antiemetics; and normalization of hyperglycemia in dia-  betic gastroparesis. For patients with refractory gastroparesis,  more aggressive therapies include decompression by gastros-  tomy tubes, consideration of gastric pacing, pyloric injection  with botulinum toxin, and, lastly, surgical treatment.   Med. 2007;356:820-829. [PMID: 17314341]  Connor FL, Di Lorenzo C. Chronic intestinal pseudo-obstruction:   S29-S36. [PMID: 16473068]  Park MI, Camilleri M. Gastroparesis: Clinical update. Am J   Gastroenterol. 2006;101:1129-1139. [PMID: 16696789]  Parkman HP, Hasler WL, Fisher RS; American Gastroenterological   During acute exacerbation of gastroparesis, dehydration,  and electrolyte imbalances should be corrected promptly.  Hypokalemia and metabolic alkalosis are common in  patients with persistent vomiting. Repletion can be instituted  orally, enterally through feeding tubes, or parenterally. If the  gastrointestinal tract is severely impaired, parenteral nutri-  tion should be considered. Prolonged enteral feeding may  require a jejunostomy tube to bypass the pylorus.   Dietary recommendations include eating frequent, smaller  sized meals. Solid foods can also be substituted for those that  are pureed or liquid, such as soups. High-fat foods delay gas-  tric emptying, as do high-fiber foods.   1. Prokinetics — Prokinetics available in the United States  include metoclopramide and erythromycin, both of which  can be administered orally and intravenously. Erythromycin  (40-250 mg three times daily) is a macrolide antibiotic that  has activity on motilin receptors. Metoclopramide (starting  with 5 mg twice daily to 10-20 mg two to three times daily)  is a dopamine antagonist with both antiemetic and proki-  netic activity. Both of these drugs have been shown in ran-  domized controlled trials to improve symptoms by 25-68%  and to increase gastric emptying in objective tests by  25-72%. Elixir forms of both drugs may have better absorp-  tion and subsequent bioavailability than pill forms.  Intravenous erythromycin at 3 mg/kg (given at 125-250 mg  three to four times daily) is more effective than placebo in  hospitalized patients with gastroparesis and has been  demonstrated to decrease symptoms, with positive objective  measures of improved emptying. Unfortunately, the benefi-  cial effect of erythromycin is often short lived due to tachy-  phylaxis, or tolerance to the medication. Rapid development  of tolerance to the medication may be due to saturation of  motilin receptors and their subsequent down-regulation.  Therefore, erythromycin may be best used during exacerba-  tions of symptoms or used on an intermittent basis.   Several other prokinetics have been used clinically for gas-  troparesis but are not widely available in the United States.  Other agents include cisapride, a parasympathomimetic that  acts as a serotonin 5-HT 4 agonist, and domperidone, a  dopamine (D,) receptor antagonist. Both drugs are available in  Canada, Mexico, and Europe. Domperidone is available in the  United States through an FDA investigational new drug (IND)  program. Cisapride has had association with long QT syn-  drome, which can predispose to torsades de pointes; this caused  the drug to be taken off the U.S. market in March 2000.  Likewise, domperidone has not been approved by the FDA due  to risk of cardiac arrhythmia and its bioavailability in breast  milk. However, both drugs have been found to be efficacious in  treating gastroparesis. Additional concerns with metoclo-  pramide and domperidone relate to CNS side effects, which  include somnolence, mental function, anxiety, and depression.  There are also medicolegal concerns about the chronic use of  metoclopramide owing to adverse reactions (ie, neurologic  effects and movement disorders). Early effects include akathisia  (a sensation of "inner restlessness") and dystonia, and later  effects may include tardive dyskinesia and parkinsonism. It is  important to note, however, that domperidone does not cross  the blood-brain barrier; therefore, the CNS effects are notably  less as compared with metoclopramide.   2. Antiemetics — Antiemetics such as diphenhydramine,  phenothiazines compounds, and even metoclopramide can help  control symptoms of nausea. The more commonly used agents  include prochlorperazine, trimethobenzamide, and promet-  hazine. Serotonin (5-HT 3 ) antagonists, such as granisetron and  ondansetron, are frequently used in chemotherapy patients but  are also useful in gastroparesis. They act on the area postrema  and peripheral afferent nerves. Similarly in cancer patients,  benzodiazepines and cannabinoids are other agents that may  be of use.   3. Novel agents — Multiple other agents with different  mechanisms have also been tried. Tegaserod (Zelnorm; 2-6 mg  twice daily) is a partial 5-HT 4 receptor agonist that enhances  gastric emptying, but no clinical trials have been undertaken  specifically in patients with gastroparesis. It has been used  with anecdotal success, but was removed from the market in  early 2007 due to concern about increased risk of myocardial  infarction and stroke. Agents with limited success and also  with notable adverse cholinergic side effects include bethane-  chol (10-20 mg two to three times daily), a muscarinic  cholinergic agent, and pyridostigmine (30 mg four times  daily), an anticholinesterase.   4. Other drugs — Bacterial overgrowth can be treated with a  course of antibiotics for 7-10 days using common antibiotics  such as doxycycline, ciprofloxacin, metronidazole, or double-  strength trimethoprim-sulfamethoxazole. More recently,  rifaximin (400-1200 mg/day), a nonabsorbable antibiotic  approved for use in traveler's diarrhea, has been effective for  small bowel bacterial overgrowth and normalizing hydrogen  breath tests.   Long-acting subcutaneous octreotide (50 meg subcuta-  neously at night) has been tried in patients with CIPO, and  studies have shown it increased MMCs in the small bowel.  This therapy should be avoided with concomitant bacterial  overgrowth.   5. Investigational drugs— Some of the drugs currently  under investigation include other prokinetics such as itopride,  a dopamine receptor antagonist, and mosapride, a 5-HT 4  receptor agonist. Ghrelin agonists are also under investigation.  A motilin receptor agonist (mitemcinal [GM-611]) is also  being studied.   There is little evidence that controlling hyperglycemia has a  direct relationship to symptom improvement. However,  there is a well-established inverse relationship between glu-  cose levels and rate of gastric emptying. Hyperglycemia is  associated with delayed gastric emptying, as is euglycemia  with normal gastric emptying, and hypoglycemia with accel-  erated gastric emptying. Moreover, acute changes in blood  glucose concentration have an effect on both gastric motor  function and upper gastrointestinal symptoms. Evidence also   suggests that response to prokinetics is partially determined  by hyperglycemia. In regard to practical care of diabetic  patients, short-acting insulin, given with meals, should be  dosed after rather than prior to eating to ensure that the  patient tolerates the entire meal.   Advanced gastroparesis or CIPO may require decompres-  sion. Venting can be accomplished by a nasogastric tube or  by a percutaneous endoscopic gastrostomy (PEG) or jejunos-  tomy tube. Several feeding tubes have both a venting port  upstream and a feeding port downstream. However, before  placing the tube in a patient with severe symptoms, it is pru-  dent to try nasal jejunal tube feeding first to test whether the  patient can tolerate enteral feeding. Criteria for tube feeding  include severe weight loss, multiple hospitalizations, and  malnutrition.   Electrical stimulation of the stomach for treatment of gas-  troparesis is done laparoscopically by implanting a device  into the antral muscular wall, with electrodes that connect to  a pacemaker pocketed into the abdominal wall. The stimula-  tion is classified based on the frequency of the electrical stim-  ulus (high or low frequency). A high-frequency electrical  stimulation device (Enterra, Medtronic) has been approved  by the FDA through a humanitarian device exemption. A  crossover controlled trial of 33 patients with idiopathic or  diabetic gastroparesis showed that the frequency of vomiting  was decreased significantly, but overall effect on symptoms  was not significant. Open-label long-term studies with follow-  up of 3.4-3.7 years have shown relief of symptoms and  decreased need for nutritional supplementation. Predictors  of treatment success in patients receiving GES include dia-  betic gastroparesis, symptoms that are predominantly nausea  and vomiting, and symptoms that do not require narcotic  therapy. Although GES is a promising therapy, further stud-  ies are needed in this area.   Abell T, McCallum R, Hocking M, et al. Gastric electrical stimula-  tion for medically refractory gastroparesis. Gastroenterology.  2003;125:421-428. [PMID: 12891544]   Abidi N, Starkebaum WL, Abell TL. An energy algorithm improves  symptoms in some patients with gastroparesis and treated with  gastric electrical stimulation. Neurogastroenterol Motil.  2006;18:334-338. [PMID: 16553589]   Gastric emptying may be facilitated by keeping the pylorus  relaxed. Injection of botulinum A toxin into the pyloric  sphincter paralyzes the smooth muscle of the pylorus and  antrum by inhibiting acetylcholine release. Uncontrolled  open-label trials have reported its efficacy in gastroparesis. A  review of 63 patients treated with botulinum A toxin found   a 43% response rate that lasted on average 5 months. One  controlled trial of patients tested before and 1 month after  botulinum injection showed enhancement of solid empty-  ing, but not liquid.   Bromer MQ, Friedenberg F, Miller LS, et al. Endoscopic pyloric  injection of botulinum toxin A for the treatment of refractory  gastroparesis. Gastrointest Endosc. 2005;61:833-839. [PMID:  15933684]   Surgical treatment is the last resort for both gastroparesis  and CIPO, and is rarely indicated. Furthermore, many  patients undergo unnecessary surgery. For gastroparesis in  particular, surgical placement of gastrostomy and jejunos-  tomy tubes may be done for feeding and decompression.  Definitive surgical treatment for gastroparesis is a complete  gastrectomy. A systematic review of surgical therapy for gas-  troparesis found that gastrectomy may help postsurgical gas-  troparesis, but issued caution on surgical therapy for diabetic  or idiopathic gastroparesis.   For CIPO, the surgical therapy aims to bypass areas of  localized disease in the small intestine, or resect the colon for  severe constipation. Again, caution is warranted when con-  sidering surgery in this condition as the original problem may  manifest itself in unresected portions of the gut. If the disease  is within the upper and lower intestinal tract, colectomy is less  likely to be beneficial. Gastrostomy, jejunostomy, or loop  enterostomy may be done to shorten the gut, facilitate transit,  and vent the bowel. Percutaneous colonoscopy in adult CIPO  patients has shown success in reducing distention.   Small bowel transplantation is indicated for patients  with end-stage parenteral nutrition-dependant pseudo-  obstruction and complications of prolonged parenteral nutri-  tion or line access.   Little is known about either the overall prognosis or the qual-  ity of life of patients with gastroparesis and CIPO. That being  said, the disease can be long-standing and have a substantial  impact on well-being. Symptom severity scales have been  developed and validated and may be useful in clinical and  research settings. The overall long-term prognosis is deter-  mined by the underlying disease process, if known.   Dumping syndrome and accelerated gastric emptying are  diseases that can occur after gastric surgery when a truncal  vagotomy or gastrectomy has been performed. With the  onset of medical treatment for PUD and Helicobacter pylori   eradication, gastric ulcer surgery has significantly decreased  and, expectedly, these postoperative accelerated gastric states  have also decreased. Presently, bariatric surgery with Roux-  en-Y gastric bypasses causes dumping syndrome in as many  as 50% of patients. Aside from the iatrogenic causes,  Zollinger-Ellison syndrome can also be associated with rapid  gastric emptying. Rapid gastric emptying is caused by high  gastric pressures, impaired gastric accommodation, and the  lack of a regulating pyloric sphincter.   Dumping syndrome can be characterized as early or late,  with different symptoms. Of note, both types of dumping  syndrome can occur in the same patient. Early dumping syn-  drome occurs during or immediately after a meal and is  characterized by nausea, vomiting, bloating, cramping, diar-  rhea, dizziness, and fatigue. These early symptoms are  hypothesized to be due to a hyperosmolar load in the small  bowel. Late dumping happens 1-3 hours after a meal and is  characterized by hypoglycemia, weakness, sweating, and  dizziness. Hypoglycemia occurs because a high carbohydrate  content absorption into the small bowel evokes a strong  insulin response with secondary hypoglycemia.   Dual-phase gastric scintigraphy using radiolabeled solids  and liquids is the best diagnostic test. Hydrogen breath tests  can be diagnostic in the appropriate clinical scenario. If early  dumping is suspected, an early peak will be noted, usually  within 1 hour of ingestion.   The treatment of dumping syndrome involves mainly  dietary modifications. These include switching to smaller,  more frequent meals; minimizing ingestion of simple carbo-  hydrates; avoiding simultaneous fluid intake with solids;  and adding supplemental pectin or guar gum to increase the  viscosity of the ingested food. Medical therapy includes  acarbose (50-100 mg three times daily), an oc-glucosidase  inhibitor that blunts the rapid absorption of glucose. Long-  acting subcutaneous octreotide (50 meg three times daily)  acts by inhibiting effects on insulin and gut hormone  release, as well as decreasing intestinal transit time. Short-  term use is initially effective, but response is less optimal  with longer use.   Didden P, Penning C, Masclee AA. Octreotide therapy in dumping  syndrome: analysis of long-term results. Aliment Pharmacol  Ther. 2006;24:1367-1375. [PMID: 17059518]   Hasler WL. Dumping syndrome. Curr Treat Options Gastroenterol.  2002;5:139-145. [PMID: 11879594]   Rapid transit of small bowel contents occurs in postvago-  tomy diarrhea, short bowel syndrome, irritable bowel, dia-  betic enteropathy, or carcinoid syndrome. These syndromes,  except for irritable bowel syndrome, can cause severe dehy-  dration and electrolyte disturbances.   Scintigraphy or the lactulose hydrogen breath test can be  diagnostic. Small bowel manometry is not widely available  but may show high-amplitude contractions, rapid peristalsis,  and prolonged duration.   The initial focus of treatment is on correction of dehydration  and electrolyte imbalance. Patients, once stabilized, should   avoid hyperosmolar drinks and receive rehydration with  isoosmolar fluids. Parenteral support with intravenous fluids  or even parenteral nutrition may be necessary for patients  with less than 1 meter of small bowel.   Loperamide (4 mg, 30 minutes prior to meals and bed-  time) can decrease the gastrocolic reflex and slow motility.  Verapamil (40 mg twice daily) or clonidine (0.1 mg twice  daily), or both, may be used in conjunction with loperamide.  Subcutaneous octreotide (50 meg twice daily) can be consid-  ered if other drugs fail.   ► Body mass index (BMI) > 25 is considered overweight;  > 30, grade I obesity; > 35, grade II obesity; > 40, grade III  obesity; and > 50, "super obesity."   ► Using these criteria two thirds of Americans are over-  weight or obese.   ► Diet, pharmacotherapy, and behavior modification are  the available nonsurgical treatment options and are of  limited efficacy, with durable weight loss rarely exceed-  ing 10 kg.   ► Patients with a BMI > 35 can be considered for bariatric  surgery if they have severe weight-related comorbid  conditions (eg, diabetes, hypertension, disabling arthri-  tis, or sleep apnea).   ► Patients with a BMI > 40 may be appropriate surgical  candidates, with or without weight-related comorbid  conditions.   ► Two long-term studies of the efficacy of bariatric sur-  gery noted a 29-40% reduction in all causes of death,  with decreased mortality from coronary artery disease,  stroke, diabetes, and cancer.   Obesity has reached epidemic proportions worldwide and  continues to exact a high cost in human and monetary terms  within the United States. This disease is second only to cig-  arette smoking as a preventable cause of death, and deaths  attributable to obesity far outnumber colon cancer. Three  hundred thousand people die annually from obesity-related  disorders in the United States. In addition, health care costs  to treat obesity and weight-related conditions exceed $100  billion annually. This problem is of particular concern  because upwards of one third of adult Americans are obese,  with 5% of the population meeting the criteria for the most   severe form of the disease. In short, obesity is a major pub-  lic health problem that requires aggressive prevention and  treatment.   Weight loss surgery has been recognized for decades as an  effective treatment of obese individuals. This has resulted in  a dramatic increase in such procedures, and currently over  140,000 bariatric operations are performed each year in the  United States alone. Surgical treatment of obesity is routinely  associated with loss of greater than 100 pounds. Hence, it is  not surprising that patients who undergo such operations  can have substantial amelioration of comorbid conditions.   Bariatric surgery may not be the ideal obesity treatment.  However, surgery is currently the most effective and durable  treatment of the obese compared with any other available  therapy in terms of weight loss, alleviation of comorbid con-  ditions, reduction in mortality risk, and decreased long-term  health care costs.   Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight  and obesity among US children, adolescents, and adults,  1999-2002. JAMA. 2004;291:2847-2850. [PMID: 15199035]   Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: sur-  gical treatment of obesity. Ann Intern Med. 2005;142:547-559.  [PMID: 15809466]   Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in  the United States. JAMA. 2000;291:1238-1245. [PMID:  15010446]   Treatment of overweight and obese individuals is based on  the degree of excess body weight and the presence or absence  of weight-related conditions. The degree and categorization  of excess body weight is routinely based on body mass index  (BMI). A patient's BMI is calculated by dividing weight in  kilograms by the height in meters squared. This index nor-  malizes weight for a given height and is independent of gen-  der. The BMI is generally considered a better classification   a Based on NIH recommendations for the treatment of overweight and obesity in adults.   scheme of excess body weight than the outdated  Metropolitan Life tables, which are gender-dependent and  require a rough estimate of body frame size.   A BMI of 18.5-25 kg/m 2 is considered "normal." A BMI  greater than 25 kg/m 2 is considered "overweight" or "obese"  (Table 19-1). Based on these criteria an astounding two  thirds of adult Americans are overweight or obese. A person  is considered obese when his or her BMI is 30 kg/m 2 or  higher, and obesity is divided into at least three categories,  classes I, II, and III. Bariatric surgeons have defined an addi-  tional "super obese" category, which is a BMI greater than  50 kg/m 2 . This extra surgical category has been used in clin-  ical studies when analyzing data and correlating outcomes  with preoperative weight class.   Although BMI correlates with excess body fat, it is possi-  ble for a highly trained, muscular athlete who in fact is quite  lean to have a high BMI. In addition, the association between  obesity and mortality appears to be weaker for African  Americans as compared with Anglo-Americans. Although  the validity of BMI may vary in some patient populations  according to their demographic characteristics, including  ethnicity, the index has proven to be a clinically relevant  measure of obesity that can be linked to disease and mortal-  ity risk. For example, the BMI associated with the lowest risk  of death is within the normal range for most men and lies  within the normal to overweight range for most women (see  Table 19-1).   Once BMI is determined, health risk is based on the BMI  classification and the presence or absence of weight-related  comorbid conditions. The National Institutes of Health  (NIH) treatment recommendations start with "healthy eat-  ing, exercise, and lifestyle changes" for those with minimal  and low health risks and then recommend the addition of  diet, pharmacotherapy, or bariatric surgery as health risk  increases to the "extremely high health risk" category  (Table 19-2). These weight loss treatment recommendations  are theoretically based on three parameters: ( 1 ) the assessment   of the risk of not treating an overweight or obese individ-  ual; (2) the risk of a particular weight loss treatment; and  (3) the likelihood and degree of benefit from the treatment.   The preceding risk-benefit calculation can be done for  those with class III obesity (ie, BMI > 40 kg/m 2 ) to determine  the treatment of choice. Untreated obesity of this degree is  well known to be associated with several conditions, includ-  ing diabetes, hypertension, sleep apnea, and cardiovascular  disease, that lead to increased mortality and years of life lost.  Fontaine and colleagues calculated the years of life lost for  obese individuals, and found that 30-year-old white men and  women with a BMI of 30 can expect to lose 10 years and 8 years  of life expectancy respectively if their obesity goes untreated.  A 20-year-old black male with a BMI of 45 can expect to lose  20 years of his life expectancy if untreated. Hence, the natu-  ral history of class III obesity is clearly associated with both  increased morbidity and mortality risk, and thus mandates  aggressive intervention.   Diets, pharmacotherapy, and behavior modification with  or without exercise are the available nonsurgical treatment   a Based on NIH recommendations for the treatment of overweight  and obesity in adults.  b See Table 19-1.   options for obesity. Diet therapy is the most common self-  and primary care provider-prescribed therapy. There is no  doubt that diets are highly effective and generally safe — for  those who adhere to dietary guidelines. This, unfortunately,  is a very small number of individuals. Average weight loss at  12 months is generally quite modest, and the long-term  recidivism rate of obesity for those who use diet therapy  exceeds 95%. A recent trial compared four popular diets on  weight loss and cardiovascular risk reduction. The investigators  randomly assigned patients to the Atkins low-carbohydrate,  high-protein, high-fat diet; the Zone balanced carbohydrate  and protein diet; the Ornish vegetarian, low-fat diet; or the  commercially popular Weight Watchers diet. They found  that average weight loss at 1 year was 3 kg and BMI was  reduced by 1 kg/m 2 . There was no difference among the diets.  The limited efficacy may be due, in part, to the fact that the  patients reported that they adhered to the diets 70% of the  time during the first month of intervention but only 30% of  the time by the 12th month.   Although the efficacy of pharmacotherapy for weight loss  is better than diet alone, it is still considered modest com-  pared with the weight loss efficacy of surgery. Two diet drugs  are currently approved by the U.S. Food and Drug  Administration (FDA): sibutramine (Meridia) and orlistat  (Xenical). At 12 months sibutramine is associated with a  mean weight loss of 4 kg for obese individuals while orlistat  is associated with a 3-kg placebo-subtracted effect. In addi-  tion, FDA approval for drugs is usually limited to 12-24  months, and it is expected that weight gain will occur with  drug cessation. This scenario has led several obesity experts  to believe that pharmacotherapy has a limited role for those  with severe obesity.   Behavior modification appears to have limited efficacy  and durability as well. For example, Christiansen and col-  leagues conducted an intensive lifestyle intervention trial in  which 249 subjects underwent a 21-week intensive treatment  with exercise, diet, and psychological counseling. Although  subjects had lost 22 kg at the end of the treatment phase, the  average weight loss was reduced to 7 kg 4 years after treat-  ment. In addition, two thirds of subjects had reduced their  weight by less than 5% at the 4-year mark after intensive  treatment, with only 28% achieving a weight loss of greater  than 10% — the authors' definition of "success" — at 4 years.  The XENDOS trial (XENical in the prevention of diabetes in  obese subjects) compared orlistat (trade name Xenical)  versus placebo plus behavior modification. This 4-year  double-blind trial found a 2.7% weight loss in the placebo  plus behavior modification group versus 5.4% in the Xenical  group.   Overall, the long-term benefit of nonsurgical treatment  of those with class III obesity is likely to be quite limited  except for a very small percentage of individuals. In contrast,  surgical intervention, as detailed below, has an acceptable  risk profile and clear, long-term benefits in terms of weight loss,  resolution of comorbid conditions, and reduction in mortality  risk. As such, bariatric surgery has the best cost-benefit   ratio and is therefore considered the weight loss treatment of  choice by the NIH for those with severe obesity.   Christiansen T, Braun JM, Madsen EL, et al. Weight loss maintenance  in severely obese adults after an intensive lifestyle intervention:  2- to 4-year follow-up. Obesity (Silver Spring). 2007;15:413-420.  [PMID: 17299115]   Clinical guidelines on the identification, evaluation, and treatment  of overweight and obesity in adults — the evidence report. National  Institutes of Health. Obes Res. 1998;6(Suppl 2): 51S-209S.  [PMID: 9813653]   Dansinger ML, Gleason JA, Griffith IL, et al. Comparison of  Atkins, Ornish, Weight Watchers and Zone diets for weight loss  and heart disease risk reduction: a randomized trial. JAMA.  2005;293:43-53. |PMID: 15632335]   Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to  obesity. JAMA. 2003;289:187-193. [PMID: 12517229]   McTigue KM, Harris R, Hemphill B, et al. Screening and interven-  tions for obesity in adults: summary of the evidence for the U.S.  preventive services task force. Ann Intern Med. 2003;139:  933-949. [PMID: 14644897]   Rucker D, Padwal R, Li SK, et al. Long term pharmacotherapy for  obesity and overweight: updated meta-analysis. BMJ. 2007;335:  1194-1203. [PMID: 18006966]   Torgerson IS, Hauptman I, Boldrin MN, et al. XENical in the pre-  vention of diabetes in obese subjects (XENDOS) study: a ran-  domized study of orlistat as an adjunct to lifestyle changes for  prevention of type 2 diabetes in obese patients. Diabetes Care.  2004;27:155-161. [PMID: 14693982]   The indications for surgical treatment of severe obesity are  based on the recommendations of the NIH Consensus  Development Conference on Gastrointestinal Surgery for  Severe Obesity. The first criterion that must be met before  considering a patient for bariatric surgery is weight as  assessed by BMI. Patients with a BMI of 35-39.9 kg/m 2  (ie, class II obesity) can be considered for surgical interven-  tion if they have severe weight-related conditions such as dia-  betes, hypertension, debilitating osteoarthritis, or sleep  apnea. Those with a BMI of 40 kg/m 2 or greater (ie, class III  obesity) may be appropriate candidates for bariatric surgery  with or without weight-related comorbid conditions.  Approval for surgery based on the preceding BMI criteria  assumes there are no contraindications to surgery.   If a patient satisfies the BMI criteria for bariatric surgery, he  or she is more fully evaluated. The patient should have an exten-  sive history of previous weight loss attempts prior to seeking  surgery. Most patients in this weight category have undergone a  wide variety of nonsurgical interventions over several years.  There should be no unstable psychological conditions or sub-  stance abuse. Many surgeons operate on patients with depres-  sion, but decline to operate on those with unstable conditions.  For example, a recent suicide attempt may preclude surgery for  at least 1 year or more depending on the ability to demonstrate  psychological stability. Patients are routinely screened for such  psychiatric issues before proceeding with surgery.   Additional consideration is given to the status of major  organs. The bariatric surgical patient should not have severe  organ dysfunction, which would make perioperative mor-  bidity and mortality risk unacceptably high. Patients with  unstable angina, end-stage pulmonary disease, or cirrhosis  may have relative or absolute contraindications to bariatric  surgery. However, optimization of treatment of such condi-  tions may improve a patient to the point where he or she may  become a bariatric surgical candidate. Generally speaking,  there are no guidelines regarding bariatric surgery in those  with chronic conditions such as HIV/ AIDS or a history of  treated cancer. The decision to operate on such individuals  must be individualized after careful consultation with the  patient, primary care provider, and other specialists who are  caring for the individual.   The appropriate age limit for patients considering  bariatric surgery is an area of controversy. Adults in the  21-60-year age range are generally deemed appropriate can-  didates assuming they have no contraindications to surgery.  Several articles have explored operative risk in individuals  older than 55 years who undergo bariatric surgery. Although  it is generally accepted that operative risk is higher in older com-  pared with younger individuals, it does not seem prohibitive.  Accordingly, some surgeons believe that operating on  severely obese patients up to age 70 to induce weight loss may  be appropriate. In general, a firm age cutoff is not necessary  if patients are selected carefully and comorbid medical con-  ditions are brought under optimal control before surgical  intervention for weight loss. It should be recognized, how-  ever, that older patients require a more extensive evaluation  looking for silent organ disease, such as asymptomatic ather-  osclerotic heart disease. Although such a workup may not  prevent a bariatric surgical complication, it will theoretically  select for those who have the physiologic reserve to better tol-  erate and survive a complication if one were to occur. In  short, the ultimate decision to proceed in older patients  should be based on the specific individual's risks relative to  the potential benefits, and not just age alone.   Adolescent bariatric surgery is being studied as well, given  the rise in type 2 diabetes and other weight-related comor-  bidities in this age group. As with operating in individuals at  the other end of the age spectrum, there are special consider-  ations. It is recommended that surgery be reserved for those  adolescents with class III obesity (ie, BMI > 40 kg/m 2 ) who  have weight-related conditions. This is stricter than the adult  criterion of class II obesity with weight-related comorbidi-  ties. Adolescents should have documented evidence of failure  of at least a 6-month nonsurgical weight loss program. In  addition, surgery should not be considered in adolescents  until the epiphyseal plates are closed and mature bone length  has been achieved. Rapid weight loss may adversely affect  bone growth due to restricted caloric intake during this crit-  ical time of development. Finally, the family support system  takes on an especially important role when operating on  younger individuals. It is the extremely rare individual who  at so young an age does not absolutely require the full support   of family. Thus, patient evaluation in the very young essen-  tially mandates extensive evaluation of the patient's family  and support network as well.   One final consideration of bariatric surgery in adoles-  cents is the relative advisability of gastric bypass versus  adjustable gastric banding (see the description of these pro-  cedures in the next section). The gastric bypass requires cut-  ting and rerouting of the intestines, permanently altering the  patient's anatomy with unknown long-term effects in adoles-  cents. The laparoscopic adjustable band does not perma-  nently alter patient anatomy and can be removed, thereby  returning the anatomy to normal if necessary. However, the  long-term (ie, 50 or more years) effects of a band in young  individuals are completely unknown, and this approach may  or may not be more appropriate for the very young.  Although there is a great deal to learn about adolescent  bariatric surgery, some form of such surgery may take on an  important role given the rapid rise of obesity and obesity-  related conditions in this age group.   In general, the decision to proceed with bariatric surgery  requires careful evaluation of the patient and analysis of both  physical and psychological well-being of the patient. This  usually requires a multidisciplinary team with a comprehen-  sive program to support patients preoperatively, during hos-  pitalization, and for a lifetime postoperatively. Procedures  available for the treatment of obesity are outlined next.   Horgan S, Holterman MJ, Jacobsen GR, et al. Laparoscopic  adjustable gastric banding for the treatment of adolescent mor-  bid obesity in the United States: a safe alternative to gastric  bypass. / Pediatr Surg. 2005;40:86-90. [PMID: 15868564]   Inge TH, Krebs NF, Garcia VF, et al. Bariatric surgery for severely  overweight adolescents: concerns and recommendations.  Pediatrics. 2004;217-223. [PMID: 15231931]   Papasavas PK, Gagne DJ, Kelly J, et al. Laparoscopic Roux-en-Y  gastric bypass is a safe and effective operation for the treatment  of morbid obesity in patients older than 55 years. Obes Surg.  2004;14:1056-1061. [PMID: 15479593]   Sjostrom L, Narbro K, Sjostrom CD, et al; Swedish Obese Subjects  Study. Effects of bariatric surgery on mortality in Swedish obese  subjects. N Engl J Med. 2007;357:741-752. [PMID: 17715408]   Sugerman HJ, DeMaria EJ, Kellum IM, et al. Effects of bariatric  surgery in older patients. Ann Surg. 2004;240:243-247. [PMID:  15273547]   Surgical treatment of obesity began in the early 1950s when  several groups proposed shortening the intestinal tract via  "bypass" procedures to produce substantial decreases in  absorptive area. This proposal was based on the observation  that massive small bowel resections for treatment of other  pathologic conditions resulted in weight loss followed by  weight stabilization. Since that time, more than 30 different  surgical techniques have been described for treating obesity.  The field underwent a recent revolution with the introduc-  tion of minimally invasive laparoscopic techniques to produce   surgical weight loss. In general, the surgical approach to obe-  sity treatment is designed to create negative energy balance  by (1) reducing caloric absorption by way of a small intes-  tinal bypass; (2) reducing caloric consumption by severely  restricting gastric capacity; or (3) producing weight loss  through a procedure that combines both malabsorption and  restriction of caloric intake. The description of every type of  bariatric procedure is beyond the scope of this chapter.  However, the commonly used, well-known, and emerging  procedures are described.   Kim JJ, Tarnoff ME, Shikora SA. Surgical treatment for extreme  obesity: evolution of a rapidly growing field. Nutr Clin Pract.  2003;18:109-123. [PMID: 16215028]   Currently, the most frequently performed operation and the  gold standard of bariatric procedures in the United States is  the Roux-en-Y gastric bypass (GBP) (Figure 19-1).  Approximately two thirds of bariatric procedures worldwide  are the GBP. In this procedure, a 30-mL pouch is constructed  to which a Roux loop of jejunum is anastomosed. This cre-  ates a short biliopancreatic limb through which bile and pan-  creatic secretions flow; an alimentary limb of 100-200 cm,   depending on a patient's preoperative weight, in which food  from the gastric pouch travels; and a common limb that con-  sists of the remainder of the small bowel just distal to the  anastomosis of the alimentary and biliopancreatic limbs. The  majority of the stomach, the duodenum, and several cen-  timeters of proximal jejunum are bypassed in this configura-  tion. Thus, the procedure is traditionally said to combine  both restrictive and malabsorptive features. In reality, how-  ever, the importance of malabsorption in contributing to the  weight loss produced by GBP has been questioned. Most now  believe that there is very little, if any, macronutrient malab-  sorption. Other neuroendocrine alterations, such as the  reduction in the orexigenic gastric peptide, ghrelin, may con-  tribute to the weight loss efficacy of this procedure. Clearly,  much more study is needed before the physiologic alterations  associated with GBP can be definitively attributed to this  hormone or any other neuroendocrine change.   The GBP procedure can be performed either laparoscop-  ically or "open," with equivalent weight loss effectiveness.  The majority of academic medical centers now perform the  GBP laparoscopically, believing that complications and out-  come other than weight loss may be superior with this  approach versus the open approach. However, a recent pub-  lication has challenged this notion and suggests that the open  approach is of equivalent, if not superior, benefit compared  with the laparoscopic approach. The in-depth analysis of this  controversy is beyond the scope of this chapter. Regardless of  whether the laparoscopic or open approach is employed, the  gastric bypass is the bariatric surgical procedure to which all  other bariatric procedures are compared in terms of efficacy,  morbidity, and mortality.   Surg. 2004;14:1157-1164. [PMID: 15527627]  Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels   after diet induced weight loss or gastric bypass surgery. M Engl   J Med. 2002;346:1623-1630. [PMID: 12023994]  lones KB Jr, Afram ID, Benotti PN, et al. Open versus laparoscopic   Obes Surg. 2006;16:721-727. [PMID: 16756731]  Nguyen NT, Hinojosa M, Fayad C, et al. Use and outcomes of   More recently, another type of malabsorptive procedure,  originally described by Scopinaro of Genoa, Italy, has been  gaining popularity in the United States (Figure 19-2).  Known as the biliopancreatic diversion (BPD), the procedure  consists of a subtotal gastrectomy leaving a gastric remnant  of 200-400 mL. The small bowel is divided 250 cm proximal  to the ileocecal valve. The distal small bowel limb is then  anastomosed to the gastric remnant. The end of the proximal  small bowel limb is anastomosed to the side of the distal  small bowel limb 50 cm proximal to the ileocecal valve. This   construction results in three small bowel limbs similar to that  described with the GBP: a long biliopancreatic limb, a  200-cm alimentary limb, and a 50-cm common limb in  which food and biliopancreatic secretions mix and most of  the digestion and absorption of consumed food occurs. This  operation produces weight loss by inducing malabsorption.  The relatively large gastric remnant does little to restrict food  intake. Similar to the GBP, the BPD can be done open or  laparoscopically. This procedure is popular in certain parts of  Europe, although only 5% of bariatric procedures done  world wide are of this type. Some believe that the malab-  sorption induced by the BPD can be overly harsh and lead to  debilitating diarrhea as a result of the typical, high-fat American  diet compared with the high-in-complex-carbohydrate diet  characteristic of Italy.   Scopinaro N, Gianetta E, Gianetta E, et al. Bilio-pancreatic bypass  for obesity: II. Initial experience in man. Br J Surg. 1979;66:  618-620. [PMID: 497645]   Weber M, Miiller MK, Bucher T, et al. Laparoscopic gastric bypass  is superior to laparoscopic gastric banding for treatment of mor-  bid obesity. Ann Surg. 2004;240:975-982. [PMID: 15570103]   Adjustable silicone gastric banding (ASGB) is a relatively new  restrictive procedure gaining popularity among patients, sur-  geons, and primary care physicians alike and approved by the  FDA for use in the United States in 2001. Overall about a  quarter of bariatric procedures world wide are of this type   and are now almost exclusively placed laparoscopically. In  the laparoscopic adjustable silicone gastric banding (LASGB)  procedure, a silicone-jacketed, beltlike device (ie, the band) is  wrapped around the upper part of the stomach near the angle  of His. This results in partitioning of the stomach into a small  30 mL proximal pouch and a larger distal stomach remnant in  continuity with the pouch. The inner part of the band has an  inflatable fluid-filled sack to which a catheter is attached. The  catheter, in turn, is attached to a port, which sits just beneath  the skin of the abdominal wall. The port can be accessed  through the skin with a syringe and a needle to either add or  remove saline from the sack, thereby tightening or loosening  the band, respectively. Thus, the band is "adjustable." Patients  have their bands adjusted depending on adequacy of weight  loss or symptoms suggesting that it is too tight.   The advantage of the LASGB is that it is a fast, relatively  safe procedure that requires no cutting or stapling of the  stomach. The adjustability of the band is also thought to be  an advantage, allowing increased durability of weight loss.  The downside of the LASGB is that weight loss is signifi-  cantly slower than that achieved using other bariatric proce-  dures; with the LASGB, up to 2-3 years may be needed to  achieve weight loss equal to that observed at 12-18 months  with the GBP and BPD. Some experts feel that those who  undergo LASGB will never achieve a maximal weight loss  equivalent to GBP or BPD. This, however, is controversial,  with some investigators suggesting that although weight loss  is slower with LASGB compared with GBP, long-term weight  loss is the same.   Buchwald H, Williams SE. Bariatric surgery worldwide 2003. Obes  Surg. 2004;14:1157-1164. [PMID: 15527627]   Jan JC, Hong D, Pereira N, et al. Laparoscopic adjustable gastric  banding versus laparoscopic gastric bypass for morbid obesity:  a single-institution comparison study of early results. /  Gastrointest Surg. 2005;9:30-39. [PMID: 15623442]   Mognol P, Chosidow D, Marmuse JP. Laparoscopic gastric bypass  versus laparoscopic adjustable banding in the super-obese: a  comparative study of 290 patients. Obes Surg. 2005;15:76-81.  [PMID: 15760503]   Weber M, Miiller MK, Bucher T, et al. Laparoscopic gastric bypass is  superior to laparoscopic gastric banding for treatment of morbid  obesity. Ann Surg. 2004;240:975-982. [PMID: 15570103]   Recently a new procedure known as the sleeve gastrectomy  has been used in some centers. This was first described by  Ren and colleagues and was born out of the notion that the  morbidity and mortality risk for a laparoscopically per-  formed BDP would be improved if the procedure was per-  formed in two stages. In the first stage, the sleeve gastrectomy  is performed. The majority of the stomach on the greater  curve side is removed, leaving a "sleeve" of stomach based on  the lesser curve (Figure 19-3). After 6-12 months of weight  loss, resolution or improvement of comorbid conditions,   and presumably marked decrease in operative risk, the second  stage is performed. In this stage, the sleeve procedure is  converted to a GBP or a BPD laparoscopically. This is thought  to be particularly appropriate for the high-risk, high-BMI  patient in whom a one-stage GBP or BPD is considered pro-  hibitively risky.   The two-stage procedure has an obvious drawback in that it  requires two separate operations. Hence, such an approach  must be balanced against the relative risks of the one-stage,  longer operation performed in a poorer surgical candidate.  Early experience with the sleeve gastrectomy has suggested that  the weight loss induced by this procedure alone (ie, without  performing the second stage) is significant enough to be used  as a definitive one-stage procedure. This evidence includes a  recent prospective, double-blind study in which the sleeve gas-  trectomy was compared with a GBP. The authors found that  weight loss for the sleeve was better than the GBP (69.7% vs  60.5% excess body weight lost at 1 year, P = 0.05 sleeve vs GBP).  This result was associated with the finding that the orexigenic  gastric peptide, ghrelin, was significantly lower in the sleeve  group as was appetite compared with that of the GBP group. It  is important to note, however, that these data are relatively  short term and several experts have expressed concern that the  gastric pouch of the sleeve will dilate over time and weight loss  efficacy may be lost. Further study is needed before determin-  ing the appropriate place of the sleeve gastrectomy in the arma-  mentarium of the bariatric surgeon.   Frezza EE. Laparoscopic vertical sleeve gastrectomy for morbid  obesity. The future procedure of choice? Surg Today. 2007;37:  275-281. [PMID: 17387557]   Karamanakos SN, Vagenas K, Kalfarentzos F, et al. Weight loss,  appetite suppression, and changes in fasting and postprandial  ghrelin and peptide- YY levels after Roux-en-Y gastric bypass  and sleeve gastrectomy. Ann Surg. 2008;247:401-407. [PMID:  18376181]   Ren CJ, Patterson E, Gagner M. Early results of laparoscopic bil-  iopancreatic diversion with duodenal switch: a case series of 40  consecutive patients. Obes Surg. 2000;10:514-523. [PMID:  11175958]   Two outdated bariatric surgical procedures require mention.  The first is the jejunoileal bypass, in which the proximal  jejunum is divided 35 cm distal to the ligament of Treitz and  anastomosed to the distal ileum, 10 cm proximal to the ileo-  cecal valve. The long bypassed or excluded segment of small  intestine is vented to the colon or small intestine to prevent  obstruction. Although quite effective in inducing weight loss,  the jejunoileal bypass is associated with debilitating diarrhea,  electrolyte imbalances, vitamin and mineral deficiencies, and  life-threatening liver dysfunction. Consequently, this proce-  dure has been abandoned.   The other well known but outdated bariatric procedure is  the vertical banded gastroplasty (VBG) originally described  by the "father" of bariatric surgery, Edward Mason. It is a  purely restrictive procedure in which a vertically oriented  15-30 mL gastric pouch is created along the lesser curve of  the proximal stomach. The outlet of this pouch, which leads  to the remaining stomach, is encircled with a band of Marlex  mesh to prevent dilation of the outlet over time. The advan-  tage of this procedure is that it is technically easier and faster  to perform than malabsorptive procedures and avoids issues  with severe diarrhea, vitamin and mineral deficiencies, and  liver dysfunction. However, the long-term weight loss is less  effective than that achieved with the GBP and BPD, and the  LASGB has supplanted VBG use by bariatric surgeons. This  is largely due to the adjustability feature of the LASGB, which  is thought to improve weight loss efficacy and durability rel-  ative to the VBG.   In high-volume centers, hospital stay for bariatric surgery  patients varies from 1 to 3 days depending on the type of  procedure performed. LASGB patients are usually discharged  within 24 hours of surgery, although some centers are mov-  ing to day surgery for LASGB in which patients are sent  home on the same day of the procedure. GBP patients who  have surgery performed laparoscopically are generally dis-  charged from the hospital in 2-3 days. Patients who have an  open GBP are generally discharged from the hospital after  2-3 days as well. Routine care during hospitalization focuses  on providing adequate pain control and ensuring adequate  oral intake. Once these are achieved, the patient can be safely  discharged to home. The diet is advanced through various   "stages" over several weeks, and patients receive extensive  education about maintaining hydration status and consum-  ing adequate protein.   The most common "complication" in bariatric surgical  patients is nausea and vomiting, which may occur in as many  as 30-40% of patients. This can lead to rehospitalization to  treat dehydration, despite no identifiable anatomic obstruc-  tion of the gastrointestinal tract. Patients usually receive intra-  venous hydration and are discharged to home in 24-48 hours  in good condition. Other complications include wound infec-  tions, which affect from 1-2% of patients undergoing laparo-  scopic procedures to as high 10-15% of those undergoing  open procedures. Long-term complications include ventral  hernia formation, which is more common in the open  approach than the laparoscopic approach. Less common issues  include pouch ulcer formation, internal hernia formation, and  small bowel obstruction from adhesion formation.   The most common life-threatening complications from  bariatric surgery include peritonitis and intra-abdominal  abscess associated with an anastomotic leak or iatrogenic,  unrecognized perforation of a viscus. Bariatric patients are  notorious for having a paucity of classic signs of peritonitis.  Instead of abdominal pain and rebound tenderness, these  patients may complain of back and left shoulder pain and  have a relatively "benign" abdominal examination until  impending death. They may also have tachypnea, tachycar-  dia, and hypoxia without clear etiology. The surgeon should  have a low threshold for obtaining radiologic evaluation with  water-soluble contrast agents if any of these symptoms  should occur without clear explanation. However, radiologic  studies may be falsely negative given the patient's body habi-  tus and technical difficulties associated with obtaining and  interpreting radiographs in the morbidly obese. Thus, a  patient requires surgical re-exploration even in the face of  negative studies if he or she is clinically unstable and without  an identifiable source of pathology. The reported incidence  of leaks is 1-2% and may be higher in those undergoing  laparoscopic procedures, especially in the first 100 cases of a  surgeon's experience.   Pulmonary embolism, although feared and often dis-  cussed, is relatively uncommon in bariatric surgery patients. It  occurs less than 1% of the time in those who receive appro-  priate prophylaxis against pulmonary embolism, which is gen-  erally "double coverage" (eg, low molecular weight heparin  and pneumatic compression boots). Pulmonary embolism  can be hard to diagnose in the morbidly obese. Persistent  tachypnea and hypoxia may be suggestive, but many obese  patients have a preoperative history of pulmonary issues with  such symptoms, which may lull practitioners into a false sense  of security. Hence, there should be a low threshold to work up  bariatric patients with ventilation-perfusion scans or spiral  chest computed tomography (CT) for even subtle changes in  pulmonary status.   High-volume centers report a mortality rate of 1 in  200-500 patients for GBP. Data from the State of Washington  suggest that the rate may be higher, at 1-2%, if one collects   data from all centers conducting bariatric surgery, which  includes those with less experience and higher mortality  rates. LASGB has a very low mortality rate of 1 in 2000. Data  are limited for emerging procedures such as the sleeve gas-  trectomy, but it is believed the mortality risk is lower com-  pared with the GBP but higher than the LASGB.   Chapman AE, Kiroff G, Game P, et al. Laparoscopic adjustable gas-  tric banding in the treatment of obesity: a systematic literature  review. Surgery. 2004;135:326-351. [PMID: 14976485]   Flum DR, Dellinger EP. Impact of gastric bypass operation on  survival: a population-based analysis. / Am Coll Surg.  2004;199:543-551. [PMID: 15454136]   Nguyen NT, Paya M, Stevens CM, et al. The relationship between  hospital volume and outcome in bariatric surgery at academic  medical centers. Ann Surg. 2004;240:586-594. [PMID: 15383786]   Nguyen NT, Silver M, Robinson M, et al. Result of a national audit  of bariatric surgery performed at academic centers: a 2004  University HealthSystem Consortium Benchmarking Project.  Arch Surg. 2006;141:445-450. [PMID: 16702515]   Sapala IA, Wood MH, Schuhknecht MP, et al. Fatal pulmonary  embolism after bariatric operations for morbid obesity: a  24-year retrospective analysis. Obes Surg. 2003;13:819-825.  [PMID: 14738663]   See C, Carter PL, Elliott D, et al. An institutional experience with  laparoscopic gastric bypass complications seen in the first year  compared with open gastric bypass complications during the  same period. Am J Surg. 2002;183:533-538. [PMID: 12034387]   Shikora SA, Kim JJ, Tarnoff ME, et al. Laparoscopic Roux-en-Y  gastric bypass: results and learning curve of a high-volume  academic program. Arch Surg. 2005;140:362-367. [PMID:  15837887]   Smith SC, Edwards CB, Goodman GN, et al. Open vs laparoscopic  Roux-en-Y gastric bypass: comparison of operative morbidity  and mortality. Obes Surg. 2004;14:73-76. [PMID: 14980037]   Nausea and vomiting with or without abdominal pain is a  common complaint after bariatric surgery. Hence, it is not  uncommon for gastroenterologists, particularly those based  at bariatric surgical centers, to be asked to evaluate patients  with these symptoms. The most common cause of nausea  and vomiting in the early postoperative period is dehydra-  tion and dietary noncompliance, as previously noted. Red  meat, bread (particularly doughy breads such as bagels),  pasta, and dry chicken are poorly tolerated and can lead to  nausea, vomiting, and subsequent dehydration. Patients may  also be lactose intolerant, and the consumption of milk-  based liquid supplements, which are frequently prescribed in  the immediate postoperative period, can precipitate symp-  toms. Nausea and vomiting purely related to dehydration  and dietary indiscretion quickly resolve with rehydration and  consultation with a knowledgeable bariatric dietitian.  However, one must be on guard when evaluating nausea and   vomiting in bariatric surgical patients: the list of differential  diagnoses is long and varies from the self-limited to the life  threatening.   The first step in evaluating the bariatric surgery patient  with nausea and vomiting is determining the type of proce-  dure the patient had. Nomenclature of procedures is variable  around the country, and those unfamiliar with bariatric sur-  gical procedures (eg, patients and primary care providers)  may use terms incorrectly to convey what procedure was per-  formed. Hence, it is advisable to obtain an operative report if  possible and time permits.   The most common patient that the gastroenterologist will  be called to evaluate is one who has had a laparoscopic or open  GBP, as this is the most commonly performed procedure.  Although dehydration and dietary noncompliance may be  immediately evident, it is possible that there are other con-  comitant problems that need to be ruled out. Regurgitation of  food and epigastric pain that occur when eating, are absent  when not eating, and may be described as the sensation of a  "knot" or "ball" in the epigastrium all suggest a problem with  the gastrojejunal anastomosis. Initial evaluation usually  includes an upper gastrointestinal (UGI) radiocontrast series  to rule out an anastomotic stricture and gastrogastric fistula  with or without an anastomotic ulcer. If the UGI series rules in  one of these findings, or the patient has persistent epigastric  pain without a known etiology, an upper endoscopy (esopha-  gogastroduodenoscopy [EGD]) is indicated.   The EGD will identify a stricture, ulcer, and possible gas-  trogastric fistula if present virtually 100% of the time.  Strictures can successfully be dilated to avoid revisional sur-  gery greater than 95% of the time by an experienced gas-  troenterologist. Some strictures may require serial dilation at  planned intervals to achieve durable results. Narrow stric-  tures (eg, 5 mm or less) should be redilated two times at  2 -week intervals for a total of three successive dilations to  ensure long-term relief of the stricture. Although dilation  may be attempted up to six times, the average number of  dilations required for durable success is two to three. Ulcers  are treated with standard medical therapy and must be  treated aggressively, particularly if associated with a stricture  or upper gastrointestinal bleeding. Similarly, gastrogastric  fistulae (ie, a channel between the gastric pouch and  bypassed stomach) should be treated for symptoms such as  ulcer formation and weight regain.   A new subspecialty within gastroenterology is emerging in  which the preceding complications and others are being treated  endoscopically by gastroenterologists who specialize in the  treatment and evaluation of the postoperative bariatric surgical  patient. Conditions that formerly were thought to mandate sur-  gical exploration and revision are now being treated success-  fully with outpatient, low-morbidity — although complex —  endoscopic procedures. For example, patients who have weight  regain or nonhealing ulcers associated with gastrogastric fistu-  lae have been treated successfully with endoscopic suturing to  close the orifice leading to the bypassed stomach pouch.  Similarly, patients who have weight gain secondary to a dilated   gastrojejunal anastomosis and pouch dilation may benefit  from an attempt at endoscopic suturing to reduce anastomotic  and pouch size. Preliminary results suggest that this approach  can restore weight loss efficacy of the GBP without surgical  revision. Finally, a small series of hemodynamically stable  patients, without diffuse peritonitis and chronic gastrojejunal  anastomotic leaks have been treated successfully by endo-  scopic techniques. These initial results, while encouraging,  must be viewed carefully. First, such procedures should be  done only by those with advanced endoscopic therapeutic  technical skills and most likely in a specialty center. Second,  long-term follow-up studies (currently underway) are neces-  sary to determine if these procedures can be recommended on  a regular basis.   Nausea and vomiting may also occur with more distal  pathology such as jejunojejunal anastomotic stricture, jeju-  nal intussusception, and an internal hernia. Usually patients  present with abdominal pain as well as vomiting with these  conditions and the initial evaluation includes abdominal CT  scanning. The CT scan may miss the diagnosis, in which case  persistent symptoms may prompt EGD interrogation down  to the jejunojejunal anastomosis. Pathology may be identi-  fied by endoscopic interrogation and may identify a diagno-  sis missed on CT scan. Chronic vomiting, particularly with  abdominal pain and unknown etiology or in the acutely ill  patient, should prompt exploratory laparotomy to rule out  internal hernias, intussusception, or jejunojejunal stricture.  Such diagnoses can be hard to make short of surgery, and  missing an internal hernia, for example, can be fatal in the  postoperative bariatric surgical patient.   The causes of nausea and vomiting in the lap band patient  include dehydration and dietary indiscretion, similar to that  observed in the GBP patient. Band-related causes include  overtightening of the band and band slippage. Patients may  find they can tolerate liquids but not solids immediately after  band tightening. This suggests overtightening of the band and  can be relieved by simple withdrawal of saline from the port.  In contrast, acute or slowly progressive dysphagia to solid and  liquids in a patient in whom band tightening has not recently  occurred should prompt an UGI study to rule out band slip-  page. Band slippage is the anterior or posterior herniation of  the stomach through the band ring. Pain and inability to  swallow food and liquids should prompt urgent evaluation to  rule out band slip. Withdrawal of saline from the port may  alleviate the pain associated with this complication and  should be done to alleviate any stomach ischemia even before  obtaining a UGI to confirm the diagnosis. The acute onset of  pain and inability to swallow food and liquids should be eval-  uated urgently to rule out band slip. An acute slip with pain is  indicative of stomach ischemia and can lead to frank stomach  necrosis if not treated promptly. Finally, LASGB port site  infection, which does not occur in the immediate postopera-  tive period, should prompt local treatment of the port site as  well as EGD to rule out band erosion. Band erosion may allow  tracking of gastric bacteria along the catheter retrograde to  the port.   It is well known that rapid weight loss is associated with the  development of cholelithiasis and cholecystitis. Controversy  still exists among bariatric surgeons regarding whether the  gallbladder, if present, should be removed in all bariatric  surgical patients. It is clear, however, that the gastroenterol-  ogist will occasionally be asked to assist with treatment of  those patients who have choledocholithiasis. This is gener-  ally straightforward in band patients, although one should  consider complete deflation of the band to assist with endo-  scopic retrograde cholangiopancreatography (ERCP) if  indicated.   In contrast, ERCP in the GBP patient can be quite chal-  lenging, although possible, by performing an EGD down to  the jejunojejunal anastomosis and going retrograde up the  biliopancreatic limb to access the duodenal ampulla of  Vater. ShapeLock technology can assist with negotiating the  route to the duodenum. If peroral ERCP is unsuccessful,  laparoscopic gastrotomy and transabdominal passage of a  sterile endoscope into the stomach and antegrade down the  duodenum to the ampulla can be done. This procedure  requires general anesthesia but generally causes less morbid-  ity than an open or laparoscopic common bile duct explo-  ration, and the gallbladder can be removed at the same time  if appropriate.   Finally, constipation is common after bariatric surgery, and  the gastroenterologist may be asked to evaluate and treat this  complex condition. The condition may be due to one or sev-  eral factors, among them:   • A history of infrequent bowel movements that antedates  the surgery. It is not generally appreciated that 2% of U.S.  women have two or fewer bowel motions per week.   • Insufficient intake of "laxative"-type foods, which may  induce bowel motions. Such foods include peaches, pears,  cherries, apples, apple juice, orange juice, milk and milk  products, cola beverages, other high-fructose beverages,  pastries, candy, chocolate, salads, Brassica vegetables (cab-  bage, cauliflower, asparagus, broccoli, Brussel sprouts),  bran cereal, and muffins. Although such foods can allevi-  ate constipation they may also produce "dumping" syn-  drome in GBP patients — a syndrome characterized by  crampy abdominal pain, nausea, vomiting, perspiration,  and diarrhea — related to rapid transit of a high osmotic  load through the small gastric pouch to the jejunum. One  must balance the goal of treating constipation with avoid-  ing this syndrome through dietary intervention.   • Insufficient fluid intake. Bariatric patients should ingest  at least l7 2 -2 quarts of fluids a day, which can be chal-  lenging given the limited size of their newly created gas-  tric reservoirs. Patients can achieve this goal by drinking  small quantities of fluid throughout the day.   • Concurrent use of medications with anticholinergic or  antimotility effects such as antihistamines, tricyclic anti-  depressants, calcium channel blockers, calcium supple-  ments, iron supplements such as ferrous sulfate, and  selective serotonin reuptake inhibitors.   • Antecedent hysterectomy. Five percent of patients under-  going a hysterectomy develop refractory constipation.   Accordingly, the approach to patients with constipation is  to take a detailed history and determine what the patient  actually means when by the term "constipation." This may  mean infrequent stools (< 3 per week) or unusually hard  stools difficult to pass. The next step is to assess fluid intake to  ensure adequate fluid intake, as discussed previously. The  third step is to review the patients' medications and consider  discontinuation of those who constipate unless clearly  needed. The fourth step is to prescribe a stool softener. The  most useful preparations are those that contain both docusate  and sorbitol. If patients do not respond to these steps, one can  add a medicine such as lubiprostone (Amitiza).   Most bariatric patients respond to the aforementioned  treatments. However, for those who do not, a Sitz marker  study can be ordered to rule out colonic inertia, or anorectal  manometry or magnetic resonance imaging defecography to  rule out pelvic floor muscle dysfunction. Patients may also  have a combination of colonic inertia and pelvic floor mus-  cle dysfunction. Treatment can be rendered depending on  the severity of constipation and the diagnoses made by these  studies.   Go MR, Muscarella P, Needleman BJ, et al. endoscopic manage-  ment of stomal stenosis after Roux-en-Y gastric bypass. Surg  Endo. 2004;18:56-59. [PMID: 14625732]   Merrifield BF, Lautz D, Thompson CC. Endoscopic repair of gastric  leaks after Roux-en-Y gastric bypass: a less invasive approach.  Gastrointest Endo. 2006;63:710-714. [PMID: 16564884]   Moore KA, Ouyang DW, Whang EE. Maternal and fetal deaths  after gastric bypass surgery for treatment of morbid obesity.  N Engl] Med. 2004;351:721-722. [PMID: 15306679]   Nguyen NT, Hinojosa MW, Slone J, et al. Laparoscopic transgas-  tric access to the biliary tree after Roux-en-Y gastric bypass.  Obes Surg. 2007;17:416-419. [PMID: 17546853]   Pai RD, Carr-Locke DL, Thompson CC. Endoscopic evaluation of  the deftinctionalized stomach by using ShapeLock technology  (with video). Gastrointest Endo. 2007;66:578-581. [PMID:  17725949]   Thompson CC, Carr-Locke DL, Saltzman J, et al. Per oral repair of  staple-line dehiscence in roux-en-Y gastric bypass: a less inva-  sive approach. Presented at the 45th annual meeting of the  Society for Surgery of the Alimentary Tract, 2004.   Thompson C, Robinson MK, Lautz D. FACS. Enteroscopic diagno-  sis of internal hernia after roux-en gastric bypass, a case study.  Presented at the annual meeting of the Society of American  Gastrointestinal and Endoscopic Surgeons, 2006.   Thompson CC, Slattery J, Bundga ME, et al. Peroral endoscopic  reduction of dilated gastrojejunal anastomosis after Roux-en Y  gastric bypass: a possible new option for patients with weight  regain. Surg Endosc. 2006;20:1744-1748. [PMID: 17024527]   Current weight loss surgical procedures are associated with  significant weight loss and resolution of weight-related con-  ditions. The Swedish Obese Subjects (SOS) study, which  examined weight reduction, reduction in cardiovascular risk  factors, and mortality over a 10-year period, is probably the  best-known study of bariatric surgery outcome. In this study,  2010 obese subjects who underwent bariatric surgery were  contemporaneously matched with 2037 control obese sub-  jects who received nonsurgical treatment. Patients were fol-  lowed for up to 15 years, and the investigators found that  weight loss for all patients undergoing surgery was signifi-  cantly greater compared with that observed in the control  patients (Figure 19-4). GBP patients lost 32% of initial body  weight at 1 year, which was maintained at a level of 28% loss  of initial body weight at 15 years. Band patients lost less than  the GBP patients but still a significant amount: 21% of initial  body weight at the 1 year mark and 13% at the 15 year mark  after surgical intervention. In contrast, conventionally  treated patients essentially had no change in weight over the  15 years of study.   When the surgical patients in the SOS study were com-  pared with the control patients, a marked, statistically signif-  icant improvement was seen in lipid profile, diabetes,  hypertension, and hyperuricemia, as well as a decrease in the  risk of developing these conditions if not present at the time  of surgery. The authors concluded that, as compared with  conventional, nonsurgical treatment, bariatric surgery results  in long-term weight loss, improved lifestyle, and ameliora-  tion of a variety of cardiovascular risk factors.   Others have also reported positive findings similar to  those of the SOS study. For example, Dixon and colleagues  randomized patients to LASGB or nonsurgical treatment and  found that not only was weight loss greater in the surgical  group, 76% of the surgical patients also had complete reso-  lution of diabetes compared with 15% for the nonsurgical  group. Others have demonstrated that the beneficial effects  of weight loss surgery extend to noncardiac risk factors such  as pregnancy and neonatal outcomes in obese women who  undergo bariatric surgery prior to conceiving. Maggard and  colleagues performed a meta-analysis of 147 published stud-  ies comparing surgical with nonsurgical treatment. They  concluded that "surgery is more effective than nonsurgical   ▲ Figure 19-4. Mean percentage of weight loss in control subjects versus patients undergoing gastric bypass, vertical  banded gastroplasty, and adjustable gastric banding in the Swedish Obese Subjects (SOS) study. (Data from Sjostrom L,  Narbro K, Sjostrom CD, et al, Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese  subjects. N Engl J Med. 2007;357:741-752.)   treatment for weight loss and control of some comorbid con-  ditions in patients with a BMI of 40 kg/m 2 or greater."   The impact of surgical treatment of the obese is not just  limited to alleviation of comorbid conditions. The SOS study  found a statistically significant (29%) reduction in death in  patients undergoing surgery compared with conventionally  treated individuals. In another study, Adams and colleagues  assessed mortality risk in 7925 gastric bypass patients com-  pared with 7925 control patients matched for age, gender, and  BMI. The adjusted long-term mortality in the surgery group  decreased by 40% compared with that in the control group.   A final question regarding use of surgery to treat morbid  obesity is the financial cost. Can we as a nation afford to offer  such treatment given the high number of patients who poten-  tially qualify for surgery? It is clear that initial health care costs  for obese individuals who undergo surgery are higher than  the costs for obese individuals who receive nonsurgical treat-  ments or go untreated. However, 3 years after surgery the  health care costs of surgical patients is less than that of those  who do not undergo obesity surgery. Over a 5 -year period, the  number of hospitalizations, total hospital days, physician vis-  its, and prescription costs are less in surgically treated obese  individuals. This is associated with up to a 25% reduction in  health care costs in these individuals compared with obese  patients who receive nonsurgical or no treatment for their  weight condition. Hence, bariatric surgery is also cost-effective  compared with nonsurgical treatments.   Although it makes intuitive sense that massive weight loss  leads to improved health and decreased mortality, the mech-  anism through which surgery exerts it salubrious affects have  yet to be fully identified. One theory is that surgery has a  beneficial affect on the inflammatory mediators associated  with obesity. Initial work has suggested that inflammatory  mediators such as angiotensinogen, transforming growth  factor-p, tumor necrosis factor-a, and interleukin-6 are all  elevated in obesity. These mediators may in part lead to the  development of several cardiovascular risk factors, such as  hypertension, diabetes, dyslipidemia, and thromboembolic  phenomena. Weight loss surgery is associated with reduction  of these factors, possibly through reduction of adipocyte  mass, and therefore may be the mechanism through which  weight loss surgery so effectively reduces cardiovascular risk  and prolongs life. Clearly, much more study is needed to  examine how weight loss in general, and obesity surgery in  particular, improves outcome. However, at this time, the evi-  dence is quite strong in favor of surgery for treatment of  severely obese individuals compared with prolonged efforts  at nonsurgical treatment.   Adams TD, Gress RE, Smith SC, et al. Long-term mortality after  gastric bypass surgery. N Engl J Med. 2007;357:753-761. [PMID:  17715409]   Cottam DR, Mattar SG, Barinas-Mitchell E, et al. The chronic  inflammatory hypothesis for the morbidity associated with  morbid obesity: implications and effects of weight loss. Obes  Surg. 2004;14:589-600. [PMID: 15186624]   Dixon JB, Dixon ME, O'Brien PE. Birth outcomes in obese women  after laparoscopic adjustable gastric banding. Obstet Gynecol  2005;106:965-972. [PMID: 1626013]   Dixon JB, O'Brien PE, Playfair J, et al. Adjustable gastric banding  and conventional therapy for type 2 diabetes: a randomized  controlled trial. JAMA. 2008;299:316-323. [PMID: 18212316]   Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: sur-  gical treatment of obesity. Ann Intern Med. 2005;142:547-559.  [PMID: 15809466]   Patel JA, Colella JI, Esaka E, et al. Improvement in infertility and  pregnancy outcomes after weight loss surgery. Med Clin North  Am. 2007;91:515-528. [PMID: 17509393]   Ramos EJ, Xu Y, Romanova I, et al. Is obesity an inflammatory  disease? Surgery. 2003;134:329-335. [PMID: 12947337]   Sampalis IS, Liberman M, Auger S, et al. The impact of weight  reduction surgery on health-care costs in morbidly obese  patients. Obes Surg. 2004;14:939-947. [PMID: 15329183]   Sjbstrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and  cardiovascular risk factors 10 years after bariatric surgery. NEngl  J Med. 2004;351:2683-2693. [PMID: 15616203]   Sjbstrom L, Narbro K, Sjbstrom D, et al; Swedish Obese Subjects  Study. Effects of bariatric surgery on mortality in Swedish obese  subjects. NEngl J Med. 2007;357:741-752. [PMID: 17715408]   Weight loss surgery is the treatment of choice for appropri-  ately selected individuals who have class II obesity with  weight-related comorbid conditions and patients with class III  obesity with or without comorbid conditions. Several surgi-  cal procedures designed to treat obese individuals and cur-  rent procedures are quite effective in inducing long-term  weight loss. However, patients require a careful, comprehen-  sive evaluation before proceeding with such treatment to  minimize surgical risks and justify such an invasive treat-  ment. In appropriately selected individuals, bariatric surgery  is associated with reduced cardiovascular and other weight-  related risks, reduced mortality, and reduced health care  costs, making such surgery appropriate in this group of indi-  viduals until equally or more effective weight loss treatments  are developed.   ► Celiac sprue— characteristic though not specific small bowel  mucosal lesion and clinical response to gluten withdrawal.   ► Tropical sprue— appropriate geographic exposure; exclude  other mucosal diseases (eg, celiac sprue and protozoal  infections) and assess response to antibiotics and folate.   ► Eosinophilic gastroenteritis— histologic demonstration  of increased gastric, intestinal, or colonic mucosal or  mural eosinophilic infiltration or eosinophilic ascites.   ► Systemic mastocytosis— demonstration of increased  mucosal mast cells (> 20 per high-power field) in stom-  ach, small bowel, colon.   ► Radiation enteritis— history of radiation with mucosal  telangiectasias, obliterative endarteriolaritis, fibrosis,  and strictures; small intestinal bacterial overgrowth  may develop.   ► Whipple disease— demonstrate Tropheryma whipplei and  characteristic periodic acid-Schiff-positive macrophages  in intestinal mucosa.   ► Small intestinal bacterial overgrowth— document evi-  dence of malabsorption, positive breath test (lactulose,  glucose), response to antibiotics.   ► Short bowel syndrome— history of small bowel resection  and confirmation by imaging (barium contrast small  bowel series or computed tomographic enterography).   ► Intestinal lymphangiectasia— hypoalbuminemia, lym-  phopenia, evidence of protein-losing enteropathy,  increased fecal loss of ex., -antitrypsin.   Normally the human gastrointestinal tract digests and  absorbs dietary nutrients with remarkable efficiency. A typical  Western diet ingested by an adult includes approximately 100 g   of fat, 400 g of carbohydrate, 100 g of protein, 2 L of fluid,  and the required sodium, potassium, chloride, calcium, vita-  mins, and other elements. Salivary, gastric, intestinal,  hepatic, and pancreatic secretions add an additional 7-8 L of  protein-, lipid-, and electrolyte-containing fluid to intestinal  contents. This massive load is reduced by the small and large  intestines to less than 200 g of stool that contains less than 8 g  of fat, 1-2 g of nitrogen, and less than 20 mM each of Na + ,  K + , CI", HCO3-, Ca 2+ , or Mg 2+ .   If there is impairment of any of the many steps involved in  the complex process of nutrient digestion and absorption,  intestinal malabsorption may ensue. If the abnormality  involves a single step in the absorptive process, as in primary  lactase deficiency, or if the disease process is limited to the  very proximal small intestine selective malabsorption of only  a single nutrient may occur. However, generalized malabsorp-  tion of multiple dietary nutrients develops when the disease  process is extensive, thus disturbing several digestive and  absorptive processes, as occurs in celiac sprue with extensive  involvement of the small intestine.   Many authors classify diseases associated with malabsorp-  tion into three major categories: (1) those associated with  impaired intraluminal digestion; (2) those associated with  impaired mucosal digestion and absorption; and (3) those  associated with impaired postmucosal nutrient transport  (Table 20-1). Indeed, these are the major mechanisms of  intestinal absorption and some disease entities fit neatly into  these specific categories. For example, impaired delivery of  pancreatic lipase, proteases, and bicarbonate in pancreatic  insufficiency and impaired delivery of hepatobiliary secre-  tions, notably bile salts in biliary obstruction, into the intes-  tinal lumen may result in profound intraluminal  maldigestion and may induce malabsorption, especially steat-  orrhea. In diseases such as abetalipoproteinemia or lactase  deficiency, in which the evident pathology is confined to the   2. Diseases in which impaired mucosal digestion, uptake,  and transport are dominant   3. Diseases and syndromes in which both impaired intraluminal  digestion and mucosal function are often operative   4. Diseases or syndromes in which impaired postmucosal transport  is dominant   intestinal mucosa, deficient mucosal digestion or absorption,  or both, produce nutrient malabsorption. Likewise, impaired  intestinal lymphatic drainage, whether due to primary or  secondary obstruction of intestinal lymphatics, results in  impaired fat absorption and fecal protein loss.   However, such a classification of malabsorption dis-  eases has its limitations; although one mechanism may  dominate in any given disease, in many instances others  contribute. For example, in short bowel syndrome the  marked reduction in mucosal surface and brush border  hydrolases results in impaired mucosal absorption and  digestion, but if the ileum is absent, bile salt deficiency  results in impaired intraluminal digestion; in small intes-  tinal bacterial overgrowth, bacteria impair intraluminal  lipid digestion but also damage brush border hydrolases  and induce significant mucosal inflammation impairing  mucosal digestion and absorption; in Whipple disease the  mucosal infiltration by macrophages and T whipplei  impair mucosal absorption but mesenteric and retroperi-  toneal lymph node involvement may produce lymphatic  obstruction, impairing postmucosal delivery and systemic  distribution of absorbed dietary lipids.   nature of the disease process causing malabsorption and its  extent, gastrointestinal symptoms may range from severe to  subtle or may even be totally absent. Diarrhea, weight loss,  flatulence, abdominal bloating, abdominal cramps, and  pain may be present. Although diarrhea is a common com-  plaint, the character and frequency of stools may vary con-  siderably ranging from over 10 watery stools per day to less  than one voluminous putty-like stool, the latter causing  some patients to complain of constipation. On the other  hand, stool mass is invariably increased in patients with  steatorrhea and generalized malabsorption above the nor-  mal with 150-200 g/day. Not only do unabsorbed nutrients  contribute to stool mass but mucosal fluid and electrolyte  secretion is also increased in diseases associated with  mucosal inflammation such as celiac sprue. In addition,  unabsorbed fatty acids, converted to hydroxy-fatty acids by  colonic flora, as well as unabsorbed bile acids both impair  absorption and induce secretion of water and electrolytes by  the colon adding to stool mass.   Weight loss is common among patients with significant  intestinal malabsorption but must be evaluated in the con-  text of caloric intake. Some patients compensate for fecal  wastage of unabsorbed nutrients by significantly increas-  ing their oral intake. Eliciting a careful dietary history from  patients with suspected malabsorption is therefore crucial.   Excessive flatus and abdominal bloating may reflect  excessive gas production due to fermentation of unabsorbed  carbohydrate, especially among patients with primary or  secondary disaccharidase deficiency. Malabsorption of  dietary nutrients and excessive fluid secretion by inflamed  small intestine also contribute to abdominal distention and  bloating.   Prevalence, severity, and character of abdominal pain  vary considerably among the various disease processes asso-  ciated with intestinal malabsorption. For example, pain is  common in patients with chronic pancreatitis or pancreatic  cancer and Crohn disease, but it is absent in many patients  with celiac sprue or postgastrectomy malabsorption.   2. Extraintestinal manifestations— Substantial num-  bers of patients with intestinal malabsorption present  initially with symptoms or laboratory abnormalities that  point to other organ systems in the absence of or over-  shadowing symptoms referable to the gastrointestinal  tract (see Table 20-2). For example, there is increasing  epidemiologic evidence that more patients with celiac  sprue present with anemia and osteopenic bone disease in  the absence of significant gastrointestinal symptoms than  present with classic gastrointestinal symptomatology.  Microcytic, macrocytic, or dimorphic anemia may reflect  impaired iron, folate, or vitamin B 12 malabsorption. Purpura,  subconjunctival hemorrhage, or even frank bleeding may    Nutrient malabsorption; small intestinal secretion of fluid and  electrolytes; action of unabsorbed bile acids and hydroxy-fatty  acids on colonic mucosa    Distention of bowel, muscle spasm, serosal and peritoneal  involvement by disease process   reflect hypoprothrombinemia secondary to vitamin K malab-  sorption. Osteopenic bone disease is common, especially in  the presence of steatorrhea. Impaired calcium and vitamin D  absorption and chelation of calcium by unabsorbed fatty  acids resulting in fecal loss of calcium may all contribute. If  calcium deficiency is prolonged, secondary hyperparathy-  roidism may develop. Prolonged malnutrition may induce  amenorrhea, infertility, and impotence. Edema and even  ascites may reflect hypoproteinemia associated with protein-  losing enteropathy caused by lymphatic obstruction or  extensive mucosal inflammation. Dermatitis and peripheral  neuropathy may be caused by malabsorption of specific vita-  mins or micronutrients and essential fatty acids.   2003;124:795-841. [PMID: 12612917]  Fine KD, Schiller LR. AGA technical review on the evaluation and   1. Stool studies — Descriptions of bowel movements by  patients are subjective and often inaccurate. Therefore, care-  ful inspection of the stool by the physician is an important  component of the malabsorption evaluation. Steatorrheic    False-negative result if inadequate ingestion  of dietary fat or recent barium ingestion;  false-positive result with castor oil or  mineral oil ingestion    Low specificity for pancreatic disease if  small intestinal disease is present    Low values may occur in normal subjects  who ingest little dietary carotene.    May be normal or increased in patients with  untreated lipoprotein abnormality    Lactose absorption (lactose tolerance  test or breath hydrogen after lactose  load)    May be abnormal in all categories if patient  has primary intestinal lactase deficiency;  requires normal gastric emptying    Requires normal gastric emptying; false-  positive results may occur in patients with  rapid small intestinal transit    Lower sensitivity in infants and all ages in  mild disease, false negative results in IgA  deficiency   stool may be loose or formed but is usually pale, greasy, often  bulky, and has a characteristic rancid odor. Sudan stain of a  spot stool sample for fat is a simple and useful screening test  for steatorrhea. Although some fat is present in normal stool  the number and size of fat droplets are markedly increased if  there is substantial steatorrhea. Quantitative determination of  fat in a pooled 48- or 72-hour stool collection, although cum-  bersome, remains the definitive test for steatorrhea. Ideally  the patient should be placed on an 80-100-g fat diet for a day  or two before the stool collection is begun and maintain that  intake throughout the collection period. Unabsorbable fat,  such as mineral oil, Olestra, and fat-based suppositories must  be avoided. The collection should be refrigerated until assay  to minimize bacterial metabolism of long-chain fatty acids.  Excretion of more than 8-9% of fat intake connotes steator-  rhea. The collection should be weighed so that stool fat con-  centration can be calculated; a stool fat concentration over  9.5% suggests intraluminal maldigestion whereas a stool fat  concentration less than 9.5% suggests mucosal disease as  intestinal fluid secretion and malabsorptions of other nutri-  ents dilute stool fat in the latter situation.   Measurements of the pancreatic enzyme, elastase, in the  stool assayed using a polyclonal enzyme-linked immunosor-  bent assay (ELISA) is useful for detecting severe pancreatic  exocrine deficiency, but its role in detecting milder disease  is less clear due to its lack of sensitivity. The secretin/  cholecystokinin stimulation test, although cumbersome and  rarely done nowadays, remains the gold standard for detect-  ing pancreatic insufficiency (see Chapter 26).   Stool samples should be evaluated for ova and parasites  and for specific parasitic antigens in patients with suspected  malabsorption, especially if diarrhea is present. Several pro-  tozoal diseases, including giardiasis, cryptosporidiosis,  microsporidiosis, and Isospora belli infection, can produce  significant malabsorption.   Bo-Linn GW, Fordtran JS. Fecal fat concentration in patients with  steatorrhea. Gastroenterology. 1984;87:318-322. [PMID: 6735076]   Simko V. Fecal fat microscopy. Acceptable predictive value in  screening for steatorrhea. Am J Gastroenterol. 1981;75:204-208.  [PMID: 7234842]   2. Blood studies — Abnormalities in the formed elements of  the peripheral blood are quite common in patients with dis-  eases that produce malabsorption. Anemia is common.  Diffuse lesions of the proximal intestine as occur in celiac  sprue or Whipple disease interfere with iron absorption and  folate absorption resulting in microcytic (iron deficiency or  blood loss), macrocytic (folate or B 12 deficiency), or dimor-  phic anemia (combined iron and folate deficiency). Ileal  resection or severe ileal disease as well as intraluminal bacte-  rial overgrowth and, rarely, severe pancreatic exocrine insuf-  ficiency interfere with vitamin B 12 absorption and may  produce macrocytic anemia. Concomitantly, serum iron sat-  uration, serum ferritin, iron, folate, and B 12 levels are decreased.  Normocytic anemia may reflect acute or subacute blood   loss as may occur in Crohn disease, intestinal lymphoma, or  Whipple disease. Peripheral leukocytosis is unusual but the  differential count may reveal eosinophilia in eosinophilic  enteritis or some parasitic diseases or profound lymphopenia  in patients with intestinal lymphangiectasia. Thrombocytosis,  if present, may reflect hyposplenism, which occurs in some  adults with celiac sprue.   A number of other blood chemistries and serologies may  be abnormal and may provide clues that malabsorption is  present, and in some instances, help define a specific diagno-  sis. Low serum carotene and cholesterol are nonspecific indi-  cators of fat malabsorption but the serum carotene also largely  reflects recent dietary carotene intake. Low serum calcium in  patients with malabsorption may reflect poor absorption in  mucosal disease, intraluminal formation of insoluble calcium  soaps by interaction with unabsorbed fatty acids, as well as  coexistent vitamin D deficiency, all resulting in fecal wastage  of calcium. Low serum calcium may also accompany hypoal-  buminemia, especially in patients with mucosal disease or  lymphangiectasia, causing exudative enteric protein loss. The  prothrombin time may be prolonged as vitamin K is fat solu-  ble, but in the absence of liver disease, the international nor-  malized ratio (INR) should normalize following intravenous  vitamin K replacement. Levels of immunoglobulin A (IgA)  anti-tissue transglutaminase or IgA antiendomysial antibody,  or both, should be obtained if celiac sprue is suspected.   D-xylose absorption test may help to differentiate malab-  sorption caused by small intestinal mucosal disease from  malabsorption due to impaired intraluminal digestion or  lymphatic obstruction. This pentose sugar requires no intra-  luminal processing and is absorbed by facilitated diffusion.  After administration of a 25-g dose orally to a well-hydrated  patient, 5 g or more are normally excreted in the urine over  5 hours and blood levels should reach 25 mg/dL 2 hours after  the test dose. Low urine excretion and blood levels suggest  disease of the mucosa of the proximal small intestine such as  celiac sprue. However, the test has significant limitations. It is  dependent on normal gastric emptying and normal renal  function; delayed gastric emptying will lower both urine  xylose excretion and blood xylose levels giving a potentially  false positive result; impaired renal function will reduce  urine xylose excretion but not blood xylose levels in the face  of normal gastric emptying. Ascites and edema may result in  sequestration of absorbed xylose and produce a false-positive  test result. Additionally, in patients with bacterial overgrowth  in the proximal small intestine, the xylose absorption test  may be positive as some bacterial species metabolize xylose.  To screen for intestinal lactase or, less commonly, sucrase  deficiency, either breath hydrogen excretion or blood glucose  can be measured following an orally administered test dose  of lactose or sucrose. Determination of breath hydrogen  excretion has virtually supplanted measurement of blood  glucose when testing for lactase deficiency because of its sim-  plicity and because no venipuncture is needed. If lactose is   malabsorbed, it travels to the distal small intestine where the  bacterial flora metabolize the sugar releasing hydrogen,  which is excreted by the lungs and can be readily measured  in the breath. After a test dose of 2 g/kg (25 g maximum) a  rise of less than 10 parts per million (PPM) is normal  whereas a rise to 20 PPM suggests lactase deficiency.  Limitations include impaired gastric emptying, chronic pul-  monary disease, recent antibiotic usage, or absence of hydro-  gen-producing bacteria, all of which reduce breath hydrogen  excretion potentially giving rise to falsely negative results. On  the other hand, proximal small bacterial overgrowth may  result in a false-positive result, causing hydrogen release  before the sugar can be normally absorbed. Disaccharidase  enzyme levels can also be directly measured biochemically if  fresh mucosal biopsy tissue is available for this purpose;  however, this is rarely done in the clinical setting today. It is  important to emphasize that neither oral absorption tests  nor hydrogen breath tests, nor direct measurement of disac-  charidase enzymes in mucosal tissues, distinguishes primary  enzyme deficiency from secondary enzyme deficiency caused  by other disease processes that damage the epithelium  mucosa of the small intestine.   Several substrates have been used in breath tests to screen  for small intestinal intraluminal bacterial overgrowth. These  include 14 C-xylose, glucose, and lactulose. In all instances, the  presence of bacteria in the proximal small intestine should  result in rapid bacterial metabolism of the sugars and hence  appearance in the breath of 14 C0 2 after 14 C-xylose and of  hydrogen after glucose as well as early peak breath hydrogen  levels after lactulose administration. Under normal circum-  stances, lactulose is not metabolized until it reaches the dis-  tal ileal and colonic flora, resulting in later peak hydrogen  levels, whereas glucose and xylose are fully absorbed in the  proximal intestine before there is opportunity for bacterial  metabolism. All three tests have significant limitations.  Delayed gastric emptying, rapid small intestinal transit,  absence of hydrogen-producing colonic flora, and significant  pulmonary disease all reduce sensitivity or specificity when  compared with the gold standard for diagnosing intralumi-  nal bacterial overgrowth, namely, quantitative culture of an  aspirate of proximal jejunal intraluminal contents.   Abdelshaheed NN, Goldberg DM. Biochemical tests in diseases of  the intestinal tract: their contribution to diagnosis, manage-  ment, and understanding the pathophysiology of specific disease  states. CritRev Clin Lab Sci. 1997;34:141. [PMID: 9143817]   Craig RM, Ehrenpreis ED. D-xylose testing. / Clin Gastroenterol.  1999;29:143-150. [PMID: 10478874]   Thomas PD, Forbes A, Green J, et al. Guidelines for the investiga-  tion of chronic diarrhoea, 2nd edition. Gut. 2003;52(Suppl 5):  1-15. [PMID: 12801941]   4. Imaging Studies — Various imaging studies are available  to help clarify the nature of pancreatic and hepatobiliary dis-  ease that may cause or contribute to intestinal malabsorption.  These include endoscopic retrograde cholangiopancreatography   (ERCP), magnetic resonance pancreatography (MRCP),  abdominal computed tomography (CT), abdominal magnetic  resonance imaging (MRI), and abdominal and endoscopic  ultrasonography. They are discussed in some detail in  Chapter 9 of this text.   For many years, conventional barium contrast studies of  the small intestine were the standard for evaluating the gross  structure of the small intestine in suspected or proven malab-  sorption. However, both sensitivity and specificity of the con-  ventional small intestinal contrast series are low. Sensitivity,  especially for detection of focal lesions, can be improved by  utilizing double-contrast enteroclysis performed by instilling  both barium and carboxymethyl cellulose into the duodenal  lumen and fluoroscopically following the contrast material as  it transits the small intestine. However, enteroclysis is labor  intensive and results in substantial exposure of the patient to  radiation. More recently, computed tomographic enterogra-  phy (CTE), where available, is very promising for detecting  small intestinal abnormalities. CTE is performed with inges-  tion of a large volume of neutral contrast material after which  and both sagittal and cross-sectional images are obtained.  This technique has been especially useful in the evaluation of  patients with Crohn disease but, as experience with this  method increases, it should also be useful in assessing the  length of remaining small intestine in patients after major  intestinal resections and in the detection of focal abnormali-  ties such as intestinal strictures and neoplasms, including lym-  phoma. MRI enterography is also being evaluated but at this  writing, data are insufficient to compare sensitivity and speci-  ficity with those obtained using CTE.   5. Endoscopic and biopsy studies— Visualization of the  mucosal surface of the small intestine within the reach of the  endoscope allows the detection of abnormal gross mucosal  surface features. These include the diminution and scallop-  ing of mucosal folds, absence or apparent blunting of villi  (common in celiac sprue), and whitish-appearing dilated  lymphatic lacteals within villi commonly found in Whipple  disease and intestinal lymphangiectasia. However, both the  sensitivity and specificity of such endoscopic findings is  low. Rather, the greatest contribution of direct endoscopy  to the evaluation of patients with malabsorption is its facil-  itation of mucosal biopsy under direct vision. As indicated in  Table 20-4, some diseases, such as Whipple disease, amyloi-  dosis, and giardiasis are associated with a specific lesion and  biopsy is often diagnostic. Other diseases are characterized  by histologic features that, although abnormal, lack speci-  ficity and require additional clinical information for a defin-  itive diagnosis. However, even when the biopsy specimen is  not in and of itself diagnostic, it is often of great value as it  establishes unequivocally the presence of mucosal disease.  The definitive diagnosis is then established by additional  diagnostic studies or by a response to specific therapy.   Because intestinal malabsorption may occur in a number  of diseases in which mucosal involvement may be patchy (see  Table 20-4), multiple biopsy specimens should be obtained   Table 20-4. Information provided by mucosal biopsy of the small intestine.   b. Mycobacterium avium-intracellulare enteritis: similar to Whipple disease but bacilli are acid fast   • Patchy infiltration of lamina propria with mast cells, eosinophils, and neutrophils   • Amyloid in lamina propria and submucosa, often in blood vessel walls, shown with Congo red stain and polarized light   • Coccidial forms on surface of (cryptosporidiosis) or within (Isospora) absorptive cells   3. Disorders in which biopsy result is abnormal but not diagnostic   b. Refractory sprue: histology indistinguishable from celiac sprue; immunocytochemistry may show abnormal lELs   • Mucosal architecture from nearly normal to flat mucosa (as in celiac sprue)   e. Intraluminal bacterial overgrowth: may be normal or indistinguishable from mild to moderate tropical or celiac sprue lesion.   from several sites in the distal duodenum or proximal  jejunum. Samples of luminal fluid can also be obtained at the  time of endoscopy, facilitating the diagnosis of parasitic infes-  tation such as giardiasis and coccidioses and, if sophisticated  culture facilities are available, intestinal intraluminal bacterial  overgrowth.   Wireless capsule endoscopy using a swallowed camera that  transmits color images of reasonable quality of the mucosal  surface as it tumbles through the gastrointestinal tract is a rel-  atively new modality for imaging of the intestinal mucosa,  including that of the mid and distal small intestine (see  Chapter 33). It has been particularly useful in detecting focal  lesions, especially among patients with gastrointestinal bleed-  ing of previously unknown cause. Like direct endoscopy, it  also provides useful views of the gross structure of the  mucosa and detects the fold scalloping, flat mucosa and dis-  tended lymphatic lacteals when these lesions are well devel-  oped. A limitation of capsule endoscopy is that it provides no  tissue for pathologic evaluation. Hence, its ultimate role in the  diagnosis of intestinal malabsorption remains to be estab-  lished. The capsule camera may cause intestinal obstruction if  tight strictures are present; hence, it must be used with cau-  tion in patients with suspected malignancy or Crohn disease  unless the absence of strictures has previously been documented  by other imaging techniques.   2006;4:1193-1198. [PMID: 16979950]  Fine KD, Schiller LR. AGA technical review on the evaluation and   Delivery of adequate amounts of pancreatic lipase, colipase,  proteases, and amylases as well as bicarbonate into the prox-  imal intestine are essential for normal intraluminal digestion  of dietary lipids, proteins, and complex carbohydrates.  Pancreatic reserve is substantial, and significant malabsorp-  tion generally does not occur unless there is 85-90% reduc-  tion in pancreatic enzyme secretion. The diagnostic and  clinical ramifications of chronic pancreatic insufficiency are  discussed in detail in the chapters that deal with pancreatitis  (see Chapter 25) and pancreatic neoplasms (see Chapter 28).  As described earlier, determination of stool fat concentration  (see Table 20-3) is useful in distinguishing malabsorption  caused by pancreatic insufficiency resulting in impaired  intraluminal digestion from malabsorption caused by  mucosal disease. In malabsorption caused by pancreatic disease,   tests of mucosal absorption, such as oral tolerance tests and  intestinal mucosal structure as assessed by biopsy and imaging  studies, are usually normal unless there is coexisting mucosal  disease.   Delivery of bile salts into the proximal intestinal lumen is  essential for normal dispersion and intraluminal digestion of  dietary lipids prior to their absorption by the intestinal  mucosa. Hence, hepatobiliary disease that reduces signifi-  cantly bile salt synthesis and delivery of bile salts into the  proximal intestinal lumen causes significant malabsorption  as does fecal bile salt loss caused by ileal disease or resection  sufficient to deplete the circulating bile salt pool. (See the dis-  cussion of "short bowel syndrome," later.)   With the recognition of gastric Helicobacter pylori coloniza-  tion as a cause of peptic ulcer disease, the development of  histamine-2 (H 2 ) blockers and proton pump inhibitors for  therapy of peptic ulcer disease, and endoscopic interven-  tional techniques to control ulcer bleeding, the need for sur-  gical intervention to treat peptic ulcer disease has diminished  strikingly in recent decades. However, occasionally patients  still require surgery to control ulcer bleeding and others  require partial or total gastric resection for malignancy, vas-  cular compromise, or gastric infections. Hence, a pool of  individuals at risk for malabsorption after gastric surgery  persists. The risk of significant malabsorption correlates with  the extent of alteration of normal anatomy. Thus, the risk is  greatest after total gastrectomy and progressively decreases  after partial gastrectomy and gastrojejunal anastomoses  (Billroth II), antrectomy and gastric duodenal anastomoses  (Billroth I), vagotomy, and pyloroplasty and is virtually non-  existent after selective proximal vagotomy.   Several mechanisms may cause malabsorption after gas-  tric surgery, and treatment varies depending on the causes  (Table 20-5). The most common has been termed "poor  mixing and poor timing." Rapid gastric emptying coupled  with decreased release of secretin and cholecystokinin results  in suboptimal exposure of the nutrient bolus to both bile  salts and pancreatic enzyme as it traverses the small intestine.  This diagnosis is made after excluding more treatable causes  of postgastrectomy malabsorption.   Intraluminal bacterial overgrowth should be excluded as  a cause of postgastrectomy malabsorption. Reduced acid  secretion and intraluminal stasis, especially in patients with  an afferent loop following total gastrectomy or a Billroth II  operation, are predisposing causes.   Recurrent ulcer disease, especially in patients who have  undergone a gastrojejunostomy, may cause a gastrocolic or  jejunocolic fistula. Reflux of colonic contents into the gastric  remnant and proximal intestine through the fistula results in  massive bacterial overgrowth. As intracolonic pressure  exceeds intrajejunal pressure, a barium enema is the diag-  nostic procedure of choice as infused barium will flow  through the fistula into the proximal bowel, bypassing the    Vitamin B 12 absorption tests, breath tests,  cultures of luminal contents   distal small intestine. Control with antibiotics is usually  unsuccessful and further surgery is indicated to correct the  cause of the recurrent ulcer and to remove or repair the fistula.   Severe malabsorption immediately after surgery has been  reported if a surgeon inadvertently creates a gastroileostomy  rather than a gastrojejunostomy. Fortunately, such surgical  misadventure is very rare and treatment is surgical revision  of the anastomoses.   Malabsorption of specific vitamins and minerals may  occur. For example, calcium and vitamin D malabsorption  may result in osteopenia and iron malabsorption may result  in anemia, especially among those in whom the duodenum  and proximal jejunum have been bypassed. Vitamin B 12 mal-  absorption may result from major gastric resections or atro-  phy of the remaining gastric mucosa. Specific therapy for  these deficiencies should be provided as indicated.   Lactose intolerance may be aggravated or first become  evident after gastric surgery due to rapid delivery of lactase-  containing nutrients into the small intestine. Treatment with  supplemental lactase or low lactose dairy products is usually  effective.   Celiac sprue is a T- cell-mediated gluten intolerance in genet-  ically predisposed individuals in whom exposure to wheat,  barley, or rye induces a characteristic mucosal lesion that  responds to dietary gluten withdrawal. With the increase in  availability during the past 15 years of reliable serologic  screening tests, it has become evident that the disease is far  more common than was previously appreciated. Whereas  the disease is rare among those of Chinese, Japanese,  Korean, and African heritage, it occurs in 0.3-1.0% of  Caucasians of European extraction. Symptoms may initially   present at virtually any age, ranging from infancy (upon addi-  tion of gluten-containing cereal to feedings) to late adulthood.   Genetic factors and altered immune function both play a  major role in the pathogenesis of celiac sprue. The disease  has a prevalence of 8-12% in first-order relatives (parents,  children, and siblings) of affected individuals. Concordance  is approximately 70-85% among identical twins, and  approximately 30% among HLA-identical siblings. Ninety to  95% of affected individuals carry the HLA-DQ2 het-  erodimer; the vast majority of the remaining 5-10% carries  the HLA-DQ8 heterodimer.   Because of their high proline content, the proteins in  wheat, barley, and rye resist intraluminal proteolytic diges-  tive processes. This results in the accumulation of large pep-  tide fragments, some of which have been shown to damage  the mucosa of individuals with celiac sprue both in vivo and  in vitro. Intestinal antigen-presenting cells from individuals  with celiac disease expressing HLA-DQ2, or HLA-DQ8,  can present these dietary gluten peptides in their antigen-  binding grooves to and thus activate gluten peptide-specific  mucosal T lymphocytes. Once activated, the T lymphocytes  release T helper- 1 cytokines that likely contribute to the  development of mucosal damage.   More recently evidence has been obtained that activation  of the innate immune system may participate in the patho-  genesis of celiac sprue in concert with the acquired immune  system. Up regulation of mucosal interleukin-15 expression  during gluten exposure ultimately imparts natural killer  cell-like properties to the lymphocytes residing among the  mucosal epithelial cells (intraepithelial lymphocytes [IELs]),  resulting in epithelial damage and increased mucosal perme-  ability. This, in turn, facilitates the exposure of mucosal anti-  gen-presenting cells to toxic gluten peptides and the resulting  T-cell activation of the adaptive immune response.   The clinical spectrum of celiac sprue is very broad. In those  with a mild lesion involving only the proximal small intes-  tine, the disease may be completely silent with no evident  clinical manifestations. In others with a lesion limited to the  proximal intestine selected nutrient deficiencies, which may  include iron, folate, or calcium, may be present with result-  ant anemia or osteopenia but with no significant gastroin-  testinal symptoms. On the other hand, if a more severe lesion  extends to the more distal intestine, panmalabsorption with  gastrointestinal symptoms, including weight loss, diarrhea,  excess flatus, and abdominal discomfort, may all be present  in concert with evidence of involvement of other systems  (see Table 20-2). Clearly, the severity of the mucosal lesion  and the extent of the intestinal involvement by the lesion are  key factors in the clinical presentation of any given patient.   Laboratory findings, like the clinical manifestations, may  vary enormously depending on extent of disease, ranging  from no abnormalities or only isolated iron or folate defi-  ciency to multiple abnormalities including steatorrhea,  hypoalbuminemia, hypoprothrombinemia, hypocalcemia,  and so on (see Table 20-3). Elevated serum transaminase  levels may be the presenting finding in some patients with  celiac sprue.   To correctly diagnose celiac sprue, the clinician obviously  must suspect that the disease may be present. This is simple  enough in those in whom gastrointestinal symptoms and  malabsorption are obvious. It is more of a challenge if only  subtle symptoms or a nonspecific laboratory abnormality is  present. Such patients are often diagnosed as having irritable  bowel syndrome, unexplained osteopenia, or unexplained  iron deficiency or folate deficiency anemia. A high index of  suspicion is essential for the correct diagnosis of the many  patients who present with subtle findings.   Serologic tests are useful screening tests for celiac sprue.  Either the IgA anti-tissue transglutaminase test (tTGA) or  the IgA antiendomysial antibody test (EMA) are useful and  have reported sensitivities of 80-95% and specificities of  95-99%, although recent reports suggest somewhat lower  sensitivities and specificities in nonresearch settings, espe-  cially among patients with mild or silent disease. Both tests  measure the autoantibody directed against the enzyme, tis-  sue transglutaminase. Tissue transglutaminase is found in  many body tissues including the intestinal mucosa. Whereas  the role of the autoantibody in the pathogenesis of celiac  sprue is unknown, tissue transglutaminase itself deaminates  toxic gluten peptides facilitating their presentation to T lym-  phocytes by mucosal antigen-presenting cells.   Both conventional tTGA and EMA measure IgA class  antibodies; therefore, some false-negative tests are inevitable  as the prevalence of selective IgA deficiency among celiac   sprue patients is 2-4%. Thus, if an anticipated positive test is  reported as negative, the serum IgA levels should be quanti-  tated. IgG-tTGA and IgG-EMA can be determined but, in  limited studies, the sensitivity of these tests appears lower  than that of their IgA counterparts.   Mucosal intestinal biopsy of the distal duodenum or  proximal jejunum, coupled with a clinical response to the  dietary withdrawal of gluten, remains the gold standard for  the diagnosis of celiac sprue. Because dietary gluten with-  drawal is a lifetime commitment with substantial cost and  social liability, a diagnostic trial of a gluten-free diet should  not be undertaken without first obtaining biopsy evidence  consistent with celiac sprue. Villi may be blunted or the  mucosal surface may appear to be flat with complete absence  of villi (Plate 21). Crypts are hyperplastic, with increased  numbers of mitotic figures. Surface absorptive cells are dam-  aged and infiltrated by increased numbers of IELs (Plate 22).  There is also extensive infiltration of the lamina propria by a  lymphoplasmacytic infiltrate. The mucosal lesion, although  characteristic, is not specific. Other diseases that may have  similar clinical manifestations and may have similar mucosal  histology include refractory sprue, tropical sprue, viral gas-  troenteritis (especially when caused by rotavirus in children),  intraluminal bacterial overgrowth, and eosinophilic gas-  troenteritis. Hence, a clinical response to gluten withdrawal  is a crucial step in establishing the diagnosis.   The role of HLA testing in celiac sprue is limited. It is of  value in patients with atypical features or incongruent sero-  logic and biopsy results for excluding celiac sprue. The absence  of either HLA-DQ2 or HLA-DQ8 makes the likelihood of the  diagnosis extremely low (< 2%). On the other hand, the test is  expensive and detection of either of these haplotypes is of no  direct diagnostic value as they are present in approximately  25% of Caucasians of European heritage.   Abrams JA, Brar P, Diamond B, et al. Utility in clinical practice of  immunoglobulin A anti-tissue transglutaminase antibody for  the diagnosis of celiac disease. Clin Gastroenterol Hepatol.  2006;4:726-730. [PMID: 16630760]   Trier JS. Diagnosis of celiac sprue. Gastroenterology. 1998;115:  211-216. [PMID: 9649477]   The cornerstone of treatment of celiac sprue is the elimina-  tion of products containing wheat, barley, and rye from the  diet (Table 20-6). There is convincing evidence that at least  moderate quantities of oats (50 g/day) are well tolerated by  celiac patients, but some brands of commercially available  oats may be contaminated with wheat and other cereal grains  during processing and shipping. Hence, it is wise, at least ini-  tially, to avoid oats unless obtained from a reliable source  that is known to supply oats free of other contaminating  cereal grains. Many other dietary carbohydrates including  rice, corn, potatoes, and soybeans are well tolerated by celiac  patients. Micronutrient deficiencies including iron and folate   • Read all labels of processed foods, be suspicious of all additives  such as hydrolyzed vegetable protein   • Replace all deficient micronutrients with specific supplements as  needed (calcium, iron, folate, vitamins)   deficiencies should be treated. If osteopenia is present (bone  density should be determined) calcium and vitamin D should  be prescribed.   Although implementation of a gluten-free diet sounds  simple, it is not. Wheat is ubiquitous in the Western diet and  is particularly hard to spot in processed foods such as ice  cream, sauces, and candies. For example, an additive as  benign sounding as "hydrolyzed vegetable protein" is often  derived from wheat and therefore may be rich in gluten.  Hence, counseling by a knowledgeable dietician and physi-  cian as well as participation in local celiac lay support groups  are important facets in the education of celiac patients and  facilitation of long-term dietary compliance.   If diarrhea and steatorrhea are present, lactose restriction  may be needed initially as clinically significant secondary lac-  tase deficiency is often present. However, dairy products are  a good source of many nutrients, including calcium and pro-  tein, and should be encouraged as symptoms disappear  unless primary lactase deficiency is also present. Pure oats  from a reliable source can be added if desired by the patients  once symptoms have cleared with gluten withdrawal. Dietary  compliance should be monitored on follow-up visits every  6-12 months. A repeat serologic test (IgA-tTGA or IgA-  EMA) is helpful 6-10 months after initiation of gluten with-  drawal as the antibodies disappear in fully compliant celiac  patients. With those exceptions and perhaps an annual  hemoglobin or hematocrit and stool for occult blood, no  other specific follow-up beyond routine medical care is  needed in the absence of symptoms and signs.   By and large, the prognosis of patients with celiac sprue is  excellent. There is a higher incidence of lymphoma, especially  of the T-cell type, among celiac patients (see Figure 9-15).  But the risk is greatest among symptomatic patients who  have had many years of gluten exposure. In contrast, the risk  is very low among those with latent or silent disease. Most of  the celiac sprue-associated lymphomas that do develop  occur in the intestine but lymphoma at distant sites may also  develop. There is increasing evidence that strict adherence to  a gluten-free diet substantially reduces the risk of subsequent  lymphoma development. Screening for lymphoma is not  recommended unless suggestive symptoms develop. The   incidence of small intestinal, esophageal, and pharyngeal car-  cinomas may also be increased in celiac sprue but available  evidence is less convincing than for lymphomas.   Rarely, celiac patients develop recurrent symptoms while  adhering strictly to a gluten-free diet. Then, thorough evalua-  tion is needed to exclude other gastrointestinal diseases such  as lymphoma, refractory sprue (see next section), micro-  scopic colitis, and irritable bowel syndrome (Table 20-7).   Given the known high prevalence of celiac sprue in first-  order relatives or patients with the disease, all immediate  family members should be screened for celiac sprue. The  prevalence of celiac sprue also is high in several other condi-  tions, many of which are associated with autoimmunity  (Table 20-8). Although studies of the cost-effectiveness of  screening for celiac sprue in these diseases are limited, evi-  dence that persistent gluten ingestion increases the risk of  malignancy and that clinical manifestations of celiac sprue  are often subtle yet damaging (eg, osteopenia) provides a  strong argument for increased serologic screening.   Rostom A, Murray JA, Kagnoff MF. American Gastroenterological  Association (AGA) Institute technical review on the diagnosis  and management of celiac disease. Gastroenterology. 2006;131:  1981-2002. [PMID: 17087937]   The clinical picture and small intestinal mucosal histology of  refractory sprue mimics that of severe celiac sprue.  Generalized malabsorption and its complications and a  severe mucosal lesion of the intestine with blunted villi or  absent villi, crypt hyperplasia, mucosal inflammation, and  increased IELs are all present. However, unlike celiac sprue,  there is no or, at best, an incomplete response to dietary  gluten withdrawal. Some patients initially respond like clas-  sical celiac sprue patients to gluten withdrawal and have  serologic tests that are consistent with celiac sprue and then,  after months or years, become refractory to gluten with-  drawal. Others are refractory to gluten elimination at presen-  tation and lack the serologic markers of celiac sprue even  before a trial of gluten withdrawal. In all, other potential  causes for the symptoms, including poor dietary compliance  or other diseases such as lymphoma, tropical sprue, intralu-  minal bacterial overgrowth, and eosinophilic enteritis, must  be excluded as refractory sprue is a diagnosis of exclusion.   There are two major categories of refractory sprue. In the  first, the expanded population of IELs consists of phenotypi-  cally normal polyclonal T cells. Many patients in this category  improve with corticosteroids or other immunosuppressive  treatment. Gluten withdrawal should also be maintained. Oral  budesonide should be tried first and systemic corticosteroids or  other immunosuppressant agents such as azathioprine should  be reserved for those who fail budesonide, given the need for  long-term treatment and potential side effects. In the second  category, epithelial cell interleukin-15 overexpression pro-  motes the emergence of clonal populations of phenotypically  aberrant IELs which may represent prelymphoma. These  abnormal T cells express CD3 in their cytoplasm but fail to  express surface CD3, CD8, or the T-cell receptor for (3-chain.   The prognosis is guarded for all patients with refractory  sprue. Many patients develop intractable nutritional defi-  ciencies requiring long-term parenteral alimentation that  may lead to complicating infections. The prognosis is most  dismal for those in the second category, many of whom  progress to T-cell lymphoma.   Cellier C, Cerf-Bensussan N. Treatment of clonal refractory celiac  disease or cryptic intraepithelial lymphoma: a long road from  bench to bedside. Clin Gastroenterol Hepatol. 2006;4: 1320-1321.  [PMID: 17110301]   Primary small intestinal lymphoma is uncommon in devel-  oped countries, occurring most often in middle-aged men  with focal involvement and with a predilection for the ileum.   As primary focal intestinal lymphomas are not usually asso-  ciated with malabsorption, they will not be considered fur-  ther in this chapter. In contrast, two variants of small  intestinal lymphoma regularly cause malabsorption, IPSID-  associated lymphoma and enteropathy-associated T-cell lym-  phoma (EATL).   IPSID occurs primarily in young adults among native  Middle-Eastern populations as well as in South Africa and  Pakistan. It is exceedingly rare in more industrialized  nations. Its cause is unknown but as IPSID occurs where  hygiene is poor, it has been suggested that bacteria or other  antigens cause excessive proliferation of lamina propria  immunocompetent cells and that poor nutrition in the at-risk  population plays a permissive role. In the early stages of the  disease there is diffuse infiltration of the mucosa and submu-  cosa with B lymphocytes and plasma cells. As the disease pro-  gresses the infiltrating cells develop histologically malignant  characteristics and mesenteric nodes become involved.  Clinical features include anorexia, weight loss, diarrhea, steat-  orrhea, and abdominal pain. As the disease progresses edema,  ascites and hepatic splenomegaly and palpable abdominal  masses may become evident.   A distinctive laboratory feature found in the majority of  patients with IPSID and IPSID-associated lymphoma is the  presence of a paraprotein consisting of the Fc portion of IgA,  devoid of light chains, that migrates as a broad band on pro-  tein electrophoresis in the 0c2 and |3 regions.   Early in the disease before frankly malignant cells are  observed, prolonged treatment (6 months or more) with  antibiotics such as, tetracycline, ampicillin, and metronidazole  has induced prolonged remission and even cures. Hence, this  stage of the disease has been likened to H py/ori-associated  gastric early mucosa-associated lymphoid tissue (MALT)  lymphomas. If the process fails to respond to antibiotics, or  once frank lymphoma has been established, either by endo-  scopic biopsy or staging laparotomy, combination chemother-  apy with or without radiotherapy and nutritional support are  the only therapeutic options as the extent of intestinal  involvement usually precludes surgical resection.   EATL is a complication of celiac sprue, as mentioned ear-  lier in the chapter. It occurs primarily in patients over the age  of 50 years who have had prolonged gluten exposure and  symptomatic celiac sprue although occasionally celiac sprue  may be undiagnosed until the initial presentation of EATL.  Clinical deterioration in a patient with established celiac  sprue despite strict compliance with a gluten-free diet or fail-  ure of a patient recently diagnosed with celiac sprue to  respond to a strict gluten-free diet should raise suspicion and  trigger further diagnostic evaluation (see Table 20-7).  Symptoms and signs are similar to those seen in IPSID and  include anorexia, weight loss, diarrhea, steatorrhea, and  abdominal pain. Rarely, perforation with resultant peritoni-  tis may occur. Useful studies include push enteroscopy with  mucosal biopsies from multiple levels of the small intestine,  capsule endoscopy, conventional abdominal CT, and CTE. If  suspicious lesions are detected or if results of studies are negative   but the suspicion of EATL is high, laparoscopy or laparotomy  with full-thickness small intestine biopsies and mesenteric  lymph node biopsies must be considered.   The prognosis is dismal. With few exceptions, responses  to intensive chemotherapy have been transient. Recently,  autologous stem cell transplantation following intensive  chemotherapy has shown some promise but further studies  are needed.   Catassi C, Bearzi I, Holmes GK. Association of celiac disease and  intestinal lymphomas and other cancers. Gastroenterology.  2005;128:S79-86. [PMID: 15825131]   Salem PA, Estephan FF, Immunoproliferative small intestinal  disease: current concepts. Cancer J. 2005;11:374-382.   Tropical sprue occurs among natives of, visitors to, and ex-  patriots from selected countries located, by and large,  between the Tropic of Cancer and the Tropic of Capricorn.  Major epidemics have been described in south Indian vil-  lages. Sporadic cases seen in the United States are largely  among immigrants and returning tourists and visitors from  the Caribbean or tropical Asia. The cause of tropical sprue  remains obscure, but its epidemiology and its response to  antibiotic therapy strongly suggest that colonization of the  intestine by an infectious agent or alterations in the intestinal  bacterial flora induced by the exposure to another environ-  mental agent is important. It must be stressed that no single  causative agent has been identified.   Clinical symptoms and signs are nonspecific and include  diarrhea, steatorrhea, weight loss, nausea, and anorexia.  Anemia is common and most often megaloblastic, reflecting  vitamin B 12 or folate deficiency, or both, although coexistent  iron deficiency may result in a dimorphic anemia. Mucosal  biopsy of the small intestine reveals a nonspecific lesion of  variable severity. Architectural changes range from minimal  villous blunting to complete absence of villi. Lamina propria  mononuclear cells are increased as are IELs. Thus, the histo-  logic lesion cannot be distinguished with certainty from that  observed in celiac sprue, viral gastroenteritis, or intraluminal  bacterial overgrowth. As there is no specific diagnostic test  for tropical sprue the diagnoses relies on excluding celiac  sprue and other diseases such as protozoal infections, which  can cause similar symptoms and are also endemic to the  tropics where sanitation may be suboptimal.   Recommended treatment includes an antibiotic such as  tetracycline and high-dose folic acid. The optimal duration  of treatment is unclear, although 1 month appears to be suf-  ficient for most travelers and expatriates. Treatment lasting  6 months to 1 year is recommended for chronically ill residents  in the tropics. Specific nutritional deficiencies such as  vitamin B p and calcium deficiencies should also be cor-  rected. The response to treatment is usually prompt; hence,  the prognosis with proper treatment is excellent although  relapses occurring months to years after treatment have been   noted. It has been suggested that overall the response among  those with tropical sprue acquired in the Caribbean is more  predictable than that observed among those with tropical  sprue acquired in Asia, but rigorous comparative studies are  not available and this perception may be confounded by the  presence of other causes of gastrointestinal symptoms  among Asian populations.   Eosinophilic gastroenteritis is a relatively uncommon, poorly  understood disease characterized by infiltration of the stom-  ach, small intestine, or colon with mature eosinophils and, in  about 80% of those affected, pronounced peripheral  eosinophilia. About 50% of patients have a history of signif-  icant atopy or specific food intolerances. The pathogenesis is  poorly understood. Presumably, chemokines such as  eotaxin- 1 and eotaxin-2 recruit eosinophils to the gut where  they are activated to release proinflammatory mediators,  including major basic protein, eosinophilic peroxidase,  eosinophilic cationic protein, and leukotrienes, but the initi-  ating trigger is not known. Deposits of eosinophilic major  basic protein have been noted in the intestinal mucosa.   Three major patterns of eosinophilic infiltration can gener-  ally induce distinctive clinical features although the features  are not necessarily syndromic and there may be substantial  overlap. The most common is associated with mucosal and  submucosal eosinophilic infiltration most pronounced in the  small intestine. Characteristic clinical features of this subset  include diarrhea, steatorrhea (usually mild), abdominal pain,  nausea and, in some cases, vomiting. Iron deficiency and  hypoalbuminemia associated with protein-losing enteropa-  thy may be present. Imaging of the small intestine may reveal  small bowel wall thickening and mucosal nodularity.   The second pattern is associated primarily with submu-  cosal and visceral muscle wall eosinophil infiltration some-  times sufficient to produce mass lesions evident on imaging  studies of the stomach, small intestine, and, rarely, colon.  Obstructive symptoms may accompany the abdominal pain.  These findings may mimic those of malignancy.   The third and least common pattern, in which there is pri-  marily serosal and subserosal eosinophilic infiltration, is asso-  ciated with ascites containing large numbers of eosinophils as  well as with abdominal discomfort and diarrhea.   The diagnosis rests on the histologic demonstration of  visceral eosinophil infiltration or eosinophilic ascites and the  exclusion of other entities that produce eosinophilia and gas-  trointestinal symptoms. These include parasitic disease, food  or drug hypersensitivities, mastocytosis, polyarteritis nodosa,   Churg-Strauss syndrome, lymphoma, inflammatory bowel  disease, and the hypereosinophilic syndrome. In patients with  mucosal involvement of the small intestine, eosinophilic infil-  tration is often patchy and the mucosa from adjacent areas  can be normal or can closely resemble the lesion observed in  celiac sprue. Hence, multiple biopsies should be obtained at  endoscopy from several intestinal levels. Even then, while the  observation of extensive eosinophilic infiltration helps to  establish the diagnosis, its absence does not exclude it given  the patchy nature of mucosal involvement. Correct diagnosis  is especially important in patients with muscle wall  eosinophilic infiltration mimicking malignancy and may  require full-thickness biopsy at laparoscopy or laparotomy to  avoid unnecessary radical resective surgery.   coexistent splenomegaly, or peptic ulcer disease, the latter  caused by mast cell histamine release, should arouse suspi-  cion and facilitate the diagnosis of symptomatic intestinal  mast cell disease. Serum tryptase concentration and urinary  histamine secretion are elevated. Small bowel imaging stud-  ies reveal an infiltrative pattern with thickened or nodular  folds. Increased mast cells and eosinophil infiltration of the  mucosa and submucosa in biopsy specimens are diagnostic if  present in the appropriate clinical setting.   Sodium cromoglycate, ketotifen, oral prednisone, H 2 -  blockers, and low-dose aspirin have been reported as being  beneficial in relieving diarrhea, abdominal pain, and other  symptoms but treatment is empiric as suitable controlled tri-  als are lacking.   Treatment with corticosteroids is remarkably effective in the  majority of patients regardless of the pattern of clinical pres-  entation. Hence, the overall prognosis in this disease is very  good. Usually sustained symptomatic remission is induced  with a 2-4 week course at moderate corticosteroid dosages  (prednisone, 20-40 mg/day) followed by a gradual taper. A  minority of patients may relapse and require repeated courses  of corticosteroids. A few unfortunate patients require contin-  uous steroid maintenance or fail to respond to corticos-  teroids. Whereas dietary avoidance of poorly tolerated foods  is obviously desired, elimination diets based on skin sensitiv-  ity and radioallergosorbent testing have been disappointing  in that sustained responses are uncommon. There are anec-  dotal reports of responses to oral cromolyn, ketotifen, and  montelukast in some but not all refractory patients.   Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID).  J Allergy Clin Immunol 2004;113:11-28. [PMID: 14713902]   Given the multiple forms of systemic mastocytosis and its  diverse clinical features, comprehensive discussion of the dis-  ease is beyond the scope of this chapter and the focus will be  on the small intestinal involvement, which may produce  malabsorption.   In selected patients with systemic mastocytosis there is  extensive infiltration of the intestinal mucosa and submu-  cosa with mast cells, occasionally in the absence of the obvi-  ous skin lesions usually associated with this disease. The mast  cell infiltration can be focal or quite diffuse. In and of itself it  may produce malabsorption and can contribute to the gas-  trointestinal symptoms, which may include weight loss, diar-  rhea, steatorrhea, nausea, vomiting, and abdominal pain.  Release of mediators such as prostaglandin D 2 from local or  distant mast cells may increase motility, contributing to diar-  rhea, malabsorption, and abdominal discomfort.   The presence of classic skin manifestations of mastocyto-  sis, including dermatographia and urticaria pigmentosa,   The small intestine and colon are especially susceptible to the  acute effects of radiation, given the rapid renewal rate of  their epithelia. Radiation inhibits epithelial cell renewal in  the exposed intestine. In the small intestine and colon this  results in true mucosal atrophy with decreased villus and  crypt height in the small intestine and decreased crypt height  in the colon and the rectum. In addition, substantial mucosal  inflammation occurs in the mucosa of both organs that lie  within the field of radiation. Although the damaged segment  of the small intestine is functionally impaired, clinically evi-  dent malabsorption is unusual as there is sufficient unex-  posed small intestine to compensate and the mucosal lesion  heals rapidly once radiation exposure ceases. On the other  hand, diarrhea and hematochezia are common features of  the colitis and proctitis that accompanies radiation therapy.  These symptoms also remit promptly, in most instances,  after radiation therapy has been completed.   In contrast, the delayed effect of radiation therapy to the  intestine can cause serious debilitating disease and may man-  ifest months to many years after radiation exposure. The  threshold dose is in the range of 4000-5000 cGY and is influ-  enced by associated risk factors, including concomitant  chemotherapy and prior surgery causing fixation of the intes-  tine in the radiation field through adhesions, and by radiation  technique. An obliterative endarteriolitis of submucosal arte-  rioles develops producing fibrosis, strictures, fistula forma-  tion, and telangiectasias and ulceration of the overlying  mucosa largely on an ischemic basis. Malabsorption develops  in some patients due to (1) bacterial overgrowth caused by  stricture-induced stasis and impaired motility if there is neu-  romuscular involvement, (2) bile salt deficiency if ileal involve-  ment is severe, (3) lymphatic obstruction, or (4) enterocolic  fistula formation.   Symptoms include diarrhea, abdominal pain, melena,  and hematochezia. Strictures may produce partial or even  complete intestinal obstruction with nausea, vomiting, and  painful abdominal distention. Imaging studies such as CT or  MRI enterography, barium enema, and small intestinal series  help to characterize the extent of disease and localize the site   of stricture but the images may resemble closely the features  of other ischemic or inflammatory lesions. If the involved  intestine is within the reach of an endoscope, biopsy is usu-  ally diagnostic with demonstration of the endarteriolaritis,  fibrosis, and the presence of bizarre-appearing submucosal  fibroblasts.   Overall, treatment is disappointing. If there is associated  bacterial overgrowth caused by stasis and strictures, treat-  ment with broad-spectrum antibiotics as detailed in the  later section dealing with that entity is often beneficial. If  ileal disease is present, bile salt-binding resins may reduce  the bile salt-induced diarrhea but may also aggravate steat-  orrhea by further reducing the bile salt pool. Supportive  measures such as polymeric dietary supplements containing  medium-chain triglycerides or even parenteral nutrition  may be needed. Dilation of strictures within endoscopic  reach may be helpful.   Surgery should be reserved for severe intestinal or  colonic strictures and enterocolic, enterovesical, or rec-  tovesical fistulas. Surgery is associated with substantial mor-  bidity because the compromised circulation of the affected  bowel interferes with normal healing. For bleeding rectal  and colonic telangiectatic lesions, laser or argon plasma  coagulation is often helpful, but treatments used for idio-  pathic inflammatory bowel disease including local or oral  corticosteroids or 5-aminosalicylate are of little or no bene-  fit. Radiation enteritis and colitis are often progressive;  hence, the prognosis is guarded.   Bismar MM, Sinicrope FA. Radiation enteritis. Curr Gastroenterol  Rep. 2002;4:361-365. [PMID: 12228037]   Intestinal amyloid deposits are most often seen among  patients with secondary amyloidosis (AA type) but have also  been noted among patients with primary amyloidosis (AL  type) and dialysis-associated amyloidosis (P 2 -microglobulin  retention). Several mechanisms may contribute to the mal-  absorption that may accompany intestinal amyloid deposi-  tion. Neuromuscular infiltration results in impaired motility  predisposing to intraluminal bacterial overgrowth. Vascular  infiltration may induce small vessel ischemia. In advanced  disease mucosal amyloid deposits may impair enterocyte  function and diffusion of absorbed nutrients to the mucosal  vasculature and lymphatics.   Symptoms and signs include weight loss, abdominal dis-  tention, diarrhea, and steatorrhea. Protein-losing enteropa-  thy may produce edema and ascites. The diagnosis should be  suggested by the presence of illnesses known to be associated  with secondary amyloidosis, involvement of other organs  (such as nephrotic syndrome), or a history of chronic dialy-  sis. Imaging studies suggesting intestinal stasis and pseudo-  obstruction or mucosal infiltrative disease are helpful.  Demonstration of amyloid deposition by biopsy of the large  or small intestine is definitive. Congo red stains should be   Treatment of secondary amyloidosis should be directed at  the underlying cause to minimize progression or even induce  improvement. Bacterial overgrowth, if present, should be  treated with antibiotics. Other treatment of malabsorption is  generally supportive, with dietary and, if needed, parenteral  supplements.   Hayman SR, Lacy MO, Kyle RA, et al. Primary systemic amyloido-  sis: a cause of malabsorption syndrome. Am J Med. 2001;111:  535-540. [PMID: 11705429]   Whipple disease is an unusual and uncommon systemic  infectious disease with protean clinical manifestations. The  small intestine is almost always involved, producing malab-  sorption in the majority of patients. Although the disease  was described in 1907, the role of bacterial infection in its  pathogenesis was not recognized until more than 50 years  later. Identification, culture, and molecular characterization  of the organism, the actinobacter Tropheryma whipplei, was  finally achieved two decades ago.   Despite characterization of T whipplei, many aspects of  the pathogenesis of Whipple disease remain enigmatic. There  is evidence that T whipplei is widely present in the environ-  ment yet the scarcity of the disease and the lack of docu-  mented person-to-person transmission is most unusual for a  disease that is caused by an infectious agent. Host factors no  doubt play an important pathogenic role as suggested by a  two- to threefold increase in the frequency of HLA-B27 anti-  gen among affected individuals. There is some evidence of  altered macrophage function and activation but, interest-  ingly, little to suggest increased susceptibility to other infec-  tions among successfully treated Whipple disease patients.   As suggested above, the clinical features may include virtually  any of the body's organ systems. In the classic presentation,  gastrointestinal symptoms are usually striking and resemble  those seen in other diseases with generalized malabsorption.  Weight loss, diarrhea, steatorrhea, and abdominal distention  are present in 80-90% of patients, and both peripheral edema  reflecting hypoproteinemia from protein-losing enteropathy  and poor nutrition are common. Fever is present in 30-50%  of patients and occasionally is the sole presenting symptom.  Arthralgia and arthritis occur in 60-75%, often involving  multiple joints and often preceding the onset of gastrointesti-  nal symptoms by months to even years. Patients with Whipple  disease may present with extraintestinal symptoms in the  absence of or overshadowing gastrointestinal manifestations.  In addition to the joint symptoms mentioned earlier, central  nervous system symptoms such as cognitive deterioration,  ophthalmoplegia, hypothalamic dysfunction, or ataxia may   be the presenting complaints. In other patients, cardiac man-  ifestations, including pericarditis and culture-negative endo-  carditis, or pleuropulmonary involvement, including pleural  effusions, cough, and sarcoid-like pulmonary infiltrates, may  be the initial manifestations.   In addition to the physical findings characteristic of malab-  sorption, skin hyperpigmentation, peripheral lymphadenopa-  thy, cardiac murmurs, signs of arthritis, and neurologic  abnormalities may be present. Anemia with or without occult  gastrointestinal bleeding, hypoalbuminemia, and hypocal-  cemia are relatively common.   The diagnosis is established by demonstration of T whip-  plei in involved tissues by microscopy together with the char-  acteristic infiltration of periodic acid-Schiff (PAS)-positive  macrophages (Plate 23). Electron microscopy reveals the  characteristic bacteria in the mucosa. Biopsy of the mucosa  of the proximal intestine is the procedure of choice because  the small intestinal mucosa is involved in the vast majority of  patients. Care must be taken to exclude Mycobacterium avium  infection in immunocompromised patients, which mimics  the intestinal histologic features of Whipple disease but can  easily be distinguished with Ziehl-Nielson staining, as M avium  is acid fast whereas T whipplei is not. Alternatively, polymerase  chain reaction (PCR) amplification of involved tissues can be  used for diagnosis. Indeed, parallel use of mucosal microscopy  and PCR has recently been recommended for definitive  diagnosis.   Empiric treatment with antibiotics results in prompt  improvement in most patients and in permanent cure in  many. Because of the danger of central nervous system  involvement even in the absence of symptoms, use of antibi-  otics that penetrate the blood-brain barrier is desirable. One  recommended regimen is ceftriaxone, 2 g/day for 2 weeks  followed by twice daily trimethoprim, 160 mg, and sul-  famethoxazole, 800 mg, for 1-3 years, but trimethoprim-  sulfamethoxazole alone has been successful in most patients.  Replacement therapy to correct specific nutritional deficien-  cies is also indicated.   The overall prognosis in the absence of central nervous  system involvement is excellent, although patients should be  carefully monitored indefinitely for signs of relapse that may  occur years after apparently successful treatment.   Fenollar F, Puechal X, Raoult D. Whipple's disease. N Engl J Med.  2007;356:55-66. [PMID: 17202456]   Crohn disease patients with extensive ileal involvement,  extensive intestinal resections, enterocolic fistulas, and stric-  tures leading to small intestinal bacterial overgrowth may  develop significant and occasionally devastating malabsorp-  tion, (see Chapter 3).   In this rare autosomal-recessive disease, mutations in the  gene encoding microsomal triglyceride transfer protein  results ultimately in absence of apoprotein B and apoprotein  B-containing lipoproteins in the circulating blood.  Absorptive cells of the small intestine are packed with huge  lipid droplets reflecting the impaired export of lipid from the  epithelium following its uptake from the gut lumen.   The disease is usually evident in infancy or childhood  when diarrhea and steatorrhea are noted. Acanthocytic red  blood cells, reflecting their altered membrane lipid content,  appear early whereas the onset of retinitis pigmentosa and  neurologic manifestations, including ataxia, tremors, periph-  eral neuropathy, and nystagmus, appear later in childhood or  adolescence in untreated patients. Laboratory features in  addition to acanthocytosis and steatorrhea include absent  serum (3-lipoproteins and very low serum cholesterol,  triglycerides, and, in untreated patients, low levels of vitamin  E and other fat-soluble vitamins.   Although specific treatment of the genetic defect is not  available, prompt institution of high-dose oral vitamin E and  A replacement at an early age markedly attenuates and some-  times prevents the development of the retinal lesions and the  neurologic complications. Other fat-soluble vitamins  should also be replaced. Cautious substitution of long-chain  dietary fats with medium-chain triglycerides can be tried to  improve nutrition, but in a few individuals cirrhosis has been  attributed to medium-chain triglyceride use.   Gregg RE, Wetterau IR. The molecular basis of abetalipoproteine-  mia. Curr Opin Lipidol. 1994;5:81-86. [PMID: 8044420]   Whereas mild infestation of the intestine with Strongyloides  stercoralis usually causes no symptoms, heavy infestation  may induce fever, nausea, vomiting, weight loss, abdominal  pain, and steatorrhea. The clinical picture may resemble  tropical sprue but eosinophilia is usually evident in severe  infestations. If stool studies are negative, duodenal aspira-  tion is indicated. A highly specific ELISA serology is avail-  able but may remain positive for years after parasitic  eradication and may be negative in immunocompromised  hosts. Ivermectin is the most effective therapy; in severe  infestations it can be combined with albendazole for greatest  efficacy.   Giardia and coccidial infestation produces malabsorp-  tion. These protozoal infestations are discussed in Chapter 5.   The terminal phase of digestion of ingested complex carbo-  hydrates such as starch as well as disaccharides, including lac-  tose, sucrose, maltose, fructose, and trehalose, occurs at the   brush border membrane of intestinal absorptive cells where  glycoprotein enzymes including lactase, sucrase-isomaltase,  fructase, and trehalase are located. Deficiency of any of these  enzymes or defects in the monosaccharide transport process  produces retention of unabsorbed sugars in the gut lumen.  These, if present in sufficient quantity, produce osmotic diar-  rhea and flatulence, the latter caused by intraluminal bacter-  ial fermentation of the unabsorbed sugars. Ingestion of  nonabsorbable sugars such as sorbitol, used to sweeten  dietary foods, or of excessive amounts of carbonated bever-  ages may cause symptoms in some individuals.   Congenital disaccharidase deficiencies and monosaccha-  ride transport defects are uncommon and produce symp-  toms in infancy upon introduction of the offending  carbohydrate into the diet. In adults, isolated acquired lactase  deficiency is the most common cause of carbohydrate intol-  erance. Low mucosal lactase levels are observed in 5-20% of  adult North American and Western European Caucasians,  50-95% of African Americans and Africans, 50% of  Hispanics, and over 90% of Asians. The diagnosis is sug-  gested by a history of the induction of diarrhea, abdominal  discomfort, and flatulence following the ingestion of dairy  products or other foods rich in lactose. However, as these  symptoms lack specificity it is not uncommon to ascribe the  symptoms of another clinical entity, such as irritable bowel  syndrome, to lactase deficiency. The diagnosis is confirmed  by the lactose breath hydrogen test. An alternative is the oral  lactose intolerance test.   Diseases that are associated with substantial mucosal  damage such as celiac sprue may produce clinically signif-  icant carbohydrate intolerance caused by impaired  mucosal digestion and absorption of carbohydrates. Unless  the individual also has isolated acquired lactase deficiency,  carbohydrate digestion and absorption should normalize as  the mucosa heals with effective therapy of the underlying  disorder.   Treatment of carbohydrate intolerance consists of  decreasing or removing the offending carbohydrate from  the diet. For lactase deficiency, reduction of dietary lactose  by limiting dairy products and lactose-rich baked or  processed foods is usually sufficient. A completely lactose-  free diet is rarely necessary. Indeed, elegant studies have  demonstrated unequivocally that most individuals with iso-  lated acquired lactase deficiency can tolerate moderate  amounts of lactose, (the equivalent of 8 oz of milk twice  daily) in their diet. Alternatively, commercially available lac-  tase preparations can be ingested in concert with lactose-  containing foods or foods pretreated with lactase can be  utilized. Supplemental calcium and vitamin D should be  recommended if there is significant dietary restriction of  dairy products.   Suarez FL, Savaiano DA, Arbisi P, et al. Tolerance to the daily inges-  tion of two cups of milk by individuals claiming lactose intoler-  ance. Am J Clin Nutr. 1997;65:1502-1506.   DISEASES CAUSED BY IMPAIRMENT OF BOTH  INTRALUMINAL INGESTION & MUCOSAL  DIGESTION/ABSORPTION   Under normal circumstances the proximal small intestinal  lumen harbors less than 10 3 bacteria per milliliter of intes-  tinal contents, most of which are derived from the oropha-  ryngeal flora. The major mechanisms limiting excessive  bacterial growth in the proximal intestine are normal intes-  tinal motor function and normal gastric acid secretion.  Secretion of immunoglobulins into the gut lumen also  inhibits proximal bacterial proliferation. The presence of any  condition that interferes with these protective mechanisms,  notably impaired intestinal motility, structural lesions pre-  disposing to intestinal stasis, profound reduction or absence  of gastric acid secretion, and immunodeficiency syndromes  may precipitate SIBO (Table 20-9).   Several mechanisms contribute to the malabsorption that  develops in SIBO. Normal bile salts secreted by the liver are  conjugated to glycine or taurine and are absorbed by a spe-  cific active transport process in the distal ileum. In SIBO, the  bacteria deconjugate the bile salts. The more lipid-soluble  deconjugated bile salts are absorbed in the proximal gut by   passive nonionic diffusion resulting in their decreased avail-  ability intraluminal!/. Moreover, the deconjugated bile salts  are poorly soluble at the normal intraluminal pH and are less  effective detergents, resulting in less effective intraluminal  dispersion of dietary lipids for absorption. Additionally, the  bacteria produce proteases and glycosidases and, in some  instances, toxins that damage the epithelium, especially  brush border hydrolases. The resulting mucosal damage may  produce an inflammatory mucosal lesion contributing to the  impaired absorption. Finally, within the gut lumen, the bac-  teria bind and metabolize vitamin B 12 preventing its absorp-  tion in the distal ileum.   The clinical features of SIBO that are caused by the bacterial  overgrowth are typical of those seen in other malabsorptive  states, with weight loss, diarrhea, steatorrhea, flatulence, and  abdominal distention being common. Extraintestinal mani-  festations may be prominent. If the condition has persisted  long enough to deplete vitamin B 12 stores, megaloblastic ane-  mia and neurologic manifestations identical to those  observed in pernicious anemia may develop. In addition, a  spectrum of additional symptoms, such as abdominal pain,  nausea, and vomiting, may reflect the primary disease process  predisposing to SIBO.   Quantitative culture of the duodenal fluid is the diagnos-  tic gold standard for documenting SIBO but is not generally  available, as the fastidious growth requirements of the gut  flora require the use of multiple media and growth condi-  tions. Breath tests utilizing lactulose, xylose, and glucose are  reasonable surrogates but are subject to limitations described  earlier in this chapter. If there is no ileal disease the two-stage  radiolabeled vitamin B 12 absorption test (Schilling test) is  helpful if available; the bacteria impair absorption both of  free vitamin B 12 and intrinsic factor-bound vitamin B [2 ;  hence urinary excretion is low. Tissue retrieved by small  intestinal mucosal biopsy may range from normal histology  to a severe but nonspecific lesion with villus blunting, crypt  hyperplasia, damaged absorptive cells, and substantial  mucosal inflammation.   If a correctable lesion such as a gastrocolic fistula or a dis-  crete intestinal stricture is the cause of SIBO, surgical repair  is the treatment of choice. If SIBO is associated with chronic  motor abnormalities, achlorhydria, or noncorrectable  anatomic abnormalities such as multiple jejunal diverticula,  antibiotics are the treatment of choice. Some patients respond  to amoxicillin-clavulanate alone; others require broader cov-  erage with the addition of metronidazole. Promising  responses have been obtained with rifaximin, a poorly  absorbed antibiotic. A single 2-week course of therapy may  effect a prolonged remission in some patients; others require   frequent intermittent courses of antibiotics when sympto-  matic or even continuous treatment for maximum benefit.  Use of prokinetic agents has shown little or no benefit. As  with all diseases associated with malabsorption, nutritional  deficiencies, including vitamin B p deficiency, should be  corrected.   Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles  of antibiotics, prebiotics, and probiotics. Gastroenterology.  2006;130:S78-S90. [PMID: 16473077]   The small intestine has sufficient reserve so that resection of  50% is well-tolerated provided that the duodenum and prox-  imal jejunum and the distal 100 cm of the ileum are not  removed and are free of disease. Resection of smaller lengths  that include the proximal or distal segments often produce  symptoms and signs related to their selective absorptive  functions (iron, folate, and calcium malabsorption for the  proximal intestine and bile salt and vitamin B 12 malabsorp-  tion for the distal ileum). On the other hand, resection of  70-80% of the small intestine often produces catastrophic  malabsorption with massive diarrhea and steatorrhea, espe-  cially if the distal ileum, ileocecal valve, and colon have been  lost. Factors contributing to the malabsorption include the  reduction of the available absorptive surface, acid hyper-  secretion that induces intestinal mucosal damage and can  inactive pancreatic lipase, depletion of the bile salt pool, and  SIBO. Conditions that may require small bowel resection of  significant magnitude to result in short bowel syndrome  include vascular catastrophes involving the mesenteric circu-  lation, refractory long-standing Crohn disease, radiation  enterocolitis, and malignant disease.   Prompt and vigorous fluid and electrolyte replacement  based on careful monitoring of losses is essential as is early  implementation of parenteral alimentation with vitamin and  mineral supplements. Early initiation of continuous enteral  feedings is desirable to minimize intestinal mucosal atrophy  and maximize adaptive mucosal hyperplasia. Protein  hydrolysate-based polymeric supplements, which contain  more fat and less carbohydrates and less of an osmotic load,  are usually better tolerated than elemental supplements. Acid  hypersecretion during the early period following massive  resection should be controlled with liberal proton pump  inhibitor administration. Although growth hormone and  glutamine have been advocated to facilitate adaptive changes  in the residual small intestine, their use is controversial due  to conflicting evidence as to their efficacy. Liberal use of  agents to increase intestinal transit time, including lop-  eramide or codeine, and hence contact of nutrients with the  intestinal mucosa is desirable. Octreotide has been beneficial  although tachyphylaxis develops and high doses reduce  secretion of pancreatic enzymes. Transition to oral feedings,  starting with multiple small meals while tapering parenteral   nutrition, is a major goal and is often feasible as intestinal  adaptation progresses over time. In patients in whom adap-  tation is not adequate and long-term parenteral nutrition is  not feasible, small intestinal transplantation is an alternative.  Two-year survival is now in excess of 50% in expert hands  but the shortage of organ donors and relatively few centers  with the requisite surgical skills and experience limit this  option to a selected few.   Buchman AL. Etiology and initial management of short bowel syn-  drome. Gastroenterology. 2006;130:S5-S15. [PMID: 16473072]   DiBaise JK, Young RJ, Vanderhoof JA. Enteric microbial flora, bac-  terial overgrowth, and short-bowel syndrome. Clin Gastroenterol  Hepatol. 2006;4:11-20. [PMID: 16431299]   Patients with Zollinger-Ellison syndrome frequently present  with symptoms and signs of malabsorption, including weight  loss, diarrhea, and steatorrhea in the absence of or overshad-  owing acid peptic symptoms. The massive gastric acid secre-  tion inactivates pancreatic lipase and impairs lipid  emulsification by bile salts resulting in impairment of intra-  luminal lipid dispersion, which is required for efficient  absorption. Moreover, the persistent and intense exposure to  acid damages the mucosa of the proximal small intestine,  impairing absorptive function. Biopsy specimens can demon-  strate a striking architectural lesion with blunting or absence  of villi and profound inflammation of the lamina propria.  Diagnosis requires a high index of suspicion and is estab-  lished by the demonstration of an elevated serum gastrin, a  positive secretin stimulation test, and the presence of a gastri-  noma by imaging studies. Treatment includes inhibition of  gastric secretion with proton pump inhibitors and surgical  resection of the gastrinoma, if feasible (see Chapter 16).   Roy PK, Venzon DJ, Shojamanesh H, et al. Zollinger-Ellison syn-  drome. Clinical presentation in 261 patients. Medicine (Baltimore).  2000;79:379-411. [PMID: 11144036]   Intestinal lymphangiectasia may be primary or secondary.  The primary form usually presents in infancy or childhood  and is associated with focal or diffuse ectasia of the mucosal  intestinal lymphatics, most likely reflecting impaired lymphatic   formation during development. Concomitant defects in lym-  phatics at other body sites such as the extremities support  this concept. Familial clustering of cases suggests a genetic  basis in some. Secondary intestinal lymphangiectasia results  from acquired obstruction of mesenteric or more proximal  lymphatics. Disruption of intestinal lymphatic drainage may  reflect trauma, retroperitoneal fibrosis, neoplasms, infections  such as tuberculosis, congestive heart failure, or severe portal  hypertension. Rupture of the lymphatics result in leakage of  protein and lymphocyte-rich lymph into the gut lumen as  well as impaired transport of dietary lipids to the systemic  circulation by the damaged lymphatics.   Clinical features in both primary and secondary types  include weight loss, growth failure, steatorrhea, and diarrhea  if disease is extensive. Edema, chylous ascites, and chylous  pleural effusions reflect associated protein-losing enteropa-  thy and impaired transport and leakage of dietary lipids.  Helpful laboratory findings include lymphopenia, which  may be striking, and low serum albumin, immunoglobulins,  transferrin, and ceruloplasmin. Increased clearance of otj-  antitrypsin pinpoints the intestinal tract as the source of pro-  tein loss, but the evaluation of the test requires adjustment in  patients with diarrhea; clearance greater than 24 mL/day in  the absence or greater than 56 mL/day in the presence of  diarrhea indicates increased enteric protein loss. Imaging  studies such as CT scan of the abdomen can help to localize  anatomic abnormalities such as fibrosis and adenopathy and  often reveals thickening and edema of the abdominal wall.  Lymphangiography, if available, may localize the site of lym-  phatic obstruction or leakage. Endoscopy may reveal whitish  villi due to distended ectatic mucosal lymphatics. Mucosal  biopsy characteristically shows tall villi, dilated lymphatics,  and mucosal edema but involvement may be patchy; hence,  absence of lymphatic dilation in available biopsy specimens  does not exclude the diagnosis.   Treatment includes reduction of dietary long-chain  triglycerides that stimulate lymph formation, increasing  intralymphatic pressure and predisposing to lymphatic rup-  ture and lymph leakage. Addition of medium-chain triglyc-  eride-containing supplements and use of medium-chain  triglyceride oil benefit nutrition as they are transported in  the portal blood, not the lymphatics. A high-protein diet uti-  lizing supplements as needed helps counter enteric protein  loss. If the responsible disease process involves a limited seg-  ment of the intestine, resection can be beneficial. Likewise, if  a surgically correctable focal obstruction of a major lym-  phatic is found, surgery should be considered. Obviously,  treatment of underlying specific diseases such as retroper-  ineal neoplasm or infection is indicated.   Diverticula are acquired herniations of the colonic mucosa  and submucosa through the muscularis propria. They occur  most commonly in the sigmoid colon and can vary in size  and number, although typically they are between 5 and 10 mm  in diameter. Diverticulosis refers to the presence of divertic-  ula in an individual who is asymptomatic, whereas divertic-  ular disease refers to the presence of diverticula associated  with symptoms, which occurs in 20% of individuals with  diverticula.   Diverticular disease is the most common structural  abnormality of the colon and, in terms of health care expen-  ditures (both direct and indirect costs), it is the fifth most  important gastrointestinal disease in Western countries, rep-  resenting total annual expenditures of over $2.6 billion. It  accounts for almost 2.2 million office visits and for more  than 230,000 hospital admissions annually in the United  States, with a mortality rate of 2.5 per 100,000 per year.   Although diverticula were described as early as 1700,  diverticulosis was uncommon until the 20th century.  Currently, it is estimated that diverticulosis affects less than  5% of people at the age 40, 30% of people by age 60, and  50-65% of people by age 80. An exception to this is in vege-  tarians, in whom the prevalence of diverticula is much lower,  presumably due to diets that are higher in fiber. Men and  women are affected equally. The prevalence and distribution   of diverticula vary throughout the world. Whereas divertic-  ula are common and predominantly left-sided in Western  countries (95% involve the sigmoid colon), in urbanized  areas of Asia, such as Japan, Hong Kong, and Singapore, the  prevalence is only 20% and the diverticula are predomi-  nantly right-sided, even among those who have adopted a  Western-style, low-fiber diet.   Segmentation within the colon is thought to play an impor-  tant role in the development of diverticula. Segmentation  refers to the process by which a short segment of the circular  muscle of the colon contracts in a nonpropulsive manner.  This produces a closed segment of colon with increased  intraluminal pressure, and likely serves to increase water and  electrolyte absorption from the colon. These elevated intra-  luminal pressures may ultimately result in herniation of  the mucosa and submucosa at sites of weakness (namely,  where the vasa recta penetrate the muscularis propria  between the taeniae coli), resulting in the formation of diver-  ticula. Diverticula are not seen in the rectum because the tae-  niae coalesce at the rectum to form the circumferential  longitudinal muscle layer.   The law of Laplace (transmural pressure gradient equals  the wall tension divided by the radius, AP = T/r) may help to  explain why diverticula are so common in the sigmoid colon.  Compared with the remainder of the colon, the sigmoid has  a smaller radius. Because the transmural pressure gradient is  inversely proportional to the bowel radius, it will be highest  at the level of the sigmoid, potentially favoring the formation  of diverticula in this region. Additionally, myochosis (thick-  ening of the circular muscle layer, shortening of the taeniae  coli, and narrowing of the lumen) is seen in most patients  with sigmoid diverticula. These changes result from increased  deposition of collagen and elastin within the taeniae, and not   from hypertrophy or hyperplasia of the bowel wall. In addi-  tion to increasing intraluminal pressure by narrowing the  lumen, these changes may also decrease the resistance of the  colon wall (see below).   Alterations in myoelectrical activity may also contribute to  the development of diverticulosis. The interstitial cells of Cajal  are thought to be responsible for the generation of slow waves.  Extracellular electrodes show that these slow waves corre-  spond to muscle contractions within the colon. Some studies  have shown increased slow-wave activity in patients with  diverticulosis, which could result in increased segmental con-  tractions. However, one study found that there were signifi-  cantly reduced numbers of interstitial cells of Cajal in patients  with diverticulosis, possibly leading to delayed transit.   As individuals age, the tensile strength of the collagen and  muscle fibers of the colonic wall decreases due to increased  cross-linking of abnormal collagen fibers and deposition of  elastin in all layers of the colonic wall. The colonic wall may  be weakened by the breakdown and damage of mature colla-  gen, as well as by the synthesis of immature collagen. This  may also contribute to the creation of more distensible mus-  cle fibers. The importance of structural changes in the  colonic wall is suggested by the early formation of diverticula  in patients with connective tissue disorders, such as Marfan  syndrome, Ehlers-Danlos syndrome, and polycystic kidney  disease.   Collagen fibers vary in conformation throughout the  colon. With increasing age, the collagen fibrils in the left colon  become smaller and more tightly packed compared with  those in the right, changes that are accentuated in diverticular  disease. This may explain why colonic compliance is lower in  the sigmoid colon and descending colon compared with the  transverse and ascending colon, and may also explain why  diverticular disease is more common in the left colon.   Extracellular matrix degradation and remodeling is  mediated in part by matrix metalloproteinases. Activation of  matrix metalloproteinases results in the degradation of the  extracellular matrix, including collagens, noncollagenous  glycoproteins, and proteoglycans. Tissue inhibitors of metal-  loproteinases serve as local regulators by blocking the effects  of matrix metalloproteinases. Patients with diverticular dis-  ease have been shown to have an increase in collagen synthe-  sis, an increase in tissue inhibitors of metalloproteinases, and  a decrease in the expression of a matrix metalloproteinase  subtype that is responsible for the degradation of collagen.  These changes may contribute to the changes in the structure  of the colonic wall seen in patients with diverticulosis.   Patients who have symptoms from uncomplicated diverticu-  lar disease resemble patients with irritable bowel syndrome.  In both groups, visceral hypersensitivity has been demonstrated   in response to rectosigmoid distention. Patients with asymp-  tomatic diverticulosis, however, do not demonstrate increased  pain perception with rectal distention. The visceral hyper-  sensitivity seen in patients with symptomatic diverticular  disease is not limited to areas of the sigmoid with diverticula  and is not associated with altered colonic wall compliance.  This suggests that there is a generalized state of visceral  hypersensitivity in symptomatic diverticular disease that is  similar to that seen in irritable bowel syndrome.   Patients with diverticulosis may exhibit low-grade colonic  inflammation that may resemble inflammatory bowel dis-  ease histologically. Histologic findings include nonspecific  mucosal inflammation, crypt abscesses, a mononuclear cell  infiltrate in the lamina propria, and occasional submucosal  inflammation or granulomas. When these findings are pres-  ent, the term segmental colitis is applied. Possible causes  include ischemia, changes in bacterial flora, mucosal pro-  lapse, and the presence of intraluminal antigens. Segmental  colitis is found in 0.25-1.5% of colonoscopies. In a study  looking at 47 patients with symptomatic diverticular disease  who underwent sigmoid resection, 76% showed histologic  evidence of acute or chronic mucosal inflammation (13%  had evidence of acute diverticulitis on endoscopy). There  was no correlation, however, of the pathologic findings with  the type or duration of symptoms.   The role of fiber in the development of diverticulosis was  first suggested by epidemiologic evidence. Diverticula rarely  develop in rural Asia or Africa (prevalence of < 0.2%), where  diets are high in fiber. However, in areas that have developed  economically and have adopted Western dietary habits,  diverticula become more prevalent. In addition, populations  that have moved from rural to urban environments show an  increased prevalence of diverticulosis.   Higher fiber in the diet leads to increased stool bulk and  decreased colonic transit times. Individuals from countries  with high-fiber diets tend to have larger diameter colons, com-  pared with those from countries with low fiber intake. Having  a larger colonic diameter may impair the segmental contrac-  tions of the colon that lead to higher intraluminal pressures.   The majority of patients with diverticulosis are asympto-  matic, with only 20% developing symptoms over their life  span. Abdominal pain is the most common symptom, and is  usually localized in the left lower quadrant. In patients with  right-sided diverticula, the pain can be felt in the right lower  quadrant. The pain may worsen after eating and in some is  relieved with the passage of stool or flatus. Patients may also   complain of nausea, cramping, irregular bowel move-  ments (intermittent diarrhea or constipation), bloating, and  flatulence.   Patients do not demonstrate abnormal vital signs, such as  tachycardia or fever in uncomplicated diverticulosis. With  palpation of the left lower quadrant, mild tenderness and  voluntary guarding may be present.   In uncomplicated diverticulosis, laboratory values, including  the hematocrit, hemoglobin, and white blood cell count, are  normal and Hemoccult testing of the stool is negative.   Diverticulosis is frequently discovered during colonoscopy as  an incidental finding (Plate 24). Additionally, because disor-  ders such as colorectal cancer, inflammatory bowel disease,  and ischemic colitis are included in the differential diagnosis  for patients with abdominal pain related to diverticulosis,  colonoscopy is the preferred diagnostic study. Colonoscopy,  however, can be difficult to perform in patients with divertic-  ulosis due to narrowing of the colonic lumen and possible  colonic fixation from prior episodes of diverticulitis resulting  in inflammation and pericolic fibrosis. Colonoscopy is rela-  tively contraindicated in patients in whom acute diverticulitis  is suspected, due to an increased risk of colonic perforation.   A double- contrast barium enema will demonstrate the  presence, localization and number of diverticula (Figure 21-1).  If segmental spasm is present, a transient saw-tooth pattern  may be seen. In uncomplicated diverticulosis, there should  be no extravasation of contrast, nor should there be evi-  dence of fistulae, strictures, or persistent spasm, all of  which suggest diverticulitis. Diverticulosis can also be seen  on abdominal computed tomography (CT) with oral or  rectal contrast.    ▲ Figure 21-1. Barium enema showing the presence of  diverticula (arrows).   The nonspecific symptoms of uncomplicated diverticulosis  can mimic many other conditions, and differentiation can  be difficult. Many of the signs and symptoms of sympto-  matic diverticulosis are also seen in irritable bowel syn-  drome. The fact that both disorders are common, and can  coexist, makes differentiation even more difficult. Irritable  bowel syndrome frequently causes diffuse abdominal pain;  thus, pain localized to the left lower quadrant in the setting  of demonstrated diverticula supports a diagnosis of uncom-  plicated diverticulosis.   Mild diverticulitis can also manifest similarly and is not  ruled out by the absence of a fever, elevated white blood cell  count, or other signs of infection. Other pelvic infections,  such as appendicitis and pelvic inflammatory disease, can  also mimic diverticulosis. Other causes of lower abdominal  pain that need to be considered are infectious colitis, inflam-  matory bowel disease, ischemic colitis, colorectal cancer, and  endometriosis.   Diverticulosis can be complicated by acute diverticulitis,  which results from the perforation of a diverticulum, as well  as by hemorrhage, which occurs when the arteriole associ-  ated with the diverticulum erodes.   Most patients with diverticulosis do not require any specific  treatment, and there are no medical treatments that will lead  to the regression of diverticula, once present. The treatment  of patients with recurrent uncomplicated diverticular disease  focuses on relieving symptoms. Therapies used to treat  uncomplicated diverticular disease include fiber-rich diets,  nonabsorbable antibiotics, mesalazine, probiotics, and prebi-  otics. Contrary to popular teaching, there is no strong evi-  dence that seeds, nuts, or popcorn lead to an increase in the  frequency of complications from diverticulosis.   Fiber is slowly or completely fermented by gut microflora,  resulting in the production of short chain fatty acids and gas.  This in turn results in shortened gut transit time, which  reduces intracolonic pressure and helps with constipation.  The recommended daily fiber intake for adults is 20-35 g/day,  and fiber supplements are available to help meet this require-  ment. Supplements contain either soluble fiber (psyllium,  ispaghula, calcium polycarbophil) or insoluble fiber (corn  fiber, wheat bran). Soluble fiber is more readily fermented by  gut microflora, whereas insoluble fiber undergoes minimal  fermentation, and likely exerts its effects by increasing stool  mass and thus increasing the luminal diameter, which in turn  decreases the transmural pressure gradient. (Recall that,  according to the law of Laplace, AP = T/r.) Studies looking at  the effect of high-fiber diets on symptoms from uncompli-  cated diverticular disease, however, have not been conclusive,  with some studies showing a benefit, while others do not.  Despite this, increasing dietary fiber, often with fiber supple-  ments, is currently the mainstay of treating uncomplicated  diverticular disease.   Rifaximin is a broad-spectrum antibiotic that acts by binding  to the (3-subunit of bacterial DNA-dependent RNA poly-  merase. Eighty to 90% of rifaximin remains within the gut.  Although the exact mechanism is unknown, rifaximin has  been shown in a few studies to improve the symptoms of  uncomplicated diverticular disease. Symptom improvement  may be due to the ability of rifaximin to influence the meta-  bolic activity of gut flora that degrade dietary fiber and pro-  duce gas. The drug may also influence the gut flora  responsible for chronic, low-grade mucosal inflammation.  Two studies in which patients were randomized either to  rifaximin plus a fiber supplement or to placebo plus a fiber  supplement for 1 year demonstrated symptom improvement  in those who received rifaximin. In one study, the number of  patients reporting no or only mild symptoms at the end of  the study was 69% in the group that received rifaximin and  39% in the group that received placebo. Another study  showed that in patients treated over the course of 10 years  with rifaximin, 5% had a relapse of symptoms, with 1%  developing complications.   Mesalazine is an anti-inflammatory drug that acts topically  on the gut mucosa and is typically used in the treatment of  inflammatory bowel disease. Because some of the symptoms  of diverticular disease may be related to chronic mucosal  inflammation, mesalazine may have a role in the treatment of  patients with symptoms related to diverticular disease. In a  2004 study, 90 patients were treated with rifaximin plus  mesalazine (800 mg three times daily) for 10 days and then  received mesalazine alone (800 mg twice daily) for another   8 weeks. At the end of the study, 81% of patients reported  being asymptomatic. From this, the investigators concluded  that mesalazine may help to maintain clinical remission.   Probiotics contain microorganisms with beneficial proper-  ties, and the goal in using them is to alter the gut's microflora  to reestablish the normal bacterial flora. Bifidobacteria and  Lactobacilli are used most frequently. Some preparations also  contain other bacteria and nonbacterial organisms, such as  Escherichia coli and Saccharomyces boulardii. In diverticular  disease, the normal bacterial flora may be altered by slowed  colonic transit and stool stasis, so it is theorized that reestab-  lishing normal gut flora may lead to symptomatic improve-  ment. In a study of patients with colonic stenosis following  an episode of diverticulitis, the combination of rifaximin and  lactobacilli for 12 months was effective in preventing symp-  tom recurrence and complications. In a second study, a small  group of patients with uncomplicated diverticular disease  were given an intestinal antimicrobial agent and an  absorbent. That was followed by administration of a non-  pathogenic E coli strain for a mean period of 5 weeks. These  patients showed improvement in all abdominal symptoms.   Prebiotics are substances that promote the growth and  metabolic activity of beneficial bacteria, especially Bifidobacteria  and Lactobacilli. Prebiotics are frequently indigestible com-  plex carbohydrates. Bacteria ferment these substances, lead-  ing to a more acidic luminal environment, which suppresses  the growth of harmful bacteria. Substances that have been  shown to promote the growth of Bifidobacteria and  Lactobacilli include psyllium fiber, lactulose, fructose,  oligosaccharides, germinated barley extracts, and inulin.   Twenty percent of patients with diverticula will develop  symptoms of uncomplicated diverticular disease, while  10-25% of patients with diverticulosis will go on to develop  a complication (75% of whom will have had no preceding  symptoms). Fortunately, most episodes of diverticulitis and  diverticular hemorrhage are self-limited and can be managed  medically. An additional small subset of patients will  develop severe pain and colonic dysmotility. Although not  life-threatening, the symptoms can be debilitating.   Di Mario F, Comparato G, Fanigliulo L, et al. Use of mesalazine in  diverticular disease. ] Clin Gastroenterol. 2006;40:S155-S159.  [PMID: 16885700]   Petruzziello L, Iacopini F, Bulajic M, et al. Review article: uncom-  plicated diverticular disease of the colon. Aliment Pharmacol  Ther. 2006;23:1379-1391. [PMID: 16669953]   Sandler RS, Everhart IE, Donowitz M, et al. The burden of selected  digestive diseases in the United States. Gastroenterology.  2002;122:1500-1511. [PMID: 11984534]   Sands BE. From symptom to diagnosis: clinical distinctions among  various forms of inflammation. Gastroenterology. 2004; 126:  1518-1532. [PMID: 15168364]   Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gas-  trointestinal and liver diseases, 2006. Am } Gastroenterol.  2006;101:2128-2138. [PMID: 16848807]   Simpson J, Scholefield JH, Spiller RC. Origin of symptoms in diver-  ticular disease. Br] Surg. 2003;90:899-908. [PMID: 12905541]   100,000 for 1968-1971. A study from England demonstrated a  16% increase in hospital admissions for diverticulitis among  males, and a 12% increase among females between 1990  and 2000.   Acute diverticulitis can be either complicated or uncom-  plicated. The severity of diverticulitis is often described using  the Hinchey classification, which categorizes diverticulitis  into four stages based on clinical and operative findings.  Modifications of the classification have also been developed  that take into account CT findings (Table 21-1).   First described in 1849, diverticulitis results from the micro-  or macroperforation of a diverticulum, resulting in anything  from subclinical inflammation to feculent peritonitis. It affects  10-25% of patients with diverticulosis and can be associated  with significant complications (abscess, fistula, obstruction,  phlegmon, bleeding or macroperforation). There is a male  predominance in patients younger than 50 years of age, with  equal gender distribution after age 60 years. Hospital admis-  sions for diverticulitis have been increasing. In a study from  Scotland, the rate of hospitalization from diverticulitis  increased from 12.8 per 100,000 for 1958-1961, to 23.5 per   Previously it was thought that diverticulitis was the result of  obstruction of a diverticulum by a fecalith leading to  increased pressure within the diverticulum, with subsequent  perforation. Currently, it is thought that diverticular  obstruction is a rare event, and that most cases of divertic-  ulitis are the result of erosion of the diverticular wall due to  increased intraluminal pressure or inspissated food particles.  This then leads to inflammation and focal necrosis, with  resultant perforation of the thin-walled diverticulum. The  role of increased pressure is supported by the observation  that most perforations occur in the sigmoid colon, where  pressures are the highest. Factors that favor increased colonic  pressures are altered autonomic activity (seen with decreased  exercise and neostigmine), activation of opioid receptors,  and decreased mechanical stretching of the colon due to a  low-fiber diet. Recall that the transmural pressure gradient  decreases with an increase in luminal diameter, which  explains why a decrease in stool bulk is associated with an   Table 21-1. Hinchey classification and modified Hinchey classification of acute diverticulitis.   Adapted, with permission, from Kaiser AM, Jiang JK, Lake JP, et al. The management of complicated diverticulitis and the role of  computed tomography. Am J Gastroenterol. 2005;100:910-917.   increased transmural pressure gradient. (Refer to the law of  Laplace, AP = T/r, discussed earlier.)   Altered microbial composition within the gut, possibly due  to effects on the innate immune system that allow normal  commensal flora to act pathologically, may impair the  mucosal barrier, resulting in chronic low-grade inflamma-  tion. Secretion of mucus and bacterial overgrowth can occur  when food particles become inspissated within a diverticu-  lum. It has also been demonstrated that the composition of  gut flora differs between rural and urban populations. One  study comparing a rural African population with a low  prevalence of diverticulitis to an English population found  that there were lower levels of Bifidobacteria and higher lev-  els of Bacteroides in the English population. The growth of  Bifidobacteria is promoted by soluble fiber, the fermentation  of which leads to the generation of short-chain fatty acids,  the preferred energy source for colonocytes. The increased  production of short-chain fatty acids may aid in maintaining  the colonic barrier.   Nonsteroidal anti-inflammatory medications (NSAIDs) have  been associated with diverticulitis and perforation. In one  study, patients with complicated diverticular disease (defined  as bleeding or perforation) were more likely to have used  NSAIDs than a matched control group from the community  (34% vs 4%). In a second study, 48% of patients with com-  plicated diverticular disease (fistula, extracolonic abscess,  purulent peritonitis, feculent peritonitis, septicemia, portal  pyemia) had used NSAIDs, compared with 20% of patients  with uncomplicated diverticular disease. A third study com-  pared 115 patients with complicated diverticulitis (fistula,  abscess, peritonitis) to 77 with uncomplicated diverticulitis  (peridiverticulitis or an inflammatory mass) and found that  NSAIDs were associated with the severe complications of  peritonitis and abscess formation. The association of NSAIDs  with diverticulitis is postulated to be related to decreased  prostaglandin synthesis and direct topical mucosal damage.  By stimulating mucin and bicarbonate secretion and increas-  ing mucosal blood flow, prostaglandins aid in maintaining  the colonic mucosal barrier. In addition, NSAIDs are weak  acids that may denude epithelial cells, resulting in increased  mucosal permeability, ulceration, and the translocation of  bacteria and toxins.   As previously mentioned, a diet low in fiber may not only  predispose to the formation of diverticula, it may also pre-  dispose to the development of diverticulitis. By increasing  stool weight and water content, fiber helps reduce colonic  segmentation pressures, which may protect against perforation.  Red meat intake has also been associated with diverticulitis.   Heterocyclic amines are products of cooking meat and have  been associated with apoptosis of colonic epithelial cells.  Heme has also been shown to produce a cytotoxic factor in  rat colons. These effects on the colonic epithelial cells may  predispose to perforation.   The data supporting smoking as a risk factor for diverticulitis  are contradictory. In one study, smoking increased the odds  for diverticular complications threefold. A large cohort study,  however, found no association between complicated divertic-  ular disease and smoking. Alcohol, coffee, and caffeine have  not been shown to increase the risk for diverticulitis.   Diverticulitis should be suspected in a patient presenting  with lower abdominal pain, fever, and leukocytosis. In the  West, left lower quadrant pain is the most common com-  plaint (70%). The onset is usually gradual, and the pain may  be present for several days prior to the patient's seeking med-  ical attention. The pain is constant, with intermittent exacer-  bations that are associated with colonic spasms and are  followed by loose bowel movements. Patients may also com-  plain of nausea and vomiting (20-62%), constipation (50%),  diarrhea (25-35%), and urinary symptoms (10-15%).   The patient's presentation is associated with the stage of  disease. The pain is typically localized in patients with  Hinchey stage I and II disease, as the inflammation is con-  fined to the pericolic tissue. Although typically in the left  lower quadrant, in patients with a large sigmoid loop or with  right-sided diverticulitis, it may extend to the mid or right  abdomen. In stage II, patients have developed pelvic, intra-  abdominal, or retroperitoneal abscesses. These patients often  complain of anorexia, nausea, and vomiting. This is espe-  cially common if the abscess is large. Urinary symptoms  (urgency, frequency) can result if the abscess is near the blad-  der. An area of localized tenderness with swelling and ery-  thema of the abdominal wall suggests an underlying abscess  progressing to form a colocutaneous fistula. Patients with  stage III and IV disease have symptoms of generalized peri-  tonitis, including severe, diffuse abdominal pain. Patients  may be reluctant to move. It is common for an ileus to  develop, resulting in bloating, nausea, and vomiting. In stage IV  disease, because free perforation has occurred, the onset of  the pain is often acute and severe.   It is important to remember that patients who are  immunosuppressed (eg, the elderly, those with cancer, HIV  infection, or who have received an organ transplant) are  much more likely to have an atypical presentation.   On examination, tenderness is usually present in the left  lower quadrant, with a tender mass being present in 20%.  Tenderness in the right lower quadrant can result from either   a large sigmoid loop or from right-sided diverticulitis. A low-  grade or high-grade fever is common. Diffuse tenderness  suggests free perforation and peritonitis. Abdominal disten-  tion and hypoactive bowel sounds may be present if an ileus  has developed. In cases of free perforation, hemodynamic  instability may develop, along with a rigid abdomen.   The most common finding is a leukocytosis, but it is not  required to make the diagnosis. In one series, a normal white  blood cell count was noted in 45% of patients. Marked  leukocytosis is suggestive of peritonitis or abscess formation.  Liver function tests are usually normal. The serum amylase is  either normal or mildly elevated. If the amylase is elevated, it  is suggestive of possible peritonitis or a perforation. Severe  episodes may also be associated with hyponatremia,  impaired renal function, and acidosis as a result of sepsis. If  the urinary bladder is involved, pyuria or hematuria may  result, and polymicrobial urinary tract infections can be seen  with a colovesical fistula.   Plain abdominal radiographs are typically normal in patients  with mild diverticulitis, but in the setting of severe disease,  there may be an ileus pattern, or, if obstruction is present,  proximal bowel dilation. A large abscess may be associated  with an air-fluid level on upright films. If there is perforation  into the retroperitoneal space, the psoas shadow may be  obliterated due to air diffusing along the psoas muscle. Free  air under the diaphragm may be seen on upright films in the  setting of intraperitoneal perforation, especially if there is  feculent peritonitis.   Ultrasound is a noninvasive method with limited utility. It  is highly operator dependent, and in the setting of an ileus may  be limited due to distention of the bowel by gas. It may iden-  tify a phlegmon, abscess, or bowel wall thickening. It can be  helpful in guiding the drainage of intra-abdominal abscesses.   Barium enema, although used in the past to diagnose acute  diverticulitis, has largely been replaced by CT scanning.  Findings on barium enema in the setting of acute diverticulitis  include persistent spasm, saw-tooth pattern of the involved seg-  ment, deformed diverticulum, sinus tract or fistula, extravasa-  tion of contrast, abscess, stricture, obstruction, mass effect  from extraluminal compression, and pneumoperitoneum.   CT scanning is currently the radiographic test of choice  for diagnosing diverticulitis. Its sensitivity is as high as 97%  and specificity is reported to be as high as 100%. The follow-  ing findings are seen with diverticulitis: soft tissue density of  the pericolic fat (98%), diverticula (84%), bowel wall thick-  ening of more than 4 mm (70%), and phlegmon or pericolic  fluid (35%). CT scanning is also helpful in classifying  patients as having mild, moderate, or severe disease; in guid-  ing therapeutic decisions; and in diagnosing the complica-  tions of diverticulitis, such as abscess formation, fistula  formation, peritonitis, or obstruction. Because CT scans   cannot reliably exclude cancer, patients who have not previ-  ously had a colonoscopy should have one 6-8 weeks after  their diverticulitis has resolved.   During an acute episode of suspected diverticulitis, rigid  proctoscopy, flexible sigmoidoscopy, and colonoscopy are  relatively contraindicated. This is due to the fact that the  required air insufflation can unseal or worsen a perforation.  However, as mentioned above, patients who have not previ-  ously had a colonoscopy should have one to exclude an  underlying malignancy or other disorder, with a waiting  period of 6-8 weeks following resolution of the episode of  diverticulitis. If an endoscopy is to be performed in order to  differentiate between acute diverticulitis and cancer or colitis  prior to surgery, it should only be attempted by an experi-  enced endoscopist, with minimal insufflation. Findings of  diverticulitis on endoscopy include edema, erythema, stric-  tures, and (rarely) purulent drainage from a diverticulum.  Following resolution of an episode of diverticulitis, endo-  scopic findings are often minimal.   Because of the proximity of the colon to other intra-abdominal  organs, and because of the varied presentations of divertic-  ulitis, many other diagnoses need to be considered. The dif-  ferential diagnosis includes inflammatory bowel disease,  ischemic colitis, infectious colitis, appendicitis, cancer, com-  plicated peptic ulcer disease, pyelonephritis, pelvic inflam-  matory disease, ovarian cyst or torsion, and ectopic  pregnancy. In patients with AIDS and colonic perforation,  cytomegalovirus infection and Kaposi sarcoma should also  be considered.   Complications of acute diverticulitis are seen in 15-20% of  patients and include pericolic or pelvic abscess formation,  perforation with purulent or feculent peritonitis, fistula for-  mation to adjacent organs, colon obstruction, and sepsis.  Fistulas most frequently arise from the sigmoid colon and  involve adjacent organs. The common fistulas are colovesical  fistulas (65%) and colovaginal fistulas (25%). Peritonitis is  associated with a significant mortality rate. Mortality is  approximately 6% if there is purulent peritonitis and 35%  if there is feculent peritonitis.   For patients with uncomplicated diverticulitis, medical ther-  apy is successful in 70-100%. Patients who are candidates for  outpatient therapy have pain that is mild, minimal evidence   of systemic infection, no signs of paralytic ileus, and good  functional status. Inpatient treatment should be considered  for patients with more severe presentations, inability to tol-  erate oral intake, or comorbid illnesses. Additional consider-  ations include the lack of available support, poor patient  reliability, and poor patient comprehension of the indica-  tions for seeking medical attention (fever, worsening pain,  inability to take in adequate fluids). Hospitalization and  intravenous administration of antibiotics is usually recom-  mended for the elderly, immunosuppressed, those with sig-  nificant comorbid illnesses, and those with a high fever or  significant leukocytosis.   Therapy consists of bowel rest and antibiotics. Antibiotic  choice is dictated by the typical bacteria associated with  diverticulitis, namely gram-negative rods and anaerobes.  Single antibiotic coverage using an antibiotic with activity  against colonic flora is as effective as combination therapy.  Examples of treatment regimens are shown in Table 21-2.  The choice of antibiotics should take into account medica-  tion allergies and prior antibiotic use. Antibiotics are typi-  cally given for 7-10 days.   Outpatients should be put on a clear liquid diet, with slow  advancement of the diet once clinical improvement is seen.  Patients who fail to show signs of improvement in 2-3 days,  develop increasing pain or fever, or are no longer able to tol-  erate fluids should be hospitalized and investigated for possi-  ble complications.   Abscesses traditionally were treated with surgery, but with  advances in CT-guided drainage, some patients can be man-  aged with percutaneously placed catheters. Drains are usually  placed through the anterior abdominal wall, although trans-  gluteal, transrectal, or transvaginal approaches are also used  for abscesses deep within the pelvis. Catheters are left in place  until the daily output drops to less than 10 mL, which may  take up to 30 days. Patients who fail to improve with catheter  drainage require surgery.   Fifteen to 30% of patients will require surgery for their first  episode of diverticulitis. Indications for surgery during an  episode of diverticulitis include diffuse peritonitis, obstruc-  tion, and failure of medical therapy. Elective surgery is also  recommended for patients with fistulas, which result from  the spontaneous drainage of an abscess. When this occurs,  the inflammation usually resolves. Fistulas, therefore, are  rarely an indication for emergency surgery.   Whether to perform elective surgery for the 20-30% of  patients with recurrent episodes of diverticulitis is contro-  versial. Based on data from 1969, it was previously recom-  mended that patients undergo elective surgery after two  episodes of uncomplicated diverticulitis. In the 1969 study,  it was noted that 7-45% of patients will have recurrent   symptoms following the first attack of diverticulitis, and that  the response rate to therapy drops with each subsequent  attack, from 70% for the first episode, to 6% for the third  episode. Other more recent studies, however, have failed to  show an increased risk of complications with subsequent  attacks. In a 2005 study of 25,058 patients hospitalized for an  initial episode of diverticulitis, 80% were managed without  surgery, 19% had recurrent diverticulitis and 5.5% under-  went emergent colectomy. The study noted that patients  younger than age 50 were more likely to have a recurrence  (27% vs 17%) and were more likely to require an emergent  colectomy (7.5% vs 5%). It may therefore be more appropri-  ate to individualize recommendations about elective colec-  tomy, instead of recommending surgery for all patients after  two episodes of diverticulitis. For example, patients who live  or work in remote locations or travel to areas where there is  decreased access to health care may be appropriate candi-  dates for elective surgery.   Prior to surgery, all patients should receive antibiotics. If  possible, bowel preparation is carried out, although in emer-  gent situations it often is not feasible. For sigmoid divertic-  ulitis, the proximal resection margin should be in an area of  healthy (soft, nonedematous) colon. The distal resection  margin is in the upper third of rectum, where the taeniae coli  coalesce. If part of the distal sigmoid colon is retained, the  recurrence rate of diverticulitis doubles. It is not necessary to  remove all of the diverticula, because recurrence proximal to  the anastomosis is unlikely.   When time allows for a bowel preparation, a one-stage  procedure can be performed. Most patients with Hinchey  stage I and II disease are able to undergo a bowel preparation  prior to surgery. In a one-stage procedure, the diseased colon  is resected and a primary anastomosis is created. In order to  create a primary anastomosis, the bowel being joined  must be well vascularized, without edema or tension, and  well prepared. Fecal peritonitis and purulent peritonitis are  contraindications to a one-stage procedure, as are poor  nutrition, immunosuppression, and other associated medical  comorbidities.   Patients requiring emergency surgery usually undergo a  two-stage procedure. In the case of sigmoid diverticulitis, in  the first stage, the diseased sigmoid is removed and an end  colostomy and a rectal stump (Hartmann pouch) are created.  An alternative approach is to resect the diseased colon, per-  form a primary anastomosis, and create a diverting colostomy  or ileostomy proximal to the anastomosis. If the diverticulitis  is right sided, the first stage is a right hemicolectomy with for-  mation of an ileostomy and a mucous fistula (a mucous fis-  tula is formed by bringing the distal resection margin through  the abdominal wall). The second stage for all of these surgical  approaches occurs 3 months later, when the colostomy or  ileostomy is taken down and an anastomosis (if not already  created) is formed.   An alternative to a two-stage procedure is an on-table  lavage, in which the colon is lavaged with 3-6 L of warm  saline, with povidone-iodine being added to the last liter of   saline. This allows for resection of the diseased colon with a  primary anastomosis (a one-stage procedure). The infection  rate associated with a one-stage procedure following an on-  table lavage is less than 20%, with an anastomotic leakage  rate of less than 6%.   A three-stage procedure is the classic approach but is  rarely used because of its higher mortality rate (26% vs 7%  for other procedures). In the first stage, the diseased segment  is drained and a proximal diverting stoma is created, but no  resection is carried out. During the second stage, the diseased  colon is resected and a primary anastomosis is created.  Finally, in the third stage, the stoma is closed. The first stage  of the procedure can be carried out to stabilize a patient who  is unstable prior to transfer to a larger medical center, or  when inflammation prevents safe dissection of the ureters or  iliac vessels.   Many surgeons are now employing laparoscopic tech-  niques to carry out the resections.   Patients requiring surgery for free perforation have a mortal-  ity rate of 30% compared with 1 % for those undergoing elec-  tive surgery. Following resolution of an initial episode of  diverticulitis, up to 30% of patients will go on to develop  recurrent diverticulitis. Four to 30% of patients will have  episodic cramps, without clinical signs of diverticulitis, and  30-40% will be asymptomatic. Patients who have recovered  after having peritonitis may develop small bowel obstruc-  tions due to adhesions. Patients with colovesical fistulas may  develop urosepsis, and those with coloenteric fistulas may  develop malabsorption due to bacterial overgrowth or due to  short gut syndrome (as a result of the bypassing of segments  of small bowel). Local irritation of the perineum or abdom-  inal wall skin can be seen with colovaginal and colocuta-  neous fistulas, respectively. These fistulas can also be  associated with fluid losses.   For patients who have undergone a surgical resection,  1.0-10.4% will develop recurrent diverticulitis, with 0-3.1%  requiring an additional resection. Twenty-seven to 33% will  complain of persisting symptoms.   Frattini J, Longo WE. Diagnosis and treatment of chronic and  recurrent diverticulitis. / Clin Gastroenterol. 2006;40:  S145-S149. [PMID: 16885698]   Janes S, Meagher A, Frizelle FA. Elective surgery after acute diver-  ticulitis. Br J Surg. 2005;92:133-142. [PMID: 15685694]   Kaiser AM, Jiang JK, Lake JP, et al. The management of compli-  cated diverticulitis and the role of computed tomography. Am J  Gastroenterol. 2005;100:910-917. [PMID: 15784040]   Korzenik JR. Case closed? Diverticulitis: epidemiology and fiber.  / Clin Gastroenterol. 2006;40:S112-116. [PMID: 16885692]   Morris CR, Harvey IM, Stebbings WS, et al. Epidemiology of per-  forated colonic diverticular disease. Postgrad Med J. 2002;78:  654-659. [PMID: 12496319]   Up to 15% of patients with diverticulosis will develop divertic-  ular bleeding, bleeding that will be massive in approximately  one third of the patients. Mortality rates for massive hemor-  rhage are significant, at 10-20%, in large part because many  patients with diverticular hemorrhage are elderly with comor-  bid illnesses.   Diverticula form at the site of penetration of the vasa recta  through the muscularis propria. Thus, each diverticulum has  an associated arteriole, and mucosa is all that separates the  vessel from the bowel lumen. Over time, due to recurrent  exposure to injury, eccentric intimal thickening and thinning  of the media may develop, leading to segmental weakness,  predisposing the artery to rupture along its luminal aspect.  In 50-90% of patients, the source of bleeding is right-sided  diverticula (despite the fact that 75% of diverticula are  located on the left). This markedly increased propensity for  right-sided diverticula to bleed may occur because right-  sided diverticula have wider necks and domes, so a longer  portion of the vasa recta is exposed to injury. In addition, the  wall of the right colon is thinner, which may also contribute.   Patients typically present with moderate to large amounts of  maroon stool or hematochezia. Clots are more commonly seen  with a distal source, as is bright red blood. Melena may occa-  sionally be seen in cases of right-sided bleeding. The bleeding is  typically painless, although patients may report cramping due  to the cathartic effects of blood within the bowel.   On examination, pallor, tachycardia, orthostatic hypoten-  sion, or shock may be noted with massive hemorrhage.  However, in one study of patients with bleeding demon-  strated on arteriogram, only 30% were tachycardic. The  abdomen may be mildly distended with active bowel sounds.  Rectal examination shows gross blood, which can range from  bright red to melenic. Nasogastric lavage should be considered   Upon initial presentation, a normal hemoglobin is not  uncommon because sufficient time may not have elapsed for  hemodilution and equilibration to have occurred. Low  hemoglobin at presentation is suggestive of either anemia  that predated the bleed, or bleeding that has been present for  hours to days. Once equilibration has occurred, red cell  indices should indicate a normochromic, normocytic ane-  mia. The presence of a hypochromic, microcytic anemia sug-  gests chronic blood loss from another source. Associated  medical conditions or drug therapy may lead to an altered  platelet count, coagulation parameters, or liver function  tests. These conditions, while not responsible for diverticular  bleeding, may contribute to its severity.   Radionuclide scanning using technetium sulfur colloid or  99m Tc pertechnetate-labeled red blood cells can be used to  identify acute bleeding and to localize the site of bleeding  (Figure 21-2). These techniques can detect bleeding at a  rate of 0.1 mL/min. Technetium sulfur colloid has a short    ▲ Figure 21-2. Tagged red blood cell scan demonstrat-  ing bleeding originating in the right upper guadrant  (arrow) along with pooling of the tagged red blood cells  (arrowhead).   half-life and thus can only detect bleeding that occurs  within a few minutes of injection. 99m Tc pertechnetate-  labeled red blood cells, which have a longer half-life and can  be used to detect bleeding up to 24 hours after injection, are  now being used instead of technetium sulfur colloid. This  allows for repeated scanning of patients with intermittent  bleeding over 24 hours. In one series, 99m Tc pertechnetate-  labeled red blood cell scanning demonstrated a sensitivity  of 97% and a specificity of 83% for active bleeding. The  major limitation of radionuclide scanning is that localiza-  tion is imprecise and can only identify an area of the  abdomen where the bleeding is occurring, and not an exact  site. The accuracy of localization ranges from 24% to 91%.  Blood can move from the site of extravasation due to peri-  staltic or antiperistaltic motion, which can lead to inaccu-  rate localization. In addition, because localization is to an  area of the abdomen, and not an area of colon, incorrect  assumptions can be made about localization. For example,  bleeding from a redundant sigmoid colon may incorrectly  be attributed to the right colon. Although radionuclide  scanning does not allow for therapeutic maneuvers, it can  aid in directing subsequent angiography.   An alternative to nuclear imaging is dynamic enhanced  helical CT scan. In a study of five patients, intravenous con-  trast was given, followed by scans at 30 seconds and 5 minutes.  In four of the patients, contrast pooling was detected, and all  studies were completed within 15 minutes.   Angiography has the advantage of being both diagnostic  and therapeutic. It requires a brisker rate of bleeding than  radionuclide scans of 0.5 mL/min. If a prior study has sug-  gested a possible location for the bleed, angiography starts  with the injection of the appropriate feeding vessels.  However, if prior localization is not available, sequential  injection of the mesenteric arteries is performed, starting  with the superior mesenteric artery, because the majority of  bleeds arise from the right colon. If results are negative, the  inferior mesenteric artery, and finally the celiac artery are  studied. Angiography is successful in identifying a source of  bleeding in 14-85% of cases. The success rate is influenced  by both the timing of the study relative to an episode of  active bleeding and by the expertise of the radiologist per-  forming the study. Angiography is 100% specific, but only  47% sensitive for an acute bleed (30% for a recurrent bleed).  Performing a radionuclide scan prior to angiography may  decrease the rate of negative examinations, but this may be  counterbalanced by an increased rate of negative tests  because of the delay introduced by performing the radionu-  clide scan prior to the angiography. If the initial study result  is negative, the angiography catheter can be left in place for a  short period to allow for rapid imaging if rebleeding occurs.  Complications of angiography, which occur in 9% of  patients, include arterial thrombosis, embolization, and renal  failure.   Plain abdominal films are not helpful in identifying a  source of lower gastrointestinal hemorrhage, and barium  enemas are contraindicated because the presence of barium   Colonoscopy is the initial examination of choice in the eval-  uation of lower gastrointestinal bleeding. Like angiography,  it allows for both diagnosis and treatment. Colonoscopy can  be limited, however, by poor visualization due to retained  blood, and by the risks of sedation in an actively bleeding  patient. Although some physicians will perform a  colonoscopy in an unprepared bowel, relying on the cathar-  tic properties of blood to empty the colon, many attempt to  cleanse the colon either with enemas or with polyethylene  glycol. A common regimen is to rapidly administer 4-8 L of  polyethylene glycol, often via a nasogastric tube. A median  dose of 5.5 L over 3-4 hours is needed to cleanse the colon.  Metoclopramide (10 mg intravenously) may help to control  nausea and to increase gastric emptying. Urgent colonoscopy  will lead to a definite or presumptive diagnosis in 74—90% of  patients (50% of these will be diverticular). Although visual-  izing active bleeding is uncommon, a presumptive source can  be identified through the visualization of an adherent clot or  a mucosal lesion. Forty percent of patients with presumed  diverticular bleeds demonstrate stigmata of recent hemor-  rhage, including a bleeding diverticulum, accumulation of  fresh blood after clearing the colon, a nonbleeding visible  vessel at the mouth of a diverticulum, or an adherent clot  that cannot be dislodged with vigorous irrigation.   The differential diagnosis for massive lower gastrointesti-  nal bleeding is broad. Diverticular bleeding is the most com-  mon cause of maroon stool or hematochezia, and accounts  for 42-56% of acute lower gastrointestinal bleeding.  Angiodysplasias are responsible for 20-30% of cases of hema-  tochezia. Colon cancer is the most common cause of lower  gastrointestinal blood loss, but accounts for less than 10% of  lower gastrointestinal hemorrhage. Although most hema-  tochezia results from lower gastrointestinal bleeding, massive  upper gastrointestinal hemorrhage or small bowel hemor-  rhage can also manifest with hematochezia (11% and 9%,  respectively, in one study). Rectal causes of lower gastroin-  testinal hemorrhage include ulcers, radiation proctopathy,  varices, and Dieulafoy lesions. Massive hemorrhoidal bleed-  ing is rare. Rarely, inflammatory bowel disease can result in  massive lower gastrointestinal hemorrhage. Although rectal  bleeding is more common with ulcerative colitis, massive  lower gastrointestinal hemorrhage is more common with  Crohn disease. This observation may stem from the fact that  Crohn disease is a transmural process and thus may involve  larger submucosal vessels. Unlike patients with other causes  of lower gastrointestinal hemorrhage, patients with inflam-  matory bowel disease usually have severe abdominal pain and  tenderness.   Complications of diverticular hemorrhage are the result of  massive blood loss, including death from exsanguination.  Ischemic injuries to the heart, brain, or kidneys are the most  common manifestations, especially in the elderly.   A general treatment algorithm is shown in Figure 21-3. In  75-90% of patients, bleeding stops spontaneously; in those  with a transfusion requirement of less than 4 units/day, the  rate of spontaneous resolution increases to 99%. Initial ther-  apy focuses on resuscitation. Patients should have large-bore  intravenous access, such as a central venous catheter, or two  18-gauge peripheral intravenous lines. Patients should ini-  tially receive saline solutions while blood is cross-matched.   Antiplatelet and anticoagulant agents should be discontin-  ued, if possible. Any coagulopathies should be reversed.  Patients with hemodynamic instability or with underlying  cardiopulmonary disease should receive care in an intensive  care unit.   Endoscopic or angiographic interventions are then  employed in an attempt to provide definitive therapy. If a  bleeding source is identified endoscopically, therapy with  injection of epinephrine (1:10,000 to 1:20,000) followed by  thermal coagulation is recommended; if a nonbleeding visi-  ble vessel is seen, electrocautery alone can be applied. It is  recommended that the multipolar electrocautery probe be  applied to the vessel with mild to moderate pressure. It  should be set at 10-15 watts, and the pulses should last 1-2  seconds. An alternative to electrocautery is the placement of  hemoclips. If an adherent clot is noted, it is recommended  that it be removed after the base is injected with epinephrine.  The clot is then shaved down using a cold guillotine technique.   * Options include repeat endoscopy, angiography, and surgery  ** Possibly preceded by tagged red blood cell scan   The pedicle of the clot, once visualized, should be treated  with electrocautery if active bleeding or a visible vessel is  seen. If the bleeding vessel within a diverticulum cannot be  identified, blind injection therapy with epinephrine can be  carried out, or the mouth of the diverticulum can be closed  with hemostatic clips. It is recommended that a tattoo or a  hemoclip be placed at the site of the bleed in case there is  recurrent hemorrhage requiring either repeat endoscopy or  surgery. Patients treated with electrocautery should be mon-  itored for signs of perforation.   If a bleeding source is identified with angiography, ther-  apy can be carried out. Vasopressin infusion will stop bleed-  ing in up to 91% of patients, but 50% will rebleed when the  vasopressin is stopped. Despite the significant rate of  rebleeding, the use of vasopressin may allow for resuscitation  and preparation for semielective surgery. Vasopressin is  started at a rate of 0.2 units/min. Angiography is then  repeated after 20 minutes, and the rate is increased to 0.4-0.6  units/min if bleeding persists. Once bleeding ceases, the infu-  sion is continued for 12-36 hours and subsequently tapered  over 24 hours. Patients receiving vasopressin should be mon-  itored in an intensive care setting. Complications of vaso-  pressin include cardiac ischemia and fluid and electrolyte  abnormalities. Transcatheter embolization using polyvinyl  alcohol particles or microcoils is a potentially more definitive  method for controlling hemorrhage; however, it is compli-  cated by intestinal infarction in up to 20% of patients.   Surgery is required for patients in whom bleeding persists  and cannot be controlled through medical means and in  those with recurrent bleeding. Persistent hemodynamic  instability will necessitate surgery in 18-25% of patients who  have required blood transfusions. Operative morbidity  ranges from 37% for emergent colectomy, to 8.6% for semi-  elective surgery. Operative mortality, which is often related to  comorbid conditions, is approximately 10%. For patients  who lack preoperative localization, exploratory laparotomy  will be successful in identifying a source in 78% of patients.  During exploratory laparotomy, the small bowel should be  examined, and if a significant portion of the small bowel   contains blood, intraoperative enteroscopy should be per-  formed to evaluate for a possible small bowel source. Once  the source of bleeding has been localized (either preopera-  tively or intraoperatively), segmental colectomy is per-  formed. A primary anastomosis is possible in most cases due  to the cathartic effects of blood. It is not necessary to remove  all diverticula in patients with extensive diverticular disease.  Blind segmental resection is contraindicated due to its  high rebleeding rate (30-42%), morbidity (83%), and mor-  tality (57%). Thus, if a bleeding source cannot be identified,  a subtotal colectomy should be performed. Although the  rebleeding rate following a subtotal colectomy is less than  10%, the morbidity and mortality rates for the procedure are  high (37% and 11-33%, respectively).   Seventy-five to 90% of patients will stop bleeding sponta-  neously. However, following an initial episode of diverticular  hemorrhage, the risk of recurrent bleeding is 10-40% (often  within 48 hours of the initial bleed), and after a second  episode, the risk of recurrent hemorrhage increases to  21-50%. The overall mortality rate for those with massive  hemorrhage is 10-20%, and is related to comorbid illnesses. In  those requiring surgery, the overall operative mortality rate is  approximately 10%, and is often related to comorbid illnesses.   Surg. 2001;386:1:8-16. [PMID: 11405093]  DeBarros J, Rosas L, Cohen J, et al. The changing paradigm for the   Gastrointest Endosc. 2004;59:402-408. [PMID: 14997144]  lensen DM, Machicado, lutabha R, et al. Urgent colonoscopy for   N Engl J Med. 2000;342:78-82. [PMID: 10631279]  Yamaguchi T, Yoshikawa K. Enhanced CT for initial localization of   Screening for colorectal cancer (CRC) can reduce disease-  related morbidity and mortality. The existing evidence has  led to the recommendation of CRC screening as a standard  component of preventive health care.   CRC is the second leading cause of cancer death in the United  States and Western Europe. The lifetime risk of CRC in the  United States is approximately 6%. In other words, 1 in 18  American men and women will be diagnosed with CRC during  their lifetime. In 2008, it was estimated that 77,250 men and  71,560 women would be diagnosed and 49,960 individuals  would die of CRC. However, overall disease survival has  improved from 51.4% in the 1970s to 64.9% in early 2000.  Increased knowledge about the pathogenesis, advances in med-  ical and surgical care, and the increasing emphasis on CRC  screening programs have contributed to these substantial gains.   CRC can be prevented through readily available screening.  Prevention efforts rely on the long time interval required for a  benign adenomatous polyp to progress into an invasive cancer.  It is estimated that the adenoma to carcinoma sequence  unfolds over a 7- to 10-year period. In addition, CRC-related  deaths are preventable if the disease is detected early. When  diagnosed early, the 5-year survival rate for CRC that is still  confined to the primary site (localized stage) is approximately  90%. Conversely, the corresponding 5-year survival for patients  with known distant metastases is only 10%. Unfortunately,  only 39% of cancers are diagnosed at an early stage.   Nevertheless, CRC screening is presently underutilized in  the United States. Less than half of the population is cur-  rently compliant with standard screening recommendations,  despite the array of available choices. CRC screening lags far  behind screening for other common malignancies, such as  breast, cervical, and prostate cancer. According to recent  results by the National Center for Health Statistics, only 54%  of Americans aged 50 years or older had undergone any type  of CRC screening and only 42% had undergone screening   within the recommended time interval. At present, issues of  sensitivity, specificity, and patient acceptance limit existing  CRC screening methods. Several factors contribute to the lack  of compliance with CRC screening, including inappropriate  perception of risk (particularly if patients are asymptomatic  and without a family history of CRC), dietary restrictions or  burdensome cathartic preparations, the invasiveness of pro-  cedures, and perceived discomfort, pain, and embarrassment  related to certain screening techniques.   American Cancer Society. Cancer Statistics 2006 Presentation.  Available at: http://www.cancer.org/downloads/STT/Cancer_  Statistics_2006_Presentation.ppt#257,2, US Mortality, 2003.  Accessed June 28, 2007.   Centers for Disease Control and Prevention. Colorectal cancer  screening rates. Available at: http://www.cdc.gov/cancer/  colorectal/ statistics/screening_rates.html. Accessed July 3, 2007.   Ries LA, Melbert D, Krapcho M, et al. Surveillance Epidemiology  and End Results (SEER) Cancer Statistics Review, 1975-2005,  National Cancer Institute. Available at: http://seer.cancer.gov/  csr/1975_2005/results_single/sect_0 l_table.01.pdf. Accessed  September 8, 2008.   Seeff LC, Nadel MR, Klabunde CN, et al. Patterns and predictors of  colorectal cancer test use in the adult U.S. population. Cancer.  2004;100:2093-2103. [PMID: 15139050]   In 1990, a stepwise, chronologic model for colorectal tumori-  genesis was proposed. It outlined sequential alterations in  key growth regulatory genes, such as APC, K-ras, and tp53,  culminating in the development of a malignant neoplasm.  This pathway contributes to the development of 85% of col-  orectal tumors that arise from preexisting adenomatous  polyps. When adenomas accumulate the necessary combina-  tion of genetic mutations in the suggested stepwise manner,  the end result is cancer (Figure 22-1).   The genes implicated in CRC can be divided into three  categories: (1) tumor-suppressor genes, (2) proto-oncogenes,  and (3) DNA repair genes.   ▲ Figure 22-1. Genetic model for colorectal tumorigenesis. (Adapted, with permission, from Fearon ER, Volgelstein.  A genetic model for colorectal tumorigenesis. Cell. 1990;61:759.)   The function of tumor-suppressor genes is to downregulate  normal growth stimulatory pathways. In CRC, the genes most  frequently inactivated are APC, tp53, and pl6. Consistent with  the Knudson "two-hit hypothesis," acquired (or somatic) muta-  tions in both alleles of the tumor-suppressor gene are required  to fully inactivate gene function and cause cancer. In autosomal-  dominant CRC syndromes, a preexisting germline mutation in  one allele ("first hit") is inherited and a "second hit" occurs  when an acquired mutation inactivates the other allele.   Proto-oncogenes, such as K-ras, are components of sig-  naling pathways that promote normal cellular growth and  proliferation. A mutation in a proto-oncogene leads to an  active gene product with a resulting tumorigenic effect.   DNA repair genes function to maintain the integrity of  the genome. Individual nucleotides can be modified by bio-  chemical reactions such as oxidation, alkylation, sponta-  neous deamination, and ultraviolet cross-linking. When  errors occur, they are corrected through a sophisticated  process known as "base excision repair." Another manner in  which errors are introduced into the genome is through mis-  pairing of nucleotides, which can occur during normal DNA  replication. These errors are corrected by a DNA "mismatch  repair" system. When either of these DNA repair processes is  dysfunctional, deleterious mutations can accumulate in  genes that directly control cellular growth and proliferation.   Fearon ER, Vogelstein B. A genetic model for colorectal tumorige-  nesis. Cell. 1990;61:759-767. [PMID: 2188735]   The approach to CRC screening in asymptomatic individu-  als depends on risk stratification and the likelihood of devel-  oping the disease. Screening for CRC takes place in persons  who have no personal or family history of adenomatous  polyps or cancer. Surveillance takes place in persons with a  personal history of either adenomatous polyps or CRC, or  one of the genetic syndromes that requires more intensive  monitoring. Individuals who have signs or symptoms sug-  gestive of CRC fall outside the domain of screening and  should be offered appropriate diagnostic evaluation.   CRC screening programs begin by classifying an individ-  ual's level of risk based on age, as well as personal and family   medical history (Figure 22-2). This vital information helps  determine when screening should be initiated, with what  appropriate tests, and the frequency of subsequent examina-  tions. CRC risk is commonly stratified into three broad cate-  gories: average risk, moderate risk, and high risk.   An average-risk individual is defined as an asymptomatic  person without a personal or family history of colonic polyps  or cancer. The majority of the general population is consid-  ered to be at average risk for CRC. Given that age is the  strongest risk factor for the development of CRC and adeno-  matous polyps, men and women at average risk should be  offered screening beginning at age 50 years.   Available screening options for average-risk individuals  fall into two broad categories: (1) tests that primarily detect  CRC, and (2) those that detect adenomatous polyps and  CRC (Table 22-1). Tests that primarily detect cancer are fecal  tests, including guaiac-based and immunochemical occult  blood tests, and fecal DNA tests. These modalities provide  limited opportunity for prevention because detection of pre-  malignant adenomatous polyps is most often incidental.  Tests that detect both adenomatous polyps and cancer  include flexible sigmoidoscopy (FS), colonoscopy, double-  contrast barium enema (DCBE), and computed tomography  colonography (CTC). Because prevention is the primary goal  of CRC screening, recent guidelines from the American  Cancer Society, the U.S. Multisociety Task Force on  Colorectal Cancer, and the American College of Radiology  strongly encourage clinicians to offer those tests that are  designed to detect both early cancer and adenomatous  polyps if resources are available and if patients are willing to  undergo an invasive examination. Noninvasive tests must be  repeated at regular intervals to be effective, are less likely to  prevent CRC than invasive examinations, and, if abnormal,  require colonoscopy.   Nevertheless, health care providers are encouraged to  focus on increasing screening rates though periodic use of  any of the recommended modalities. Providers should present   A Figure 22-2. Algorithm for colorectal cancer screening. FAP, familial adenomatous polyposis; HNPCC, hereditary  nonpolyposis colorectal cancer; *, either colorectal cancer or adenomatous polyps; hee text. (Adapted, with permission,  from Winawer SJ, Fletcher R, Rex D, et al. Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance:  clinical guidelines and rational-update based on new evidence. Gastroenterology. 2003;1 24:546.)   their patients with information about the advantages and  disadvantages associated with the multiple available screen-  ing tests. In turn, patients have the opportunity to select how  they wish to be screened based on their own preferences. The  rationale for such an approach is that it may increase the   Table 22-1. Testing options for asymptomatic adults  aged 50 years and older.   Double-contrast barium enema  Computed tomography colonography  Tests that primarily detect CRC  Guaiac-based fecal occult blood testing  Fecal immunochemical tests  Stool DNA   Adapted, with permission, from Levin B, Lieberman DA, McFarland  B, et al. Screening and surveillance for the early detection of col-  orectal cancer and adenomatous polyps, 2008: a joint guideline  from the American Cancer Society, the US Multi-Society Task Force  on Colorectal Cancer, and the American College of Radiology.  Gastroenterology. 2008;134:1570-1595.   likelihood that screening will occur. Even though the currently  available screening techniques are not equal in effectiveness,  cost, or associated risks, they all have been demonstrated to be  cost-effective compared with no screening at all.   Levin B, Lieberman DA, McFarland B, et al. Screening and surveil-  lance for the early detection of colorectal cancer and adenoma-  tous polyps, 2008: a joint guideline from the American Cancer  Society, the US Multi-Society Task Force on Colorectal Cancer,  and the American College of Radiology. Gastroenterology.  2008;134:1570-1595. [PMID: 18384785]   Smith RA, Mettlin CJ, Davis KJ, et al. American Cancer Society  guidelines for the early detection of cancer. CA Cancer ] Clin.  2000;50:34-49. [PMID: 10735014]   Winawer S, Fletcher R, Rex D, et al. Gastrointestinal Consortium  Panel. Colorectal cancer screening and surveillance: Clinical  guidelines and rationale-Update based on new evidence.  Gastroenterology. 2003;124:544-560. [PMID: 12557258]   Individuals with a personal or family history of adenoma-  tous polyps or CRC are considered to be at intermediate risk  for the development of CRC. For these patients, colonoscopy  is the recommended screening method. Other conventional  screening modalities are not typically recommended in this  setting.   Certain characteristics of colorectal adenomas at baseline  colonoscopy are the basis for decisions about surveillance  intervals. Existing data from the National Polyp Study (NPS),  a pooled analysis of chemoprevention studies, as well as  observational cohort studies support the presence of the fol-  lowing predictors for the development of future advanced  adenomas or cancers: (1) three or more adenomas, (2) adenoma  size greater than 1 cm, (3) adenoma with villous features or  high-grade dysplasia. A proximal location of adenomas  (ascending colon or cecum) may also predict metachronous  advanced adenomas but this has not been well studied to  date. In addition, there is a general consensus among many  of the studies that individuals with adenomas with lesser  findings (eg, one or two subcentimeter adenomas without  high-grade dysplasia or villous features) are at lower risk for  subsequent advanced adenomas.   By stratifying patients into "lower risk" and "higher risk"  groups for future advanced adenoma development based on  findings from initial colonoscopy, the NPS has provided  evidence-based guidelines for surveillance of postpolypec-  tomy patients. In a randomized comparison of surveillance  intervals after colonoscopic removal of newly diagnosed ade-  nomatous polyps, there was no better detection of advanced  lesions with surveillance examination 1 year after the initial  colonoscopy than with follow-up examination in 3 years. The  inference made is that the rate of developing metachronous  adenomas with advanced pathology is slow; therefore, the  current recommendation for patients with a personal history  of three or more adenomas, adenomas of 1 cm or larger, or  adenomas with villous or high-grade dysplasia, or any combi-  nation of these findings, is surveillance colonoscopy in 3 years.  In addition, patients who have more than 10 adenomas  removed during one endoscopic examination should be  examined in a shorter time interval (< 3 years) based on clin-  ical judgment and should be considered for the possibility  of an underlying familial syndrome. The standard of care for  a sessile, malignant polyp removed by piecemeal fashion is  3-6 months after the initial endoscopic resection.   However, it is important to acknowledge that the timing of  surveillance colonoscopy in patients with a history of adeno-  matous polyps is still evolving. The existing studies assessing  subsequent risk for neoplasia after colonoscopic polypectomy  have only followed patients for 5-6 years. This is a significant  limitation and has led to the current projection that patients  without advanced adenomas can wait at least 5 years (and  perhaps up to 10 years) for repeat colonoscopy. As a result,  further studies are needed to evaluate this "low risk" group in  order to confirm the strategy of these intervals.   Winawer SI, Zauber AG, Ho MN, et al. Prevention of colorectal  cancer by colonoscopic polypectomy. The National Polyp Study  Workgroup. N Engl J Med. 1993;329:1977-1981. [PMID:  8247072]   Individuals with a history of CRC are at risk for recurrent  cancer and metachronous neoplasms and require endoscopic  surveillance after surgical resection. Anywhere from 2% to  7% of patients with CRC have one or more synchronous can-  cers in the colon or rectum at the time of initial diagnosis; it  is therefore important to perform a complete colonoscopy in  the preoperative period. In cases where an obstructing colonic  or rectal lesion is detected, CTC or DBCE should be consid-  ered perioperatively and a complete colonoscopy should be  performed 3-6 months after surgery. Once the colon is  cleared of any synchronous lesions, a postoperative surveil-  lance colonoscopy is recommended at 1 year to evaluate for  any metachronous lesions. If the examination at 1 year is nor-  mal, the subsequent examination should be at 3 years. If this  examination is also found to be normal, surveillance  colonoscopy can thereafter be extended to every 5 years.  Neither individual randomized controlled clinical trials of  intense surveillance with annual colonoscopy nor a meta-  analysis of these trials for the purpose of detecting recurrent  disease have shown a survival benefit for patients with CRC.   Colonoscopy at 1 year after surgical resection is recom-  mended based on reports of a high incidence of metachro-  nous second cancers noted within the first 2 years after  resection. Among an aggregate of studies reporting results  from postcancer surveillance colonoscopy, there was an inci-  dence rate of 0.7% metachronous cancers in the first 2 years  after resection of the initial primary cancer. This estimate is  consistent with data from a tumor registry review in  Nebraska, which calculated an annual incidence of 0.35% per  year for metachronous cancers. This is considered sufficient  information to warrant a colonoscopy at 1 year following  surgical resection. However, this should not diminish the  importance of a high-quality colonoscopic examination in  the perioperative period to exclude synchronous neoplasms.   In addition, it is important to distinguish between rectal  and colon cancer because of the differing rates of local recur-  rence. The recurrence of colon cancer at the anastomotic site  occurs in only 2-4% of patients. In contrast, local recurrence  rates of rectal cancer when patients have undergone a low  anterior resection can be 10 or more times higher. High  recurrence rates of rectal cancer are partly a function of sur-  gical technique. Local recurrence rates of cancer can be  reduced by using a surgical technique called mesorectal exci-  sion, as well as administering radiation and chemotherapy in  the neoadjuvant, preoperative setting to patients with locally  advanced disease. However, because reported local recur-  rence rates for rectal cancer across the United States are gen-  erally higher than those achieved in case series using total  mesorectal excision, there is a rationale for performing peri-  odic examinations of the rectum. Although effectiveness has  not been proven, performing proctoscopy at 6-month inter-  vals for the first 2 years after surgical resection can be consid-  ered for the detection of a surgically curable recurrence of  the original rectal cancer.   When colon or rectal cancer is endoscopically resected  and surgery is not needed, follow-up endoscopic examina-  tion to inspect the biopsy site within 1 year is a reasonable  strategy. As previously noted, colonoscopy is considered the  test of choice for the detection of metachronous neoplasms  in patients with a history of CRC. CTC has not been evalu-  ated adequately in this setting, and guaiac-based fecal occult  testing (FOBT) has been considered to have a very low posi-  tive predictive value after colonoscopic evaluation.   Rex D, Kahi CJ, Levin B, et al. Guidelines for colonoscopy surveil-  lance after cancer resection: a consensus update by the  American Cancer Society and the US Multi- Society Task Force  on Colorectal Cancer. Gastroenterology. 2006;130:1865-1871.  [PMID: 16737948]   Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for  colonoscopy surveillance after polypectomy: a consensus  update by the US Multi-Society Task Force on Colorectal  Cancer and the American Cancer Society. Gastroenterology.  2006;130:1872-1885. [PMID: 16697750]   An individual's risk of CRC is increased if there is a family  history of adenomatous polyps or CRC. The screening rec-  ommendations based on familial risk are derived largely  from the observed colon cancer risk in relatives of patients  with CRC and adenomas diagnosed before age 60 years  (Table 22-2). Data from a meta-analysis of 27 studies assess-  ing familial risk of CRC and adenomatous polyps report a  relative risk of CRC when a first-degree relative was affected  with CRC to be 2.4. The relative risk for CRC if the first-  degree relative had an adenomatous polyp was 1.9, with age  effects similar to those observed for cancer. In addition, if  more than one relative was affected and CRC was diagnosed  before age 45 years, the relative risk increased to 4.2 and  diminished to 2.2 and 1.8 for ages 45-59 years and older than  59 years, respectively. Therefore, familial risk needs to be  readily identified and should prompt the early initiation of  screening with colonoscopy.   Table 22-2. Relative risk of colorectal cancer (CRC)  based on family history. 3   FDR, first-degree relative; SDR, second-degree relative.  Compares individuals at moderate risk with average risk based on  family history.   At present, the U.S. Multisociety Task Force on Colorectal  Cancer recommends that for patients who report one first-  degree relative under 60 years or two first-degree relatives of any  age with adenomatous polyps or CRC, screening colonoscopy  should start at age 40 years or 10 years younger than the earliest  diagnosis of an affected relative (whichever one comes first) and  continue every 5 years (Figure 22-2, Table 22-3). Screening  should start at the same time for those patients with a single  first-degree relative with CRC or adenomas diagnosed after age  60 years, but surveillance should be performed as for average-  risk individuals. The rationale for starting screening at age  40 years is that the incidence of CRC in these patients resembles  the risk in persons with no family history but precedes it by  approximately 10 years. In addition, a patient reporting a second-  or third-degree relative with adenomatous polyps or CRC does  not confer additional risk and therefore average risk screening  recommendations are sufficient.   However, it is important to note that no studies to date  have reported a reduction in mortality in persons with a fam-  ily history of CRC or adenomatous polyps who undergo  screening. Therefore, the present screening recommendations  are considered provisional, and further evidence is needed to  better delineate the CRC risk in relatives with adenomatous  polyps or CRC as this information continues to evolve.   Johns LE, Houlston, RS. A systematic review and meta-analysis of  familial colorectal cancer risk. Am J Gastroenterol. 2001;96:  2992-3003. [PMID: 11693338]   For individuals with a hereditary CRC syndrome, such as  familial adenomatous polyposis (FAP) or Lynch syndrome  (also known as hereditary nonpolyposis colorectal cancer, or  HNPCC), genetic counseling and special screening protocols  are recommended (Table 22-4). Readily identifying these  individuals is of great importance given the known benefit of  intensive endoscopic surveillance and prophylactic surgery  on morbidity and mortality. Recognizing these syndromes  also has an impact on referral for predictive genetic testing,  wherein identifying gene carriers improves the efficiency of  cancer surveillance and helps identify family members who  require intense management versus those who can receive  the standard of care. Additionally, for patients with long-  standing inflammatory bowel disease such as Crohn disease  or ulcerative colitis, surveillance colonoscopy with systematic  biopsies should be performed because the risk of CRC is  increased in both conditions.   Jo WS, Chung DC. Genetics of hereditary colorectal cancer. Semin  Oncol 2005;32:11-23. [PMID: 15726502]   Engelsgjerd M, Farraye FA, Odze RD. Polypectomy may be adequate  treatment for adenoma-like dysplastic lesions in chronic ulcerative  colitis. Gastroenterology. 1999;117:1288-1294. [PMID: 10579969]   Ullman T, Croog V, Harpaz N, et al. Progression of flat low-grade  dysplasia to advanced neoplasia in patients with ulcerative coli-  tis. Gastroenterology. 2003;125:1311-1319. [PMID: 14598247]   > 3 adenomas < 1 cm d  Adenoma > 1 cm  Adenoma with villous features  Adenomas with HGD complete resection  Piecemeal resection   Family history:  FDR with CRC/adenoma < 60 y  FDR with CRC/adenoma > 60 y   10 y earlier than first polyps/  CRC diagnosed in family  20-25 years   CRC, colorectal cancer; CTC, computed tomography colonography; DCBE, double-contrast barium enema; FDR, first-degree relative; FOBT, fecal  occult blood test; FS, flexible sigmoidoscopy; HGD, high-grade dysplasia; sDNA, stool DNA; FAR, Familial Adenomatous Polyposis,  interval for sDNA testing to be determined.  b DCBE not endorsed by all professional gastroenterologic societies.  Interval for CTC testing to be determined.  d lf > 10 adenomatous polyps consider attenuated FAP diagnosis.  e 5hort interval of 3-6 months to ensure complete resection.  'Consider clinical diagnosis of Lynch syndrome.  sConsider germline genetic testing.   Reproduced, with permission, from Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorec-  tal cancer and adenomatous polyps, 2008. Gastroenterology. 2008;134(5):26.   FAP is an autosomal-dominant syndrome that is associated  with mutations in the adenomatous polyposis coli (APC) gene.  Affected individuals classically develop hundreds to thou-  sands of colorectal adenomas at a young age and have a risk  of CRC approaching TOO% in the absence of prophylactic   colectomy. Annual sigmoidoscopy beginning at age 10-12 years  is recommended for persons who have a genetic diagnosis or  are at risk of having FAP in order to determine if they are  expressing the genetic abnormality. Germline genetic testing  should be recommended in persons with an FAP phenotype  and should be performed after patients (or parents of chil-  dren) undergo genetic counseling. If a mutation is identified,   Table 22-4. Colon cancer screening recommendations  for people with familial or inherited risk.    First-degree relative affected with  colorectal cancer or an adenoma-  tous polyp at age > 60 y, or  2 second-degree relatives affected  with colorectal cancer    Two or more first-degree relatives 3  with colon cancer, or a single first-  degree relative with colon cancer  or adenomatous polyps diagnosed  at an age < 60 y    Colonoscopy every 5 y, beginning  at age 40 y or 10 y younger than  the earliest diagnosis in the family  whichever comes first    One second-degree or any third-  degree relative 51 with colorectal  cancer   a First-degree relatives include patients, siblings, and children.  b Second-degree relatives include grandparents, aunts, and uncles.  c Third-degree relatives include great-grandparents and cousins.  Adapted, with permission, from Winawer SJ, Fletcher R, Rex D, et  al. Gastrointestinal Consortium Panel. Colorectal cancer screening  and surveillance: clinical guidelines and rational-update based on  new evidence. Gastroenterology. 2003;124:544-560.   other family members can be tested to discern the presence or  absence of the same mutation with nearly 100% accuracy.  Sigmoidoscopy is performed until affected individuals develop  polyps, at which point total colectomy is recommended.  Family members who test negative for the gene mutation are  considered to be at average risk for CRC.   Although classic FAP can be readily identified, a subset of  patients has a less obvious phenotype. Patients with 10 or  more cumulative colorectal adenomas but less than 100, are  risk for a variant of FAP called attenuated FAP (AFAP). In  these patients, the age of onset of adenomas is approximately  10 years later than with classic FAP. AFAP also has an  autosomal-dominant mode of inheritance and, as with clas-  sic FAP, is due to mutations in the APC gene. The true inci-  dence and frequency of AFAP is unknown; however, it may  account for up to 10% of adenomatous polyposis families and  should be considered in individuals with multiple adenomas.  Colonoscopy should be used as the initial screening modality  in patients suspected of having AFAP, and the age to initiate  screening is based on the age of polyp expression or CRC  diagnosis in the family. It is reasonable to start colonoscopic  screening 10 years earlier than the earliest age of known polyp  or CRC diagnosis in the family. As with FAP, germline genetic  testing should be considered in persons presenting with the  AFAP phenotype.   Lynch syndrome exhibits an autosomal-dominant pattern of  inheritance, and affected individuals have a near 80% life-  time risk of developing CRC without intervention. It is pre-  dominantly caused by a mutation in one of four of the DNA  mismatch repair genes, MSH2, MLH1, MSH6, and PMS2.  There are several classification systems for the clinical diag-  nosis of Lynch syndrome, ranging from the most exclusive  Amsterdam Classification to the most inclusive revised  Bethesda Guidelines, all relying on personal or family med-  ical histories, or both. Commercial genetic testing is cur-  rently available for individuals suspected of having Lynch  syndrome, as well as for family members who are at risk for  the condition.   Once Lynch syndrome has been diagnosed based on clin-  ical criteria or through genetic testing, an intensive screening  program should be instituted. Screening colonoscopy should  be recommended every 1-2 years beginning at age 20 and  25 years, or 10 years prior to the youngest CRC case diagnosed  within the family (whichever occurs earlier). Annual  colonoscopy is recommended after the age of 40 years.   The CRC risk is similar in both Crohn colitis and ulcerative  colitis, with an estimated lifetime risk of 15-40%. Although  direct supporting evidence is lacking, an expert consensus  panel has recommended colonoscopic surveillance every 1-2  years for patients after 8 years of pancolitis or after 15 years in  those with limited left-sided colitis. If the extent of disease  cannot be accurately assessed, patients should undergo sur-  veillance colonoscopy beginning within 8-10 years of disease.   To consider surveillance effective, an extensive biopsy  protocol during colonoscopy should be followed. Experts  have recommended that biopsy specimens should be taken  every 10 cm in all four quadrants and that additional biopsy  specimens should be obtained from anastomotic sites (in  cases of previous colonic resections), strictures, and mass  lesions (other than pseudopolyps). Polyps should be  removed by polypectomy, with biopsies of the adjacent flat  mucosa to discern if dysplasia is present. In cases where high-  grade dysplasia or multifocal dysplasia is found in flat  mucosa, patients should be advised to undergo colectomy.  However, it is imperative that pathologic confirmation be  made by an experienced pathologist in the field of dysplasia  in inflammatory bowel disease prior to colectomy.  Controversy exists in cases of low-grade dysplasia in flat  mucosa and the need for colectomy. If low-grade dysplasia is  unifocal or found in areas of inflammation, attempts should  first be made to treat the active colitis.   In cases where a mass lesion is detected, it is important to  differentiate whether it is a dysplasia-associated lesion or  mass (DALM) or if it has arisen from a sporadic adenoma. A  DALM is a dysplastic lesion believed to have arisen because of  the cancer potential of the colitis and is an indication for   colectomy. In contrast, a lesion arising from a sporadic ade-  noma should be removed in its entirety during colonoscopy  and does not require colectomy unless the lesion is not  amenable to complete endoscopic resection. Differentiating  between DALMs and adenoma-related masses can be difficult  and requires extensive review of the endoscopic appearance,  histologic findings, presence of dysplasia in the surrounding  flat mucosa, patient's age, and duration of disease.   The decision for colectomy should be individualized in  cases of long-standing disease based on a number of con-  comitant factors known to increase CRC risk. These factors  include extensive active colitis or ongoing colitis-related  symptoms, personal history of primary sclerosing cholangi-  tis, a family history of CRC, age, and life expectancy.   At this time, there is no evidence to suggest that patients with a  few small, distally located hyperplastic polyps are at increased  risk for CRC. Therefore, such patients should undergo surveil-  lance for CRC similar to that of average-risk individuals.   However, there has been recent literature to suggest that  all hyperplastic polyps are not histologically similar and that  some variants of hyperplastic polyps may evolve into a  unique type of adenoma, called a serrated adenoma. Serrated  adenomas resemble hyperplastic polyps with dysplasia and  have been linked to the development of sporadic adenocarci-  noma with microsatelhte instability. Hyperplastic polyps of  this type are often large, sessile, and located in the proximal  colon. It is important for these neoplastic lesions to be com-  pletely removed, and surveillance should follow those recom-  mendations as for typical adenomas.   In addition, there is a recently described syndrome of  "hyperplastic polyposis". The following features have been  used to define this entity: ( 1 ) at least five histologically diag-  nosed hyperplastic polyps proximal to the sigmoid colon, of  which two are greater than 1 cm in diameter, or (2) any num-  ber of hyperplastic polyps occurring proximal to the sig-  moid colon in an individual who has a first-degree relative  with hyperplastic polyposis, or (3) more than 30 hyperplas-  tic polyps of any size distributed throughout the colon. A  limited number of studies have suggested and increased risk  of CRC in such individuals, although the magnitude of risk  has not been determined. A case series of 15 patients fulfill-  ing the preceding criteria did not find any CRC cases within  3 years of follow-up colonoscopic evaluation. Presently, the  optimal management for these patients is unclear and requires  further study.   Fernandez A, Samowitz W, DiSario JA, et al. Phenotypic character-  istics and risk of cancer development in hyperplastic polyposis:  case series and literature review. Am J Gastroenterol. 2004;99:  2012-2018. [PMID: 15447765]   Leggett BA, Devereaux B, Biden K, et al. Hyperplastic polyposis:  association with colorectal cancer. Am J Surg Pathol. 2001;25:  177-184. [PMID: 11176066]   Fecal occult blood testing (FOBT) is the most widely avail-  able screening modality for CRC. It is a noninvasive and  inexpensive test used to detect the presence of occult blood  in the stool of asymptomatic persons. FOBT is recom-  mended as an annual examination and is the only screening  test for which randomized controlled trials have shown a  reduction in CRC-related incidence by 33%, and mortality  benefits ranging from 15% to 20%. This is due primarily to  the detection of CRC at an earlier stage or the detection of  adenomatous polyps with the ability to remove these lesions  during colonoscopy. It is important to emphasize that posi-  tive FOBT results need to be appropriately followed by com-  plete visualization of the colon through colonoscopy.   Two types of FOBT exist: the standard guaiac test and the  newer immunochemical tests. Both tests are performed by  the patient at home and require the collection of six stool  samples from three consecutive stools. The guaiac test detects  blood by reacting with peroxidase activity of the heme por-  tion of hemoglobin. As a result, false-positive tests may result  from the ingestion of red meat or peroxidase-containing  foods.   When using the guaiac-based test, patients must be made  aware of the necessary dietary restrictions. In addition, rehy-  dration results in an increase in the false-positive rate, and  should not be performed.   The newer immunochemical tests react with antibodies  that are specific for the globin portion of the human hemo-  globin molecule. Immunochemical tests have been reported  to have a better sensitivity and specificity than guaiac-based  tests and do not require dietary restrictions. Multiple studies  have provided information on the sensitivity and specificity  of immunochemical FOBT for the detection of CRC, in  which the sensitivity ranged from 47.1% to 69% and the  specificity ranged from 88.2% to 97.1%. In contrast, the sen-  sitivity of the guaiac test for detecting CRC has been reported  to be as low as 37.1%, with a specificity of 86.7%. However,  the immunochemical tests are more expensive than the guaiac-  based tests.   When FOBT is used alone as a screening strategy, it is only  33-50% sensitive in one-time testing, with some improve-  ment if testing is repeated every 1-2 years. The specificity  of FOBT as a screening modality is high (estimated to be  > 95%). False-positive results can stem from other causes of  gastrointestinal blood loss or other substances in the stool  that might cause a positive guaiac reaction. Patients are  instructed to avoid ingestion of vitamin C, iron, aspirin, and  nonsteroidal anti-inflammatory medications for 3 days prior  to performing FOBT as these substances may interfere with  the accuracy of the test. False-negative results can also occur  because colorectal lesions can bleed intermittently and blood  may not always be present throughout the entire stool.  Therefore, a single test of a stool sample during digital rectal   examination is not an adequate substitute for FOBT. There is  an estimated fivefold decrease in sensitivity with a single test  performed during digital rectal examination, and a higher  yield has been noted when sampling three consecutive stools  for occult blood.   The disadvantages related to FOBT are that current tests  fail to detect many polyps and some cancers. Also, individu-  als who have a false-positive result will subsequently need to  undergo the discomfort, cost, and risk of colonoscopy with-  out benefit. In addition, there is reported evidence of low  referral rates for colonoscopy following an abnormal FOBT.  In the United States, one survey found that up to 30% of  patients with positive FOBT did not receive a recommenda-  tion for colonoscopy.   In evaluating an FOBT screening program it is also  important to measure programmatic adherence and per-  formance over time. FOBT is ineffective if patients have one  test but do not return for repeat testing or do not have  colonoscopy for positive tests. When FOBT is recommended,  patients must be informed that the test needs to be repeated  every 1-2 years if negative and that colonoscopy should be  performed if the test is positive.   Collins IF, Lieberman DA, Durbin TE, et al. Accuracy of screening  for fecal occult blood on a single stool sample obtained by dig-  ital rectal exam: a comparison with recommended sampling  practice. Ann Intern Med. 2005;142:81-85. [PMID: 15657155]   Leiberman DA, Weiss DG. Veteran's Affairs Cooperative Study  Group 380. One-time screening for colorectal cancer with com-  bined fecal occult blood testing and examination of the distal  colon. N Engl J Med. 2001;345:555-560. [PMID: 11529208]   Mandel JS, Bond IH, Church TR, et al. Reducing mortality from  colorectal cancer by screening for fecal occult blood. Minnesota  Colon Cancer Control Study. N Engl J Med. 1993;328:  1365-1371. [PMID: 8474513]   Mandel IS, Church TR, Bond JH, et al. The effect of fecal occult-  blood screening on the incidence of colorectal cancer. N Engl J  Med. 2000;343:1603-1607. [PMID: 11096167]   Morikawa T, Kato J, Yamaji Y, et al. A comparison of the immuno-  chemical fecal occult blood test and total colonoscopy in the  asymptomatic population. Gastroenterology. 2005;129:422-428.  [PMID: 16083699]   FS allows for direct visualization of the distal third of the  colon, ideally from the rectum to the splenic flexure. Several  retrospective, case-controlled studies have suggested that FS  is associated with a near 70% reduction in cancer mortality  resulting from tumors found within reach of the endoscope.  However, there are currently no prospective, randomized  controlled trials to support these findings.   FS is recommended every 5 years for average-risk individ-  uals. A 5-year interval is supported by a number of case-  controlled trials and cohort studies reporting a mortality  benefit from the use of FS up to 10 years from the last screening  examination. In a recent study comparing the appropriateness   of a 5-year interval with a 3-year interval, there was no  difference in the detection of advanced neoplasia (0.9% vs  1.1% at 3- and 5-year intervals respectively). In addition,  multiple studies have reported a low frequency of low-risk  and advanced lesions, and there is some speculation that an  even longer interval than 5 years between sigmoidoscopic  examinations may be reasonable.   To improve the use of FS as a screening modality, certain  clinical factors as well as endoscopic findings noted on FS  have been considered important predictors of proximal  colonic disease. These predictors include the presence of  multiple adenomas, any adenoma with villous histology or  dysplasia, age older than 65 years, male gender, and a family  history of CRC. Hyperplastic polyps detected on FS are not  associated with increased adenoma detection elsewhere in  the colon.   The advantages cited for FS are that it is inexpensive,  requires no sedation, involves a simple bowel preparation,  and can be performed by primary care physicians and non-  physicians, including physician assistants and nurse practi-  tioners. In addition, the risk of perforation is lower than that  associated with colonoscopy. However, the interval for sur-  veillance is shorter with FS than with colonoscopy because  FS is a less sensitive examination. This reduced sensitivity is  partly due to variable operator experience as a wider varia-  tion in adenoma detection rates among different providers  has been reported. In addition, the preparation used for  colon cleansing prior to FS may be less than optimal, and dis-  comfort in a nonsedated patient may interfere with the com-  pleteness of the examination.   Currently, any adenomatous polyp found on FS warrants  complete colonic visualization by colonoscopy to exclude the  presence of proximal lesions. Such a strategy has been asso-  ciated with an increase in the adenoma detection rate to  approximately 70%. However, these findings highlight a  major drawback of FS in that it can miss anywhere from  30% to 65% of advanced neoplasia located proximally. This  may be a particular concern for the use of FS in older  patients and women, in whom higher rates of proximal neo-  plasia have been reported. Recent data comparing the per-  formance of FS to colonoscopy in the detection of advanced  neoplasia reported that in subjects between 55 and 59 years  of age, the incremental benefit of colonoscopy over FS was  very small and statistically insignificant. In contrast, for  patients 60 years of age or older, the detection rate for  colonoscopy was significantly higher than for FS (odds ratio  [OR], 2.00, 95% CI: 1.30-3.09). When considered with prior  studies, these results suggest that FS could achieve high  detection of advanced neoplasia in patients younger than  60 years and is less effective with those older than 60 years.  Future studies to determine a combined approach for CRC  screening using FS for persons in the sixth decade followed  by colonoscopy once subjects are older than 60 years may  provide valuable information that may, in turn, conserve  colonoscopy resources.   A second shortcoming of FS is that patient compliance  with this screening modality is poor. Only 1 5-30% of eligible  persons regularly undergo FS, and this invariably limits its  utility in CRC prevention. Lastly, low rates of referral for  colonoscopy and colonoscopy completion have been  reported, and better measures to assure appropriate follow-  up are warranted.   Burke CA, Elder K, Lopez R. Screening for colorectal cancer with  flexible sigmoidoscopy: Is a 5-yr interval appropriate? A com-  parison of the detection of neoplasia 3 yr versus 5 yr after a nor-  mal examination. Am J Gastroenterol. 2006;101:1329-1332.  [PMID: 16771957]   Newcomb PA, Norfleet RG, Storer BE, et al. Screening sigmoi-  doscopy and colorectal cancer mortality. / Natl Cancer Inst.  1992;84:1572-1575. [PMID: 1404450]   Selby JV, Friedman GD, Quesenberry CP, et al. A case-control study  of screening sigmoidoscopy and mortality from colorectal can-  cer. JV Engl J Med. 1992;326:653-657. [PMID: 1736103]   This combined approach couples annual FOBT with sigmoi-  doscopy every 5 years. The occult blood test is performed  prior to sigmoidoscopy given that a positive result would war-  rant colonoscopy. A single nonrandomized study reported a  43% reduction in CRC-related deaths by this combination  approach compared with sigmoidoscopy alone. In addition,  this approach can increase the yield of adenoma detection  fourfold compared with FOBT alone. However, more recent  studies have not shown such promising results. The addition  of FOBT to FS was estimated to increase the adenoma detec-  tion rate only from 70% to 75%. Additionally, undergoing a  single FS and FOBT was not as effective as biennial FOBT in  detecting CRC over a 16-year period. The lack of improve-  ment in detection noted in this long-term case-control study  may have been due to lack of compliance associated with  undergoing FS.   Rasmussen M, Fenger C, Kronborg O. Diagnostic yield in biennial  Hemoccult-II screening program compared to a once-only  screening with flexible sigmoidoscopy and Hemoccult-II. Scand  J Gastroenterol. 2003;38:114-118. [PMID: 12608473]   Segnan N, Senore NC, Andreoni B, et al. Comparing attendance  and detection rate of colonoscopy to sigmoidoscopy and FIT for  colorectal cancer screening. Gastroenterology. 2007;132:  2304-2312. [PMID: 17570205]   DCBE has not been studied as a screening test for CRC in  prospective randomized trials, and several recent studies  have highlighted some major limitations associated with the  examination. In a number of comparative studies of  colonoscopy and DCBE in screening and surveillance popu-  lations, DCBE detected only 45-48% of polyps greater than   1 cm. In a large prospective study, the sensitivity for detect-  ing CRC was 83% for DCBE versus 95% for colonoscopy.  Overall, DCBE is less sensitive than colonoscopy for the  detection of large lesions, and this examination has fallen out  of favor among certain endorsing societies as a primary  screening strategy in average-risk persons.   However, given the number of deterrents to the wide-  spread use of colonoscopy, DBCE is considered an alternative  CRC screening modality to be performed every 5 years. It is  a radiologic examination of the colon that requires a cathar-  tic preparation similar to that given prior to colonoscopy and  requires the instillation of barium and air to define the con-  tour of the colon. It is included as a screening option because  it can evaluate the entire colon, is generally widely available,  and has a low risk of serious adverse events. However, this  procedure does not allow for polyp removal or biopsy of can-  cer if detected. Artifact, such as stool appearing as polyps, is  common and causes many false-positive tests. All patients  with an abnormal barium examination need to undergo  colonoscopy.   Although DCBE is an acceptable option for CRC screen-  ing in average-risk adults, its utilization has declined over  the past few years. This has had an impact on radiology  training programs as fewer trainees are able to acquire the  necessary skills needed to perform the labor-intensive pro-  cedure properly due to the low volume of DBCE studies being  requested. This trend is expected to continue as increased  efforts are being made to provide training related to computed  tomography colonography (CTC) among radiologists.   Winawer SJ, Stewart ET, Zauber AG, et al. A comparison of  colonoscopy and double-contrast barium enema for surveil-  lance after polypectomy. National Polyp Study Work Group.  N Engl J Med. 2000;342:1766-1772. [PMID: 10852998]   Colonoscopy is considered by many to be the gold standard  for CRC screening. Despite the lack of evidence from large-  scale randomized trials of screening colonoscopy, the proce-  dure has been shown in cohort studies to decrease the  expected incidence of CRC through the removal of adeno-  matous polyps. The NPS demonstrated that the removal of  adenomas led to the decreased incidence of CRC and that  colonoscopy was the only single test that could provide  screening, diagnosis, and treatment. In the NPS, a group of  patients who underwent colonoscopy with clearing of  colonic adenomas yielded a 76-90% reduction in CRC com-  pared with reference populations. Given the potential bene-  fits of colonoscopy, multiple gastroenterologic professional  societies have recommended colonoscopy as the preferred  modality among the menu of screening options.   However, several published studies have addressed the short-  comings of colonoscopy as currendy practiced. Indirect evidence  from several studies has questioned the accuracy of colonoscopy.   In one study, an audit of CRC cases revealed that 5% of sub-  jects with CRC had undergone screening colonoscopy within  3 years of diagnosis. Chemoprevention studies that included  follow-up colonoscopy as a means of measuring the efficacy  of chemoprevention on polyp recurrence have also demon-  strated a higher rate of developing interval cancers (1.7-2.2  cases per 1000 person-years) when compared with NPS results  (0.6 cases per 1000 person-years). Existing data have attrib-  uted the interval findings to lesions missed on screening  colonoscopy or the incomplete removal of polyps, suggesting  the potential need for establishing and validating quality  improvement measures in the practice of colonoscopy.   Characteristics of the baseline colonoscopy are also an  important predictor for subsequent neoplasia. A recent  prospective study examining the incidence of advanced neo-  plasia within 5.5 years of screening colonoscopy revealed a  strong association between baseline colonoscopy results and  the rate of serious incident lesions detected during the sur-  veillance period. It has been shown that the baseline  colonoscopy is the most beneficial in that it is responsible for  the major benefit of polypectomy and that subsequent exam-  inations may not add significant benefit except in people at  high risk for future advanced adenomas. Therefore, the cur-  rent opinion is that increased efforts must be made to help  ensure that the baseline colonoscopy is of the highest quality  in order to best detect adenomas. In turn, the U.S.  Multisociety Task Force on Colorectal Cancer and the  American Society for Gastrointestinal Endoscopy/ American  College of Gastroenterology Taskforce on Quality in  Endoscopy have proposed several measurable factors of rou-  tine colonoscopy to serve as quality indicators. They include  appropriate cecal intubation rates, adequate colonic cleans-  ing with minimal fecal residue, and a minimum withdrawal  time from the cecum of 6 minutes. Although these practices  are presently thought to translate into better quality-related  outcomes, there are no population-based studies from the  United States assessing the impact of measuring the pro-  posed quality indicators for the performance of screening  colonoscopy. Nevertheless, it is anticipated that the accuracy  (sensitivity) of colonoscopy can be increased through quality  improvement initiatives for enhanced performance.   Even though colonoscopy can fail to detect lesions, it is  still considered the most sensitive of the screening methods.  The advantages of this approach, in addition to the diagno-  sis and treatment of a lesion in a single session, include a long  interval of "protection" in the setting of polypectomy and  improved patient satisfaction due to the use of intravenous  conscious sedation. However, colonoscopy involves greater  cost and risk than other screening modalities. Serious com-  plications associated with colonoscopy include bleeding and  perforation and, while extremely rare, these occur at higher  rates than with other screening options.   Colonoscopy may be the "preferred" screening modality  for some, but it is important to emphasize that the evidence for  its efficacy is indirect and that there are no randomized con-  trolled trials demonstrating the superiority of colonoscopy to   other screening modalities. In addition, no direct information  indicates that a program of periodic colonoscopic surveillance  leads to a reduction in CRC incidence or mortality in average  risk individuals.   Barclay RL, Vicari IJ, Doughty AS, et al. Colonoscopic withdrawal  times and adenoma detection during screening colonoscopy.  N Engl J Med. 2006;355:2533-2541. [PMID: 17167136]   Imperiale TF, Wagner DR, Lin CY, et al. Risk of advanced proximal  neoplasms in asymptomatic adults according to the distal col-  orectal findings. N Engl J Med. 2000;343:169-174. [PMID:  10900275]   Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to  screen asymptomatic adults for colorectal cancer. Veterans  Affairs Cooperative Study Group 380. New Engl J Med. 2000;  343:162-168. [PMID: 10900274]   Lieberman DA, Weiss DG, Harford WV, et al. Five-year colon sur-  veillance after screening colonoscopy. Gastroenterology. 2007;133:  1077-1085. [PMID: 17698067]   Rex D. Maximizing detection of adenomas and cancers during  colonoscopy. Am J Gastroenterol. 2006;101:2866-2877. [PMID:  17227527]   Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopy miss rates of  adenomas determined by back-to-back colonoscopies.  Gastroenterology. 1997;112:24-28. [PMID: 8978338]   Robertson DJ, Greenberg ER, Beach M, et al. Colorectal cancer in  patients under close colonoscopic surveillance. Gastroenterology.  2005;129:34-41. [PMID: 16012932]   Singh H, Turner D, Xue L, et al. Risk of developing colorectal can-  cer following a negative colonoscopy examination. JAMA.  2006;295:2366-2373. [PMID: 16720822]   Noninvasive procedures to screen for CRC have been pro-  moted as possible ways to increase compliance with CRC  screening strategies. The 2008 consensus guidelines from the  American Cancer Society, the U.S. Multisociety Task Force on  Colorectal Cancer, and the American College of Radiology  include CTC and fecal DNA in the testing options for CRC  screening in asymptomatic, average-risk adults aged 50 years  and older.   Bromer MQ, Weinberg DS. Screening for colorectal cancer-now  and the near future. Semin Oncol. 2005;32:3-10. [PMID:  15726501]   Levin B, Lieberman DA, McFarland B, et al. Screening and surveil-  lance for the early detection of colorectal cancer and adenoma-  tous polyps, 2008: a joint guideline from the American Cancer  Society, the US Multi Society Task Force on Colorectal Cancer,  and the American College of Radiology. Gastroenterology.  2008;134:1570-1595. [PMID: 18384785]   Over the last decade, CTC (or virtual colonoscopy) was intro-  duced as a possible alternative noninvasive test for the exam-  ination of the colon. It provides a two- and three-dimensional   image of the colon using computer programming to combine  data from multiple helical CT scans. CTC requires a colon  preparation similar to that used for conventional colonoscopy  and involves air insufflation through a rectal tube to distend  the colon to enhance imaging. After the examination, a radi-  ologist examines the scans; if an abnormality is noted,  patients should undergo colonoscopy.   Results from early studies assessing the accuracy of CTC  have found it to be comparable to that of conventional  colonoscopy for the detection of polyps greater than 1 cm,  with a high sensitivity and specificity of 94% and 96%,  respectively. Similar results have not been reproduced in  other studies, and subsequent sensitivities of approximately  50% have been reported. The inconsistency in the examina-  tion's efficacy is likely related to the selection bias of the pop-  ulation studied, because most studies on CTC have been  performed in patient populations at increased risk for col-  orectal neoplasia and more likely to have occult disease. In  addition, only highly trained radiologists were involved in  interpreting the results of CTC in the majority of these studies.  Therefore, the generalizability of the results of these studies  remains unclear.   The technology related to CTC has improved over the  past few years and several screening trials using advanced  CTC techniques have demonstrated its favorable perform-  ance. In a meta-analysis reviewing the cumulative published  CTC performance data (including high-risk and screening  cohorts), the pooled sensitivity and specificity for large (> 1 cm)  polyps was 85-93% and 97%, respectively, and for small  polyps (6-9 mm) was 70-86% and 86-93%, respectively. The  overall sensitivity for invasive CRC was comparable to that of  conventional colonoscopy (96%).   There are a number of limitations and unresolved issues  related to CTC. The examination is not widely available and  most often is performed at large, academic centers, usually in  the setting of research studies. In addition, the false-positive  rate is estimated to be about 15% and is related to retained  stool mistaken for polyps, diverticular disease that limits colon  distensibility, and thickened colonic folds mistaken for lesions.  CTC is also not therapeutic, as polyps cannot be removed and  masses cannot be sampled for tissue diagnosis during the pro-  cedure. Lastly, it is estimated that 27% of patients undergoing  CTC will have an incidental finding warranting further diag-  nostic evaluation. This may increase patient anxiety and lead  to an increase in medical costs, because most incidental find-  ings are expected to be benign. It is estimated that there is  only a 2% potential clinical benefit to an extensive evaluation  for incidental findings noted on CTC.   Although there is variability regarding the optimal man-  ner in which to perform the examination, as well as inconsis-  tent radiology training and competency, the available data  supporting its efficacy has rendered CTC an acceptable  option for CRC screening in average-risk adults aged 50 years  and older. However, the interval for repeat examinations is  uncertain and future studies are warranted to determine the  appropriate surveillance interval following an initial negative   CTC. Presently, there is consensus that all patients with one  or more polyps greater than 1 cm or three or more polyps  greater than 6 mm should be referred for conventional  colonoscopy. The management of patients with fewer than  three polyps or polyps of 6-9 mm remains controversial.  Research studies using CTC surveillance to evaluate the nat-  ural history of polyps in this size range are ongoing. At this  time, a reasonable approach for patients with 6-9 mm polyps  identified by CTC is to offer therapeutic colonoscopy. There  is also a need for multidisciplinary consensus regarding the  management of polyps smaller than 6 mm.   For effective implementation of CRC screening, the  evolving technology needs to be standardized along with the  reporting of findings. Additional information is also needed  regarding the safety profile of CTC, including the radiation  dose effects for computed tomography examinations for  average-risk CRC screening.   Chin M, Mendelson R, Edwards J, et al. Computed tomographic  colonography: prevalence, nature, and clinical significance of  extracolonic findings in a community screening program. Am f  Gastroenterol. 2005;100:2271-2276. [PMID: 16393234]   Cotton PB, Durkalski VL, Pineau BC, et al. Computed tomographic  colonography (virtual colonoscopy): a multicenter comparison  with standard colonoscopy for detection of colorectal neoplasia.  JAMA. 2004;291:1713-1719. [PMID: 15082698]   Halligan S, Altman DG, Taylor SA, et al. CTC in the detection of  colorectal polyps and cancer: systematic review, meta-analysis,  and proposed minimum data set for study level reporting.  Radiology. 2005;237:893-904. [PMID: 16304111]   lohnson CD, Harmsen WS, Wilson LA, et al. Comparison of the  relative sensitivity of CT colonography and double-contrast  barium enema for screen detection of colorectal polyps. Clin  Gastroenterol Hepatol. 2004;2:314-321. [PMID: 15067626]   lohnson CD, Harmsen WS, Wilson LA, et al. Prospective blinded  evaluation of computed tomographic colonography for screen  detection of colorectal polyps. Gastroenterology. 2003;125:  311-319. [PMID: 12891530]   Mulhall BP, Veerappan GR, Jackson JL. Metaanalysis: computed  tomographic colonography. Ann Intern Med 2005;142:635-650.  [PMID: 15838071]   Pickhardt PJ, Choi JR, Hwand I, et al. Computed tomographic vir-  tual colonoscopy to screen for colorectal neoplasia in asympto-  matic adults. N Eng } Med. 2003;349:2191-2200. [PMID:  1465426]   Rockey DC, Paulson E, Niedzwiecki D, et al. Analysis of air contrast  barium enema, computed tomographic colonography, and  colonoscopy: prospective comparison. Lancet. 2005;354:  305-311. [PMID: 15664225]   Testing to detect genetic abnormalities (somatic mutations)  in fecal samples has been proposed as a potential screening  test for CRC screening. Colorectal epithelial cells are shed in  stool, and stable DNA can be extracted from stool and ampli-  fied using polymerase chain reaction (PCR). This process  allows for the detection of mutations in several genes, includ-  ing K-ras, APC, BAT-26, and tp53.   Data from a small cohort has revealed a sensitivity of 91%  for cancer, 82% for adenomatous polyps greater than 1 cm,  and specificity of over 90% for either. However, these results  have not been duplicated, and other studies have reported  sensitivities between 52-91% for cancer and 27-82% for ade-  nomatous polyps. It is presently not known what proportion  of advanced adenomas is identified by fecal DNA testing.   As fecal DNA testing is able to identify the majority of  CRC cases, there has been an expert consensus to include this  modality as an acceptable option for CRC screening in  average-risk adults. It is important to recognize that the vari-  able results assessing the sensitivity of fecal DNA testing to  date may be related to the test's evolving technology as improve-  ments continue to be made. Newer fecal DNA tests, whether  they involve technological advances made on existing tests or  are new variants, warrant careful evaluation in future studies  evaluating screening cohorts. At this time, the interval for  routine screening between normal examinations is unclear  and there is no societal recommendations given the insuffi-  cient data. Nevertheless, the effectiveness of any screening  program utilizing fecal DNA will depend on quality and  adherence, as well as the sensitivity and specificity of the test.   Ahlquist DA, Skoletsky IE, Boynton KA, et al. Colorectal cancer  screening by detection of altered human DNA in stool: feasibil-  ity of a multitarget assay panel. Gastroenterology. 2000;119(5):  1219-1227. [PMID: 11054379]   Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Fecal DNA versus  fecal occult blood for colorectal cancer screening in an average-  risk population. N Engl J Med. 2004;351:2704-2714. [PMID:  15616205]   Itzkowitz SH, Jandorf L, Brand R, et al. Improved fecal DNA test  for colorectal cancer screening. Clin Gastroenterol Hepatol.  2007;5:111-117. |PMID: 17161655]   Osborn NK, Ahlquist DA. Stool screening for colorectal cancer:  molecular approaches. Gastroenterology. 2005;128:192-206.  |PMID: 15633136]   CRC is a preventable cancer. The appropriate identification of  individuals at risk dictates the necessary screening and surveil-  lance approach and plays an important role in decreasing CRC  mortality. There are several acceptable options presendy avail-  able for CRC screening, and they provide the means to improv-  ing screening compliance. Although a number of randomized  trials provide evidence to support the use of FOBT for CRC  screening, colonoscopy is considered the current gold standard  given its ability to detect and remove adenomatous polyps,  which in turn decreases CRC incidence and related mortality.   Approximately 3-5% of colorectal cancers are caused by  inherited gene mutations associated with hereditary  nonpolyposis colorectal cancer (Lynch syndrome) or  familial adenomatous polyposis.   Genetic testing is clinically available for several heredi-  tary gastrointestinal cancer syndromes and can be used  to guide cancer screening recommendations.   The majority of cases of gastrointestinal cancer are believed  to be sporadic events; however, inherited factors play a role in  development of some tumors, with an estimated 5% being  attributable to a single gene mutation. Hereditary gastroin-  testinal cancer syndromes convey a markedly increased risk  for developing cancer and require specific strategies for diag-  nosis and management.   Identification of hereditary gastrointestinal cancer syn-  dromes requires a thorough evaluation of patients' personal  and family history of cancer. Clinical genetic testing can be  useful in confirming the diagnosis of certain hereditary can-  cer syndromes and guiding cancer screening for family mem-  bers. Tables 23-1 and 23-2 summarize clinical characteristics  and cancer screening recommendations for the hereditary  gastrointestinal cancer syndromes discussed in detail in this  chapter.   American Society of Clinical Oncology. American Society of  Clinical Oncology policy statement update: genetic testing for  cancer susceptibility. / Clin Oncol. 2003;21:2397-2406. [PMID:  12692171]   Giardiello FM, Brensinger JD, Petersen CM. AGA technical review on  hereditary colorectal cancer and genetic testing. Gastroenterology.  2001;121:198-213. [PMID: 11438509]   Colorectal cancer (CRC) is the most common gastrointesti-  nal malignancy, with more than 150,000 cases diagnosed  each year in the United States. Although most CRC patients  do not have a striking family history of CRC, approximately  30% report having one or more family members with a diag-  nosis of CRC. The lifetime risk of developing CRC is approx-  imately 5% for the average American; however, individuals  who have a first-degree relative with CRC have a twofold  higher risk for developing colorectal neoplasia compared  with individuals who have no family history of CRC. For  individuals with numerous relatives with CRC, the cancer  risk may be markedly higher; those who have inherited  mutations in genes involved in mismatch repair or tumor  suppression have a lifetime risk of CRC of 80-100% in the  absence of medical intervention.   Identification of patients at risk for hereditary CRC syn-  dromes relies on careful family history evaluation, because  many individuals may not demonstrate a characteristic phe-  notype. Cancer risk stratification for every patient should  involve eliciting a family history of cancers, including type of  cancer and age of onset as well as family history of colorectal  adenomas. Individuals whose family history includes multi-  ple individuals with cancer, individuals diagnosed with two  or more primary cancers, or with tumors diagnosed at young  ages, should undergo more extensive family history evalua-  tion of first-, second-, and third-degree relatives to deter-  mine whether there is evidence of an autosomal-dominant  or autosomal-recessive pattern of inheritance.   Lynch syndrome, also known as hereditary nonpolyposis col-  orectal cancer (HNPCC), is the most common hereditary  CRC syndrome and is estimated to account for 3-5% of CRC  cases. This syndrome was first described by Dr Henry Lynch  in families in which multiple cases of CRC were diagnosed at   or third decade  CRC risk 100% if colon is not removed  Increased risk for duodenal and ampullary adenocarcinoma  Risk of desmoid tumors   intussusception)  Pigmented lesions on lips  Increased risk for breast cancer, pancreatic cancer,    3 or more family members with pancreatic cancer  May be present as part of other hereditary cancer syndromes,  eg, breast/ovarian cancer (HBOC), melanoma (FAMMM),  or colorectal/gynecologic cancers (Lynch syndrome)   CRC, colorectal cancer; FAMMM, familiar atypical multiple mole melanoma; Gl, gastrointestinal; HBOC, hereditary breast/ovarian cancer;   a Genetic testing has limited sensitivity with mutations detected in < 50% of affected individuals.   Comprehensive testing is only performed by selected research laboratories on affected probands.    1. Sigmoidoscopy or colonoscopy until polyps are too  numerous to remove, then surgical colectomy   2. Every 1-3 y, depending on polyp burden, beginning  when colonic polyps develop   CT, computed tomography; HNPCC, hereditary nonpolyposis colorectal cancer; MRI, magnetic resonance imaging.   2. Synchronous or metachronous colorectal or other HNPCC-associated  tumors b regardless of age   3. Colorectal cancer diagnosed at age < 60 y with histologic findings  of infiltrating lymphocytes, Crohn-like lymphocytic reaction,  mucinous/signet ring differentiation or medullary growth pattern   4. Colorectal cancer in > 1 first-degree relative(s) with an HNPCC-related  tumor b , with one of the cancers being diagnosed at age < 50 y   5. Colorectal cancer diagnosed in > 2 first- or second- degree relatives  with HNPCC-related tumors' 1 , regardless of age   Data from Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda   young ages. The original Lynch syndrome families were  identified as having three or more cases of CRC with at  least one diagnosed before age 50 years, as described by the  Amsterdam criteria; however, additional studies have  demonstrated that the cancer spectrum in these families  includes other cancers, such as gastrointestinal, gynecologic,  urinary tract, and sebaceous neoplasms of the skin. Because  as many as 50% of families with Lynch syndrome do not  meet the classic Amsterdam criteria, clinical diagnostic crite-  ria have been expanded and modified to improve diagnostic  sensitivity. As outlined by the recent revised Bethesda guide-  lines (Table 23-3), Lynch syndrome should be suspected in  families that have multiple relatives affected with CRC or  related extracolonic tumors, or both, and in individuals who  are diagnosed with CRC at a young age, have synchronous or  metachronous colorectal cancers, or develop multiple  HNPCC-associated tumors. Figure 23-1 shows a pedigree of  a family fulfilling criteria for Lynch syndrome.   CRC is usually the predominant cancer in most families with  Lynch syndrome. Initial studies suggested that the mean age of  onset of CRC is 44 years; however, there is wide variation in  ages of diagnosis among families. Although colonic tumors in  Lynch syndrome are often right-sided, many patients develop  tumors in the left colon and rectum. Synchronous or  metachronous tumors are common, and any individual diag-  nosed with two primary colon cancers warrants evaluation for  Lynch syndrome. Although Lynch syndrome is also referred to   ▲ Figure 23-1. Pedigree of a family fulfilling modified  Amsterdam criteria for hereditary nonpolyposis colorectal  cancer (HNPCC)/Lynch syndrome. Ca, cancer.   as nonpolyposis colorectal cancer, most of the colorectal can-  cers noted do appear to arise from adenomatous polyps,  although these polyps may be few in number and are often  small and flat. The colorectal adenoma-carcinoma sequence  appears to be accelerated in Lynch syndrome, and there are  many reports of tumors arising within 3 years of a normal  colonoscopy.   Endometrial (uterine) cancer is the second most common  cancer described in Lynch syndrome families, and women  have a 40-60% lifetime risk for developing this malignancy,  which is an unusual cancer in the general population. The  lifetime risks for developing other Lynch-associated cancers,  such as urinary tract cancers, ovarian cancer, and other gas-  trointestinal cancers (stomach, pancreas, small intestine), are  also increased for individuals with Lynch syndrome and are  estimated to be between 10-20%. Brain tumors (eg, glioblas-  tomas and astrocytomas) have been described in the Turcot  syndrome variant of Lynch syndrome. Cutaneous sebaceous  adenomas and sebaceous carcinomas are rare skin tumors  seen in the Muir-Torre variant, and it is currently recom-  mended that any individual affected with sebaceous neo-  plasms of the skin undergo evaluation for Lynch syndrome  regardless of his or her family history.   The increased predisposition to developing cancer in Lynch  syndrome is the result of autosomal dominantly inherited  mutations in genes involved in DNA mismatch repair  (MMR). Mutations in the genes hMLHl and hMSH2  account for more than 80% of the identified MMR alter-  ations in Lynch syndrome families. Mutations in the MMR  gene hMSH6 have been identified in approximately 10% of  Lynch syndrome families, and in hPMS2 in rare families.   The protein products of MMR genes are involved in iden-  tifying and repairing errors that arise during DNA replica-  tion. In the setting of defective MMR gene function, these  errors accumulate in segments of DNA containing repeated  sequences known as microsatellites. DNA errors that disrupt  the function of genes involved in growth regulation can lead  to the development of tumors. More than 90% of the col-  orectal tumors in Lynch syndrome patients demonstrate  microsatellite instability, a characteristic of defective MMR  gene function. Analysis of colorectal tumors for expression of  MMR proteins MLH1, MSH2, MSH6, and PMS2 frequently  reveals loss of staining of the gene with the mutation.   MMR gene mutations are identified in approximately  60% of families that meet classic Amsterdam criteria. Recent  studies suggest that these classic Amsterdam families with  multiple CRC diagnoses may include not only Lynch syn-  drome families, but also families with familial colorectal can-  cer syndrome X, which may or may not have a genetic basis.  Like Lynch syndrome, familial colorectal cancer syndrome X  families have multiple cases of CRC with apparent autoso-  mal-dominant pattern of inheritance; however, the colorec-  tal tumors in patients with familial colorectal cancer  syndrome X do not have features of microsatellite instability  and affected individuals do not appear to be at increased risk  for extracolonic cancers.   The high lifetime risk of colorectal and other extracolonic  cancers, the accelerated progression of adenomas to adeno-  carcinomas, and the young age of onset of colorectal neopla-  sia require specialized strategies for cancer prevention.   Individuals who are at risk for Lynch syndrome should begin  having colonoscopies at age 20-25 years, with repeat exami-  nations every 1-2 years. The need for a shorter interval  between examinations became evident from European stud-  ies that demonstrated a reduction in CRC mortality for indi-  viduals who had colonoscopies every 3 years; however,  cancers were still detected during that screening interval. The  endoscopist should be vigilant for small or flat lesions, which  may be associated with higher malignant potential in Lynch  syndrome patients than in the general population.   Expert panels recommend that women at risk for Lynch syn-  drome undergo endometrial cancer screening with annual  transvaginal ultrasound and endometrial biopsy beginning  at ages 25-35 years. At present there are no data to support  the efficacy of this endometrial cancer screening regimen  and women who have completed childbearing should be  counseled to consider prophylactic hysterectomy as a more  definitive measure to reduce their cancer risk.   Although the risk for other extracolonic cancers is increased  in Lynch syndrome, there is insufficient evidence to defini-  tively recommend screening for many of these other cancers.  For urinary tract cancer screening, expert panels have rec-  ommended annual urine cytology, although its efficacy  remains unproven. Screening for ovarian cancer includes  transvaginal ultrasound and checking serum CA-125 levels  once yearly. Screening for gastric cancer and small intestinal  cancer using upper endoscopy has been proposed by some  experts, but this has not been recommended in published  U.S. guidelines. Individuals with Lynch syndrome from fam-  ilies with Muir- Torre should have annual dermatologic  examinations to screen for cutaneous sebaceous neoplasms.  At present there are no recommendations for screening for  pancreatic or central nervous system tumors because of lack  of evidence to support effectiveness.   Prophylactic surgery may be considered as an alternative to  annual screening. For the majority of Lynch syndrome  patients who are compliant with surveillance colonoscopies,  prophylactic surgery is unlikely to be necessary. For some  who develop early or multiple adenomas or for whom  colonoscopy is painful, prophylactic colectomy may be a  good option. Individuals who develop colorectal neoplasms  requiring surgical resection should be offered extended  resections with a subtotal colectomy, because the risk for  metachronous lesions is high. Individuals who have had  subtotal colectomies can then have screening of their resid-  ual colonic mucosa via flexible sigmoidoscopy.   Women should be counseled that there is limited evi-  dence regarding the impact of endometrial screening on  morbidity and mortality from endometrial cancer, and that  prophylactic hysterectomy and oophorectomy may be the  most effective way to reduce risks of gynecologic cancer.   Genetic testing for MMR gene mutations associated with  Lynch syndrome is increasingly available in clinical settings  and provides the opportunity to confirm the diagnosis of  Lynch syndrome in a family and to test other individuals in  order to stratify their cancer risk.   The PREMM1.2 model is a Web-based clinical prediction  rule designed for use by health care professionals to estimate  the probability that an individual carries a mutation in  MLH1 or MSH2 (available from the Dana Farber Cancer  Institute, at http://www.dfci.org/premm). Individuals whose  personal and family history produces a PREMM1,2 model  score of more than 5% should undergo molecular evaluation  for Lynch syndrome.   The most efficient strategy for genetic testing is to begin  genetic evaluation with an individual who has a cancer diag-  nosis. For individuals who meet the Bethesda guidelines, the   American Gastroenterological Association recommends  starting with evaluation of a CRC tumor specimen for fea-  tures of microsatellite instability and loss of immunohisto-  chemical staining for MLH1, MSH2, MSH6, and PMS2  proteins. As 90% of the CRC tumors in MM R gene mutation  carriers demonstrate high levels of microsatellite instability  or abnormal staining for MMR proteins, this pathologic test-  ing can serve as a prescreening method to select individuals  who should undergo germline testing for MMR mutations.   Clinical genetic testing for germline mutations in the  MLH1, MSH2, and MSH6 genes can be performed on DNA  extracted from a peripheral blood sample. Clinical laborato-  ries specializing in genetic testing perform full gene sequenc-  ing and southern blot analysis for large genomic deletions in  these MMR genes. If testing reveals a pathogenic mutation in  any of these genes, then testing is considered informative and  mutation-specific testing can be offered (at greatly reduced  cost) to other family members to determine who has and has  not inherited the genetic predisposition to cancer. If testing  in a cancer-affected individual fails to reveal a mutation, then  genetic testing is considered uninformative and a clinical  determination must be made about whether the suspicion  for Lynch syndrome is sufficiently high to recommend Lynch  syndrome cancer surveillance to all members of the family.   Cost-effectiveness models support the use of genetic test-  ing for cancer risk stratification in Lynch syndrome families,  and evidence supports the idea that knowledge of a gene  mutation makes individuals more likely to comply with the  intense cancer screening required for cancer prevention. The  high cost of commercial genetic testing for germline MMR  mutations (at present, -$2000 U.S.), the difficulties in inter-  preting and explaining uninformative genetic testing results,  and the complexities of family dynamics are challenges in  clinical genetic testing. The American Society for Clinical  Oncology recommends that genetic testing be performed in  conjunction with genetic counseling, which is available  through most major cancer centers.   Aarnio M, Mecklin JP, Aaltonen LA, et al. Life-time risk of differ-  ent cancers in hereditary non-polyposis colorectal cancer  (HNPCC) syndrome, hit J Cancer. 1995;64:430-433. [PMID:  8550246]   Balmana J, Stockwell D, Steyerberg E, et al. Prediction of MLH1  and MSH2 mutations in Lynch syndrome. JAMA. 2006;296:  1469-1478. [PMID: 17003395]   Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in  Amsterdam-I criteria families without mismatch repair defi-  ciency: familial colorectal cancer type X. JAMA. 2005;293:  1979-1985. [PMID: 15855431]   Lindor NM, Petersen GM, Hadley DW, et al. Recommendations  for the care of individuals with an inherited predisposition to  Lynch syndrome: a systematic review. JAMA. 2006;296:  1507-1517. [PMID: 17003399]   Ramsey SD, Clarke L, Etzioni R, et al. Cost-effectiveness of micro-  satellite instability screening as a method for detecting heredi-  tary nonpolyposis colorectal cancer. Ann Intern Med. 2001;135  (8 Pt l):577-588. [PMID: 11601929]   Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda  Guidelines for hereditary nonpolyposis colorectal cancer  (Lynch syndrome) and microsatellite instability. / Natl Cancer  Inst. 2004;96:261-268. [PMID: 14970275]   Familial adenomatous polyposis (FAP) is the second most  common inherited CRC syndrome. The classic FAP pheno-  type is one of hundreds to thousands of adenomatous polyps  in the colon, with a nearly 100% risk of developing CRC by  middle age if the affected individual's colon is not surgically  removed. FAP accounts for approximately 1% of CRC cases.  The incidence of FAP is approximately 1 in 10,000 persons.  Although most cases arise in families with a known history  through autosomal-dominant inheritance, approximately  30% of cases emerge as de-novo gene mutations in the APC  gene. Consequently, absence of a family history of polyposis  does not exclude FAP.   Most individuals with classic familial polyposis develop  numerous colorectal adenomas by the second or third  decade of life. These adenomas are usually discovered during  endoscopic evaluation for symptoms such as bleeding or  diarrhea, or during routine screening in individuals with a  known family history of FAP. Unfortunately, affected indi-  viduals who do not undergo early endoscopic evaluation and  prophylactic colectomy often present with CRC by the fifth  decade of life.   More than half of individuals affected with colonic poly-  posis develop adenomatous polyps in the upper gastrointesti-  nal tract. After adenocarcinoma of the colorectum, duodenal  and ampullary adenocarcinoma is the second leading cause of  cancer death for FAP patients. Fundic gland polyps are com-  mon in the stomach; however, these are not known to have  significant potential for malignant transformation.   Extracolonic malignancies associated with FAP include  papillary thyroid cancer, adrenal carcinomas, and central  nervous system tumors (Turcot syndrome). Children have an  increased risk of developing hepatoblastomas and require  screening with liver ultrasound scans and serum a- fetoprotein  during the first 7 years of life. Intra-abdominal desmoid tumors  can appear in some individuals with FAP, often arising after  abdominal surgery. Although not considered malignancies,  desmoid tumors can result in significant morbidity when  they involve the mesentery and vasculature. Desmoid tumors  define the Gardner syndrome variant of FAP and may be  associated with mutations in a certain region of the APC  gene.   Other physical findings associated with FAP include the  presence of extra teeth, osteomas of the jaw and skull, and epi-  dermoid cysts. Congenital hypertrophy of the retinal pigment   epithelium is an ophthalmologic finding that should prompt  evaluation for FAP.   Most cases of FAP are caused by germline mutations in the  adenomatous polyposis coli {APC) gene. Although most indi-  viduals with APC gene mutations inherited them from an  affected parent, approximately one third of patients with  FAP have new mutations in the APC gene and consequently  do not have a family history of the disease.   The APC gene functions as a tumor suppressor. Loss of  APC function in colonic epithelial cells is the first step  toward neoplastic transformation, and somatic mutations in  APC can be found in 80% of sporadic colon cancer tumors.  Germline mutations in APC are believed to be 100% pene-  trant and result in the development of hundreds to thou-  sands of colorectal adenomas.   Mutations in the APC gene are detected in more than  80% of patients with the classic FAP phenotype of hundreds  to thousands of adenomas. Recent reports indicate that up to  30% of individuals with classic polyposis phenotypes with-  out detectable APC mutations may have homozygous muta-  tions in MYH, sl base excision repair gene. Patients with  MYH-associated polyposis can present with a similar pheno-  type to classic APC-associated FAP, but with an autosomal-  recessive pattern of inheritance.   Patients at risk of developing FAP should begin annual col-  orectal screening for polyps with flexible sigmoidoscopy or  colonoscopy by age 1 1 . Most affected individuals will develop  colorectal adenomas during their teenage years or early  twenties. Once colorectal adenomas are too numerous to be  removed endoscopically, surgical removal of the colon is  required. Total proctocolectomy with ileoanal anastomosis is  the preferred operation. Other less-extensive surgeries, such  as total colectomy with ileorectal anastomosis, leave some  colonic mucosa behind that is at risk for neoplastic transfor-  mation and requires frequent endoscopies or use of chemo-  preventive agents (eg, cyclooxygenase-2 [COX-2] inhibitors  or sulindac) to control the growth of polyps.   Once patients are found to have colorectal adenomas,  upper endoscopy is recommended to assess for adenomas in  the duodenum and ampulla. A side-viewing upper endoscope  should be used to examine the ampulla and perform biopsies.  Duodenal or ampullary adenomas can be managed through  endoscopic resection or medications (COX-2 inhibitors, sulin-  dac) to reduce polyp burden. In rare cases, extensive adeno-  matous involvement, severe dysplasia, or adenocarcinoma is  present, which requires surgical resection of the duodenum.   Patients with FAP are at increased risk for papillary thy-  roid cancer, and some guidelines recommend screening   Family members of individuals with FAP should be  offered genetic testing for the gene mutation identified in the  family in order to stratify their risk. In cases in which an indi-  vidual does not undergo genetic testing or a genetic mutation  cannot be identified in the family, at-risk family members  should undergo colorectal screening with flexible sigmoi-  doscopy or colonoscopy every 1-2 years starting at age 11.   Genetic testing is now part of standard of care for risk strat-  ification of family members of patients with a clinical diag-  nosis of FAP. Genetic evaluation should start with the  proband with the polyposis phenotype, and should begin  with testing for mutations in the APC gene. Full gene  sequencing tests identify APC gene mutations in more than  80% of patients with classic polyposis phenotypes. If an APC  mutation is not identified, then testing for biallelic mutations  in the MYH gene may be considered. At present, Y165C and  G382D are the two most common mutations in the MYH  gene, and full gene sequencing of MYH is performed in indi-  viduals who are found to have one of these two mutations.  When genetic testing for APC and MYH in patients with clas-  sic polyposis fails to identify a genetic mutation, all family  members must be considered at risk for developing FAP and  should undergo colorectal screening as previously described.   Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adeno-  mas, classic adenomatous polyposis, and germ-line mutations  in MYH. N Engl] Med. 2003;348:791-799. [PMID: 12606733]   Individuals with 10-100 colorectal adenomas are considered  to have a phenotype of multiple or attenuated polyposis.  There is marked phenotypic and genotypic heterogeneity  among patients with attenuated polyposis and estimates of  the risk of CRC vary widely, ranging from two times above  population risk to as high as 80% for some patients. Some  individuals with APC gene mutations in the 3' or 5' ends of  the gene or with biallelic MYH mutations present with an  attenuated polyposis phenotype, rather than with classic  FAP. Current practice guidelines recommend genetic evalua-  tion for patients with more than 20 colorectal adenomas;  however, genetic testing for APC and MYH mutations is  uninformative for many individuals with fewer than 100 ade-  nomas and it is possible that other genetic or environmental  factors may be involved in the pathogenesis.   Cancer prevention in patients with attenuated polyposis  focuses on frequent endoscopic surveillance with polypec-  tomies to clear the colonic mucosa of adenomas; if adeno-  mas are too numerous or recur too quickly to be managed  endoscopically, then surgical colectomy may be indicated.   Individuals with attenuated polyposis may require colono-  scopies every 1-2 years, with the option to increase or  shorten the surveillance interval based on the rate of polyp  growth. Family members of affected individuals should  begin colonoscopic screening 5-10 years younger than the  age at which polyps appeared in the proband. In cases of  attenuated polyposis associated with an APC mutation, it is  recommended that at-risk individuals follow FAP screening  guidelines (see earlier discussion), because classic and  attenuated phenotypes have been described among mem-  bers of the same family. Individuals with biallelic MYH  gene mutations should have colonoscopies and upper  endoscopies every 1-2 years beginning at age 25.   Peutz-Jeghers syndrome (PJS) is characterized by multiple  intestinal hamartomatous polyps; mucocutaneous pigmenta-  tion, which characteristically involves the lips; and a high life-  time risk of gastrointestinal, pancreatic, and breast cancers.   Individuals with PJS develop hamartomatous polyps  throughout their gastrointestinal tract and can typically  present with abdominal pain, stool that is positive for occult  blood, obstruction, or intussusception. The clinical diagnosis  of PJS can be made in individuals who have hamartomatous  polyps and two of the following features: (1) labial melanin  deposits, (2) small bowel polyps, or (3) family history of PJS.  PJS is also associated with increased risk for gastrointesti-  nal cancers (colon, small intestine, stomach, pancreas), breast  cancer, and sex cord tumors. Recent reports suggest patients  with PJS have greater than 85% risk of developing cancer by  age 70. Lifetime risks for colon, pancreatic, and breast can-  cers are estimated at 39%, 36%, and 54%, respectively.   PJS demonstrates an autosomal-dominant pattern of inheri-  tance. Mutations in STK-11, a serene/threonine kinase gene  with tumor suppressor function, have been found in approx-  imately 50% of PJS patients. Research is ongoing to identify  other genes that may be implicated in other PJS patients.   Patients with PJS require careful endoscopic surveillance for  removal of polyps and screening for extraintestinal cancers.  Recommendations include upper endoscopy, colonoscopy,  and small bowel imaging (with small bowel series or capsule  endoscopy) every 2-3 years, with removal of all polyps  greater than 1-1.5 cm, which may require double-balloon   enteroscopy or intraoperative enteroscopy. Women should  have annual transvaginal ultrasound scans and serum CA-125  to screen for sex cord tumors and mammograms annually  starting at age 25. Boys may be offered annual testicular ultra-  sound scans from ages 2-12 years. Recent studies have sug-  gested that patients with PJS may benefit from pancreatic  cancer screening with endoscopic ultrasound every 1-2 years.   Giardiello FM, Trimbath JD. Peutz-Jeghers syndrome and man-  agement recommendations. Clin Gastroenterol Hepatol.  2006;4:408-415. [PMID: 16616343]   Wirtzfeld DA, Petrelli NJ, Rodriguez-Bigas MA. Hamartomatous  polyposis syndromes: molecular genetics, neoplastic risk, and  surveillance recommendations. Ann Surg Oncol. 2001;8:319-327.  [PMID: 11352305]   Juvenile polyposis is characterized by the appearance of mul-  tiple juvenile polyps and increased risk for gastrointestinal   Patients with juvenile polyposis typically have multiple  (more than five) juvenile polyps and a family history of gas-  trointestinal cancer. Many affected individuals present with  symptoms such as anemia, bleeding, or abdominal pain dur-  ing childhood. There is also an association with cardiac  abnormalities and other congenital anomalies. Patients are at  increased risk for colorectal, gastric, duodenal, and pancre-  atic cancers, many of which appear at young ages.   Juvenile polyposis has an autosomal-dominant pattern of  inheritance. Mutations in the SMAD4 and BMPRla genes, as  well as in the PTEN gene, have been identified in some  patients. Clinical genetic testing is available, but in many  cases is uninformative, because many affected individuals do  not have detectable mutations.   Patients with a family history of juvenile polyposis should  undergo colorectal screening every 1-3 years starting at age 12.  Affected individuals should have frequent upper endoscopy  and colonoscopy for removal of polyps; in some cases colec-  tomy is required for management of polyp burden.   This hereditary syndrome is characterized by juvenile polyps  in the gastrointestinal tract, skin lesions (trichilemmomas),  macrocephaly, and increased risk for breast and thyroid   cancers. Cowden syndrome is associated with mutations in  the PTEN gene. In contrast to juvenile polyposis, there does  not appear to be an increased risk for gastrointestinal cancers  in Cowden syndrome.   Hereditary diffuse gastric cancer (HDGC) manifests as dif-  fuse infiltrative adenocarcinoma of the stomach occurring in  families in a pattern of autosomal-dominant inheritance,  often affecting young individuals.   In contrast to most gastric cancers which appear as ulcers or  masses, diffuse gastric cancer usually presents as diffuse  thickening of the stomach wall or linitis plastica, without an  obvious endoscopic lesion. The International Gastric Cancer  Linkage Consortium has defined HDGC as (1) two or more  relatives with diffuse gastric cancer diagnosed before age 50  or (2) three or more relatives with diffuse gastric cancer diag-  nosed at any age. The lifetime risk of gastric cancer for indi-  viduals in these families has been estimated to be as high as  70%, and there are numerous reports of cancer diagnoses in  individuals younger than 18 years of age. Studies have sug-  gested there is also an increased risk of breast cancer in  affected families.   One third of families who meet criteria for HDGC have  germline mutations in the E-cadherin/CDHl tumor suppres-  sor gene. E-cadherin/CDHl gene mutations were first identi-  fied in Maori families with gastric cancer in New Zealand.  Genetic testing for HDGC is not yet widely available, how-  ever, clinical testing for CDH1 gene mutations can be per-  formed by select laboratories. If a pathogenic mutation is  identified in a proband, then the mutation can be confirmed  by commercial laboratories and testing can be offered to  other family members.   Prevention of gastric cancer among individuals at increased  risk is challenging because endoscopic screening has been  shown to have poor sensitivity for detecting diffuse gastric  cancer. Consequently, prophylactic gastrectomy is recom-  mended for mutation carriers and other patients at highest  risk. Prophylactic gastrectomy carries with it considerable  morbidity; however, expert panels have concluded that the   70% risk of developing gastric cancer among CDH1 muta-  tion carriers justifies prophylactic gastrectomy. Given the  increased risk of breast cancer among CDH1 mutation carri-  ers, early screening with mammography or breast magnetic  resonance imaging scan, or both, is recommended.   Blair V, Martin I, Shaw D, et al. Hereditary diffuse gastric cancer:  diagnosis and management. Clin Gastroenterol Hepatol.  2006;4:262-275. [PMID: 11561603]   Although the vast majority of cases of pancreatic adenocar-  cinoma are sporadic, 3-10% seem to have a hereditary com-  ponent. Risk varies from twofold to as high as 18-57-fold for  families with two or three affected relatives. FPC is most  often defined as families in which there are two or more first-  degree relatives or three or more relatives with pancreatic  adenocarcinoma.   Studies of FPC kindreds have identified pathogenic  genetic mutations in approximately 20% of cases; thus, for  the majority of families a genetic cause of the pancreatic can-  cer cannot be found. FPC families may benefit from genetic  evaluation for the following hereditary cancer syndromes:   1. Hereditary breast/ovarian cancer (HBOC; BRCA1/  BRCA2)— Mutations in the BRCA1 and BRCA2 genes  account for the great majority of genetic mutations identi-  fied among pancreatic cancer families. Several studies have  reported that prevalence of pancreatic cancer among families  with HBOC is increased. The relative risk of developing pan-  creatic cancer for mutation carriers has been estimated as  2.26 for BRCA1 and 3.5-8 for BRCA2. In some HBOC fami-  lies, the pancreatic cancer history overshadows the breast  cancers. Consequently, it is recommended that evaluations  for FPC begin with testing for mutations in BRCA1 and  BRCA2.   2. Familial atypical multiple mole melanoma  (FAMMM; P16/CDKN2A)— FAMMM is defined as more  than 50 atypical nevi and malignant melanoma in two or  more first- or second-degree relatives. Pancreatic cancer has  been reported in nearly one fourth of FAMMM families.  Many of these FAMMM families with pancreatic cancer  appear to have germline mutations in the gene P16/CDKN2A  (cyclin dependent kinase 2A). Carriers of a specific type of  CDKN2A mutation appear to have a cumulative risk of pan-  creatic cancer of approximately 17% by age 75.   3. Peutz-Jeghers syndrome— Individuals with PJS are  most commonly characterized by their hamartomatous gas-  trointestinal polyps and mucocutaneous pigmentation, and  approximately half are found to have germline mutations in  the STK11 gene. In addition to conferring increased risk for  breast cancer, PIS also confers an increased predisposition to  pancreatic adenocarcinoma, with a lifetime risk of 36%.   4. Lynch syndrome (HNPCC)— Pancreatic cancer is one of  the gastrointestinal cancers that has been reported in  HNPCC, and lifetime risk appears to be approximately  5-10% for MMR gene mutation carriers.   5. Hereditary pancreatitis— Hereditary pancreatitis often  presents as repeated episodes of pancreatic inflammation,  ultimately resulting in chronic pancreatitis. In familial cases,  there is evidence of autosomal-dominant inheritance and  mutations of the cationic trypsinogen gene (PRSS1) are  found in 70% of kindreds. Mutations in the serene protease  inhibitor Kazal 1 (SPINK1) gene have also been identified in  some families. These mutations cause failure to inactivate  trypsin, resulting in chronic pancreatitis, and confer a life-  time risk of pancreatic cancer of 40% by age 70.   Genetic counseling in patients with a genetic predisposition  for pancreatic cancer should emphasize that in the majority  of cases genetic testing does not reveal mutations in any of  the genes known to be associated with pancreatic cancer.  Advantages of pursuing genetic testing include the potential  for identifying a mutation so that at-risk family members can   undergo predisposition genetic testing and risk stratification.  Also, identifying a mutation may affect cancer screening rec-  ommendations for the affected proband, as well as for the at-  risk family members. Disadvantages include the fact that  genetic testing may need to be repeated for many different  genes, may be costly, and may not identify a genetic cause.   Patients with a family history of pancreatic cancer should  be advised to stop cigarette smoking, as this has been found  consistently to be an important risk factor for pancreatic can-  cer. Studies are ongoing to assess the utility of specialized pan-  creatic cancer screening for early detection and prevention of  pancreatic cancer in individuals at increased risk. Endoscopic  ultrasound, helical computed tomography scanning, magnetic  resonance cholangiopancreatography, and endoscopic retro-  grade cholangiopancreatography have been used alone and in  combination to try to detect abnormalities that may be precur-  sors to pancreatic cancer, with the goal of timely pancreatic  resection for high-risk lesions. As total pancreatectomy can be  associated with significant morbidity, experts currently recom-  mend that patients at high risk for pancreatic cancer undergo  screening as part of a research study.   Klein AP, Hruban RH, Brune KA, et al. Familial pancreatic cancer.  Cancer J. 2001;7:266-273. [PMID: 11561603]   ► In the United States, irritable bowel syndrome (IBS) is  most common in young women.   ► Rome III criteria include recurrent abdominal pain or  discomfort at least 3 days per month in the last 3 months  associated with two or more of the following:   ► Onset associated with a change in form (appearance) of  stool.   ► Criteria fulfilled for the past 3 months, with symptom  onset at least 6 months prior to diagnosis.   ► Rule out "red flag" symptoms before making a diagnosis  of IBS.   ► IBS can be mild, moderate, or severe; four different sub-  types are constipation predominant, diarrhea predomi-  nant, mixed, and unsubtyped.   ► The Bristol Stool Form Scale is helpful clinically in defining  the spectrum of diarrhea to constipation.   IBS affects 10-20% of the adult U.S. population, is the most  common diagnosis made by gastroenterologists, and is one  of the top 10 reasons for visits to primary care physicians. IBS  is the most common functional bowel disorder and affects  predominantly women (70% of patients). This may be due to  the fact that women more easily report their symptoms of  abdominal pain, gas, bloating, and altered bowel movements.  It may also be due to hormonal differences between men and  women that may affect gut function and alter perception of  pain related to abdominal distention. IBS can cause great dis-  comfort, sometimes intermittent or continuous, for many  decades in a patient's life and can have a significantly nega-  tive impact on quality of life.   The prevalence of IBS in a typical primary care practice is  12% and in a typical gastroenterology practice, 28%. The  estimated total yearly cost of IBS in the United States is  $21 billion. One billion dollars is spent in direct costs such  as diagnostic tests, physician and emergency department  visits, hospitalizations, surgeries, and medications; $20 billion  is spent on intangible costs such as reduced work produc-  tivity, absenteeism, and travel to consultations. The intangible  costs of IBS are human suffering and impaired quality of life.  IBS sufferers incur 74% more health care costs than non-IBS  sufferers.   IBS primarily affects people in the prime of their lives,  mostly between the ages of 20 and 40 years. Patient surveys  from both the United States and the United Kingdom report  an average disease duration of 11 years, with one third of  patients having symptoms for much longer. For many  patients, symptoms occur frequently and significantly impair  emotional, physical, and social well-being. Almost three  fourths of patients report symptoms more than once a week  and about half report daily symptoms. In a telephone survey  of female IBS sufferers in the United States, almost 40%  reported pain and discomfort as intolerable without relief.  Women with IBS reported 71% more abdominal surgeries  than women without IBS (58% vs 34%). The rates of gall-  bladder operations, hysterectomies, and appendectomies  were twice as high or higher among women with IBS. Twenty-  five percent had been hospitalized overnight due to symp-  toms. Seventy-eight percent of women had limits on what  they ate, 43% had limits on sports and recreational activity,  43% on social activity, 40% on vacation or travel, and 28% on  sexual activity. Two thirds of women were concerned about  restroom availability wherever they went, one third avoided  group meetings, and 25% got up earlier for work. Even more  frustrating was that only 39% of women were diagnosed with  IBS by the first physician they saw; 3% saw eight or more  physicians before receiving a diagnosis. Time from onset to  diagnosis took an average of 3 years, and patients saw an aver-  age of three physicians before getting a diagnosis.   Patients with IBS were absent from work or school an  average of 13 days per year compared with 5 days per year  (P < .001) in patients without IBS. In another study, the qual-  ity of life of patients with IBS was significantly worse than  that of patients with migraines, asthma, or gastroesophageal  reflux disease. For this study, quality of life was measured in  multiple domains, including physical functioning, pain, general  health, vitality, social functioning, emotional functioning, and  mental health.   Only about 25% of IBS patients actually consult a physi-  cian for their symptoms. Of these, only a small percentage  visit a gastroenterologist. Patients who consult a primary  care physician for their symptoms usually have mild symp-  toms and effective coping skills and social support. Of IBS  patients who consult subspecialists, 60% or more may have  psychological disturbances, including anxiety, somatoform  or personality disorders, or chronic pain syndromes. Up to  35% of women who consult subspecialists for IBS have a his-  tory of sexual abuse.   Creed F, Ratcliffe J, Fernandez L et al. Health-related quality of life  and health care costs in severe, refractory irritable bowel syn-  drome. Ann Intern Med. 2001;134:860-868. [PMID: 11346322]   Drossman DA. The functional gastrointestinal disorders and the  Rome III process. Gastroenterology. 2006;130:1377-1390. [PMID:  16678553]   Drossman DA, Morris CB, Hu Y, et al. A prospective assessment of  bowel habit in irritable bowel syndrome in women: defining  an alternator. Gastroenterology. 2005;128:580-589. [PMID:  15765393]   Faresjo A, Grodzinsky E, Johansson S, et al. A population-based  case-control study of work and psychological problems in  patients with irritable bowel syndrome-women are more seri-  ously affected than men. Am J Gastroenterol. 2007;102: 371-379.  [PMID: 17156145]   Houghton LA, Lea R, Agrawal A, et al. Relationship of abdominal  bloating to distention in irritable bowel syndrome and effect of  bowel habit. Gastroenterology. 2006;131:1003-1010. [PMID:  17030170]   Locke GR III, Zinsmeister AR, Fett SL, et al. Overlap of gastroin-  testinal symptom complexes in a US community. Neurogastroenterol  Motil. 2005;17:29-34. [PMID: 15670261]   Longstreth GF, Thompson WG, Chey WD, et al. Functional  bowel disorders. Gastroenterology. 2006;130:1480-1491. [PMID:  16678561]   Although disturbances in small bowel motility have been  reported in IBS, none appear specific for the condition. Small  bowel motility shows marked diurnal variability and hence  consistent results can only be obtained with prolonged (at  least 24 hour) recordings and large numbers of subjects. Small  bowel motor disturbances reported include increased fre-  quency and duration of discrete cluster contractions (DCC),  increased frequency of the migrating motor complex (MMC),   more retrograde duodenal and jejunal contractions, and an  exaggerated motor response to meal ingestion, ileal disten-  tion, and cholecystokinin (CCK). Corticotrophin-releasing  hormone (CRH) has been reported to increase the number  of DCCs. Small bowel transit is faster in IBS patients with  diarrhea (IBS-D) compared with constipation (IBS-C) and  unlike in healthy controls, colonic distention does not  appear to reduce duodenal motility in IBS patients, suggest-  ing an impaired intestine-intestinal inhibitory reflex. The  most consistent abnormality in the colon is an exaggerated  motility response to meal ingestion. Rectal compliance or  increased tension, or both, has also been reported in some  studies in patients with IBS. This has been proposed as a pos-  sible mechanism for enhanced visceral sensation to balloon  distention in IBS.   Abdominal pain and discomfort cause considerable morbid-  ity in IBS patients and are essential components of the  Rome III criteria for diagnosis of IBS. Approximately two  thirds of IBS patients demonstrate heightened pain sensitivity  to experimental gut stimulation, a phenomenon known as  visceral hypersensitivity. Visceral hypersensitivity is thought  to play an important role in the development of chronic pain  and discomfort in IBS patients. It results from a combination  of factors that involve both the peripheral and central nervous  systems. During tissue injury, peripheral nociceptor terminals  are exposed to a mixture of immune and inflammatory  mediators, such as prostaglandins, leukotrienes, serotonin,  histamine, cytokines, neurotrophic factors, and reactive  metabolites. These inflammatory mediators act on nociceptor  terminals, leading to the activation of intracellular signaling  pathways, which in turn upregulate their sensitivity and  excitability. This phenomenon has been termed peripheral  sensitization. Peripheral sensitization is believed to cause  pain hypersensitivity at the site of injury or inflammation,  also known as primary hyperalgesia (increased sensitivity  to painful stimuli) and allodynia (nonpainful stimuli are  perceived as painful).   A secondary consequence of peripheral sensitization is  the development of an area of hypersensitivity in the  surrounding uninjured tissue (secondary hyperalgesia or  allodynia). This phenomenon occurs due to an increase in  the excitability and receptive fields of spinal neurons and  results in recruitment and amplification of both non-nociceptive  and nociceptive inputs from the adjacent healthy tissue.   Depending on the setting, about 6-17% of patients with  IBS report their symptoms began with an episode of gut  inflammation due to gastroenteritis. In addition, an increase  in mucosal T lymphocytes has been reported in patients with  IBS. Therefore, the environment of nociceptor terminals in  the gut of IBS patients is likely to be altered, suggesting a role  for peripheral sensitization. Evidence for central sensitization  as an important mechanism for the development of visceral   hypersensitivity in IBS patients conies from three main  observations. First, in response to colon stimulation,  patients with IBS have greater radiation of pain to somatic  structures in comparison with healthy subjects. Second, a  proportion of IBS patients also suffer from fibromyalgia, a  condition characterized by somatic hyperalgesia. Finally,  patients with IBS also often demonstrate hypersensitivity of  proximal areas of the gut. The innervation of the different  gut organs overlaps and converges with that of the somatic  structures at the level of the spinal cord, and these phenom-  ena can be explained by central sensitization of the spinal  segments that demonstrate viscerovisceral and visceroso-  matic convergence.   Alterations in brain processing in IBS patients can also  contribute to visceral hypersensitivity. Brain imaging studies  have begun to address the possible neural mechanisms of  hypersensitivity in IBS patients, and a common finding has  been compared with healthy controls; patients with IBS  exhibit altered or enhanced activation of regions involved in  pain processing, such as the anterior cingulated cortex, thal-  amus, insula, and prefrontal cortices, in response to experi-  mental rectal pain.   The prevalence of postinfective IBS varies from 17% in pri-  mary care in the United Kingdom to as little as 6% in terti-  ary care in the United States. Population surveys indicate a  relative risk of 11.1-11.9% of developing IBS in the year fol-  lowing a bout of gastroenteritis. Known risk factors include  the severity of the initial illness; bacterial toxigenicity; female  sex; a range of adverse psychological factors, including neu-  roticism, hypochondriasis, anxiety, and depression; and  adverse life events. Postinfective IBS has been reported after  Shigella, Salmonella, and Campylobacter infections and does  not appear specific to any organism.   Histologic studies indicate that postinfective IBS is char-  acterized by increased lymphocyte numbers in mucosal  biopsies, an effect that is seen throughout the colon. Where  the terminal ileum has been biopsied, increased mast cells  have also been noted. Another change following inflamma-  tion is enterochromaffin cell hyperplasia. Whereas in most  subjects, these changes resolve within 3 months, in IBS  patients the levels of both lymphocytes and enteroen-  docrine cells remain elevated. Increased enterochromaffin  cell numbers are associated with an increase in post-  prandial 5-HT release, an abnormality shown in both  postinfective IBS and in diarrhea-predominant IBS without  an obvious postinfective origin. Immediately after gas-  troenteritis affecting the small bowel, there may be tran-  sient lactose intolerance, which is particularly obvious in  young children. However, in adults with postinfective IBS,  who by definition have had symptoms for over 6 months, the  incidence of lactose malabsorption is no different from unin-  fected controls.   The response of an organism to external stressors is mediated  through the integration of the hypofhalamic-pituitary-adrenal  axis (HPA) and the sympathetic branch of the autonomic  nervous system with the host immune system. A recent  model for the pathogenesis of IBS proposes altered stress cir-  cuits in predisposed individuals, which are triggered by  external stressors resulting in the development of gut symp-  toms. In postinfective IBS, the persistence of chronic inflam-  matory mucosal changes and enterochromaffin cell  hyperplasia that persists after eradication of the infectious  organism are consistent with an inadequate physiologic  response to gut inflammation, in particular, an inadequate  Cortisol or altered sympathetic response. The key interplay  between the autonomic nervous system and the HPA axis in  regulating gut mucosal immunology has been explored  through research looking at how the stress response, which  activates both of these systems, may be important in IBS.  Environmental stressors are important in predisposing  toward IBS and in perpetuating the symptoms of IBS. Prior  life stressors and a history of childhood abuse predispose  toward developing IBS in later life. Psychiatric illness  episodes or anxiety-provoking situations preceded the onset  of bowel symptoms in two thirds of IBS patients being  treated in tertiary care centers; in addition, IBS patients  report significantly more negative life events than matched  peptic ulcer patients. In addition, psychological traits such  as hypochondriasis, anxiety, and depression predispose pre-  viously healthy individuals who develop gastroenteritis to  go on to develop symptoms of IBS. In fact, a subgroup of  IBS patients have an exaggerated endocrine stress response,  as shown by a heightened release of adrenocorticotropic  hormone and Cortisol in response to exogenous corti-  cotropin-releasing factor administration. This exaggerated  stress response seems to be associated with mucosal  immune activation.   Arroll B, Goodyear-Smith F, Kerse N, et al. Effect of the addition of  a "help" question to two screening questions on specificity for  diagnosis of depression in general practice: diagnostic validity  study. BMJ. 2005;331:884. [PMID: 16166106]   Bengtson MB, Ronning T, Vatn MH, et al. Irritable bowel syn-  drome in twins: genes and environment. Gut. 2006;55:1754-1759.  [PMID: 17008364]   Braun T, Voland P, Kunz L, et al. Enterochromaffin cells of the  human gut: sensors for spices and odorants. Gastroenterology.  2007;132:1890-1901. [PMID: 17484882]   Creed F, Ratcliffe J, Fernandez L, et al. Outcome in severe irritable  bowel syndrome with and without accompanying depressive,  panic, and neurasthenic disorders. Br } Psychiatry. 2005;186:  507-515. [PMID: 11346322]   Dickhaus B, Mayer EA, Firooz N, et al. Irritable bowel syndrome  patients show enhanced modulation of visceral perception by  auditory stress. Am ] Gastroenterol. 2003;98:135-143. [PMID:  12526949]   Dinan TG, Quigley EM, Ahmed SM, et al. Hypothalamic-pituitary-  gut axis dysregulation in irritable bowel syndrome: plasma  cytokines as a potential marker? Gastroenterology. 2006; 130:  304-311. [PMID: 16472586]   Guilarte M, Santos J, de Torres I, et al. Diarrhoea-predominant IBS  patients show mast cell activation and hyperplasia in the  jejunum. Gut. 2007;56:203-209. [PMID: 17005763]   Liegregts T, Adam B, Bredack C, et al. Immune activation in  patients with irritable bowel syndrome. Gastroenterology.  2007;132:913-920. [PMID: 17383420]   Marshall JK, Thabane M, Borgaonkar MR, et al. Postinfectious irri-  table bowel syndrome after a food-borne outbreak of acute gas-  troenteritis attributed to a viral pathogen. Clin Gastroenterol  Hepatol. 2007;5:457-460. [PMID: 17289440]   Naliboff BD, Berman S, Suyenobu B, et al. Longitudinal change in  perceptual and brain activation response to visceral stimuli in  irritable bowel syndrome patients. Gastroenterology. 2006;131:  352-365. [PMID: 16890589]   Table 24-1. Rome III diagnostic criteria 3 for irritable  bowel syndrome.   Recurrent abdominal pain or discomfort' at least 3 days per month in  the last 3 months associated with 2 or more of the following:   • Onset associated with a change in form (appearance) of stool   Criteria fulfilled for the last 3 months with symptoms onset at least  6 months prior to diagnosis.   b Discomfort means an uncomfortable sensation not described as  pain. In pathophysiology research and clinical trials, pain or discom-  fort freguency of at least 2 days a week during screening evaluation  for subject eligibility   IBS is a disease that can be caused by many factors. Disturbed  bowel motility, visceral hypersensitivity, bacterial over-  growth, and psychological problems can all contribute to  causing or exacerbating IBS. There are several important,  take-home points in treating IBS. First, clinicians must take a  good history and rule out "red flags." Celiac sprue, bacterial  overgrowth, and microscopic colitis, among many other con-  ditions, can masquerade as IBS. Second, clinicians should  provide reassurance and close follow-up at first to make sure  the diagnosis is correct. Recall that the Rome III criteria have  high specificity in making the diagnosis of IBS. Third, despite  the lack of evidence-based studies, diet plays a role in exacer-  bating gastrointestinal symptoms and a good dietary history  should be taken. Fourth, clinicians should not forget the psy-  chological component of IBS. Many patients with IBS have  coexisting depression and anxiety, and patients with severe  IBS often have a history of physical and sexual abuse. Lastly,  there are only a few newer medications with good data from  randomized controlled trials. Given the paucity of specific  medicines with positive results in the evidence-based medical  literature, treatment is often a trial and error process. However,  a combination of dietary and lifestyle changes, relaxation  training or psychotherapy, and individualized IBS medicines  tailored to each patient's symptoms usually improves quality  of life.   As the Rome III criteria indicate (Table 24-1), the key fea-  tures are abdominal pain or discomfort that is clearly linked  to bowel function, either being relieved by defecation or  associated with a change in stool form or consistency.  These symptoms are not explained by biochemical or struc-  tural abnormalities. Symptoms should be present for at least  6 months to clearly distinguish those from other conditions  such as infections, which often pass quickly, or progressive   diseases such as bowel cancer that are usually diagnosed  within 6 months of symptoms onset. Symptoms that are  common in IBS but are not part of the Rome III criteria  include bloating, abnormal stool form (hard, loose, or both),  abnormal stool frequency (< 3 times/week or > 3 times/week),  straining at defecation, urgency, feeling of incomplete evac-  uation, and the passage of mucus per rectum. Most patients  experience flares intermittently, with symptoms lasting 2-4  days followed by periods of remission. In women, symp-  toms can be worse at the time of menstruation and can  cycle with the menstrual cycle. One common symptom of  IBS not part of the Rome III criteria is repeated defeca-  tion in the morning (morning rush) when stool consis-  tency changes from solid to liquid as the colon contents are  evacuated.   One important exception to the Rome III criteria is  patients who feel abdominal pain continuously. The diagno-  sis in this case is likely functional abdominal pain, an  unusual, particularly severe condition in which patients  respond poorly to treatment and often have severe underly-  ing psychological disturbances.   IBS is considered a painful condition and those with  painless bowel dysfunction are labeled as having "functional  constipation" or "functional diarrhea." Some of the distin-  guishing characteristics of IBS-C and functional constipation  are detailed in Table 24-2.   1. IBS subtype classification— The Rome III subclassifica-  tion is based solely on stool consistency and not frequency,  urgency, and straining and is thus easy to use (Table 24-3).  To better differentiate the different IBS subtypes, the Bristol  Stool Form Scale is very helpful clinically in defining the  spectrum of diarrhea to constipation (Table 24-4). Patients  with hard stools more than 25% of the time and loose stools  less than 25% of the time are classified as IBS-C, whereas  patients classified as having IBS with diarrhea (IBS-D) have  loose stools more than 25% of the time and hard stools less  than 25% of the time. About one third to one half of patients   Table 24-2. Comparison of irritable bowel syndrome  with constipation (IBS-C) with functional constipation.   are termed IBS-mixed (IBS-M) and have hard stools more  than 25% of the time and loose stools more than 25% of the  time. A small (4%) group of patients has unclassified IBS  (IBS-U), with neither loose nor hard stools more than 25% of  the time. Patients whose bowel habits change from one subtype  to another over months or years are known as "alternators."   2. IBS-associated nongastrointestinal symptoms and  comorbidity with other diseases— Nongastrointestinal  symptoms associated with IBS include backache; headache;  urinary symptoms such as nocturia, frequency, and urgency  of micturition; incomplete bladder emptying; and, in  women, dyspareunia. Helpful diagnostic behavioral features   Table 24-3. Subtyping of irritable bowel syndrome  by predominant stool pattern.    Hard or lumpy stools > 25% and  loose (mushy) or watery stools  < 25% of bowel movements    toose mushy or watery stools > 25%  of the time and hard or lumpy stool  < 25% of bowel movements    Hard or lumpy stools > 25% and  loose (mushy) or watery stools >  25% of bowel movements    Insufficient abnormality of stool  consistency to meet criteria for  IBS-C, D, or M   of IBS in general practice include symptoms present for more  than 6 months, frequent consultations for nongastrointestinal  symptoms, previous medically unexplained symptoms, and  patient reports that stress aggravates symptoms.   Between 20% and 50% of IBS patients also have  fibromyalgia. IBS is common is several other chronic pain  disorders, being found in 51% of patients with chronic  fatigue syndrome, 64% of those with temporomandibular  joint disorder, and 50% of those with chronic pelvic pain.  The lifetime rates of IBS in patients with these syndromes are  even higher: 77% in fibromyalgia, 92% in chronic fatigue  syndrome, and 64% in temporomandibular joint disorder. In  addition, those with overlap syndromes tend to have more  severe IBS. IBS patients in primary care with numerous other  somatic complaints report high levels of mood disorder,  health anxiety, neuroticism, adverse life events, and reduced  quality of life and increased health care seeking.   3. Psychological features— At least half of IBS patients can  be described as depressed, anxious, or hypochondriacal.  Studies from tertiary care centers suggest that up to two  thirds have a psychiatric disorder — most commonly depres-  sive or anxiety disorder. The clinician should always ask the  patients about any psychological problems, as well as take a  history of physical and sexual abuse. Suggested questions to  help assess mood include the following:   "During the past month, have you often been bothered by  feeling down, depressed, or hopeless?"   "During the past month have you been bothered by little  interest or pleasure in doing things?"   4. "Alarm" features— Certain "alarm" features indicate  that the diagnosis might not be IBS. It is very important to  take a careful history and perform a thorough physical   examination to rule out any such red flag symptoms, which  are detailed in Table 24-5. A follow-up observational study  lasting 24 months found that, in the absence of alarm fea-  tures, after full history, examination, and investigation no  IBS patients meeting Rome II criteria (the prior Rome criteria)  had another diagnosis. By contrast, a substantial number of  those not meeting the Rome II criteria were left with a final  diagnosis of IBS, suggesting that the Rome criteria in the  absence of alarm symptoms were highly specific but not  highly sensitive. A more recent study, which looked at a range  of alarm features, found that age greater than 50 years at  onset of symptoms, male sex, blood mixed in the stool, and  blood on the toilet paper were all predictors for an organic  diagnosis. Characteristic features of IBS in this study were  pain more than six times in the last year, pain that radiated  outside the abdomen, and pain that was associated with  looser bowel movements, all of which were much more com-  mon in IBS than in organic disease. Other features more  common in IBS included a childhood history of abdominal  pain, which was found in a quarter of subjects.   5. Physical findings — Physical examination of the patient  with IBS usually reveals no relevant abnormality. Important  red flags to look for are thyroid abnormalities, lym-  phadenopathy, abdominal masses, and perianal disease such as  anal fistulas, fissures, or skin tags. Abdominal wall pain origi-  nating from a hernia, local muscle injury, or a trapped nerve  can be elucidated by the Carnett test. This involves asking  patients to fold their arms across their chest and raise their  head off the pillow against gentle resistance from the physi-  cian's hand. Exacerbation of pain indicates a positive Carnett  test. Painful rib syndrome is characterized by point tenderness  and pain upon springing the rib cage and has a benign cause.  Checking for both of these common musculoskeletal prob-  lems can save a lot of time and money on diagnostic testing.   Basic laboratory screening should include compete blood  count, thyroid-stimulating hormone, and serologies for  celiac disease. All patients should have stool tested for fecal  occult blood (FOBT).   The basic indications for colonoscopy in this setting are age  50 or greater, positive FOBT or frank rectal bleeding, and a  family history of colon cancer.   Lactose intolerance is very common and has similar symp-  toms to IBS. It is seen in 7-20% of Caucasians, as high as  80-95% of Native Americans, 65-75% of Africans and  African Americans, and 50% of Hispanics. The prevalence is  greater than 90% in some populations in East Asia. The pre-  ferred method of testing is a hydrogen breath test. For  patients who are lactose intolerant, lactase preparations such  as Lactaid, Lactase, and Dairy Ease may help, but many patients  still have symptoms and will have to avoid all lactose-  containing food products.   Although there have been no controlled trials on diet and  IBS, certain foods can cause or exacerbate IBS symptoms and  a physicians should not forget to take a dietary history. Once  lactose intolerance is excluded, the biggest offenders are  sugar-free and carbohydrate-free or low-carbohydrate foods.  These foods contain sugar alcohols such as sorbitol, maltitol,  and xylitol. They are meant to be indigestible and as such can  cause cramping, flatulence, and diarrhea. Sorbitol is even  commercially available as a laxative. Diet soft drinks, flavored  water, chewing gum, and candies often contain these sugar  alcohols. Monosodium glutamate (MSG) can cause symp-  toms in sensitive individuals and is used as a flavoring in  Chinese food and other preparations commonly purchased at  the supermarket. Carbonated beverages contribute to gas and  bloating, and alcohol can cause gastritis and diarrhea.  Caffeine found in coffee, tea, soft drinks, or chocolate can  exacerbate abdominal cramps and diarrhea. Other specific  diets should be individualized, keeping in mind that there is  no evidence-based literature. A suggested diet plan created by  Christine Frissora, MD, and successful with her IBS patients  at Columbia University is detailed in Table 24-6. True food  allergies are rare in adults and particular patients in whom  there is a high suspicion should be referred to an allergist.   Most bowel infections should be transient and symptoms will  not be present for 6 months in order to meet the Rome III  criteria. Broad-spectrum antibiotics lead to transient diar-  rhea in 10% of cases which, if severe and persistent, should  lead to consideration of testing for Clostridium difficile toxin  or sigmoidoscopy to exclude pseudomembranous colitis.  Chronic giardiasis can last for months and manifest with  bloating, abdominal pain, and diarrhea. Stool enzyme-linked    • Chew food well, eat slowly, eat small meals (6 per day), and take in liguids between meals, don't use a straw    • Broccoli and cauliflower are best tolerated in a puree soup    • Eat small pieces of cooked carrots, celery, or zucchini with rice, pasta, or couscous   Reproduced, with permission, from Frissora CL. Nuances in treating irritable bowel syndrome. Rev Gastroenterol Disord. 2007;7:89-96.  Copyright © MedReviews, LLC.)   immunosorbent assay testing for Giardia antigen is the most  sensitive (90-100%) and specific (95-100%) method to test  for Giardia and should be considered in patients who have  histories of exposure to poor sanitary conditions.   Celiac disease occurs in about 1 in 250 people in the United  States. It can be identified through blood analysis of  immunoglobulin A (IgA) level, anti-endomysial antibody,  and anti-transglutaminase antibody. IgA level should be  checked, because IgA deficiency is more common in patients  with celiac disease. Patients who are antibody positive or in   whom there is a high suspicion should undergo upper  endoscopy and biopsy. Genetic testing is helpful in certain  cases. More than 99% of patients with celiac disease have  HLA DQ2, DQ8, or both, compared with about 40% of the  general population. Thus, celiac disease is highly unlikely in  patients without these haplotypes. The treatment of celiac  disease is a strict gluten-free diet.   The key diagnostic test in tropical sprue is small intestinal  mucosal biopsy, which is usually obtained at esophagogas-  troduodenoscopy. Gross findings at endoscopy include   flattening of duodenal folds and so-called scalloping. The lat-  ter finding was originally thought to be pathognomonic of  celiac disease but also occurs in tropical sprue and other  small bowel diseases. The major histologic findings are  shortened, blunted villi and elongated crypts with increased  inflammatory cells in the lamina propria. These histologic  changes are similar but not identical to those occurring in  patients with untreated celiac disease. Most authorities rec-  ommend tetracycline (250 mg orally, four times daily) plus  folic acid (5 mg/day) for 3-6 months for the treatment of  tropical sprue. Even on this regimen, relapses or reinfection  occur in up to 20% of patients living in the tropics.   Small bowel bacterial overgrowth is characterized by nutri-  ent malabsorption associated with an increased number or  type of bacteria in the upper gastrointestinal tract. Affected  patients can have abdominal pain, watery diarrhea, dyspep-  sia, and weight loss. The most frequent presenting symp-  toms in one series of 100 adult patients were diarrhea,  weight loss, bloating, and excess flatulence. A [ 14 C]-D-xylose  breath test is helpful in making the diagnosis. Xylose is a  pentose sugar that is catabolized by gram-negative aerobes,  which are invariably part of the microflora implicated in  bacterial overgrowth. Bacterial action on the sugar releases  the radioactive isotope 14 C0 2 , which, after absorption, is  detectable in breath samples. Breath hydrogen testing is per-  formed by administering a test dose of carbohydrate (usu-  ally lactose or glucose), which, in patients with bacterial  overgrowth, is associated with a rise in breath hydrogen lev-  els. It is possible to have no rise in hydrogen production dur-  ing a lactulose breath hydrogen test if hydrogen is converted  to methane or hydrogen sulfide by hydrogen consumptive  microbes. Concurrent testing with methane may enhance  sensitivity.   Most patients with bacterial overgrowth require treat-  ment with antibiotics. Effective antibiotic treatment should  cover both aerobic and anaerobic enteric bacteria, and  adequate antimicrobial coverage can be achieved with  the following combinations: amoxicillin-clavulanate plus  metronidazole; a combination of a cephalosporin with  metronidazole, norfloxacin, or rifaximin. A single course of  therapy for 7-10 days may improve symptoms and have an  effect lasting for months. However, some patients require  prolonged therapy (eg, 1-2 months) before a response is  seen. It is usually unnecessary to repeat diagnostic testing if  symptoms or objective measures of malabsorption respond  to treatment. In one paper, rifaximin has been shown to help  symptoms of bloating and flatulence. One hundred and  twenty-four patients received rifaximin (400 mg twice daily)  versus placebo for 10 days. Patients reported decreased  bloating and flatulence after 10 days (P = 0.03) and 20 days  (P = 0.02). There was decreased hydrogen breath excretion  among responders (P = 0.01). The differential diagnosis of  IBS-D is detailed in Table 24-7.   Table 24-7. Differential diagnosis of irritable bowel  syndrome with diarrhea (IBS-D).   Crohn disease and ulcerative colitis are fairly easy to distin-  guish from IBS with modern diagnostic testing. Most  patients with inflammatory bowel disease present with  weight loss, bleeding, and abdominal pain. Laboratory stud-  ies often reveal anemia, increased sedimentation rate, and  sometimes leukocytosis. Colonoscopy in patients with coli-  tis reveals inflammation, erythema, exudates, and some-  times ulcerations. Pathologic examination shows chronic  changes in the mucosa. Subtle Crohn disease of the small  bowel is almost always found by computed tomographic  enterography or capsule endoscopy in cases that are difficult  to diagnose.   Collagenous and lymphocytic colitis are more difficult to  distinguish from IBS because patients present with chronic  watery diarrhea and often no weight loss. In addition, these  forms of colitis have completely normal endoscopic appear-  ances. Collagenous colitis has two main histologic compo-  nents: increased subepithelial collagen deposition and colitis  with increased intraepithelial lymphocytes. The female-to-  male ratio is 9:1, and most patients present in the sixth or  seventh decades of life. Treatments range from sulfasalazine  or mesalamine and diphenoxylate hydrochloride-atropine  sulfate (Lomotil) to bismuth, budesonide, and prednisone  for refractory disease.   Lymphocytic colitis has features similar to collagenous  colitis, including age at onset and clinical presentation, but  it has almost equal incidence in men and women and no  subepithelial collagen deposition on pathologic section.  However, intraepithelial lymphocytes are increased. The  frequency of celiac disease is increased in lymphocytic  colitis and ranges from 9% to 27%. Celiac disease should  be excluded in all patients with lymphocytic colitis, partic-  ularly if diarrhea does not respond to conventional ther-  apy. Treatment is similar to that of collagenous colitis with  the exception of a gluten-free diet for those who have celiac  disease.   Frissora CL. Nuances in treating irritable bowel syndrome. Rev  Gastroenterol Disord. 2007;7:89-96. [PMID: 17597676]   Hammer J, Eslick GD, Howell SC, et al. Diagnostic yield of alarm  features in irritable bowel syndrome and functional dyspepsia.  Gut. 2004;53:666-672. [PMID: 15082584]   Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed  oral antibiotic (rifaximin) on the symptoms of the irritable  bowel syndrome. Ann Intern Med. 2006;145:557-563. [PMID:  17043337]   Posserud I, Stotzer PO, Bjornsson ES, et al. Small intestinal bacte-  rial overgrowth in patients with irritable bowel syndrome. Gut.  2007;56:802-808. [PMID: 17148502]   Scarpellini E, Gabrielli M, Lauritano CE, et al. High dosage rifax-  imin for the treatment of small intestinal bacterial over-  growth. Aliment Pharmacol Ther. 2007;25:781-786. [PMID:  17373916]   Sharara Al, Aoun E, Adbul-Baki H, et al. A randomized double-  blind placebo-controlled trial of rifaximin in patients with  abdominal bloating and flatulence. Am J Gastroenterol.  2006;101:326-333. [PMID: 16454838]   The complications of IBS are decreased quality of life, time  off from work and school, personal expenses of medications  and physician visits, and psychological problems such as  depression and anxiety. It is commonplace for IBS patients to  undergo unnecessary procedures and surgeries, and it is the  role of the treating physician to avoid these complications.  Comprehensive patient appointments, close follow-up, and  much reassurance by the physician are recommended. When  asked what they want from their health care professional, IBS  patients in England offered 10 top requests, which are listed  in Table 24-8.   Current treatment options for IBS are limited and include  dietary modification, fiber supplements, pharmacologic  agents (Table 24-9), and psychotherapy.   Fiber found in whole grains, fruits, nuts, seeds, and vegeta-  bles and also in the form of fiber supplements containing  psyllium (Metamucil), guar gum (Benefiber), calcium poly-  carbophil (FiberCon), and methylcellulose (Citrucel) helps  to regulate bowel movements and improve stool consistency.  Although it may help individual patients and is used com-  monly for patients with IBS-mixed disease or alternators,  there is no high-quality evidence-based literature supporting  the benefits of fiber in treating IBS.   Loperamide (Imodium) and diphenoxylate hydrochloride-  atropine sulfate (Lomotil) decrease diarrhea but they have no  effect on bloating or abdominal pain. Cholestyramine resin  binds bile salts and slows down diarrhea but similarly has no  effect on abdominal pain or bloating. These agents can be  helpful for IBS in combination with other antispasmotics or  can be used to provide as-needed therapy for diarrhea.   Among patients who need these agents for intractable con-  stipation, the majority will use them only occasionally. The  safest suppository to use is a glycerin suppository because it  is not a stimulant laxative and has no lasting ill effects on the  gut. Fleets, tap water, or mineral oil enemas can be used occa-  sionally for refractory constipation but insertion of air that  comes with the enema fluid will only exacerbate bloating and  abdominal pain.   Table 24-8. Top 10 patient requests compiled by the  IBS Network in the United Kingdom.   "When I visit my health professional about my IBS I would like them  to give me . . ."   3. A clear indication that it is my body, my illness and that it is up to  me to take control   4. A clear explanation that there will be good days and bad days but  there will be light at the end of the tunnel   Various laxatives are available for the constipation compo-  nent of IBS. They include the stimulant laxatives (senna,  bisacodyl, cascara) and the osmotic laxatives (polyethylene  glycol, lactulose, sorbitol). The stimulant laxatives may cause  permanent damage to the myenteric plexus but studies are  conflicting. In any case, they do exacerbate abdominal  cramps and bloating when used chronically Abdominal  cramps and excess gas and bloating are seen with the osmotic  laxative but MiraLax was deemed effective for chronic con-  stipation in one long-term study.   There is only minimal evidence-based literature that anti-  spasmotics are effective in treating the pain component of  IBS. Antispasmotics relax the smooth muscle of the gut and  include dicyclomine hydrochloride (Bentyl), hyoscyamine   Table 24-9. Possible drugs for dominant symptoms in irritable bowel syndrome.    2-6 mg twice daily for women but now off the market    24 meg twice daily (for chronic constipation), 8 meg  twice daily (for IBS-C)   sulfate (Levsin), scopolamine and phenobarbital (Donnatal),  and clidinium bromide with chlordiazepoxide (Librax). These  medicines are usually given before meals to inhibit abdominal  pain and immediate, uncontrolled bowel movements.   Tricyclic antidepressants, such as amitriptyline hydrochlo-  ride (Elavil) and nortriptyline hydrochloride (Pamelor), pre-  scribed at low doses, are beneficial in patients with and  without diagnosed depression and anxiety because their ben-  efit derives more from pain reduction than depression. There  is some evidence-based literature favoring amitriptyline in  treating visceral hypersensitivity. Side effects of both anti-  spasmotics and tricyclics include dry mouth, dry eyes, and  fatigue. Weight gain is a side effect particular to tricyclics.   More recently, citalopram hydrobromide (Celexa) has been  tested in patients with IBS. One study found that this SSRI,  which is commonly used for depression, was effective in  patients with IBS. Citalopram significantly improved symp-  toms of abdominal pain and bloating and improved quality   of life and overall well-being. Fluoxetine hydrochloride  (Prozac), an SSRI commonly used in the treatment of  depression, is also effective in treating IBS. In a recent study  in patients with IBS-C, fluoxetine decreased abdominal dis-  comfort and bloating and increased bowel movements.   Two newer medical therapies for inflammatory bowel disease  focus on the serotonin receptor in the gut. Alosetron  (Lotronex) is a 5-HT 3 antagonist approved for use in women  with severe IBS-D who have failed conventional therapy.  Alosetron slows colonic transit, decreases rectal urgency, and  decreases abdominal pain. The drug was launched in February  of 2000 and temporarily withdrawn from the market in  November of that year due to isolated reports of constipation  and ischemic colitis. There were 3 deaths and 77 hospi-  talizations. Public outcry resulted in approval by the U.S.  Food and Drug Administration (FDA) to allow the reintro-  duction of alosetron on a limited basis, and the drug was  reintroduced in November 2002 under a new risk-management  program. Restrictions on the use of alosetron include  updated warnings in the complete Prescribing Information;  including a Medication Guide for patients that explains what   to do if they become constipated or have signs of ischemic  colitis; a lower starting dose than previously approved; and a  prescribing program for physicians to be enrolled in, based  on self-attestation of qualifications and acceptance of certain  responsibilities in prescribing alosetron. There is significant  evidence-based literature to recommend use of alosetron in  women with severe IBS-D, and it is an important drug in the  IBS armamentarium. Studies show a statistically significant  increase in global improvement in IBS symptoms, adequate  relief of IBS pain and discomfort, and improvement in bowel  symptoms.   Tegaserod maleate (Zelnorm) is a partial 5-HT 4 receptor  agonist. It stimulates the peristaltic reflex, increases velocity  of propulsion through the colon, reduces the firing rate of  rectal afferent nerves, alters chloride secretion in the intes-  tine, and reduces visceral sensitivity. Tegaserod normalizes  bowel function and relieves abdominal pain and discomfort  in IBS patients. It is indicated for IBS-C in women and  chronic constipation in men and women.   On March 30, 2007, Novartis announced it was comply-  ing with a request from the FDA to suspend U.S. marketing  and sales of tegaserod due to an analysis of clinical trial data  identifying a small but statistically significant imbalance in  the number of cardiovascular ischemic events in patients tak-  ing tegaserod. The data showed that events occurred in 13 out  of 11,614 patients treated with tegaserod (0.11%), compared  with one case in 7031 placebo-treated patients (0.01%). These  events included heart attack, stroke, and unstable angina. The  cardiovascular ischemic events occurred in patients who had  preexisting cardiovascular disease or cardiovascular risk fac-  tors, or both. No causal relationship has been demonstrated  between tegaserod and these events, and on luly 27, 2007,  tegaserod again become available through a special FDA IND  program restricted to gastroenterologists prescribing this  medication for female patients younger than 55 years with  IBS-C or chronic constipation.   High-quality, evidence-based literature supports the effi-  cacy of tegaserod in IBS. In several randomized-controlled tri-  als, tegaserod was superior to placebo for relief of abdominal  discomfort or pain, bloating, and constipation. Patients taking  tegaserod had a statistically significant increase in stool fre-  quency and consistency. In one study, a response to tegaserod  was observed within the first treatment week. In addition,  tegaserod produced greater satisfaction, work productivity,  and improved quality of life than placebo (P < 0.05).   Lubiprostone (Amitiza) is specific chloride channel-2 activa-  tor that enhances intestinal fluid secretion to facilitate  increased motility. It is currently indicated for the treatment  of chronic constipation and has recently been approved for  IBS-C. Lubiprostone increases weekly spontaneous bowel   movements, and a significant number of patients respond  within 24 hours. It is the only medicine for constipation with  an indication for patients 65 years of age and older. There is  one high-quality study published on lubiprostone in chronic  constipation and the rest of the data is in abstract form only.  The main side effect is nausea, which can be alleviated by  taking the medicine with food.   Rifaximin (Xifaxan) is a nonsystemic (< 0.4%) semisynthetic  antibiotic whose spectrum includes most gram-positive and  gram-negative bacteria, both aerobes and anaerobes. In one  questionnaire study in patients with IBS, there was a statisti-  cally significant improvement in overall symptoms and less  bloating (P = 0.020) over placebo. There was no difference in  pain, diarrhea, or constipation. The dosage of rifaximin used  in this study (400 mg orally, three times daily for 10 days) is  higher than that approved by the FDA for traveler's diarrhea.   In a recent study, Bifidobacterium infantis 35624 was shown  to alleviate abdominal pain and bloating and bowel move-  ment difficulty. Another probiotic, which contains eight dif-  ferent strains of bacteria including lactobacillus and  bifidobacteria, alleviated flatulence and slowed down stools  in IBS patients.   Chey WD, Chey WY, Heath AT, et al. Long-term safety and effi-  cacy of alosetron in women with severe diarrhea-predominant  irritable bowel syndrome. Am J Gastroenterol. 2004;99: 2195-2203.  [PMID: 15555002]   DiPalma IA, Cleveland MB, McGowan I, et al. A randomized, mul-  ticenter, placebo-controlled trial of polyethylene glycol laxative  for chronic treatment of chronic constipation. Am J  Gastroenterol. 2007;102:1436-1441. [PMID: 17984738]   lohanson IF, Ueno R. Lubiprostone, a locally acting chloride chan-  nel activator, in adult patients with chronic constipation: a dou-  ble-blind, placebo-controlled, dose-ranging study to evaluate  efficacy and safety. Aliment Pharmacol Ther. 2007;25:1351-1361.  [PMID: 17509103]   Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic  constipation: a randomized double-blind, controlled trial. Clin  Gastroenterol Hepatol. 2004;2:796-805. [PMID: 15354280]   Krause R, Ameen V, Gordon SH, et al. A randomized, double-  blind, placebo-controlled study to assess efficacy and safety of  0.5 mg and 1 mg alosetron in women with severe diarrhea-  predominant IBS. Am ] Gastroenterol. 2007;102:1709-1719.  [PMID: 17509028]   Morgan V, Pickens D, Gautam S, et al. Amitriptyline reduces rec-  tal pain related activation of the anterior cingulate cortex in  patients with irritable bowel syndrome. Gut. 2005;54:601-607.  [PMID: 15831901]   Miiller-Lissner S, Holtmann G, Rueegg P, et al. Tegaserod is effec-  tive in the initial and retreatment of irritable bowel syndrome  with constipation. Aliment Pharmacol Ther. 2005;21:11-20.  [PMID: 15644040]   Muller-Lissner S, Kamm MA, Musoglu A, et al. Safety, tolerability,  and efficacy of tegaserod over 13 months in patients with  chronic constipation. Am J Gastroenterol. 2006;101: 2558-2569.  [PMID: 17090282]   Novick J, Miner P, Krause R, et al. A randomized double-blind,  placebo-controlled trial of tegaserod in female patients suffer-  ing from irritable bowel syndrome with constipation. Aliment  Pharmacol Ther. 2002;16:1877-1888. [PMID: 12390096]   O'Mahoney L, McCarthy J, Kelly P, et al. Lactobacillus and  Bifidobacterium in irritable bowel syndrome: symptom  responses and relationship to cytokine profiles. Gastroenterology.  2005;128:541-551. [PMID: 15765388]   Tack J, Broekaert D, Fischler B, et al. A controlled crossover  study of the selective serotonin reuptake inhibitor citalopram  in irritable bowel syndrome. Gut. 2006;55:1096-1103. [PMID:  16401691]   Tougas G, Snape WJJr, Otten MH, et al. Long-term safety of  tegaserod in patients with constipation-predominant irritable  bowel syndrome. Aliment Pharmacol Ther. 2002;16:1701-1708.  [PMID: 12269961]   Vahedi H, Merat S, Rashidioon A, et al. The effect of fluoxetine in  patients with pain and constipation-predominant irritable  bowel syndrome: a double-blind randomized-controlled study.  Aliment Pharmacol Ther. 2005;22:381-385. [PMID: 16128675]   Gallstone disease and alcohol are the most common  causes of acute pancreatitis; other causes include  hypertriglyceridemia, drugs, and specific disorders of  the biliary tree and pancreas.   Diagnosis is usually made based on a history of acute  abdominal pain; a threefold elevation in serum amylase  or lipase, or both; or an abnormal abdominal computed  tomography (CT) scan showing changes of acute  pancreatitis.   Severe necrotizing acute pancreatitis is characterized by  persistent (> 48 hours) systemic inflammatory response  syndrome (SIRS), hemoconcentration, and organ failure  (systemic blood pressure < 90 mm Hg, Pa0 2 < 60 mm Hg,  creatinine > 2.0 mg/dL).   Acute pancreatitis is an acute inflammatory disorder of the  pancreas that involves the pancreas and peripancreatic tis-  sues but can sometimes affect other organ systems. The ini-  tial evaluation of patients with acute pancreatitis involves  determining the cause and assessing the severity of disease  since this guides subsequent management.   Acute pancreatitis is the third most common inpatient gas-  trointestinal diagnosis in the United States. There were  243,332 hospitalizations in 2002 for acute pancreatitis with a  median length of stay of 4 days and median charges amount-  ing to $11,402. The incidence rate of acute pancreatitis  appears to be increasing without any changes in the short-  term or long-term case fatality rates.   The most common causes of acute pancreatitis in the United  States are gallstones and alcohol abuse, accounting for  70-80% of cases. Table 25-1 lists other causes, including  hypertriglyceridemia, drug reactions, iatrogenic causes (eg,  postsurgical or endoscopic retrograde cholangiopancreatog-  raphy [ERCP]), hereditary factors, and idiopathic causes.   The first attack of alcohol-induced acute pancreatitis typi-  cally occurs after many (eg, 8-10) years of heavy alcohol con-  sumption, and recurrent episodes can be anticipated if alcohol  abuse continues. Gallstone-induced pancreatitis occurs in the  setting of choledocholithiasis and is believed to be related to  transient or complete blockade of pancreatic ductal flow or  reflux of bile into the pancreatic duct. Hypertriglyceridemia  associated acute pancreatitis does not typically occur unless  the triglyceride level exceeds 1000 mg/dL and is often seen in  patients with type I and V hyperlipidemia as well as in alco-  holics. Because triglyceride levels fall by one half in patients  who have been fasting for 24 hours, levels are best assessed  after an episode of acute pancreatitis with a fasting lipid pro-  file in patients who are consuming a normal diet.   Although many drugs have been associated with acute  pancreatitis, the strength of association between the use of a  particular drug and the development of acute pancreatitis  warrants careful scrutiny. Table 25-2 lists drugs that have a  strong association with acute pancreatitis based on a recent  review.   ERCP-induced acute pancreatitis is another common  cause of pancreatic injury at centers with a large volume of  therapeutic endoscopy cases. Acute pancreatitis is seen in  5-7% of ERCP cases and, despite extensive research into the  medical and endoscopic prevention of post-ERCP pancreati-  tis, there has been little decline in the rates of occurrence.  Recent use of prophylactic pancreatic duct stenting after ret-  rograde pancreatography has shown promise but requires  further prospective evaluation. Risk factors for post-ERCP  pancreatitis, based on a recent prospective study, include  minor papilla sphincterotomy, sphincter of Oddi dysfunction,   PRSS1 (cationic trypsinogen) mutations  Metabolic (eg, hypercalcemia, hypertriglyceridemia)  Neoplastic (eg, pancreatic or ampullary tumors)  Structural (eg, pancreatic divisum, annular pancreas, sphincter of Oddi   enteritis  Toxic (eg, organophosphates, scorpion venom)  Traumatic (especially motor vehicle accidents)  Vascular   prior history of post-ERCP pancreatitis, age younger than  60 years, more than two contrast injections into the pan-  creatic duct, and involvement of endoscopic trainees in the  procedure.   In recent years, molecular genetic techniques have  revealed mutations in the trypsinogen and cystic fibrosis  transmembrane conductance regulator (CFTR) gene that  have increased our understanding of acute pancreatitis.  Hereditary pancreatitis is an autosomal-dominant disease  with incomplete penetrance. It occurs due to autodigestion  of the pancreatic acinar cell from the inability to deactivate  intracellular trypsin. It should be suspected in patients with  early-onset (before 20 years of age) acute pancreatitis or  those with a strong family history of idiopathic acute pan-  creatitis in first- or second-degree relatives. Cystic fibrosis  mutations are increasingly being recognized as a cause of  both acute and chronic pancreatitis. The mechanism of  injury is not completely known but is most likely related to  decreased pancreatic juice flow due to duct cell secretory dys-  function. Patients with a family history of cystic fibrosis or a  history of recurrent pulmonary symptoms (eg, bronchitis,  asthma) nasal polyps, or sterility among males should be  considered for genetic testing.   Badalov N, Baradarian R, Iswara K, et al. Drug-induced acute pan-  creatitis: an evidence-based review. Clin Gastroenterol Hepatol.  2007;5:648-661. [PMID: 17395548]   Cheng CL, Sherman S, Watkins JL, et al. Risk factors for post-  ERCP pancreatitis: a prospective multicenter study. Am f  Gastroenterol. 2006;101:139-147. [PMID: 16405547]   Frank CD, Adler DC Post-ERCP pancreatitis and its prevention.  Nat Clin Pract Gastroenterol Hepatol. 2006;3:680-688. [PMID:  17130878]   Frey CF, Zhou H, Harvey DJ, et al. The incidence and case-fatality  rates of acute biliary, alcoholic, and idiopathic pancreatitis in  California, 1994-2001. Pancreas. 2006;33:336-344. [PMID:  17079936]   Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and  SPINK1 mutations in 381 patients with pancreatitis. Pancreas.  2006;33:221-227. [PMID 17003641]   Shaheen NT, Hansen RA, Morgan DR, et al. The burden of gas-  trointestinal and liver disease, 2006. Am J Gastroenterol.  2006;101:2128-2138. [PMID: 16848807]   Acute pancreatitis develops in response to premature activa-  tion of intracellular trypsinogen (which causes acinar cell  injury) and the release of chemokines and cytokines (which  results in the recruitment of neutrophils and macrophages).  Recent advances in our understanding of hereditary pancre-  atitis include the discovery of trypsinogen gene mutations,  PRSS1 and SPINK1. Mutations in these genes lead to an  imbalance of proteases and their inhibitors within the pan-  creatic parenchyma, resulting in inappropriate activation of  pancreatic zymogens with subsequent autodigestion and  inflammation. This, in turn, produces further injury to the  acinar cells and elevation of proinflammatory mediators.   The exact mechanisms leading to alcoholic and biliary  acute pancreatitis remain to be defined. Excessive alcohol  consumption is the most common basis for acute pancreati-  tis, but only a small proportion of patients who abuse alco-  hol develop pancreatitis. Alcohol metabolism is governed by  oxidative and nonoxidative processes. The oxidative pathway  lies primarily in the liver while the nonoxidative pathway lies  primarily in the pancreas. The nonoxidative pathway leads to  the formation of fatty acid ethanol esters (FAEEs). It is pos-  tulated that accumulation of FAEEs may result in alcoholic  acute pancreatitis. Biliary pancreatitis is most commonly  caused by the passage of a stone from the gallbladder through  the cystic duct into the common bile duct; impaction at the  ampulla of Vater causes either reflux of bile into the pancre-  atic duct (Opie 1) or outflow obstruction of the pancreatic  duct (Opie 2).   Abdominal pain is the most common symptom in patients  presenting with acute pancreatitis. The pain is typically epi-  gastric and radiates to the back. Patients also often present   a Class IA: at least one case report with positive rechallenge, excluding all other causes of acute pancreatitis.   b Class IB: at least one case report with positive rechallenge; however, other causes of acute pancreatitis not   c Class II: at least four cases in the literature, consistent latency in > 75% of cases (period between initiation of   Adapted, with permission, from Badalov N, Baradarian R, Iswara K, et al. Drug-induced acute pancreatitis: an   with nausea and vomiting. In patients with severe acute  pancreatitis, signs and symptoms parallel the presence of a  systemic inflammatory response and organ dysfunction.  Patients with SIRS (temperature > 30°C, respiratory rate of  > 24 per minute, heart rate > 90 per minute, white blood  count > 12,000, or > 10% bands), which arises in response to  proinflammatory mediators, can present with fever, tachycar-  dia, tachypnea, or a combination of these findings. Other  examination findings include respiratory distress, crackles or  absent breathe sounds on lung auscultation, cool extremities,  impaired mental status, decreased bowel sounds, abdominal  distention, oliguria, and anuria. Cullen sign (periumbilical  ecchymoses) and Grey Turner sign (flank ecchymoses) are rare  but can be seen in cases of acute pancreatitis with hemorrhage  and are associated with increased mortality.   Serum amylase and lipase are the principle serologic data  that aid in the diagnosis of acute pancreatitis. Elevations   greater than three times the upper limit of normal are typi-  cally used to diagnose acute pancreatitis. However, both  enzymes can be elevated in other disease states. For example,  amylase is also produced by nonpancreatic organs such as  salivary glands, ovaries, and fallopian tubes; thus, diseases of  these organs can increase the serum amylase level. Pancreatic  amylase and lipase can be elevated in other intra-abdominal  disease states such as a perforated ulcer, intestinal obstruc-  tion, and mesenteric infarction. Both amylase and lipase are  elevated in patients with renal insufficiency; therefore, many  of these patients will require a CT scan for radiologic confir-  mation if acute pancreatitis is suspected.   Serum amylase has rapid clearance and a short half-life  and therefore is best measured when there is a brief interval  between symptom onset and diagnosis. Serum lipase begins  to rise later after symptom onset, but its longer half-life  makes it useful to measure when there has been a delay in  seeking care. Serum lipase is a more sensitive and specific  indicator than amylase. The combination of both serum  amylase and lipase does not appear to increase the accuracy   of diagnosis. The degree of elevation of both serum amylase  and lipase does not correlate with severity of acute pancreati-  tis, nor does the daily assessment of serum pancreatic enzymes  help to determine clinical deterioration or resolution.   Elevated findings on liver biochemical tests in a patient  with suspected acute pancreatitis usually signify a biliary  cause. A threefold elevation in alanine aminotransferase in  the setting of acute pancreatitis has been shown to have a  95% positive predictive value for gallstone pancreatitis.   Contrast-enhanced CT is the single most important test in  diagnosing acute pancreatitis, determining its severity, and  assessing for complications. CT will determine if the pancre-  atic perfusion is normal (interstitial acute pancreatitis,  Figure 25-1) or has been disrupted (necrotizing acute pancre-  atitis, Figure 25-2). This is an important distinction in deter-  mining the severity of acute pancreatitis and the risk of  subsequent complications. Findings of interstitial acute pan-  creatitis typically seen on CT scan include enlargement of the  pancreas with edema, heterogeneous pancreatic parenchyma,  peripancreatic fat stranding, and peripancreatic fluid collec-  tions. Acute pancreatic necrosis typically appears as focal or  diffuse areas of nonenhanced pancreatic parenchyma (see  Figure 25-2). Although ultrasonography is useful for specifi-  cally evaluating biliary etiologies and excluding acute chole-  cystitis or hepatic abscesses, it has limited utility in diagnosing  and determining other etiologies of acute pancreatitis. CT  affords the possibility of evaluating for other potential causes   ▲ Figure 25-1. CT scan showing interstitial acute pan-  creatitis. There is uniform enhancement of the pancreatic  parenchyma, indicating that pancreatic perfusion is  preserved. (Benign right renal cyst.)   A Figure 25-2. CT scan showing necrotizing acute  pancreatitis. Pancreatic perfusion is diminished on  contrast enhancement.   of abdominal pain, including a perforated ulcer, mesenteric  infarction, and intestinal obstruction. A CT scan may also pro-  vide clues to the cause of acute pancreatitis, including visuali-  zation of gallstones (Figure 25-3), cystic lesion, mass, or  pancreatic calcifications.   Timing of CT imaging is important. If an admission diag-  nosis of acute pancreatitis can be made on the basis of his-  tory, physical examination, and elevated pancreatic enzymes,  a CT scan should generally be deferred. Given that some  patients will present with or develop renal failure, aggressive  fluid resuscitation with correction of renal function and  intravascular volume resuscitation should take place prior to  a contrast-enhanced CT due to the risk of inducing renal  insufficiency. Alternatively, a non-contrast-enhanced study  can be performed.   Patients diagnosed on admission with acute pancreatitis  who subsequently develop organ failure and do not improve  with supportive care during hospitalization will require a  contrast-enhanced CT scan to assess for the presence of  necrosis and determine any potential complications such as  acute fluid collection or abscess formation.   Magnetic resonance cholangiopancreatography (MRCP)  is equivalent to CT in its ability to detect necrosis and deter-  mine severity of acute pancreatitis. It affords unparalleled  visualization of the biliary and pancreatic ducts. Gadolinium  should not be used in patients with renal impairment.   1. Confirmation of the diagnosis— The diagnosis of acute  pancreatitis is usually made when there is a history of acute  abdominal pain and a threefold elevation in serum amylase    ▲ Figure 25-3. CT scan in a patient with gallstone  pancreatitis. A: Axial image with walled-off necrosis and  gallbladder stone. B: Coronal image showing extent of  necrosis and presence of a calcified gallstone.   or lipase, or both, or an abnormal abdominal CT scan  demonstrating changes consistent with acute pancreatitis.   after a careful history and physical examination, laboratory  evaluation, abdominal ultrasonography, and CT scan, the  cause of 20-30% of cases of acute pancreatitis cannot be elu-  cidated. These cases are termed idiopathic or unexplained.  Recent reports suggest that nearly 70% of patient with a sin-  gle or recurrent episode of idiopathic acute pancreatitis have  biliary microlithiasis or sludge from cholesterol monohy-  drate crystals or calcium bilirubinate granules.   There is considerable debate regarding which subgroup of  patients requires more extensive evaluation after being diag-  nosed with idiopathic acute pancreatitis. It has been suggested   that patients younger than age 40, who have had only a single  episode of acute pancreatitis, need no further evaluation as  the recurrence rate is low. However, patients older than 40 years  who have had a single episode and patients who have had  two or more episodes of idiopathic pancreatitis require more  extensive evaluation. Patients older than 40 years are thought  to have an increased risk of pancreatic malignancy. Therefore,  a contrast-enhanced CT scan should be part of the initial  evaluation. If the CT scan is negative, then attention is  directed at the pancreaticobiliary anatomy. A reasonable and  safe strategy for this secondary evaluation of ductal anatomy  is a combination of MRCP and endoscopic ultrasound, if  available. Abnormalities noted on either endoscopic ultra-  sound evaluation or magnetic resonance imaging should  prompt consideration of endoscopic or surgical therapy  (Figure 25-4). Causes of idiopathic or unexplained acute  pancreatitis commonly found during endoscopic evaluation  are listed in Table 25-3.   Wilcox CM, Varadarajulu S, Eloubeidi M. Role of endoscopic eval-  uation in idiopathic pancreatitis: a systematic review.  Gastrointest Endosc. 2006;63:1037-1045. [PMID: 16733122]   3. Criteria for assessing severity in acute pancreatitis-  Assessing severity in patients with acute pancreatitis is essen-  tial for appropriate triage and management as patients with  severe disease are at greatest risk of death. The basis for the  classification, severity, and complications of acute pancreati-  tis was established at the International Symposium held in  Atlanta in 1992. Although the definitions have come under  greater scrutiny in recent years, they still serve as the common  language for clinical care and research in acute pancreatitis.  The criteria for severe acute pancreatitis were defined as  organ failure of at least one organ system (systolic blood pres-  sure < 90 mm Hg, Pao 2 < 60 mm Hg, creatinine > 2.0 mg/dL  after rehydration, and gastrointestinal bleeding > 500 mL/24 h)  and the presence of local complications such as necrosis,  pseudocyst, and abscess.   A pseudocyst was defined as a collection of pancreatic  fluid enclosed by a nonepithelialized wall that occurs due to  trauma, acute pancreatitis, or chronic pancreatitis. An  infected pseudocyst is an abscess. An abscess can also form if  an area of necrosis undergoes liquefaction and becomes sec-  ondarily infected. Early predictors of severity at 48 hours  included three or more Ranson signs and an APACHE II  score of 8 or higher. Traditional severity indices such as  APACHE II and Ranson criteria have not been seen as clini-  cally useful since they are cumbersome, require collection of  a large number of clinical and laboratory variables over time,  and do not have acceptable positive and negative predictive  value for severe acute pancreatitis. Ongoing research seeks to  determine a simple set of admission clinical, laboratory, and  imaging variables that can identify patients who are at great-  est risk of severe acute pancreatitis and death.   Apart from the severity indices, additional factors can be  used to assess severity in acute pancreatitis. They are best   ▲ Figure 25-4. Algorithm for the evaluation and management of idiopathic pancreatitis. CBD, common bile duct;  CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound;  MRCP, magnetic resonance cholangiopancreatography; PD, pancreatic duct.   separated into risk factors for severity on admission and pre-  dictors of severity on admission or while a patient is hospital-  ized. Risk factors for severe acute pancreatitis on admission  include older age (> 55 years), obesity (basal metabolic index  > 30), and comorbid disease. There is also evidence to support   Table 25-3. Causes of idiopathic or unexplained acute  pancreatitis diagnosed by endoscopic evaluation. 3   initial episode and alcohol use as additional risk factors for  severity. At admission, predictors of severity in acute pancre-  atitis include APACHE II scores, SIRS, hemoconcentration,  presence of pleural effusions, and organ failure.   The importance of differentiating interstitial from necro-  tizing acute pancreatitis has led to the development of a CT  severity index as another measure of severity. It is best evalu-  ated 2-3 days into hospitalization because it may not be pos-  sible to distinguish interstitial from necrotizing pancreatitis  on contrast-enhanced CT scan on the day of admission. CT  identification of local complications, particularly necrosis, is  essential because patients with infected and sterile necrosis  are at greatest risk of death, with a median mortality rate of  30% and 12%, respectively. The median prevalence of organ  failure is 54% in necrotizing pancreatitis. The prevalence of  organ failure is about the same in infected versus sterile  necrosis. Mortality is 3% with single organ system failure but  increases to 47% with multisystem failure. Thus, patients  with infected necrosis and multisystem organ failure are the  most likely to die.   It should be noted that necrotizing pancreatitis is uncom-  mon (10-20% of all patients with acute pancreatitis) and the  far greater proportion of patients presenting in clinical prac-  tice have interstitial pancreatitis, which is associated with  organ failure in 10% and death in 3% of cases. These percent-  ages roughly translate to similar absolute mortality figures in  populations with interstitial and necrotizing pancreatitis since  interstitial disease is far more prevalent.   It is important to exclude other potential intra-abdominal  diseases in patients for whom the diagnosis of acute pancre-  atitis is not certain, especially when management calls for  potential surgical intervention. Table 25-4 lists conditions of  which the clinician should be particularly aware.   The complications observed in acute pancreatitis are primarily  seen in patients with severe disease and organ failure.  Commonly seen complications include pancreatic pseudocyst,  abscess formation, and pancreatic ascites from pancreas duct  disruption. Pancreatic pseudocyst should only be drained if it  causes symptoms such as abdominal pain or gastric obstruc-  tion. Drainage can safely be performed endoscopically or sur-  gically. Pancreatic abscess formation usually requires surgical  drainage and intravenous antibiotics. Pancreatic ascites can be  managed conservatively with endoscopic therapy if the disrup-  tion can be "bridged" with a pancreatic stent. Otherwise, surgi-  cal therapy is recommended. Bleeding complications from  esophagogastric varices can occur from splenic vein obstruc-  tion or pseudoaneurysm formation associated with a pseudo-  cyst or pancreatic necrosis.   Less commonly seen complications include pancreatic  encephalopathy, subcutaneous fat necrosis, or splenic com-  plications such as a subcapsular hematoma.   The majority of patients with mild acute pancreatitis  respond to simple supportive care measures that form the   hallmark of treatment in acute pancreatitis: bowel rest, intra-  venous hydration with crystalloid, and analgesia. Oral intake  can be resumed once the patient is pain free in the absence of  parenteral analgesia, has no nausea or vomiting, has normal  bowel sounds, and is hungry. Typically, a clear or full liquid  diet has been recommended for the initial meal, but a low- fat  solid diet is a reasonable choice following recovery from mild  acute pancreatitis.   Patients with gallstone pancreatitis are at increased risk of  recurrence. Therefore, following recovery from mild pancre-  atitis, consideration should be given to performing a laparo-  scopic cholecystectomy during the same admission. An  alternative for patients who are not surgical candidates  would be to perform an endoscopic biliary sphincterotomy.   Patients with predictors of severity on admission such as  obesity or hemoconcentration are also managed with the  supportive measures outlined above. It is recommended that  vigorous fluid resuscitation be initiated. Measurement of  hematocrit every 12 hours is recommended to ensure ade-  quacy of fluid resuscitation. A decrease in hematocrit during  the first 12-24 hours is strong evidence that sufficient fluids  are being administered. If the hematocrit remains elevated or  increases further (particularly among those whose hemat-  ocrit on admission is > 44), fluid resuscitation is inadequate.   Patients with sustained organ failure that does not  respond to increased fluids (to counteract hypotension and  increased serum creatinine) or nasal oxygen (to overcome  hypoxemia), as well as patients with labored respirations that  may herald respiratory failure, should be transferred to an  intensive care unit for aggressive hydration and close moni-  toring as these patients may require intubation with mechan-  ical ventilation, hemodialysis, and support of blood pressure.   Once it is clear that a patient will not be able to tolerate  oral feeding (a determination that can usually be made  within 48-72 hours), enteral nutrition (rather than total par-  enteral nutrition) should be considered. Enteral nutrition  maintains gut barrier integrity, thereby preventing bacterial  translocation, is less expensive, and is associated with fewer  complications than parenteral nutrition. The best route for  administration of enteral feeding has been debated. The  nasogastric route is easier to establish and may be as safe as  the nasojejunal route; however, enteral nutrition that  bypasses the stomach and duodenum is believed to stimulate  pancreatic secretions less, and this rationale theoretically  supports the use of the nasojejunal route. Neither route has  been shown to alter morbidity and mortality. When patients  with necrotizing pancreatitis begin oral intake of food, con-  sideration should also be given to the addition of pancreatic  enzyme supplementation to assist with fat digestion, and  proton pump inhibitor therapy to reduce gastric acid (thus  reducing the need for pancreatic bicarbonate secretion).   There is currently no role for prophylactic antibiotics in  either interstitial or necrotizing pancreatitis. Prior randomized   prospective studies supporting this practice have not been dou-  ble-blinded. It is reasonable to start antibiotics in a patient who  appears septic while awaiting the results of cultures. If culture  results are negative, the antibiotics should be discontinued to  minimize the risk of developing fungal superinfection.   Percutaneous aspiration of necrosis with Gram stain and  culture should generally not be performed until at least 7-10  days after establishing a diagnosis of necrotizing pancreatitis,  and then only if there are ongoing signs of possible pancre-  atic infection such as sustained leukocytosis, fever, or organ  failure. Once the diagnosis of infected necrosis is established,  appropriate antibiotics should be initiated and surgical  debridement should be undertaken. There exist minimally  invasive alternative therapies such as endoscopic, percuta-  neous catheter, and retroperitoneal techniques for necrosec-  tomy. These have been reserved for patients who are too ill to  undergo surgical necrosectomy. However, there are currently  no large randomized studies supporting the use of one over  another modality. For patients with sterile necrosis, medical  management is preferred to surgical management unless  patients continue to exhibit abdominal pain and are unable  to resume oral intake. Surgical debridement should not take  place for at least 3-4 weeks after initial presentation as this  allows for resolution of inflammation and the development  of organized necrosis.   There are several clearly defined roles for ERCP in acute  pancreatitis. Urgent ERCP (within 24 hours) is indicated in  patients who have severe acute biliary pancreatitis with organ  failure or cholangitis, or both. Elective ERCP with sphinc-  terotomy can be considered in patients with persistent or  incipient biliary obstruction, those deemed to be poor can-  didates for cholecystectomy, and those in whom there is  strong suspicion of bile duct stones after cholecystectomy  (see Figure 25-3). ERCP also is indicated for pancreatic duc-  tal disruptions that occur as part of the inflammatory  process and result in peripancreatic fluid collections.   Clin North Am. 2007;36:65-74. [PMID: 17472875]  Pandol SJ, Saluja AK, Imrie CW, et al. Acute pancreatitis: bench to   ► Diagnosis relies on a combination of clinical findings,  imaging tests, and pancreatic function testing.   ► Pancreatic calcifications, dilated pancreatic ducts, diabetes  mellitus, and maldigestion characterize advanced disease.   ► Early-stage diagnosis remains a clinical challenge, espe-  cially in patients with chronic or episodic abdominal pain  and no imaging abnormalities.   Although several risk factors for the development of chronic  pancreatitis have been identified, the cause of pancreatitis in  some instances remains uncertain. Among established risk  factors, alcohol ingestion is associated with up to 60-70%  of cases of chronic pancreatitis. In addition, ductal obstruc-  tion, autoimmune disease, tropical disease, and an associa-  tion with further systemic illnesses such as scleroderma and  hypertriglyceridemia have been described. Recently new  insights have been gained into the genetic and molecular  basis associated with hereditary forms of chronic pancreati-  tis. The most widely accepted system of etiologic classifica-  tion for chronic pancreatitis is the TIGAR-0 system, which  categorizes risk factors according to mechanism and preva-  lence (Table 26-1).   Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classifica-  tion, and new genetic developments. Gastroenterology. 2001;120:  682-707. [PMID: 11179244]   Witt H, Apte MV, Keim V, et al. Chronic pancreatitis: challenges  and advances in pathogenesis, genetics, diagnosis, and therapy.  Gastroenterology. 2007;132:1557-1573. [PMID: 17466744]   Morphologic changes associated with chronic pancreatitis  include both ductal and parenchymal changes. Pancreatic   ducts may become dilated, irregular, or strictured. Meanwhile,  the glandular tissue itself is often characterized by irregular  and patchy replacement of normal acinar cell architecture  with fibrosis.   Several hypotheses have been proposed to explain the mech-  anisms underlying the pathogenesis of chronic pancreatitis. These  focus on (1) the role of oxidative stress, (2) toxic-metabolic  causes, (3) obstructive causes, and (4) necrosis-fibrosis (also  referred to as the sentinel acute pancreatitis episode [SAPE]  theory). The oxidative-stress hypothesis attributes pancreatic  damage to reflux of bile rich in reactive oxidation byproducts.  The toxic-metabolic theory involves direct damage to pancre-  atic acinar cells from noxious stimuli such as alcohol. The  obstructive theory attributes the majority of injury to pancreatic  ductal injury resulting from obstruction related to increased  lithogenicity, the latter, in turn, caused by either genetic or envi-  ronmental exposures (eg, alcohol). Finally, the necrosis-fibrosis  hypothesis describes chronic pancreatitis as a continuum that is  initiated early on by an attack of acute pancreatitis; the subse-  quent injury and remodeling lead to pancreatic fibrosis. This  hypothesis has gained further support with the observation of  progression to chronic pancreatitis from childhood through  adulthood of patients with a rare disorder known as hereditary  pancreatitis. This disorder, which is caused by a gain of function  mutation in cationic trypsinogen, leads to recurrent bouts of  acute pancreatitis with later onset of chronic pancreatitis. These  explanations are not necessarily mutually exclusive, and a unify-  ing model explaining the precise mechanisms leading to  impaired ductal bicarbonate secretion and the patchy inflam-  matory changes seen on histopathologic examination remains  to be further elucidated.   Recent characterization of pancreatic stellate cells (PSC)  has added insight to the underlying cellular responses behind  development of chronic pancreatitis. Specifically, PSCs are  believed to play a role in maintaining normal pancreatic  architecture, which can shift toward fibrogenesis in the case of  chronic pancreatitis. It is believed that alcohol or additional  stimuli lead to matrix metalloproteinase-mediated destruc-  tion of normal collagen in pancreatic parenchyma that later   Postnecrotic (severe acute pancreatitis)  Vascular diseases/ischemia  Postradiation exposure  Obstructive  Pancreas divisum (controversial)  Sphincter of Oddi dysfunction (controversial)  Duct obstruction (tumors, post-traumatic)   allows for pancreatic remodeling. Proinflammatory cytokines  tumor necrosis factor-cx (TNFoc), interleukin (IL)-l, and  IL-6, as well as oxidant complexes, are able to induce PSC  activity with subsequent new collagen synthesis. In addition  to being stimulated by cytokines, oxidants, or growth fac-  tors, PSCs also possess transforming growth factor-(3  (TGFp)-mediated self-activating autocrine pathways, which  may explain disease progression in chronic pancreatitis even  after removal of noxious stimuli.   Conwell DL, Vargo JJ, Zuccaro G, et al. Role of differential neu-  roaxial blockade in the evaluation and management of pain in  chronic pancreatitis. Am J Gastroenterol. 2001;96:431-436.  [PMID: 11232686]   Di Sebastiano P, di Mola FF, Di Febbo C, et al. Expression of inter-  leukin 8 (IL-8) and substance P in human chronic pancreatitis.  Gut. 2000;47:423-428. [PMID: 10940282]   Hoogerwerf WA, Gondesen K, Xiao SY, et al. The role of mast cells  in the pathogenesis of pain in chronic pancreatitis. BMC  Gastroenterol. 2005;5:8. [PMID: 15745445]   Mews P, Phillips P, Fahmy R, et al. Pancreatic stellate cells respond  to inflammatory cytokines: potential role in chronic pancreati-  tis. Gut. 2002;50:535-541. [PMID: 11889076]   Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pan-  creatitis: an evidence-based review of past theories and recent  developments. Am J Gastroenterol. 2004;99:2256-2270. [PMID:  15555009]   The hallmark features of chronic pancreatitis are abdominal  pain and pancreatic insufficiency. Advanced disease can also  be associated with weight loss and diabetes. The possibility of  chronic pancreatitis should be entertained in any patient  with symptoms of chronic abdominal pain. Further support-  ing features on history include post-prandial pain triggered  by high-fat or protein-rich meals. In addition, predisposing  etiologic factors according to the TIGAR-O classification  should be actively sought with attention paid to indicators of  possible inherited pancreatic disease such as family history of  pancreatitis, pancreatic cancer, or cystic fibrosis.   1 . Abdominal pain — The pain associated with chronic pan-  creatitis is classically described as epigastric, often with radi-  ation to the back. Pain is often unrelenting and difficult to  treat. Pain may be post-prandial, associated with nausea and  vomiting. Early in the disease course, pain is described as  occurring in discrete episodes (type A pain). However, as the  disease progresses pain may become continuous (type B  pain). Ultimately, the pattern and course of pain symptoms  is highly variable among patients with chronic pancreatitis.  Up to 20-45% of patients having objective evidence of pan-  creatic endocrine or exocrine dysfunction may not have pain.  Thus, pain is not a prerequisite for the diagnosis of chronic  pancreatitis.   2. Pancreatic insufficiency— The second cardinal feature  of chronic pancreatitis is the development of pancreatic  exocrine and endocrine dysfunction with advanced dis-  ease. By comparison to the pain of chronic pancreatitis, the  complications of pancreatic insufficiency are relatively eas-  ily managed. Clinically significant protein malabsorption  and fat deficiency does not occur until over 90% of pan-  creatic function is lost. Typically steatorrhea precedes the  onset of protein malabsorption. Fat malabsorption can  manifest clinically as poorly formed greasy, malodorous  stools. Although absorption of fat-soluble vitamins may be  reduced, clinically significant vitamin deficiency is rarely  reported.   Pancreatic endocrine insufficiency presenting as diabetes  is a distinctly late occurrence. Patients with chronic calcific  pancreatitis or with a family history of diabetes have been  observed to be at increased risk of developing this complica-  tion. Although diabetes associated with chronic pancreatitis  is insulin-requiring, these patients are also at increased risk  of hypoglycemia due to impaired glucagon synthesis result-  ing from pancreatic a cell destruction.   Initial evaluation of chronic pancreatitis should begin with  relatively simple and inexpensive testing. Amylase and lipase  are often elevated during acute pain episodes early in the nat-  ural history of the disease. By contrast, normal or even low  levels of amylase or lipase can be found in patients with  moderate to advanced chronic pancreatitis. Fecal pancreatic  elastase-1 (FPE-1) is a marker of exocrine pancreatic func-  tion. FPE-1 is assessed by an enzyme-linked immunosorbent  assay (ELISA) performed on stool specimens. A level greater  than 200 mcg/g of stool is considered normal, and FPE-1  levels less than 100 mcg/g of stool correlate with severe exocrine  pancreatic insufficiency. Of note, pancreatic enzyme supple-  mentation does not interfere with interpretation of test  results. The widespread availability of FPE-1 testing has  reduced the need for 24-hour fecal fat quantitation as a means  of evaluating steatorrhea.   Additional tests that may be useful in evaluating chronic  pancreatitis include hemoglobin A lc (to investigate glucose  intolerance) and markers of autoimmune chronic pancreati-  tis, including immunoglobulin G 4 , rheumatoid factor, and  antinuclear antibody. Elevation of liver function tests may  signal compression of the pancreatic portion of the bile duct  from fibrosis, edema, or tumor development.   Plain abdominal radiographs may reveal calcifications  within the pancreas (common in alcoholic and tropical pan-  creatitis). In general, transabdominal ultrasound has been  associated with low sensitivity in diagnosing chronic pancre-  atitis except in patients with severe disease. Contrast-  enhanced computed tomography (CT) and magnetic  resonance imaging (MRI) offer enhanced visualization of  the pancreas and adjoining structures. These latter two imag-  ing modalities have increasingly become the mainstay of  noninvasive imaging techniques for the diagnosis of chronic  pancreatitis.   In addition to visualizing calcifications, contrast-  enhanced CT allows evaluation of the parenchymal architec-  ture (see Figure 9-51). Complications such as pseudocysts,  pseudoaneurysms, and venous thromboses are well charac-  terized by CT.   MRI technology, specifically magnetic resonance cholan-  giopancreatography (MRCP), has the ability to visualize  fluid-filled structures allowing characterization of the pan-  creatic duct. When compared with endoscopic retrograde  cholangiopancreatography (ERCP), MRI demonstrates simi-  lar ability to detect main duct abnormalities but is not as  accurate in evaluating side branch disease. Although defini-  tive studies have not been published, the administration of  secretin has been demonstrated to enhance visualization of  both the main pancreatic duct and side branches, which may  be particularly useful in patients with early disease prior to  the onset of clear ductal dilation.   1 . Endoscopic ultrasound (EUS)— One of the challenges for  noninvasive testing remains the diagnosis of early-mild  chronic pancreatitis. Increasingly EUS has played a role in  this disease group. Previously established endosonographic  criteria for the diagnosis of chronic pancreatitis include  parenchymal features (atrophy, hyperechoic foci, stranding,  cysts, and lobularity) and ductal features (narrowing, dila-  tion, irregularity, calculi, side branch dilation, and hypere-  choic walls). The diagnosis usually requires identification of  5 (or more) of 11 criteria. EUS appears to be particularly  beneficial when evaluating cystic lesions believed to be aris-  ing in the backdrop of chronic pancreatitis as well as exam-  ining parenchyma when presence of disease is equivocal.  New variations of EUS imaging including elastography and  digital imaging enhancement may decrease the subjectivity  of image interpretation.   2. Endoscopic retrograde cholangiopancreatography  (ERCP) — While providing excellent views of the pancreatic  main duct and side branches, ERCP also offers the possibil-  ity of therapeutic intervention. However, given the associated  risks of inducing acute pancreatitis, ERCP is generally  reserved for situations in which intervention is likely.   Conwell DL, Zuccaro G Jr, Vargo II, et al. An endoscopic pancre-  atic function test with cholecystokinin-octapeptide for the diag-  nosis of chronic pancreatitis. Clin Gastroenterol Hepatol  2003;1:189-194. [PMID: 15017490]   Conwell DL, Zuccaro G Jr, Vargo JJ, et al. An endoscopic pancre-  atic function test with synthetic porcine secretin for the eval-  uation of chronic abdominal pain and suspected chronic  pancreatitis. Gastrointest Enclose. 2003;57:37-40. [PMID:  12518128]   Stevens T, Conwell D, Zuccaro G, et al. Analysis of pancreatic  elastase-1 concentrations in duodenal aspirates from healthy  subjects and patients with chronic pancreatitis. Digest Dis Sei.  2004;49:1405-1411. [PMID: 15481311]   Wallace MB, Hawes RH, Durkalski V, et al. The reliability of EUS  for the diagnosis of chronic pancreatitis: interobserver agree-  ment among experienced endosonographers. Gastrointest  Endosc. 2001;53:294-299. [PMID: 11231386]   1. Gene testing — The role of genetic testing for patients  with suspected hereditary forms of chronic pancreatitis con-  tinues to evolve. Hereditary and idiopathic forms of chronic  pancreatitis account for up to 20-30% of cases. Genetic alter-  ations associated with chronic pancreatitis include muta-  tions in the cationic trypsinogen gene PRSS1 (carriers bear a  markedly increased lifetime risk of pancreatic cancer), the  cystic fibrosis transmembrane conductance regulator ( CFTR,  an apical membrane chloride channel), and the serine pro-  tease inhibitor, Kazal type 1 (SPINK1). Although widespread  screening has yet to come into routine practice, it is indicated  in patients with otherwise unexplained onset of chronic pan-  creatitis or suggestive family history.   Rolston RK, Kant JA. Genetic testing in acute and chronic pancre-  atitis. Curr Gastroenterol Rep. 2001;3:115-120. [PMID: 11276378]   Witt H, Luck W, Becker M, et al. Mutation in the SPINK1 trypsin  inhibitor gene, alcohol use, and chronic pancreatitis. JAMA.  2001;285:2716-2717. [PMID: 11386926]   2. Pancreatic function testing— Sampling of secretin-  stimulated pancreatic fluid from duodenal aspirates theoreti-  cally allows detection of impaired pancreatic function prior  to the onset of structural abnormalities. The most widespread  technique consists of aspiration of duodenal juice through a  dual lumen (Dreiling tube) every 15 minutes for a total of  60 minutes following administration of secretin. A peak bicar-  bonate concentration less than 80 mEq/L is consistent with  the diagnosis of chronic pancreatitis. More recently endo-  scopic pancreatic function testing has emerged at specialized  centers as an alternative modality for direct sampling of duo-  denal aspirates. Furthermore, breath testing has recently been  shown to be equivalent to fecal fat measurements and may  allow a noninvasive means of monitoring therapy.   3. Mixed triglyceride breath test— Recently, the 13C-  mixed triglyceride breath test (MTG) has been evaluated as  a potential tool for evaluating the effect of enzyme therapy  on fat digestion in chronic pancreatitis. The MTG is equiv-  alent to coefficient of fat absorption (CFA) at detecting  steatorrhea and can be used to target enzyme therapy to  improve nutritional parameters and fat maldigestion. One-  year follow-up of patients with chronic pancreatitis using  MTG to adjust pancreatic enzyme supplementation  showed improvement in body mass index, retinal binding  protein, and serum albumin. Of note, MTG-targeted ther-  apy revealed dosages of enzyme requirements were as high  as 60,000 units of lipase per meal and in some cases  required a proton pump inhibitor.   Dominguez-Munoz JE, Iglesias-Garcia I, Vilarino-Insua M, et al.  13C-mixed triglyceride breath test to assess oral enzyme substi-  tution therapy in patients with chronic pancreatitis. Clin  Gastroenterol Hepatol. 2007;5:484-488. [PMID: 17445754]   The diagnosis of chronic pancreatitis can be challenging due  to overlap with several other chronic pain syndromes and in  many cases the late occurrence of objective laboratory or  radiographic abnormalities. Moreover, repeated instrumen-  tation of the pancreas itself can often lead to significant  pathologic changes in the pancreatic parenchyma and duct  architecture. Ultimately, a rational diagnostic approach to  diagnosing chronic pancreatitis requires the appropriate use  of clinical history, laboratory testing, and radiographic and  endoscopic investigation. The role of genetic testing contin-  ues to be defined.   The differential diagnosis of patients presenting with pain  from chronic pancreatitis often includes peptic ulcer disease,  inflammatory bowel disease, gastric dysmotility, and irritable  bowel syndrome in addition to psychogenic or factitious/  drug-seeking disorders. These must be further discriminated  through careful clinical evaluation. The maldigestion associ-  ated with chronic pancreatitis must be distinguished from  other malabsorptive disorders such as carbohydrate malab-  sorption and celiac disease. It may help to ask about a history  of "sticky" or greasy stools as well as the presence of oil drops  separating from the main stool. These are features often asso-  ciated with significant steatorrhea and strongly suggest the  diagnosis of pancreatic insufficiency.   Complications associated with chronic pancreatitis include  pseudocyst, biliary ductal or duodenal obstruction, pancre-  atic ascites or pleural effusion, splenic vein thrombosis, pan-  creatic fistulae, pseudoaneurysms, and an increased risk of  pancreatic cancer.   Treatment for chronic pancreatitis begins with lifestyle mod-  ifications, including cessation of alcohol, consumption of  smaller low-fat meals, and quitting smoking. Further therapy  should be directed toward treatment of symptoms and  guided by the underlying suspected cause.   By far the most difficult aspect of treatment of chronic pancre-  atitis relates to management of chronic pain. Treatment should  be aimed at analgesia, reducing inflammation, and overcoming  intrapancreatic pressure. In addition, investigations are cur-  rently under way to evaluate means of altering neural trans-  mission in order to improve analgesia. Increasingly, it has  become recognized that many patients labeled with the diag-  nosis of chronic pancreatitis may not actually have visceral  pain. These patients are much less likely to respond to therapy.  The mechanisms causing pain in pancreatitis have been  the focus of intense study due to their enigmatic nature.  Likely multifactorial, previously reported factors contributing  to pain in chronic pancreatitis have included recurrent tissue  inflammation, necrosis, pancreatic ductal hypertension,  increased interstitial fluid pressure, pancreatic ischemia, and  fibrotic encasement of sensory nerves (Figure 26-1). More  recently, attention has focused on pain in chronic pancreatitis  as a neurobiologic phenomenon. Researchers have reported  increased changes in the brain cortex of patients with chronic  pancreatitis when compared with controls. Recent studies  have also demonstrated up-regulation of the pain mediators  substance P and calcitonin gene-related peptide in tissue   ▲ Figure 26-1. Sources of pain in chronic pancreatitis. (Reproduced, with permission, from the American  Gastroenterological Association Gastroenterology Teaching Project.)   samples from patients with chronic pancreatitis, as well as  nerve growth factor-dependent nociceptors. TrkA, a high-  affinity receptor for a nerve growth receptor, has been found  to be overexpressed in acinar cells in chronic pancreatitis and  may serve as a link between inflammation and hyperalgesia.  Additional nociceptive pathways implicated in chronic pan-  creatitis include brain-derived neurotrophic factor as well as  proteinase-activated receptor-2 (PAR-2)-mediated stimula-  tion of nociceptive neurons by trypsin activation. Two emerg-  ing concepts with respect to pain mediation in chronic  pancreatitis include "mechanical allodynia," whereby pain is  sensed even in the absence of noxious stimuli given prior sen-  sitization of the nociceptive system, and "inflammatory  hyperalgesia," in which relatively minor episodes of inflam-  mation may trigger increased pain response due to already  "primed" pancreatic nociceptors.   Analgesics should be administered in conjunction with  pain specialists. Patients should be asked to maintain a daily  log of pain while receiving both non-narcotic and narcotic  analgesics.   1. Inflammation and pancreatic pressure— Attempts to  reduce pancreatic inflammation should include smoking  cessation, trial of total parenteral nutrition or enteral feed-  ing, surgery for obstructive pancreatitis, and corticosteroids  for autoimmune chronic pancreatitis (Table 26-2). Methods  of reducing pancreatic pressure include suppression of  secretion via administration of a proton pump inhibitor,  pancreatic enzymes, and potentially octreotide. In the rare   but now increasingly recognized instance where autoim-  mune pancreatitis is suspected, therapy with corticosteroids  has also been found to be beneficial (see Chapter 27).   2. Obstruction — If ductal obstruction is present due to stric-  ture, stone, or pseudocyst with mass effect, invasive therapy  may be necessary. In the case of ductal stones, endoscopic clear-  ance, surgical therapy, or extracorporeal shock wave lithotripsy  may be attempted although evidence for individual treatment  modalities is limited. Symptomatic pseudocysts may be  drained percutaneously, endoscopically, or surgically. Recent  data from randomized head-to-head trials indicate somewhat  improved outcomes with surgical drainage over endoscopic  therapy. Surgical options for chronic pancreatitis include lateral  pancreaticojejunostomy for decompression of a dilated main  duct, removal of localized disease by either a Whipple proce-  dure or tail resection, and, finally, total pancreatectomy.   modifying the nociceptive process involved in chronic pan-  creatitis include EUS-guided celiac plexus block, bilateral  thorascopic splanchnicectomy, transcranial magnetic stimu-  lation, as well as additional investigational techniques. One  study examining celiac plexus block via EUS found that 55%  of subjects had decreased pain after 8 weeks with only 10%  experiencing decreased pain after 24 weeks. For the most  part, these modalities have achieved success only in producing  moderate short-term pain relief, with high rates of relapse  after long-term follow-up.   Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical  drainage of the pancreatic duct in chronic pancreatitis. N Engl J  Med. 2007;356:676-684. [PMID: 17301298]   Dite P, Ruzicka M, Zboril V, et al. A prospective, randomized trial  comparing endoscopic and surgical therapy for chronic pancre-  atitis. Endoscopy. 2003;35:553-558. [PMID: 12822088]   Gress F, Schmitt C, Sherman S, et al. Endoscopic ultrasound-guided  celiac plexus block for managing abdominal pain associated with  chronic pancreatitis: a prospective single center experience. Am J  Gastroenterol. 2001;96:409-416. [PMID: 11232683]   Talamini G, Bassi C. The "natural" history of pain in chronic pancre-  atitis. Gastroenterology. 2000;118:235-237. [PMID: 10644178]   Pancreatic enzyme supplementation can aid in addressing the  difficulty in digesting protein and lipid products in patients  with severe chronic pancreatitis. In addition, it appears that  patients with small duct disease may receive an added benefit  from high-dose non-enteric-coated pancreatic enzyme sup-  plementation in terms of pain relief, believed to be mediated  through reduced duodenal cholecystokinin release. Typically,  these enzymes should be given with each meal. Recent evi-  dence suggests that 13C-MTG breath testing may help target  appropriate enzyme therapy dosages in chronic pancreatitis.   The natural history of chronic pancreatitis remains ill-  defined in part because of its highly variable nature. The rela-  tionship between etiologic factors, genetic predisposition,  and the pace of disease progression requires further clarifica-  tion. Modifiable risks factors need to be identified and  treated. It appears that discontinuance of alcohol, cessation  of smoking, and early administration of corticosteroids in  autoimmune disease may affect the natural history and prog-  nosis of the disease.   ► Diffuse swelling and enlargement of the pancreas, especially  the head, the latter mimicking carcinoma of the pancreas.   ► Diffuse irregular narrowing of the pancreatic duct on ERCP  orMRCP.   ► Extrapancreatic bile duct changes (ie, stricture of the com-  mon bile duct and intrahepatic ducts) mimicking primary  sclerosing cholangitis.   ► Resolution or marked improvement in pancreatic and extra-  pancreatic manifestations after corticosteroid treatment.   Mild symptoms, usually abdominal pain, are present but  attacks of acute pancreatitis are unusual. Furthermore,  autoimmune pancreatitis is not a common cause of idio-  pathic recurrent pancreatitis. In the United States, three  quarters of patients with autoimmune pancreatitis present  with obstructive jaundice. Weight loss and new onset of dia-  betes may also occur. Patients who have associated autoim-  mune conditions have corresponding clinical features. In this  regard, Sjogren syndrome, rheumatoid arthritis, retroperi-  toneal fibrosis, ulcerative colitis, and mediastinal adenopathy  have all been reported in patients with autoimmune pancre-  atitis (Table 27-1).   Autoimmune pancreatitis is a rare disorder of presumed  autoimmune causation with characteristic chemical, histo-  logic, and morphologic findings. It is referred to by various  names, including nonalcoholic destructive pancreatitis,  tumefactive pancreatitis, and sclerosing pancreatitis, depend-  ing in part on specific pathologic findings and on the pres-  ence of extrapancreatic manifestations. However, it is  believed that the pathologic heterogeneity may reflect differ-  ent stages or manifestations of the same disease.   Autoimmune pancreatitis has been described as a pri-  mary pancreatic disorder and is also associated with other  disorders of presumed autoimmune etiology, including pri-  mary sclerosing cholangitis, primary biliary sclerosis,  retroperitoneal fibrosis, rheumatoid arthritis, and Sjogren  syndrome. As a result, it has been proposed that autoimmune  pancreatitis represents a systemic autoimmune disease.   Finkelberg DL, Sahani D, Deshpande V, et al. Autoimmune pan-  creatitis. N Engl} Med. 2006;355:2670-2676. [PMID: 17182992]   An obstructive pattern on liver tests is common (ie, dispro-  portionately elevated serum alkaline phosphatase and min-  imally elevated serum aminotransferases). Elevated serum  levels of immunoglobulin G 4 (IgG 4 ) provide a marker for  the disease, particularly in Western populations. Serum IgG 4  normally accounts for only 5-6% of the total IgG 4 in  healthy patients but is elevated in those with autoimmune  pancreatitis.   A large study compared serum IgG 4 levels in 20 patients  diagnosed with autoimmune pancreatitis based on clinical  features and response to corticosteroids with 20 age- and sex-  matched controls and 104 patients with pancreatic cancer,  chronic pancreatitis, primary biliary sclerosis, primary  cholangitis, and Sjogren syndrome. The median serum IgG 4  concentration in the patients with autoimmune pancreatitis  was 663 mg/dL compared with 51 mg/dL in healthy controls  (in whom normal values ranged from 8-140 mg/dL). Using  a cutoff of 135 mg/dL, the sensitivity and specificity of the  serum IgG 4 value for distinguishing autoimmune pancreatitis  from pancreatic cancer was 95-97%.   It has also been demonstrated that IgG 4 levels may decline  during treatment with corticosteroids, and this can be used  as a parameter to follow the response of patients to such  therapy. These and other observations suggest that serum  levels of IgG 4 may be useful to distinguish autoimmune pan-  creatitis from pancreatic cancer. Additionally, other antibod-  ies such as antinuclear antibodies and rheumatoid factor  may be present.   Table 27-2 summarizes the imaging findings observed in two  large series, one from Massachusetts General Hospital  (MGH) and the other from the Mayo Clinic. Pancreatic  abnormalities were present in the majority of the patients  and included diffuse enlargement, focal enlargement, and a  distinct enlargement at the head of the pancreas. Noteworthy  was the lack of vascular encasement calcification or pancre-  atic fluid; however, enlarged pancreatic lymph nodes were  noted (Figure 27-1).   Endoscopic retrograde cholangiopancreatography  (ERCP) or magnetic resonance pancreatography (MRCP)  reveals strictures in the bile duct in over one third of patients  with autoimmune pancreatitis; these may be common bile  duct strictures, intrahepatic bile duct strictures, or proximal  bile duct strictures, with accompanying narrowing of the  pancreatic bile duct (Figure 27-2). Rimlike enhancement of  the pancreatic head can be found on magnetic resonance  imaging (MRI) examination. Endoscopic ultrasound is  increasingly being used to support a diagnosis of autoim-  mune pancreatitis, and characteristic findings appear to be  diffuse pancreatic enlargement and focal irregular hypoe-  choic masses.   ERCP, endoscopic retrograde cholangiopancreatography; MRCP, mag-  netic resonance cholangiopancreatography.  a Data from Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoim-  mune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol  Hepatol. 2006;4:1010-1016.   b Data from Sahani DV, Kalva SP, Farrell J, et al. Autoimmune  pancreatitis: imaging features in 29 patients. Radiology. 2004;233:  345-352.    ▲ Figure 27-1. CT findings in autoimmune pancreatitis.  A: Diffuse homogenous appearance. B: "Halo" around  the pancreas (arrows), focal enlargement of the head  and uncinate, and lack of vascular invasion and peripan-  creatic changes in all segments. (Courtesy of Dr. Dushyant  V. Sahani, Massachusetts General Hospital.)    ▲ Figure 27-2. ERCP findings in autoimmune pancreati-  tis. A: Common bile duct stricture, stricture of intrahepatic  radicals, diffuse pancreatic duct (PD) narrowing, and PD  stenosis. B: Note the diffuse narrowed pancreatic duct.   Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune   Hepatol. 2006;4:1010-1016. [PMID: 16843735]  Sahani DV, Kalva SP, Farrell J, et al. Autoimmune pancreatitis:   Characteristic findings include extensive lymphoplasmacytic  infiltrates with dense fibrosis, and infiltration of polymor-  phic leukocytes extending transmurally, ultimately resulting   in an obliterative phlebitis (see Table 27-1). Inflammatory  cells cluster in the walls of the small veins and nerves. Varying  degrees of pancreatic parenchymal atrophy may be present,  and islets may be encased with intralobular fibrosis.  Importantly, pancreatic ducts exhibit no calcification or  plugging but are slitlike or star shaped.   To date, there have been few published reports describing  cytologic diagnosis of autoimmune pancreatitis. It has been  suggested that smears rich in inflammatory cells (lympho-  cytes, plasma cells, and polymorphonuclear leukocytes with  sparse epithelial cells lacking atypia) may be useful in sup-  porting the diagnosis. It is important to emphasize that the   diagnosis of autoimmune pancreatitis can be missed in core  biopsies because of the sampling area or patchy involvement  of the parenchyma.   Deheragoda MG, Church NI, Rodriguez-Justo M, et al. The use of  immunoglobulin g4 immunostaining in diagnosis pancreatic  and extrapancreatic involvement in autoimmune pancreatitis.  Clin Gastroenterol Hepatol. 2007;5:1229-1234. [PMID:  17702660]   Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concen-  trations in patients with sclerosing pancreatitis. N Engl J Med.  2001;344:732-738. [PMID: 11236777]   Japanese Pancreatic Society. Diagnostic criteria for autoimmune  pancreatitis. J Jpn Pancreas Soc. 2002;17:585-587   Autoimmune pancreatitis should be considered in the differ-  ential diagnosis of patients presenting with the varied symp-  toms described earlier that are referable to the pancreas and  biliary tract, particularly in conjunction with other autoim-  mune conditions. It was formerly believed that the sine qua  non for establishing a diagnosis of autoimmune pancreatitis  was pancreatic histopathologic abnormalities, including  extensive lymphoplasmacytic infiltrates with dense fibrosis.  It is now recognized that in addition to histologic findings  (H), a diagnosis of autoimmune pancreatitis can be made  based on pancreatic imaging (I) and serology (S) (IgG 4  level) after organ involvement (O) and response to corticos-  teroid treatment (R) have been determined; these have been  termed the HISORT criteria. Utilizing this concept, the pro-  posed Mayo Clinic criteria suggest that autoimmune pancre-  atitis can be diagnosed with at least one of three  abnormalities: (1) diagnostic histology, (2) characteristic  findings on computed tomography (CT) and pancreatogra-  phy, with elevated IgG 4 levels; and (3) response to corticos-  teroid therapy, with improvement in pancreatic and  extrapancreatic manifestations.   Patients with autoimmune pancreatitis sometimes pres-  ent with features that mimic pancreatic cancer, including a  mass on the head of the pancreas. Although autoimmune  pancreatitis is diagnosed much less frequently than pancre-  atic cancer, making the correct diagnosis is necessary to avert  the consequences of unnecessary surgery. As detailed in the  treatment section, response to corticosteroids within a 2-4  week period is an important parameter by which the diag-  nosis of autoimmune pancreatitis can be supported.  Autoimmune pancreatitis is usually first suggested by imag-  ing procedures such as contrast-enhanced CT or MRI. Of  note, characteristic features more suggestive of pancreatic  carcinoma (eg, vascular encasement, peripancreatic changes,  etc) are usually lacking. Imaging differences between  autoimmune pancreatitis and pancreatic cancer are  detailed in Table 27-3. A characteristic feature of autoim-  mune pancreatitis is rimlike enhancement of the pancre-  atic head on MRI. Endoscopic ultrasound is also being used   Table 27-3. Differences between autoimmune pancreatitis  and pancreatic cancer on computed tomography scan.   to diagnose autoimmune pancreatitis, and some of the find-  ings that have been noted are listed in Table 27-2.   IgG 4 can also be useful in diagnosing pancreatic and  extrapancreatic involvement in autoimmune pancreatitis. In  one study that examined both pancreatic and extrapancreatic  tissues (gallbladder, stomach, duodenum, colon, salivary  glands, and kidney), high levels of IgG 4 -immunostaining  plasma cells (> 10 IgG 4 plasma cells per high-power field  [HPF]) were found in 17 of 20 (85%) specimens from  patients with autoimmune pancreatitis compared with 1 of  175 (0.6%) specimens from controls. Immunostaining of  involved tissue for IgG 4 may be particularly useful when  autoimmune pancreatitis is suspected clinically but the  serum IgG 4 level is normal.   At the outset, several issues should be raised regarding treat-  ment. First, there have been no controlled trials of treatment  approaches in autoimmune pancreatitis. Second, patients  groups described in existing reports have been heteroge-  neous, with over 50% of the patients having undergone a  Whipple procedure. Third, until recently, uniform diagnostic  criteria were lacking, with the exception of typical pathologic  changes in resected pancreatic specimens. Fourth, criteria for  initiating treatment and assessing response often have not  been uniformly delineated. Nonetheless, after a diagnosis of  autoimmune pancreatitis has been made based on the previ-  ously outlined criteria, treatment with corticosteroids should  be strongly considered.   Corticosteroids have shown efficacy in alleviating symptoms,  decreasing the size of the pancreas, and reversing histopatho-  logic features in patients with autoimmune pancreatitis.   Patients may respond dramatically to corticosteroid therapy  within a 2- to 4-week period. Prednisone is usually adminis-  tered at an initial dose of 40 mg/day for 4 weeks followed by  a taper of the daily dosage by 5 mg/week based on monitor-  ing of clinical parameters. Relief of symptoms, serial changes  in abdominal imaging of the pancreas and bile ducts,  decreased serum y-globulin and IgG 4 levels, and improve-  ments in liver tests are suggested parameters to follow.  Improvement in histologic findings after steroid therapy has  also been reported. In the Mayo Clinic series mentioned ear-  lier, the median duration of treatment was 12 weeks. A poor  response to corticosteroids over a 2- to 4-week period should  raise suspicion of pancreatic cancer or other forms of  chronic pancreatitis.   In most reports, 50-70% of patients responded to corti-  costeroids, but about 25% required a second course of treat-  ment while a smaller number required maintenance  treatment with prednisone at a dosage of 5-10 mg/day. In the  Mayo Clinic series, 15 of 29 patients had resolution of biliary  strictures or pancreatic masses, or both, with steroid treat-  ment. In a series of 21 patients reported by Wakabayashi and  colleagues, initial assessment showed mean pancreatic duct  narrowing in 20 patients and common bile duct stenosis in  18. Imaging findings after treatment showed decreased pan-  creatic swelling in 21 patients, improvement in common bile  duct stenosis in 18, and pancreatic duct narrowing in 20.  Four patients relapsed during corticosteroid treatment,  3 were reported to be in clinical remission off steroids, and  14 required maintenance steroid treatment at some time. In  particular, patients with bile duct strictures may require  maintenance therapy.   Kamisawa T, Yoshiike M, Egawa N, et al. Treating patients with  autoimmune pancreatitis: results from a long-term follow-up  study. Pancreatology. 2005;5:234-238. [PMID: 1585582]   Saito T, Tanaka S, Yoshida H, et al. A case of autoimmune pancre-  atitis responding to steroid therapy. Evidence of histologic  recovery. Pancreatology. 2002;2:550-556. [PMID: 12435868]   Wakabayashi T, Kawaura Y, Satomura Y, et al. Long-term diagno-  sis of duct narrowing chronic pancreatitis: a strategy for steroid  treatment. Pancreas. 2005;30:31-39. [PMID: 15632697]   IgG 4 -associated cholangitis (IAC), which can mimic scleros-  ing cholangitis, is the biliary manifestation of a steroid-  responsive multisystem fibroinflammatory disorder (ie,  autoimmune pancreatitis). The affected organs have a lym-  phoplasmacytic infiltrate rich in IgG 4 -positive cells. A  recent study described clinical, serologic, and imaging char-  acteristics and treatment response in 53 IAC patients.  Among the study participants, 85% were male, 77% pre-  sented with obstructive jaundice, 92% had associated  autoimmune pancreatitis, 74% showed increased serum  IgG 4 levels, and 88% had IgG 4 -positive cells in bile duct   biopsy specimens (> 10/HPF). Bile duct strictures were com-  mon, with isolated intrapancreatic bile duct strictures in  51% of patients, proximal extrahepatic or intrahepatic bile  duct strictures in 49%, and multifocal structures in 32%.   Thirty patients received prednisone at a dose of 40 mg/day  for 4 weeks, which was then tapered to 5 mg/week for a total  of 11 weeks; 18 patients underwent surgical resection; and  5 patients were treated conservatively and had spontaneous  resolution of their disease. The following treatment  responses were observed. Of the 30 patients treated with  prednisone, 29 (97%) had an initial response, and 18 (60% of  patients) had resolution of strictures and normalization of  liver enzymes. Twelve of 17 patients (71%) with proximal  bile duct strictures relapsed less than 6 months after pred-  nisone was discontinued; in these patients, the presence of  proximal extrahepatic or intrahepatic stricture was predic-  tive of relapse. Fifteen patients were retreated with steroids  for relapse, and 7 patients required additional immunomod-  ulating drugs (azathioprine, cyclophosphamide, or mycophe-  nolate mofetil) to remain in steroid-free remission during  more than 6 months of follow-up. Eight of the 15 patients  retreated with steroids (44%) relapsed.   The authors of the study drew the following conclusions  from these findings: first, IAC should be suspected in patients  with unexplained biliary strictures associated with increased  IgG 4 and unexplained pancreatic disease; second, relapses are  common after steroid withdrawal, especially in patients with  proximal strictures; and third, the role of immunomodulat-  ing drugs for relapses needs to be explored through further  study.   Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated  cholangitis: clinical profile and response to therapy. Gastroenterology.  2008;134:706-715. [PMID: 18222442]   Hirano and colleagues reported outcomes and clinical fea-  tures in 42 patients with autoimmune pancreatitis.  Nineteen patients were treated with corticosteroids (pred-  nisolone) and 23 without. The average observation period  was 25 months but ranged up to 7 years. Unfavorable events  (sclerosing cholangitis, distal bile duct stenosis, and  retroperitoneal fibrosis) developed in 16 of the 23 patients  (70%) not treated with corticosteroids but in only 3 of 19  patients (32%) treated with prednisolone. These data sup-  port the recommendation that patients with autoimmune  pancreatitis, especially those with obstructive jaundice and  bile duct strictures, should be treated and maintained on  corticosteroids.   Hirano K, Tada M, Isayama H, et al. Long-term prognosis of  autoimmune pancreatitis with and without corticosteroid treat-  ment. Gut. 2007;56:1719-1724. [PMID: 17525092]   ► Helical pancreatic protocol computed tomography (PPCT)  is generally the best initial modality for diagnosis and  staging.   ► Endoscopic ultrasound (EUS) is superior to CT in diagnos-  ing small tumors, and portal and splenic vein invasion.   ► Less than 15% of tumors are resectable at the time of  diagnosis.   Pancreatic cancer is the second most common gastrointesti-  nal malignancy, and the fourth leading cause of cancer-  related deaths in the United States. Less than 4% of patients  are alive 5 years after diagnosis. Approximately 34,000 new  cases were diagnosed in 2006, and 37,000 new cases were  expected to be diagnosed in 2008.   The disease is more common in men than in women (1.3:1)  and in certain ethnic and racial groups (eg, blacks, Polynesians,  and native New Zealanders). It is rare before the age of 45 years,  but the incidence increases sharply after the seventh decade.   lemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer  J Clin. 2008;58:71-96. [PMID: 18287387]   Shaib YH, Davila IA, El-Serag HB. The epidemiology of pancreatic  cancer in the United States: changes below the surface. Aliment  Pharmacol Ther. 2006;24:87-94. [PMID: 16803606]   Most pancreatic neoplasms arise from the three different  types of the epithelial cells found in the pancreas. Acinar cells   account for 80% of the volume of the gland but constitute  1% of exocrine tumors. Ductal cells constitute 10-15% of the  volume but give rise to 90% of all tumors. Endocrine cells are  1-2% of volume and account for 1-2% of the tumors.  Nonepithelial tumors are very rare.   Approximately 70% of ductal tumors are localized to the  head of the pancreas, 5-10% to the body, and 10-15% to the  tail. These tumors are hard in consistency due to the strong  desmoplastic response they elicit.   Acinar tumors present as large pancreatic masses in the  elderly, and distant metastasis is usually present at the time of  diagnosis.   It has been proposed that pancreatic cancer develops from  small intraductal precursor lesions (pancreatic intraepithe-  lial neoplasia), following an evolution similar to the adenoma-  carcinoma sequence seen in colorectal tumors. Although the  precise mechanism and sequence of genetic mutations  responsible for the development of pancreatic cancer  remains unclear, genetic alterations found in these tumors  can be classified into three categories: (1) activation of  oncogenes; (2) inactivation of tumor suppressor genes; and  (3) defect in DNA mismatch repair genes. The sonic hedge-  hog signaling pathway also appears to play a role. The sonic  hedgehog gene, which is involved with embryonic development,  appears to be unregulated in early and late stages of pancreatic  carcinogenesis.   1. Activation of oncogenes— Mutations of the K-ras onco-  gene are seen in 90% of tumors and are the hallmark of  pancreatic adenocarcinoma. Although this mutation may be  seen in nonmalignant conditions such as chronic pancreatitis,  it appears to be an early genetic alteration in pancreatic  carcinogenesis.   2. Inactivation of tumor suppressor genes— Inactivation  and loss of function of tumor suppressor genes results in   critical disruption of the cell cycle involving cellular differen-  tiation, growth inhibition, regulation of transcription, DNA  repair, and apoptosis. The genes most frequently involved are  CDKN2A (95%), P53 (60%), DPC4 (50%), BRCA2, and  STK11. About 10% of patients with hereditary pancreatic  cancer harbor germline mutations of the BRCA2 gene.   3. Defect of DNA mismatch repair gene— Mutations of  mismatch repair genes, such as MLH1 and MSH2, have been  found in 4% of pancreatic tumors.   1. Family history of pancreatic cancer— Genetic predis-  position is the greatest risk factor for the development of  pancreatic cancer. About 8-10% of patients with pancreatic  cancer have a first-degree relative with the disease. These  patients present at an earlier age, and smoking appears to  contribute to the development of the cancer.   2. Hereditary chronic pancreatitis— This autosomal-  dominant condition is strongly associated with pancreatic  cancer although it accounts for a small fraction of the total  number of cases. It presents as recurrent attacks of acute  pancreatitis early in life that may progress to chronic pancre-  atitis. The risk of an affected family member developing can-  cer is as high as 40% by age 70 and is highest among those  who smoke.   3. Other conditions — The risk of pancreatic cancer is also  increased in patients with certain familial cancer syndromes  such as Peutz-Jeghers syndrome, ataxia-telangiectasia, famil-  ial adenomatous polyposis, and Lynch syndrome II.   Diabetes mellitus is associated with pancreatic cancer,  and in most cases there is no family history. In most patients  the diagnosis of pancreatic cancer is made within 2 years of  the onset of diabetes mellitus. Although some studies have  shown that high prediagnosis serum concentrations of glu-  cose and insulin, along with insulin resistance, correlate with  an increased risk of pancreatic cancer, other studies suggest  that the tumor may be responsible for the diabetogenic state.   The best-established environmental risk factor associated  with pancreatic cancer is cigarette smoking. The relative risk  of pancreatic cancer among current smokers is 2.5. The risk  increases with the number of cigarettes consumed and  returns to baseline 15 years after the patient stops smoking.   Diet appears to be another important environmental fac-  tor. Diets high in fat and meat appear to be linked to the  development of pancreatic cancer, while consumption of  fruits and vegetables seem to have a protective effect. Low  levels of selenium and lycopene have been associated with  the development of pancreatic cancer.   Data on coffee and alcohol consumption, use of aspirin  and other nonsteroidal anti-inflammatory drugs, and the  development of pancreatic cancer have been conflicting, and   recent studies show no definite relationship. In a recent  study, obesity significantly increased the risk of pancreatic  cancer. Some studies have shown an association between  Helicobacter pylori infection, particularly the Cag A strain, and  pancreatic cancer.   The risk of pancreatic adenocarcinoma is about 4% in patients  with nonhereditary chronic pancreatitis 20 years after disease  onset.   Owing to the lack of characteristic signs and symptoms, most  patients with pancreatic tumors present late in the course of  the disease. As a result, less than 15% of tumors are resectable  at the time of diagnosis. Even after surgical resection with  negative margins, the 5-year survival rate is between 10%  and 25%, with a median survival between 10 and 20  months. Patients may present with vague, low-intensity, dull  abdominal discomfort or pain that radiates to the back and  may be associated with weight loss, anorexia, weakness, diar-  rhea, and vomiting (Table 28-1). The pain is primarily due to  the invasion of the celiac and superior mesenteric plexus.   Location of the tumor also defines the symptoms and the  prognosis. Tumors of the head of the pancreas produce  symptoms early, and painless jaundice is seen in more than  50% of cases due to obstruction of the extrahepatic bile duct.  In less than one third of patients, obstruction of the bile  duct by pancreatic neoplasm is accompanied by a palpable,  nontender gallbladder referred to as Courvoisier sign. This  finding also may be seen in bile duct obstruction by cholan-  giocarcinoma, duodenal carcinoma, and carcinoma of the  ampulla of Vater.   Tumors of the body and tail are either "asymptomatic" or  manifest with nonspecific symptoms, such as abdominal  discomfort, and the diagnosis is mostly made after metastatic  disease has developed.   Table 28-1. Clinical manifestations that may be associated  with pancreatic cancer.   Obstruction of the pancreatic duct may lead to pancre-  atic exocrine insufficiency in the form of steatorrhea and  malabsorption. New-onset diabetes mellitus after the age of  50 years has been associated with the development of pan-  creatic cancer, especially in the absence of a family history  of diabetes. Other uncommon manifestations of pancre-  atic neoplasm include acute pancreatitis in the elderly  without any obvious cause, thrombophlebitis, psychiatric  disturbances, pruritus due to cholestasis, signs and symp-  toms of gastrointestinal bleeding, and obstruction due to  erosion and growth of the pancreatic neoplasm into the  duodenal lumen. In patients older than age 50, pancreatic  cancer can present with features of irritable bowel syndrome  or early-onset diabetes.   Malignant obstruction of the distal bile duct by a neoplasm  of the pancreatic head characteristically produces an alkaline  phosphatase level that is four to five times the upper limits of  normal, and the increase is disproportionate to the bilirubin  level until late in the course of the disease. The rise in  transaminases is usually mild. Despite biliary stasis, cholan-  gitis is uncommon. Lipase and amylase are elevated in  tumors that cause pancreatic duct obstruction and present as  acute pancreatitis.   1. Tumor markers— CA 19-9 is a sialylated Lewis antigen  that has been found to be clinically useful in both diagnosis  and monitoring of the treatment response. The sensitivity  and specificity, using a cutoff level of 37 units/mL, is 86%  and 87%, respectively. Biliary tract obstruction with cholan-  gitis due to a nonmalignant cause can result in high levels of  CA 19-9. In one study, levels as high as 32,000 were reported.   Pancreatic adenocarcinoma is staged using a TNM classifica-  tion (Table 28-2). It consists of evaluating the characteristics  of the primary tumor, namely tumor size and infiltration  into major vessels (T stage), regional lymph node involve-  ment (N stage), and the presence and absence of distant  metastasis (M stage). Various modalities are available for the  diagnosis and staging of pancreatic tumors, including those  described below.   1. Computed tomography (CT) scan— Transabdominal  ultrasound and the CT scan remain the most common imag-  ing modalities used in patients with suspected pancreatic  cancer. A pancreatic protocol helical CT scan is probably the  best initial modality for diagnosis and staging of pancreatic  adenocarcinoma. Based on the imaging features, a correct  diagnosis of pancreatic cancer is made in more than 90% of  cases. In addition to detecting metastasis, based on the  involvement adjacent organs, and vascular invasion, the helical    Tumor limited to the pancreas, < 2 cm in greatest  dimension    Tumor limited to the pancreas, > 2 cm in greatest  dimension    Tumor extends beyond pancreas but without involve-  ment of celiac axis or superior mesenteric artery    Tumor involves celiac axis or superior mesenteric  artery (unresectable primary tumor)   CT scan can predict unresectability with more than 90%  accuracy. The major drawback is that a significant propor-  tion of patients found to have resectable disease on CT scan  have unresectable disease at laparotomy due to small tumor  implants in the liver and peritoneum.   2. Endoscopic ultrasound (EUS)— EUS has a diagnostic  sensitivity similar to helical CT scan but may be superior in  diagnosing small pancreatic tumors, and portal and splenic  vein invasion. EUS-guided fine needle aspiration (EUS-FNA)  has a diagnostic sensitivity of about 85-90% with a false-  negative rate of 10-15%. It is safe procedure with minimal  risk of tumor seeding. EUS is less accurate in predicting  superior mesenteric vein and superior mesenteric artery  involvement by the tumor.   3. Endoscopic retrograde cholangiopancreatography  (ERCP) — Pancreatic tumors appear as strictures of the pan-  creatic duct or the bile duct on ERCP. This stricturing of  both the bile duct and the pancreatic duct is referred to as  the "double duct sign." Advances in pancreatic imaging such  as helical CT have made ERCP unnecessary as an initial test.  Major limitations of ERCP are the limited ability to obtain a  tissue diagnosis in malignant bile duct obstruction (positive  in < 50% of cases); limited utility for pancreatic tumor stag-  ing, as it provides no information about tumor extent, vas-  cular invasion, or involvement of the lymph nodes; and risk  of complications such as pancreatitis, perforation, and rarely,  death.   4. Magnetic resonance imaging (MRI)— Accuracy of MRI  to determine respectability appears comparable to the dual-  phase helical CT scan. Magnetic resonance cholangiopancre-  atography (MRCP) is as sensitive as ERCP in the diagnosis of  pancreatic tumors.   5. Positron emission tomography (PET)— PET scanning  is not routinely used in diagnosis of pancreatic cancers. It can  be useful in diagnosing tumor reoccurrence after pancreatic  resection.   6. Laparoscopy — Studies have shown that standard preop-  erative imaging modalities, including CT scan in 15-40%  cases, are unable to detect small peritoneal and liver metastasis.  In select patients, staging laparoscopy along with peritoneal  cytologic examination can detect unsuspected metastasis and  prevent unwarranted surgery.   Figure 28-1 presents an algorithm for the diagnosis and  treatment of suspected pancreatic cancer. The need for tis-  sue to establish a diagnosis in a suspected pancreatic cancer  remains controversial. Although consensus on an optimal  approach is lacking, any diagnostic strategy should aim to  reliably and safely establish a diagnosis, if necessary; deter-  mine resectability to avoid costs; and avoid morbidity and  mortality associated with unnecessary surgical intervention.  Comparison of imaging modalities (EUS, MRI, and CT)  has methodologic limitations, such as patient selection,  study design, and quality. EUS has been generally found to  be superior to CT and MRI in detection and characterization   of smaller lesions. It has been found to be superior to helical  CT scan and MRI for tumor and nodal staging, with a sen-  sitivity of greater than 90%. EUS does not offer any advan-  tage over helical CT in determining resectability of  preoperatively suspected pancreatic adenocarcinoma, and  the two modalities are considered complementary.   Helical pancreatic protocol CT (PPCT) scan is usually the  preferred initial test for loco-regional staging and detection  of distant metastasis. Based on the CT scan findings, pancre-  atic masses fall into one of the following four broad cate-  gories: (1) no mass, (2) unresectable mass, (3) resectable  mass, and (4) equivocal findings.   Based on clinical suspicion and pretest probability, fur-  ther imaging by MRCP, EUS, ERCP, or a combination of  these methods may be necessary, even if the initial CT find-  ings are negative for any mass lesion. EUS can identify lesions  not seen on CT or MRI.   If a clearly unresectable mass is identified on CT scan, a  tissue diagnosis is usually indicated prior to starting any  palliative chemotherapy or radiotherapy. EUS-FNA, or a  percutaneous approach using a CT or transabdominal  ultrasound, can be used. In patients with pancreatic cancer  who experience pain, EUS can be used to perform celiac  plexus neurolysis during the initial diagnostic and staging  examination.   Patients identified as having a resectable mass on CT scan  should be considered for EUS as a complementary test  because it is more accurate for local tumor staging and pre-  dicting vascular invasion. The need to obtain a tissue diagno-  sis in this group is controversial. Beyond the patient's desire  for a tissue diagnosis, pretest probability of a tumor, and  available local expertise, the major consideration determin-  ing whether to obtain a tissue diagnosis should be its impact  on clinical decision-making and management.   The major drawback of pursuing a tissue diagnosis is that  the sensitivity of EUS-FNA is 85-90%, giving it an unaccept-  ably high false-negative rate of 10-15%. If the pretest proba-  bility based on the clinical presentation laboratory data and  radiological findings for cancer is high, then a negative tissue  diagnosis does not influence the decision to proceed with  surgery. Although minimal, the potential for complications  such as bleeding, pancreatitis, and tumor seeding during  Fine needle aspiration should also be considered.   Besides confirming the diagnosis of pancreatic cancer in  the majority of patients, the advantages of obtaining tissue  are that it helps identify other malignancies, such as neu-  roendocrine tumors, lymphoma, and small-cell carcinoma,  as well as nonmalignant conditions such as autoimmune  pancreatitis and chronic pancreatitis, resulting in changes in  treatment and prognosis.   Complications from surgery are another major concern.  Pancreatoduodenectomy is associated with significant mor-  bidity, and the mortality rate can range from less than 1% in  a large-volume center to about 15% in centers performing  few such surgeries per year. This must be taken into account   ▲ Figure 28-1. Algorithm for the diagnosis and treatment of suspected pancreatic carcinoma. CT, computed tomography;  ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FNA, fine needle aspiration; MRCP,  magnetic resonance cholangiopancreatography.   by the physicians and the patient prior to surgical resection  of the pancreas.   Patients with tumors localized to the body and tail of  the pancreas and resectable by helical CT criteria should  be considered for laparoscopy prior to surgery as these  tumors are usually advanced at presentation and frequency  of unsuspected spread to the peritoneum can be as high  as 50%.   In patients whose CT findings are equivocal regarding  the presence of a mass or potential for resectability, EUS is  indicated, as it is the most sensitive method to detect small  tumors of the pancreas and evaluate for vascular invasion.   Adamek HE, Albert J, Breer H, et al. Pancreatic cancer detection  with magnetic resonance cholangiopancreatography and  endoscopic retrograde cholangiopancreatography: A prospec-  tive controlled study. Lancet. 2000;356:190-193. [PMID:  10963196]   ASGE Standards of Practice Committee, Gan SI, Rajan E, et al.  Role of EUS: communication from the ASGE standards of prac-  tice committee. Gastrointest Endosc. 2007;66:425-434. [PMID:  17643438]   Dewitt J, Devereaux BM, Lehman GA, et al. Comparison of endo-  scopic ultrasound and computed tomography for the preopera-  tive evaluation of pancreatic cancer: a systemic review. Clin  Gastroenterol Hepatol. 2006;4:717-725. [PMID: 16675307]   Mertz HR, Sechopoulos P, Delbeke D, et al. EUS, PET, and CT  scanning for evaluation of pancreatic adenocarcinoma  Gastrointest Endosc. 2000;52:367-371. [PMID: 10968852]   Soriano A, Castells A, Ayuso C, et al. Preoperative staging and  tumor resectability assessment of pancreatic cancer: prospective  study comparing endoscopic ultrasonography, helical com-  puted tomography, magnetic resonance imaging, and angiogra-  phy. Am J Gastroenterol. 2004;99:492-501. [PMID: 15056091]   Wiersema MJ, Norton ID, Clain JE. Role of EUS in the evaluation  of pancreatic adenocarcinoma. Gastrointest Endosc. 2000;52:  578-582. [PMID: 11023593]   Pancreatic adenocarcinoma must be differentiated from the  following conditions of the pancreas that can mimic its  symptoms: autoimmune pancreatitis, chronic pancreatitis,  pancreatic lymphoma, neuroendocrine tumors of the pan-  creas, and cystic lesions of the pancreas.   Autoimmune pancreatitis is a rare disorder of presumed  autoimmune etiology that can manifest with obstructive  jaundice, weight loss, abdominal pain, and new-onset dia-  betes. Imaging studies show diffuse enlargement of the pan-  creas, irregular narrowing of the pancreatic duct, strictures of  the common bile duct, and stricture of the intrahepatic rad-  icals similar to that seen in primary sclerosing cholangitis  (refer to Table 27-3 in the preceding chapter). Increased lev-  els of serum y-globulins, especially immunoglobulin G 4 , are  present. Lymphoplasmacytic infiltration with fibrosis and  obliterative phlebitis is seen on histologic examination.  Corticosteroids are effective in alleviating symptoms and  reversing histopathologic changes.   The incidence of pancreatic adenocarcinoma in patients with  chronic pancreatitis increases about 2% per decade after  onset of the disease. Abdominal pain, weight loss, and jaun-  dice may occur in patients with chronic pancreatitis, making  it difficult to differentiate chronic pancreatitis complicated  by adenocarcinoma.   Imaging studies are not always useful as patients with  chronic pancreatitis can present with strictures of the pancre-  atic and bile duct on ERCP, a mass lesion on CT (variant of  AIP), or with changes in the echo texture of pancreatic tissue,  making EUS images difficult to interpret. EUS appears to be  superior to CT scan for detection of coexistent malignancy.   Although CA 19-9 is elevated in about 80% of patients  with adenocarcinoma, it can also be elevated in patients with  chronic pancreatitis, and very high values may occur in  patients with obstructive jaundice and cholangitis.   K-ras mutations do not seem to be clinically useful in dif-  ferentiating chronic pancreatitis and pancreatic cancer.   Patients with pancreatic cancer can be subdivided into three  categories based on the extent of tumor spread: (1) tumor  confined to the pancreas (resectable disease at diagnosis),  representing approximately 15-20% of patients; (2) locally  advanced disease (unresectable), 40%; and (3) metastatic  disease, 40%.   Surgical resection is the only curative treatment for pancre-  atic cancer. Owing to the characteristically late presentation,  only 15% of patients are candidates for pancreatectomy. The  most common surgery is the Whipple pancreaticoduo-  denectomy, used in patients with cancers located in the head  of the pancreas. The procedure involves en bloc removal of  the gastric antrum, pancreas, and duodenum. Removal of  regional lymph nodes has not been shown to be associated  with improved survival. Mortality rates for this procedure  are about 1-3% at centers that perform a large number of  these procedures.   As noted earlier, even after surgical resection with nega-  tive margins, patients have a 5 -year survival rate of only  10-25%, with median survival of 10-20 months. Involvement  of the lymph nodes in resected patients is the most important  prognostic factor; 5-year survival after the Whipple procedure  is 10% for patients with node-positive disease and 25-30%  for those with node-negative disease. Tumor size less than  3 cm, well-differentiated tumors, negative surgical margins,  and absence of lymph node metastasis are associated with  improved survival.   Surgical resection of tumors located on the body and the  tail consists of distal subtotal pancreatectomy along with  splenectomy.   Endoscopic stent placement in patients with resectable  tumors to relieve jaundice prior to surgery does not alter  postoperative morbidity and mortality and is not recom-  mended. If the surgery is scheduled for several weeks later, a  plastic stent can be placed to relieve jaundice and reduce the  risk of cholangitis.   Birkmeyer ID, Stukel TA, Siewers AE, et al. Surgeon volume and  operative mortality in the United States. N Engl J Med.  2003;349:2117-2127. [PMID: 14645640]   Blackstock AW, Mornex F, Partensky C, et al. Adjuvant gemcitabine  and concurrent radiation for patients with resected pancreatic  cancer: a phase II study. Br J Cancer. 2006;95:260-265. [PMID:  16868545]   Neoptolemos IP, Stocken DD, Friess H, et al. A randomized trial of  chemoradiotherapy and chemotherapy after resection of pan-  creatic cancer. N Engl J Med. 2004;350:1200-1210. [PMID:  15028824]   Stojadinovic A, Brooks A, Hoos A, et al. An evidence-based  approach to the surgical management of resectable pancreatic  adenocarcinoma. / Am Coll Surg. 2003;196:954-964. [PMID:  12788434]   Optimal treatment in these patients remains controversial.  The combination of chemotherapy and radiation is associ-  ated with modest improvements in median survival but may  produce significant side effects. 5-Fluorouracil, gemcitabine,  and paclitaxel are some of the common chemotherapeutic  agents used with radiotherapy.   Symptom palliation is an essential component of care for  patients with locally advanced disease. Patients with tumors  localized to the pancreatic head can develop obstructive  jaundice and gastric outlet obstruction; severe abdominal  pain is more common with tumors involving the body and  tail of the pancreas.   Sohn TA, Yeo CJ, Cameron JL, et al. Do preoperative biliary stents  increase postpancreaticoduodenectomy complications? / Gastrointest  Surg. 2000;4:258-267. [PMID: 10769088]   1. Obstructive jaundice— Compression of the bile duct by  the tumor can cause obstructive jaundice. Endoscopic stent  placement is the most effective approach to relieve malignant  bile duct obstruction. Metal stents are preferred over plastic  ones for palliation once the patient is no longer considered a  surgical candidate. Unlike plastic stents, which require fre-  quent periodic changes due to occlusion, metal stents have a  significantly higher patency rate; however, once placed they  cannot be removed endoscopically. The stents may be placed  percutaneously if an endoscopic approach is not possible as a  result of tumor in-growth or previous surgery. Rarely, a surgi-  cal biliary enteric bypass is required to relieve the obstruction.   2. Gastric outlet obstruction— Obstruction of the gastric  outlet is caused by extension of the pancreatic cancer and can  be treated by gastrojejunostomy or by endoscopically placed  expanding metal stents.   3. Pain — Narcotic medications are usually required to con-  trol pain associated with pancreatic cancers. Celiac plexus  block (chemical neurolysis) can be achieved though a percu-  taneous approach, or the block can be performed using EUS.  Radiation can be used to control intractable pain.   Chemotherapy is used for palliation and results in slight sur-  vival benefits. Gemcitabine-based combination therapy is  the treatment of choice and associated with better pain con-  trol, decreased weight loss, and improvement in performance  status.   These lesions represent a spectrum of benign and malignant  tumors and account for 1% of pancreatic neoplasms. The  most common — mucinous cystic neoplasms, serous cyst  adenomas, intraductal papillary mucinous neoplasms (IPMNs),  and solid cystic papillary neoplasms (rare) — are described in   Characteristic manifestations for each lesion are described in  detail later in this section.   CT and MRI are excellent tests for initial detection and char-  acterization of cystic lesions of the pancreas, but differentia-  tion of benign and malignant disease on the basis of imaging  alone is difficult (see Figures 9-46, 9-47, and 9-48). Besides  providing better characterization of the cystic lesion, MRI  may also be able to show the communication between the  cyst and the pancreatic duct. EUS findings alone are not  accurate to determine the type of cystic lesion or its malig-  nant potential. EUS-FNA has emerged as the technique of  choice for obtaining cyst fluid for evaluation of tumor mak-  ers and cells. It also assists in detecting malignant transfor-  mation by providing cells from the cyst walls. EUS-FNA  carries a 2-3% risk of pancreatitis. ERCP is useful in detect-  ing intraductal neoplasms, especially IPMN, but its role has  become limited by advances in pancreatic imaging.   Cytologic analysis of the cyst fluid has high specificity for  mucinous lesions as well as presence of malignancy, but its  sensitivity is low (Table 28-4). The yield of cells obtained  from EUS-FNA can be insufficient to make a definitive diag-  nosis or confirm malignant transformation as the lining of  the cystic lesions is often denuded. Tumor markers have been  shown to improve diagnostic accuracy and differentiation of  cystic lesions. Levels of carcinoembryonic antigen (CEA) and  CA 72-4 are usually high in mucinous lesions. A CEA cutoff  level of 192 ng/mL was found to be most accurate for differ-  entiating between mucinous and nonmucinous cystic lesions  with a sensitivity of 73% and specificity of 84%.   Serous cyst adenomas can contain high numbers of  glycogen cells whereas mucinous lesions can have fluid high  in mucin. The presence of mucin-like antigen as a marker for  mucinous tumors has also been used.   Amylase levels are high in both pseudocysts and IPMN, and  low in serous cyst adenomas and most mucinous cyst adeno-  mas. CA 19-9 is not elevated in cystic lesions of the pancreas.   Brandwein SL, Farrell JJ, Centeno BA, et al. Detection and tumor  staging of malignancy in cystic, intraductal, and solid tumors of  the pancreas by EUS. Gastrointest Endosc. 2001;53:722-727.  [PMID: 11375578]   Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis  of pancreatic cystic neoplasms: a report of the cooperative pan-  creatic cyst study. Gastroenterology. 2004;126:1330-1336. [PMID:  15131794]    Resection curative, regardless of degree of epithe-  lial dysplasia; poor prognosis when invasive  adenocarcinoma present    Excellent prognosis for lesions showing only adeno-  matous and borderline cytologic atypia; poor  prognosis when invasive carcinoma present    Indolent neoplasm with rare nodal and extranodal  metastases; excellent prognosis when completely  resected    Similar to solid type; aggressive neoplasm  with slightly better prognosis than ductal  adenocarcinoma   Jacobson BC, Baron TH, Adler DG, et al. ASGE guideline: the role  of endoscopy in the diagnosis and the management of cystic  lesions and inflammatory fluid collections of the pancreas.  Gastrointest Endosc. 2005;61:363-370. [PMID: 15758904]   Khalid A, McGrath KM, Zahid M, et al. The role of pancreatic cyst  fluid molecular analysis in predicting cyst pathology. Clin  Gastroenterol Hepatol 2005;3:967-973. [PMID: 16234041]   True cystic neoplasms of the pancreas must be differentiated  from inflammatory pseudocysts, which are the most com-  mon cystic lesions of the pancreas. Pseudocysts are collec-  tions of pancreatic secretions without an epithelial lining  that occur as a result of inflammation of the pancreas, or  obstruction or disruption of the pancreatic duct. Clinical   history and associated radiologic findings of acute or chronic  pancreatitis, gland atrophy, ductal dilation, and calcification  help differentiate pseudocysts from cystic neoplasms. High  levels of amylase and low CEA are usually noted in the  pseudocyst fluid.   Mucinous cystic neoplasms are the most common cystic  tumors of the pancreas, comprising 40-50% of these neo-  plasms. They occur predominantly in middle-aged women  (> 80%) and are mostly localized to the body or tail of the  pancreas.   These tumors are premalignant lesions and are classified as  benign (adenomatous), low-grade malignant (borderline),  or malignant (carcinoma in situ and invasive cancer) based  on the degree of tissue dysplasia. The presence of malignancy  in these tumors as estimated in published reports is esti-  mated to be between 10% and 50%.   These tumors are filled with mesenchymal-like stroma  with high viscosity and generally elevated CEA levels. Unlike  IPMNs, these tumors do not communicate with the pancre-  atic ductal system. Larger size, presence of peripheral  eggshell calcification on imaging, and association of a solid  component with the cystic lesion are features suggestive of  malignant progression.   Mucinous cystic tumors can be incidental findings on  abdominal imaging or can manifest with abdominal pain,  palpable mass, recurrent pancreatitis, and vomiting due to  gastric outlet obstruction. Jaundice and weight loss are more  common with malignant transformation.   These tumors appear unilocular or multilocular on CT and  MRI, with few discrete compartments. EUS can be helpful to  further characterize the lesion and obtain cells for evaluation  of malignant transformation.   Surgical resection is recommended, because of the signifi-  cant potential for malignant transformation. Resection is  associated with an excellent 5-year survival rate (> 95% for  benign and borderline tumors and 50-75% for malignant  tumors with negative margins,). As most of these lesions are  localized to the tail of the pancreas, distal pancreatectomy is  the most common surgery performed.   These tumors, seen mostly in women, are the second most  common cystic tumors of the pancreas. About 70% of serous  cyst adenomas occur in the body or tail of the pancreas and  have a very low potential for malignant transformation.   Serous cyst adenomas are usually asymptomatic, but patients  can present with abdominal discomfort, a palpable mass,  and, if the tumor is large, with bile duct and gastric outlet  obstruction.   On CT scan the tumor consists of multiple tiny cysts sepa-  rated by delicate fibrous septa arranged around a central stel-  late scar that may be calcified, giving them a honeycomb  appearance. The pathognomonic CT finding of a "sunburst"  due to the central scar is seen in 20% of patients.   The cyst fluid has low viscosity (clear and watery), and is  high in glycogen, with low CEA levels.   Surgery is indicated in symptomatic patients and in those  with rapidly enlarging serous cystadenomas. In asympto-  matic patients, observation with serial imaging is a valid  strategy because of the low risk of malignant transformation.   IPMNs are papillary tumors of the pancreatic duct that are  associated with mucin hypersecretion. They occur equally in  men and women, and the median age at presentation is  65 years. These tumors occur predominantly in the head of  the pancreas. IPMNs may involve the main pancreatic duct,  a side branch, or both.   The role of smoking, alcohol, and genetic predisposition in  the development of IPMN remains unclear. Although genetic  alterations such as P53 overexpression, K-ras mutations, and  DPC4 overexpression have been identified, their role in the  development of IPMN is not understood. Unlike pancreatic  cancers, where DPC4 inactivation is seen in most tumors,  DPC4 is expressed in almost all IPMNs.   IPMNs are classified into two types, based on the involve-  ment of the main pancreatic duct or the side branches. The  main duct type IPMN is more aggressive and has a higher  incidence of malignancy.   IPMNs are categorized as benign, borderline, or malig-  nant based on tissue histology. Malignant lesions may  account for the majority of these tumors (> 50%). The malig-  nant tumors are further classified as noninvasive (carcinoma  in situ) or invasive, based on the absence or presence of  extension beyond the basement membrane.   The symptoms of IPMN — abdominal pain, weight loss,  recurrent pancreatitis, new-onset diabetes, jaundice, and  steatorrhea — are similar to those observed in other pancre-  atic disorders. About 75% of cases are symptomatic at diag-  nosis, and acute pancreatitis is the initial presentation in 25%  of patients. Many patients have a history of recurrent bouts  of acute pancreatitis as a result of obstruction of the pancre-  atic duct by mucus plugs.   Cystic lesions in the pancreas in communication with a  dilated pancreatic duct can be seen on CT scan, EUS, and  MRI. The presence of mural nodules, segmental or diffuse  dilation of the main pancreatic duct greater than 15 mm in  diameter, is associated with malignant disease. On ERCP, the  pathognomonic sign is a patulous ampulla of Vater with  extruding mucus. Pancreatography may also show filling   defects due to mucus and communication between the pan-  creatic duct and cystic areas.   Surgical resection, the treatment of choice, is associated with a  5-year survival rate of 75%. During surgery the resected mar-  gins must be examined by frozen section to confirm clearance  of the tumor as IPMNs tend to grow longitudinally along the  pancreatic ducts rather than radially into the parenchyma.  Surveillance with periodic imaging is recommended in  patients with invasive IPMN, as reoccurrence (most often  within the first 3 years) occurs in 12-65% of cases.   These rare neoplasms with low malignant potential are seen  in young women, and are characterized by necrotic and hem-  orrhagic areas.   Pancreatic lymphoma represents 1-2% of all pancreatic  tumors. It presents as large mass, usually without bile duct  obstruction, pain, or weight loss. Treatment consists of com-  bination of chemotherapy and radiation, and is associated  with good 5-year survival rates.   Many epithelial tumors of the gastrointestinal tract develop  as benign polyps before becoming malignant, as discussed in  detail in earlier sections of this book. These may be sympto-  matic or asymptomatic, pedunculated or sessile, and range in  size from millimeters to many centimeters in diameter. If  confined to the mucosa or superficial submucosa, they are  nearly all amenable to endoscopic removal by one of a vari-  ety of polypectomy techniques, endoscopic mucosal resec-  tion (EMR), or endoscopic submucosal dissection (ESD).   The principles of endoscopic polypectomy have evolved  to a standardized set of techniques since their introduction  almost 40 years ago. EMR and ESD techniques continue to be  developed as more recent innovations. Endoscopic resection  aims to remove a tumor in its entirety for cure, for complete  pathologic assessment, and to reduce or abolish the risk of  recurrence while maintaining the integrity of the gastroin-  testinal tract wall and avoiding procedure-related morbidity  (bleeding and perforation).   Polypectomy, EMR, and ESD can all be accomplished in  the conscious patient as there are no pain receptors in the  mucosa and submucosa. The muscularis propria and serosa  together with the mesentery are capable of generating pain  sensation caused by mechanical forces (eg, stretching) and the  thermal effects of electrosurgery. A wide range of accessories is  now available for endoscopic polypectomy and the last decade  has also seen improvements in electrosurgical generators with  respect to ease of use, safety, and efficacy. All endoscopists  should be equipped to remove small- to medium-sized sessile  polyps and nearly all pedunculated polyps in the colon, as this  is the most common site for these to be detected. Larger sessile  polyps (> 2 cm in diameter), very large pedunculated polyps  in the colon, and polyps of all types in the esophagus, stomach,  duodenum, and small bowel require additional expertise and  technology and are usually referred to colleagues or centers  with experience in these areas.   As confidence and safety in endoscopic tumor resection  have increased, so have the results of removing not only   benign polyps but also those with high-grade dysplasia (pre-  viously called carcinoma-in-situ) and Tl cancers, because the  results are comparable to surgery without the associated  morbidity. The two main complications of polypectomy are  bleeding and perforation.   Removal of polyps throughout the gastrointestinal tract  requires appropriate access with an endoscope bearing an  instrumentation channel diameter adequate to take standard  accessories. Most of these will pass through a 2.8-mm channel  but some may require 3.2 mm or greater. Accessories include  biopsy forceps, snares, injection needles, combination devices  marrying more than one function in a single instrument,  hemostatic clips and loops, bipolar and multipolar probes, and  EMR sets providing a spray catheter, injector needle, special  snare, and transparent cap, which comes in many shapes and  diameters. Accessories for ESD are not yet generally available  in the United States. Most accessories designed for  colonoscopy will also be long enough for some enteroscopes  when therapy in the small bowel is being planned. Special  stains for surface chromoendoscopy (eg, indigo carmine,  Lugol iodine, methylene blue, and cresyl violet) may be needed  prior to resection, and marking agents, which are ready-made  vials of sterile India ink, are used for permanent documenta-  tion of a tumor site for future endoscopic or surgical reference.  Submucosal injection of fluid for EMR and ESD most often  uses 0.9% saline with or without additives (eg, epinephrine or  methylene blue), but some experts prefer to inject a fluid of  higher viscosity (eg, hyaluronic acid or glycerol), which dissi-  pates less rapidly during resection. Many endoscopes also  carry the potential for imaging with restricted wavelengths of  light in different parts of the visible spectrum (eg, narrow  band imaging or multiband imaging), which allows visualiza-  tion of morphology and vasculature in the submucosa,  enhancing the endoscopist's ability to recognize the edges of  polyps and any malignant features.   Many electrosurgical generators are manufactured specif-  ically for endoscopic applications. Most now incorporate  computer-controlled outputs modified by feedback through  the accessory to achieve the desired tissue effect with the least  power necessary. They also incorporate menus for specific  endoscopic procedures with defaults set by the manufacturer.  All endoscopists and assistants performing electrosurgery  must have a thorough knowledge of monopolar high-frequency  circuits and their properties in order to understand the safe  principles of cutting and coagulation, and to troubleshoot  any problems that occur during polypectomy. The concept of  current density (power per unit area) is essential to compre-  hend because this is how snare polypectomy cuts and coagu-  lates tissue as it is being mechanically cut by the closing snare.  A module for argon plasma coagulation is also essential  whenever large polyps are being removed; this is a useful  adjunct for tissue ablation and superficial coagulation. Bowel  preparation must be good to excellent both for visibility and  to reduce the risk of ignition of bowel gases such as hydrogen  and methane. All fluid must be removed from around the  polyp to be resected in order to maximize the current density  where it is desired at the point of resection.   Small polyps less than 5 mm in diameter are often referred to  as "diminutive." Irrespective of their site in the gastrointesti-  nal tract, they can usually be removed by any of a number of  simple methods that include "cold" biopsy forceps with stan-  dard or so-called jumbo forceps, "hot" (ie, combined with  electrocautery) biopsy forceps, "cold" snare, and "hot" (ie,  combined with electrocautery) snare. A common practice is  to place a small diameter snare (eg, 1 cm oval) over the polyp,  including a small cuff of normal surrounding mucosa, and  then close the snare handle and mechanically cut through the  trapped tissue, which will excise the polyp. Because the  postremoval bleeding risk of simple mechanical cutting and  avulsion with cold techniques is minimal, these are favored  for such small lesions, which can usually be removed by one  pass of the forceps or snare. Such methods are quick and  effective and provide the necessary specimen for histopatho-  logic evaluation (Plates 25 and 26) with almost no risk.  Resected tissue can be aspirated into the endoscope suction  system, to which a specimen trap can be added.   Sessile polyps larger than 5 mm and up to a diameter of  2 cm can usually be removed using electrocautery without addi-  tional measures (Plates 27, 28, and 29). Snares are available in  many sizes and shapes, with choice being determined by per-  sonal or endoscopy unit preference. The principle is to place  the snare over the entire polyp and either (1) close it as a cut-  ting or combined cutting and coagulation current is applied  until the polyp is detached from the submucosa, or, more  commonly, (2) close it as far as possible before applying a pure  coagulating current, and then continue closing until the polyp  is removed. In both sequences it is important to lift the  entrapped tissue away from the wall of the gastrointestinal   tract to minimize any deep injury. Specimen retrieval is  accomplished by suction through the endoscope into a speci-  men trap or, if larger, by capturing with the same snare fol-  lowed by endoscope withdrawal. Multiple polyps or those too  large for aspiration- retrieval can be collected by a retrieval net  (see later discussion).   Several safe methods are available to achieve hemostasis  when excessive bleeding occurs immediately after cold or hot  snare polypectomy or, very rarely, after forceps removal, and  does not stop spontaneously within a minute or so. Placement  of one or more hemostatic clips, injection of diluted epineph-  rine 1:10,000, application of monopolar coagulation with the  snare tip or by argon plasma coagulation, bipolar or multipo-  lar coagulation with a dedicated probe, and band ligation are  all used, with clips now being the most popular.   Suspected perforation or inadvertent deep submucosal  injury can be promptly closed by placing clips to appose the  mucosa on either side of the defect (see later discussion).   Pedunculated polyps are so-called because the tumor is situ-  ated at the end of a stalk or pedicle and protrudes into the gas-  trointestinal tract lumen. The principle of polypectomy with  these lesions is to resect through the stalk at a sufficient dis-  tance from the tumor to ensure its complete removal but not  so close to the gut wall as to risk deep thermal injury. A point  approximately one third to one half way along the stalk from  the polyp head is usually chosen for placement of the snare  loop (Plate 30); electrocautery is then applied, using one of the  two methods already described, until the stalk is completely  severed. The polyp is then retrieved using either the aspiration  method, if small enough, or by snare or net capture.   In contrast to sessile polyps, pedunculated polyps may be  so large that the proximal side of the lesion may not be visible  endoscopically during snare placement and polypectomy  (Plate 31). The endoscopist must then take special precautions  (1) to avoid inadvertendy trapping normal mucosa in the  snare and (2) to avoid injury to the opposite bowel wall if the  polyp is touching it. Safe snare position can be confirmed by  securing the snare tip on the proximal (further) side first by  pulling it toward the endoscope and confirming that the polyp  stalk, only, is ensnared before closing it prior to applying  cautery. The large polyp extending across the bowel lumen can  be removed safely by moving the snare back and forth to pre-  vent any stray current from passing through an undesired site  with enough current density to cause injury. This also reduces  the power required to achieve the polypectomy. For very large  stalks with vessels presumed to be larger than usual, some  experts pretreat the stalk with an injection of diluted epineph-  rine or place an additional mechanical device such as a clip or  endoloop before proceeding with polypectomy.   Bleeding from the cut polyp stalk is most readily con-  trolled by resnaring it immediately for tamponade, without  applying further cautery, and waiting for natural hemostasis  to occur. If this fails, or if the snare has already been removed,   any of the methods mentioned earlier can be used. Clips have  become popular because of their ease of use and mechanical  mechanism of action, which does not risk deep injury to the  bowel wall after polypectomy (Plate 32).   Suspected perforation or inadvertent deep submucosal  injury can be promptly closed by placing clips to appose the  mucosa on either side of the defect.   For sessile polyps larger than 2 cm in the colon or duodenum  and almost any sized sessile polyp or early cancer in certain  anatomic locations, such as the esophagus or stomach, a dif-  ferent set of techniques has been developed, collectively  known as EMR. Although there are many technical varia-  tions and accessories, the principle of EMR is the same for  all. The lesion is lifted or separated from the underlying sub-  mucosa before resection is performed either by physical trac-  tion or by injecting fluid. One technique employs a  two-channel endoscope to lift the lesion first with a grasping  device, such as a biopsy forceps passed through one channel  of the endoscope, over which is placed a snare, passed through  the second channel, to complete the removal. This method,  however, has never gained popularity in the United States. A  second technique, originally developed in Japan, employs a  transparent cap fitted to the tip of an endoscope into which,  after submucosal injection of fluid, the lesion is aspirated,  and a specially designed ultra-flexible snare placed around  the "pseudopolyp" so created. Suction is then released and  the polyp resected using the same electrocautery settings as  for standard polypectomy (Plates 33 and 34). This method is  particularly applicable in the esophagus, stomach, and rec-  tum but is rarely used elsewhere in the gastrointestinal tract.  A third technique employs a band ligation system to raise  the lesion into a pseudopolyp before snare resection; this has  become popular for small sessile lesions in the upper gastroin-  testinal tract (Plates 35 and 36). A fourth method, which has  become the dominant technique for EMR, is the use of an  injection needle to instill fluid around and deep to the polyp  to lift it away from the submucosa (Plate 37). Alternative  needleless methods for elevation with fluid are also becoming  available. This not only ensures that the lesion is safe to resect,   as it is not invading deep to the mucosa, but also provides a  cushion of safety, protecting the bowel wall from thermal  injury. The nonlifting sign after such an attempted injection is  an accurate indication of submucosal invasion. After injection,  the polyp is snared piecemeal (Plate 38) until the entire area of  mucosa has been removed (Plate 39). Any bleeding can be  controlled using the methods already outlined. The specimens  are retrieved by aspiration, if they are small enough, or by a net  (Plate 40). The site may be left to heal, or this can be acceler-  ated and possible complications reduced by closing the defect  with clips (Plate 41). Although the scar may be visible for  follow-up examinations (Plate 42), the site may also be marked  with an injection of a permanent ink for future endoscopic  surveillance or surgical resection (Plate 43).   A recent extension of EMR developed in Japan is ESD. This  collection of techniques aims to remove the sessile lesion as  one piece by injecting fluid deep to the lesion, as for EMR,  then incising the perimeter of the polyp with a small margin  of normal mucosa, followed by careful dissection in the  superficial submucosal plane until the resection is complete  (Plates 44, 45, and 46). Several accessories are available but  none has yet been approved by the U.S. Food and Drug  Administration. Although originally intended for removing  early gastric cancers, ESD has now been successfully applied  to the colon.   Carpenter S, Petersen BT, Chuttani R, et al. Polypectomy devices.  Gastrointest Endosc. 2007;65:741-749. [PMID: 17397841]   Fatima H, Rex DK. Minimizing endoscopic complications: colono-  scopic polypectomy. Gastrointest Endosc Clin N Am. 2007;17:  145-156. [PMID: 17397781]   Larghi A, Waxman I. State of the art on endoscopic mucosal resec-  tion and endoscopic submucosal dissection. Gastrointest Endosc  Clin NAm. 2007;17:441-469. [PMID: 17640576]   Saito Y, Uraoka T, Matsuda T, et al. Endoscopic treatment of large  superficial colorectal tumors: a case series of 200 endoscopic sub-  mucosal dissections (with video). Gastrointest Endosc. 2007;66:  966-973. [PMID: 17524403]   Tolliver KA, Rex DK. Colonoscopic polypectomy. Gastroenterol  Clin North Am. 2008;37:229-251. [PMID: 18313548]   Patients with acute upper Gl bleeding can present with  hematemesis, melena, or hematochezia.   Risk assessment based on clinical and endoscopic crite-  ria can help predict risk for good and bad outcomes.   Clinical guidelines are used to predict outcomes, includ-  ing length of hospital stay, rebleeding, and mortality.   Nonvariceal upper gastrointestinal (GI) bleeding is a com-  mon reason for emergency department visits and admis-  sions to the hospital. It has been estimated that upper GI  bleeding is responsible for over 300,000 hospitalizations per  year in the United States. An additional 100,000-150,000  patients develop upper GI bleeding during hospitalizations  for other reasons.   The source of upper GI bleeding is by definition proximal  to the ligament of Treitz. The natural history of nonvariceal  upper GI bleeding is that approximately 80% of patients will  stop bleeding spontaneously and in this group, no further  urgent intervention will be needed. However, if a patient  rebleeds, there is a tenfold increased mortality rate.   The overall mortality rate is 5-10% for patients with non-  variceal upper GI bleeding. This mortality rate is essentially  unchanged since 1945, despite the development of new med-  ications, endoscopy (both diagnostic and therapeutic), inten-  sive care units, and advances in surgical management. Current  mortality is typically due to factors other than GI bleeding and  occurs primarily in patients who are older and use medications  such as nonsteroidal anti-inflammatory drugs (and, more  recently, antiplatelet agents such as clopidogrel).   Among patients on long-term, low-dose aspirin, the risk  of overt GI bleeding is increased twofold compared to placebo  with an annual incidence of major GI bleeding of 0.13%.  Compared with aspirin alone, the combination of aspirin and  clopidogrel causes a two- to threefold increase in the number  of patients with major GI bleeding. Definite risk factors for  bleeding in patients taking aspirin and clopidogrel are a his-  tory of peptic ulcers and prior GI bleeding, and likely risk fac-  tors are male gender, age more than 70 years, and Helicobacter  pylori infection. Mortality among patients with upper GI  bleeding is often due to cardiovascular complications and  comorbidities, and not due to uncontrollable GI hemorrhage.   McQuaid KR, Laine L. Systematic review and meta-analysis of  adverse events of low-dose aspirin and clopidogrel in random-  ized controlled trials. Am J Med. 2006;119:624-638. [PMID:  16887404]   The type of bleeding should be characterized. Hematemesis  is defined as overt bleeding with vomiting of fresh blood or  clots. Melena refers to dark black and tarry- appearing stool,  with a distinctive smell. The term "coffee grounds" describes  gastric aspirates or vomitus that contains dark specks of old  blood. Hematochezia is the passage of fresh blood or clots  per rectum. Although bright red blood per rectum is usually  indicative of a lower GI source, it may be seen in patients  with massive upper GI bleeding.   Concurrent with the initial evaluation of patients with  suspected upper GI bleeding is resuscitation, with the goal of  achieving hemodynamic stability. The evaluation must assess  vital signs, the presence or absence of shock and hypov-  olemia, and medical comorbidities (malignancy, chronic  obstructive pulmonary disease, coronary artery disease, etc).  Patients with postural hypotension have a significant blood  volume loss of at least 10% and those with shock have a   blood volume loss of at least 20%, a predictor of poor out-  come. Medications used by the patient are reviewed with  special attention given to anticoagulants (heparin and war-  farin), antiplatelet agents (clopidogrel), aspirin, and nons-  teroidal anti-inflammatory drugs (NSAIDs).   1. Clinical predictors — Factors that predict a good or a poor  prognosis in patients with nonvariceal upper GI bleeding can  be used to appropriately triage and manage patients. The role  of nasogastric tube aspiration is controversial. The nasogastric  tube aspirate can provide useful information depending on its  contents, and this information can be correlated with the stool  color. The mortality rate in patients with a clear aspirate is 6%;  in patients with red blood from hematemesis or nasogastric  tune aspirate, 18%; and in those with red blood from above as  well as hematochezia, 30%. Nasogastric tube aspirates, how-  ever, can be falsely negative; false negatives occur in patients  with bleeding from duodenal ulcers due to spasm of the  pylorus and can occur in other conditions, including gastric  ulcers and, rarely, esophageal varices (if the tube is positioned  in a nondependant area of the stomach).   In patients presenting with upper GI bleeding, several clin-  ical prognostic factors have been shown to be helpful in pre-  dicting a poor outcome (Table 30-1). Patients who experience  onset of GI bleeding as outpatients have a mortality rate of  7.1%, compared with a rate of 32.7% in those who are inpa-  tients hospitalized for other reasons. In patients younger than  age 60, the mortality rate is 8.7%; in those older than age 60, it  is 13.4%. The mortality rate increases along with the number  of comorbidities: patients with two comorbidities have a mor-  tality rate of 2.6%; those with four comorbidities, 9.9%; those  with six comorbidities, 27.0%; and those with eight, 66.7%.   Das A, Wong RC. Prediction of outcome of acute GI hemorrhage:  a review of risk scores and predictive models. Gastrointest  Endosc. 2004;60:85-93. [PMID: 15229431]   Gralnick IM, Dulai GS. Incremental value of upper endoscopy for  triage of patients with acute non-variceal upper-GI hemor-  rhage. Gastrointest Endosc. 2004;60:9-14. [PMID: 15229418]   Table 30-1. Risk factors for poor outcome in upper  gastrointestinal bleeding.   Shock (systolic blood pressure < 100 mm Hg); pulse > 100 beats/min   2. Guidelines — Clinical guidelines have been developed to  help optimize the management of patients with nonvariceal  upper GI bleeding. The aim of these guidelines is to identify  low-risk patients who can be discharged either directly from  the emergency department or at an early stage of hospital-  ization, and to identify high-risk patients who will need the  most resources. Most clinical guidelines include both clinical  data and information obtained at the time of endoscopy.  These guidelines can be incorporated as part of routine clin-  ical care to help direct triage decisions.   Hay and colleagues developed practice guidelines with a  risk score calculated using a combination of both clinical and  endoscopic data. Use of the guidelines resulted in a reduced  length of stay with no significant change in patient complica-  tions, patient health status, or patient satisfaction 1 month  postdischarge. This demonstrates that guidelines can be suc-  cessfully implemented and have a meaningful impact in  improving the efficiency of clinical care without reducing qual-  ity of care.   The Rockall score is a scoring system used to predict  rebleeding and mortality in patients with nonvariceal upper  GI bleeding. The Rockall scoring system assigns scores of zero  to three to the factors of age, the presence of shock, comor-  bidity, diagnosis, and endoscopic stigmata (Table 30-2). A  low-risk patient has a score of two or less, which accounted  for 29.4% of patients. In this low-risk group, there was a 4.3%  risk of rebleeding and 0.1% mortality. Patients with Rockall  scores of three to five have intermediate rates of rebleeding  and mortality (2.0-7.9%), whereas patients with a score of six  or greater have a high rebleeding and mortality rate  (15.1-39.1%).   A scoring system that only uses clinical information  obtained at the time of presentation, and does not include  endoscopic data, has been developed by Blatchford and col-  leagues. The clinical information incorporated in this scoring  system includes hemoglobin, blood urea nitrogen, pulse, sys-  tolic blood pressure, presence of syncope, melena, liver dis-  ease, and heart failure. This is a unique scoring system for  upper GI bleeding, because all the information is available at  initial presentation, and it does not require endoscopic per-  formance to calculate.   The value of clinical guidelines is dependent on treating  physicians adhering to the recommendations of the guide-  lines. Bjorkman and colleagues randomized 93 patients to an  urgent endoscopy performed less than 3 hours after presenta-  tion with upper GI bleeding or elective endoscopy performed  up to 48 hours after presentation. They found the timing of  the upper endoscopy did not influence resource utilization or  patient outcomes such as overall length of stay or time in the  intensive care unit. After urgent upper endoscopy, outpatient  care was recommended in 40% of the patients in the study,  although actually done in only 9% of the patients, as patients  were admitted to the hospital by treating physicians (not the  endoscopists). This finding emphasizes the importance of  adherence to guidelines by treating physicians, if there is to be  a meaningful impact (Figure 30-1).   Data from Rockall TA, Logan RFA, Devlin HB, et al. Risk assessment after acute upper gastrointestinal hem-  orrhage. Gut. 1996;38:316-321; and Rockall TA, Logan RF, Devlin HB, et al. Selection of patients for early  discharge or outpatient care after acute upper gastrointestinal hemorrhage. National Audit of Acute Upper  Gastrointestinal Haemorrhage. Lancet. 1996;347:1138-1140.   ▲ Figure 30-1. Algorithm for the management of acute  upper gastrointestinal bleeding. ER, emergency room;  ICU, intensive care unit. (Adapted, with permission, from  Eisen GM, DominitzJA, Faigel DO, et al. American Society  for Gastroenterology. Standards of Practice Committee. An  annotated algorithmic approach to upper gastrointestinal  bleeding. Gastrointest Endosc. 2001;53:853-858.)   Barkun A, Bardou M, Marshall JK. Nonvariceal Upper Gl Bleeding  Consensus Conference Group. Consensus recommendations  for managing patients with nonvariceal upper gastrointesti-  nal bleeding. Ann Intern Med. 2003;139:843-857. [PMID:  14623622]   Bjorkman DJ, Zaman A, Fennerty MB, et al. Urgent vs. elective  endoscopy for acute non-variceal upper-GI bleeding: an effec-  tiveness study. Gastrointest Endosc. 2004;60:1-8. [PMID:  15229417]   Blatchford O, Murray WR, Blatchford M. A risk score to predict need  for treatment for upper-gastrointestinal hemorrhage. Lancet.  2000;356:1318-1321. [PMID: 11073021]   Eisen GM, Dominitz TA, Faigel DO. American Society for  Gastrointestinal Endoscopy. Standards of Practice Committee.  An annotated algorithmic approach to upper gastrointestinal  bleeding. Gastrointest Endosc. 2001;53:853-858. [PMID:  11375616]   Gralnek AM, Barkun AN, Bardou M. Management of acute bleed-  ing from a peptic ulcer. N Engl J Med. 2008;359:928-937.   Hay TA, Maldonado L, Weingarten SR, et al. Prospective evaluation of  a clinical guideline recommending hospital length of stay in upper  gastrointestinal tract hemorrhage. JAMA. 1997;278:2151-2156.  [PMID: 9417008]   Rockall TA, Logan RF, Devlin HB, et al. Risk assessment after acute  upper gastrointestinal hemorrhage. Gut. 1996;38:316-321.  [PMID: 8675081]   Rockall TA, Logan RF, Devlin HB, et al. Selection of patients  for early discharge or outpatient care after acute upper gas-  trointestinal hemorrhage. National Audit of Acute Upper  Gastrointestinal Haemorrhage. Lancet. 1996;347:1138-1140.  [PMID: 8609747]   1. Initial therapy — Patients need to have at least two large-  bore peripheral intravenous access catheters (at least 18 gauge)  or central venous access. Crystalloid fluids (normal saline or  lactated Ringer) should be initially administered to maintain  an adequate blood pressure. Supplemental oxygen is  administered routinely. Patients who are not able to ade-  quately protect their airways or patients with ongoing severe  hematemesis and at risk for aspiration should be considered  for elective endotracheal intubation.   Patients who are high risk, such as the elderly or those  with coronary artery disease, should be transfused to main-  tain a hematocrit above 30%. Young and healthy patients  should be transfused to maintain a hematocrit above 20%. In  patients with a coagulopathy, the coagulopathy should be cor-  rected if possible with transfusion of fresh frozen plasma or  administration of vitamin K. In patients with a low platelet  count (< 50,000), platelet transfusion should be considered.   2. Medications — Various medications have been used to  treat patients with nonvariceal upper GI bleeding, including  antacids, histamine-2 (H 2 )-receptor antagonists, proton  pump inhibitors (PPIs), and octreotide. The use of antacids  and H 2 -receptor antagonists has not been shown to alter the  natural history of patients with acute upper GI bleeding.   A. Proton pump inhibitors — In recent studies of PPIs in  selected patients with nonvariceal upper GI bleeding, a ben-  efit of medical treatment has been demonstrated. The use of  PPIs in the treatment of patients with upper GI bleeding has  been widely adopted.   An improvement in outcomes with the use of PPIs in  nonvariceal upper GI bleeding was first demonstrated by  Khuroo and colleagues in a double-blind, placebo-controlled  trial of oral omeprazole (40 mg twice daily) versus placebo.  Patients enrolled were a select group of 220 patients with  peptic ulcers at endoscopy shown to have active bleeding,  nonbleeding visible vessels, or adherent clots. Unlike the  standard of care in most parts of the world, endoscopic ther-  apy was not performed in this study. Outcomes were further  bleeding, surgery, and death. There was a significant advan-  tage to oral omeprazole use in patients who had findings of a  visible vessel or an adherent clot. However, there was no  advantage to prevent further bleeding in patients who had  spurting or oozing lesions.   PPIs are the only drugs that can maintain a gastric pH of  greater than 6.0 and can thus prevent fibrinolysis of an ulcer  clot. This study, however, did not address whether patients  who underwent therapy with endoscopic treatment at the  time of endoscopy would attain additional benefit with the  use of PPIs.   There have now been several studies showing the benefits  of the use of PPIs in patients who have undergone endoscopic   therapy with successful hemostasis. Lau and colleagues studied  patients who had successful hemostasis using combination  therapy of epinephrine injection and application of a bipolar  cautery probe. Patients were then randomized to a bolus infu-  sion of omeprazole, 80 mg, followed by a continuous infusion  of 8 mg/h, versus a placebo infusion. In these patients, who  had all undergone successful endoscopic therapy, the use of  omeprazole reduced the rebleeding rates overall and the  rebleeding rate within 3 days. There also was a trend toward  reduction in surgery and death rates. Thus, with omeprazole  use, bleeding is reduced in patients who have undergone endo-  scopic therapy and receive high-dose PPIs relative to those  who undergo endoscopic therapy alone.   Additional studies have been performed that support com-  bined endoscopic and medical management in select patients  with upper GI bleeding. Sung and colleagues studied 158  patients with nonvisible vessels or adherent clots receiving  omeprazole infusions, randomized to endoscopic therapy or  sham therapy. Patients who received both omeprazole infu-  sions and endoscopic therapy had a lower median transfusion  rate, less recurrent bleeding, and a trend toward decreased  mortality.   In patients initially treated with a bolus infusion of  omeprazole followed by a continuous infusion, the need for  endoscopic therapy has been shown to be reduced. With the  use of initial high-dose PPIs, the number of patients with  actively bleeding lesions found at endoscopy is reduced and  the number of patients with clean-based ulcers at the time of  endoscopy is increased.   At the present time, there are no available studies that  compare PPIs to one another in the management of acute  upper GI bleeding. The available data suggest that the ben-  efit is a class effect and that dosing should be similar, using  the available intravenous PPIs. The current recommenda-  tion is for an 80-mg bolus followed by an 8 mg/h infusion  for 72 hours after endoscopic therapy. Patients who remain  stable may then be switched to the standard dose of oral  PPIs.   B. Octreotide — Octreotide can be used to treat patients  with nonvariceal upper GI bleeding. Although this med-  ication is widely used in patients with variceal bleeding,  there is evidence that it may also be helpful in patients with  nonvariceal bleeding. In a meta-analysis by Imperiale and  Birgisson, 1829 patients from 14 trials using octreotide or  somatostatin in nonvariceal upper GI bleeding had a rela-  tive risk for further bleeding of 0.53 (0.43-0.63), suggest-  ing that octreotide reduces the risk for continued bleeding  from nonvariceal upper GI bleeding. Although a useful  adjunctive treatment, octreotide should not, in general, be  given as the primary treatment to patients with nonva-  riceal upper GI bleeding. The use of octreotide should be  considered in patients who have persistent bleeding on  optimal medical management, including PPIs, and are  poor surgical risks (eg, those with multiple comorbidities  already in the hospital).   Bianco MA, Rotondano G, Marmo R, et al. Combined epinephrine  and bipolar coagulation vs. bipolar probe coagulation alone for  bleeding peptic ulcer: a randomized, controlled trial. Gastrointest  Endosc. 2004;60:910-915. [PMID: 15605005]   Bleau BL, Gostout CJ, Sherman KE, et al. Recurrent bleeding from  peptic ulcer associated with adherent clot: a randomized study  comparing endoscopic treatment with medical therapy.  Gastrointest Endosc. 2002;56:1-6. [PMID: 12085028]   Imperiale TF, Birgisson S. Somatostatin or octreotide compared  with H antagonist and placebo in the management of acute  nonvariceal upper gastrointestinal hemorrhage: a meta-analysis.  Ann Intern Med. 1997;127:1062-1071. [PMID: 9412308]   lensen DM, Kovacs TO, Jutabha R, et al. Randomized trial of med-  ical or endoscopic therapy to prevent recurrent ulcer hemorrhage  in patients with adherent clots. Gastroenterology. 2002;123:  407-413. [PMID: 12145792]   Khuroo MS, Yatoo GN, lavid G, et al. A comparison of omeprazole  and placebo for bleeding peptic ulcer. N Engl ] Med.  1997;336:1054-1058. [PMID: 9091801]   Park CH, Lee SJ, Park JH, et al. Optimal injection volume of epi-  nephrine for endoscopic prevention of recurrent peptic ulcer  bleeding. Gastrointest Endosc. 2004;60:875-80. [PMID: 15605000]   Sung IJ, Chan FK, Lau JY, et al. The effect of endoscopic therapy in  patients receiving omeprazole for bleeding ulcers with nonbleed-  ing visible vessels or adherent clots: a randomized comparison.  Ann Intern Med. 2003;139:237-243. [PMID: 12965978]   The goal of endoscopic therapy is to eliminate persistent  bleeding and prevent rebleeding. Rebleeding is the greatest  contributor to both morbidity and mortality. The ability to  achieve sustained hemostasis is dependent on controlled  access to the bleeding vessel, a relatively small vessel size, and  the absence of significant coagulation defects.   Upper endoscopy provides diagnosis, prognosis, and ther-  apy in patients with acute upper GI bleeding and is reason-  ably safe to perform in patients with upper GI bleeding (50%  of complications are cardiopulmonary). Upper endoscopy is   90-95% sensitive at locating the bleeding site. Sensitivity  increases when the procedure is done closer to the onset of  the bleeding and decreases with increasing duration from  time of onset. Endoscopy can offer therapeutic options  including injection, cautery, placement of endoclips, or a  combination of therapies. Endoscopy can also predict the  likelihood of persistent or recurrent bleeding based on recog-  nition of the endoscopic stigmata of recent hemorrhage.   1. Stigmata of recent hemorrhage— It is important to rec-  ognize the stigmata of recent hemorrhage, which are endo-  scopic findings in patients with bleeding peptic ulcers  (Table 30-3). Patients with active bleeding seen at the time of  upper endoscopy have a very high rate of ongoing bleeding,  with rates as high as 90% if no intervention is performed  (Plate 47). Patients who have nonbleeding visible vessels are  also at high risk of further bleeding, as despite not having  active bleeding at the time of endoscopy, rebleeding occurs in  approximately 45% (Plates 48 and 49). Patients who have  adherent clots that do not easily wash off have an intermediate  probability of further bleeding (Plate 50). Approximately 25%  of patients with adherent clots will have further bleeding,  depending on what is underneath the clot; if there is a non-  bleeding visible vessel the rate is much higher, and if the clot  base is clean the rate is much lower. Patients who are consid-  ered to be at low risk based on endoscopic stigmata of recent  hemorrhage include those with flat spots, which have a 10%  risk of further bleeding (Plate 51). Patients who have clean  ulcer bases (Plate 52) or Mallory-Weiss tears, who do not have  concomitant coagulopathies or use of medications that alter  clotting, have a very low rate of further bleeding (< 5%).   The endoscopic stigmata of hemorrhage can be difficult to  interpret. Nonbleeding visible vessels cause the most difficulty.  Nonbleeding visible vessels are raised protuberances from an  ulcer bed that can be of any color, but they can be confused  with flat spots. These may represent vessels, pseudoaneurysms,  or clots and have a variable appearance.   Table 30-3. Stigmata of recent hemorrhage: risk of rebleeding, mortality, and prevalence.   2. Utility of endoscopic therapy— The utility of endo-  scopic therapy for patients with bleeding peptic ulcers was  first shown in 1987 in a placebo-controlled trial of multipo-  lar electrocoagulation versus sham endoscopic therapy.  Endoscopic therapy resulted in a significant improvement in  hemostasis, number of units of blood transfused, number of  emergency interventions, hospital stay (in days), and hospi-  tal costs. The mortality rate showed a trend toward being  lower in the group treated with endoscopic therapy. Since  this report, endoscopic therapy has been the standard of care  for patients with high-risk stigmata of recent hemorrhage.  Patients who have active bleeding or are found to have non-  bleeding visible vessels should undergo endoscopic hemosta-  sis to improve outcomes.   Adherent clots are found in about 10% of ulcers and are  associated with a rebleeding rate of 20-35% (lower in young  patients without comorbid illnesses and higher in elderly  patients with comorbid conditions). The management of  adherent clots has been controversial. National Institutes of  Health consensus guidelines for management of GI bleeding  from 1989 recommended against endoscopic treatment of  adherent clots. However, this assertion has been challenged  by several studies showing the efficacy of endoscopic treat-  ment of adherent clots. The technique to treat an adherent  clot starts with the use of epinephrine injection in four quad-  rants at the pedicle of the clot. A snare is used to cold guillo-  tine the clot 3-4 mm above its base. Care is taken not to shear  off the clot, further irritate the area, or provoke bleeding. The  base of the ulcer is then vigorously irrigated with fluid to  expose any underlying stigmata. This technique appears safe  and facilitates endoscopic therapy. Any visible vessel or active  bleeding is treated with cautery therapy.   3. Optimizing endoscopic visualization— One of the chal-  lenges of managing patients with GI bleeding is visualization  due to blood within the GI tract. This problem can be over-  come by the use of a variety of techniques, individually or in  combination. It is helpful to use double-channel or large  channel endoscopes, which allow for vigorous aspiration  (Figure 30-2). It is also useful to use a water pump or water  jet, which allows for vigorous irrigation. There are several  reports of the use of 3% hydrogen peroxide to dissolve clots  within the GI tract. It is not necessary to routinely lavage  patients with large volumes prior to upper endoscopy, even  in those with large upper GI bleeds. However, large tubes  placed into the stomach to lavage clots and blood before the  endoscopy can improve gastric visualization. Additional suc-  tion devices can be placed on the endoscope to facilitate  removal of blood and clots directly during endoscopy.   Intravenous erythromycin (250 mg bolus or 3 mg/kg over  30 minutes) can be used as a prokinetic drug to increase gas-  tric emptying and clear the stomach of blood. Erythromycin is  given intravenously 30-120 minutes prior to endoscopy. The  use of erythromycin significantly improves the quality of the  gastric examination. This is a useful adjunctive treatment in  patients with large GI bleeds. It can be used either initially or    ▲ Figure 30-2. Large channel therapeutic endoscope  (left) and double-channel therapeutic endoscope (right).   after an endoscopy shows large amounts of blood remaining  in the stomach with withdrawal of the endoscope and the use  of erythromycin before proceeding again with endoscopy.   Coffin B, Pocard M, Panis Y, et al. Erythromycin improves the  quality of EGD in patients with upper gastrointestinal bleeding:  a randomized controlled study. Gastrointest Endosc. 2002;  56:174-179. [PMID: 12145593]   Lee SD, Kearney DJ. A randomized controlled trial of gastric lavage  prior to endoscopy for acute upper gastrointestinal bleeding.  7 Clin Gastroenterol 2004;38:861-865. [PMID: 15492601]   4. Methods to control bleeding — The current endoscopic  modalities to treat nonvariceal GI bleeding include the use of  injection therapies (primarily with dilute epinephrine), con-  tact thermal therapies including heater and bipolar probes,  the use of noncontact thermal methods (predominantly  argon plasma coagulation, but Nd:YAG lasers can also be  used), mechanical treatments including a variety of endo-  clips and band ligation techniques, and a combination of the  preceding treatment modalities (typically injection therapies  combined with one of the other modalities).   Injection therapies reduce blood flow primarily by local  tamponade. However, the use of vasoconstricting agents,  such as epinephrine (diluted 1:10,000 to 1:20,000), can further  reduce blood flow. Several other agents also can be used,  including sclerosants such as ethanolamine, and thrombo-  genic agents, although these are less effective. These therapies  may not be beneficial in the setting of active bleeding of  fibrotic or penetrating ulcers. Injection therapy as monother-  apy is not felt to be as efficacious as other monotherapies and  should not be used as the only modality of treatment.  Emerging data indicate that a high dose of injection therapy  (eg, the use of 20-30 ml of total injectate) may be more ben-  eficial and more efficacious than the lower volumes (< 10 ml)  traditionally used; however, high doses of injected epinephrine   are more likely to cause cardiovascular side effects (especially  when injected in the region of the esophagus).   Use of thermal methods to control nonvariceal upper GI  bleeding is quite widespread. At the current time, bipolar  cautery is used most extensively, as it has the advantage of  being able to be used perpendicularly or tangentially. The  bleeding vessel is compressed and then coagulated to pro-  vide "coaptive coagulation." The larger 10 French probes  can be placed via a therapeutic instrument and are gener-  ally more effective than the smaller 7 French probes. A rel-  atively low wattage (15-20 watts) is used for a prolonged  time (8- to 12-second pulses) for each treatment pulse.  Four to six pulses are typically used to provide effective  treatment. The end point of treatment is reached when the  involved vessel completely flattens out and there is no fur-  ther bleeding.   Combination therapies are commonly used and typically  involve injection therapies with a dilute 1:10,000 epineph-  rine, combined with a thermocoagulation technique. Probes  are available that allow for both injection and cauterization.  Combination therapy is a safe and effective method. Only  limited data are available comparing endoscopic therapies  directly. Lin and colleagues compared epinephrine injection  alone versus bipolar cautery alone versus combination ther-  apy in 96 patients with active bleeding or a nonbleeding vis-  ible vessel. Although the rates of initial hemostasis were  similar in all three groups, there was a significant reduction  in rebleeding rates in the combination therapy group. Thus  combination therapy provides a more durable control of  bleeding than monotherapies.   Although widely utilized in other countries, endoclips  have not been used extensively in the United States until  recently (Plates 53 and 54). Comparative studies of endoclip  use show a similar primary efficacy at providing initial  hemostasis; however, the rebleeding rate may be reduced  with the use of endoclips compared with other modalities.  In a study that compared use of combination therapy with  use of endoclips in the United States, no significant differ-  ences were noted in the efficacy of these two therapies. Thus,  at the current time, patients requiring endoscopic control of  nonvariceal bleeding should be treated with either combina-  tion therapy using an injection of dilute epinephrine com-  bined with a thermocoagulation method or with endoclip  use (with or without injection therapy). Because some  lesions or locations are better suited to one type of therapy,  ideally an endoscopist should be familiar with both treat-  ment options.   Lin HJ, Lo WC, Lee FY, et al. A prospective randomized com-  parative trial showing that omeprazole prevents rebleeding  in patients with bleeding peptic ulcer after successful endo-  scopic therapy. Arch Intern Med. 1998;158:54-58. [PMID:  9437379]   Lin HJ, Tseng GY, Perng CL, et al. Comparison of adrenaline injec-  tion and bipolar electrocoagulation for the arrest of peptic ulcer  bleeding. Gut. 1999;44:715-719. [PMID: 10205211]   Paspatis GA, Charoniti I, Papanikolaou N, et al. A prospective, ran-  domized comparison of 10-Fr versus 7-Fr bipolar electrocoagula-  tion catheter in combination with adrenaline injection in the  endoscopic treatment of bleeding peptic ulcers. Am J Gastroenterol.  2003;98:2192-2197. [PMID: 14572567]   Saltzman J, Strate L, Di Sena V, et al. Prospective trial of endoscopic  clips versus combination therapy in upper GI bleeding  (PROTECCT— UGI Bleeding). Am } Gastroenterol. 2005;100:  1503-1508. [PMID: 15984972]   5. Second-look endoscopy — Second-look endoscopy is the  performance of endoscopy at a regularly scheduled interval  after a first therapeutic endoscopy. Typically, this is done about  24 hours after the initial endoscopy. During the second  endoscopy, any additional stigmata of hemorrhage are treated,  such as the continued presence of a visible vessel. This endo-  scopic practice is common in many parts of the world,  although it has not been widely used in the United States.   There is increasing evidence that second-look endoscopy  is beneficial in certain circumstances. A meta-analysis by  Calvet and colleagues evaluated 16 studies with over 1600  patients in randomized controlled trials undergoing second-  look endoscopy after an initial epinephrine injection. In the  meta-analysis, the rebleeding risk decreased from 18.4% to  10.6% (odds ratio [OR] = 0.53). The surgery rate decreased  from 11.3% to 7.6% (OR = 0.64). The mortality rate also  decreased from 5.1% to 2.6% (OR = 0.51). Second-look  endoscopy with additional endoscopic therapy may be help-  ful at reducing rebleeding, surgery, and mortality rates after  patients receive initial epinephrine injection. However, as  mentioned previously, epinephrine injection as monother-  apy is not as effective as other therapies, and whether patients  who receive standard treatment, such as combination ther-  apy or endoclip treatment, would benefit from second-look  endoscopy was not addressed by this study.   There has been a randomized trial of second-look  endoscopy with a therapeutic procedure performed, if needed,  in patients who underwent combination therapy with epi-  nephrine injection followed by heater probe treatment. Chiu  and colleagues studied 100 patients who had a second-look  endoscopy within 24 hours, and 94 patients who were closely  observed. Rebleeding was noted in 5 of the patients random-  ized to the second-look endoscopy group versus 13 of the con-  trol patients (P = .03). Only one second-look endoscopy  patient needed surgery, compared with six patients random-  ized to the control group (P = .05). Although the group of  patients who benefit from a second-look endoscopy and treat-  ment has not been adequately defined in studies in Western  populations, a second-look endoscopy may be prudent in  high-risk patients such as those with multiple comorbidities  or those with a suboptimal index endoscopy, due to technical  difficulties or poor visualization.   Calvet X, Vergara M, Brullet E, et al. Addition of a second endo-  scopic treatment following epinephrine injection improves  outcome in high-risk bleeding ulcers. Gastroenterology.  2004;126:441-450. [PMID: 14762781]   Chiu PW, Lam CY, Lee SW, et al. Effect of scheduled second ther-  apeutic endoscopy on peptic ulcer rebleeding: a prospective  randomised trial. Gut. 2003;52:1403-1407. [PMID: 12970130]   Marmo R, Rotondano G, Bianco MA, et al. Outcome of endoscopic  treatment for peptic ulcer bleeding: Is a second look necessary?  A meta-analysis. Gastrointest Endosc. 2003;57:62-67. [PMID:  12518133]   The natural history of patients who are treated with endo-  scopic therapy is that 80-90% of patients will have perma-  nent control of their bleeding (Figure 30-3). However,  10-20% of patients will have recurrent bleeding despite ini-  tially successful endoscopic therapy. In these patients, further  attempts at endoscopic therapy are less effective at achieving  permanent control, as only approximately 50% of patients  will ultimately be controlled by a second endoscopic therapy.  In patients who fail a second therapeutic endoscopy, other  modalities or treatments should be offered, including  angiography and surgery.   In patients with rebleeding after an initially successful ther-  apeutic endoscopy, an important question has been whether a  second therapeutic endoscopy should be performed (given the  reduced success rates), or whether patients should directly  undergo definitive treatment such as surgery. This question was  evaluated by Lau and colleagues in a study of 48 patients with  rebleeding after endoscopic treatment who were randomized  to either endoscopy or surgery. Ultimately, half the patients  who were randomized to endoscopic treatment underwent sal-  vage surgery as would be expected. Patients who were initially  randomized to a second endoscopic therapy or surgery showed  similar outcomes in terms of mortality, length of hospital stay,  and number of blood transfusions. However, there was a higher  complication rate in patients who were initially randomized to  surgery (16 vs 7 complications, P = .03). Predictors of failure of  a second endoscopic therapy were an ulcer greater than 2 cm in   diameter and the presence of hypotension. Endoscopic treat-  ment reduces the need for surgery without increasing the com-  plication rate. In most patients, a second attempt at endoscopic  therapy should be offered before other modalities, such as sur-  gery, are utilized.   It is important to identify patients who will ultimately  need surgery and to proceed to surgery as appropriate.  Involve surgeons early in the care of patients who may need  surgery, such as those who are determined to be at high risk.  There is a need for further research in this area to determine  which patients would benefit from surgery at an early stage  (who ultimately fail endoscopic treatment).   Lau 1Y, Leung WK, Wu IC, et al. Omeprazole before endoscopy in  patients with gastrointestinal bleeding. N Engl } Med. 2007;356:  1631-1640. [PMID: 17442905]   Lau IY, Sung IJ, Lam YH, et al. Endoscopic retreatment compared  with surgery in patients with recurrent bleeding after initial  endoscopic control of bleeding ulcers. N Engl J Med. 1999;340:  751-756. [PMID: 10072409]   Lau JY, Sung JJ, Lee KK, et al. Effect of intravenous omeprazole on  recurrent bleeding after endoscopic treatment of bleeding pep-  tic ulcers. N Engl J Med. 2000;343:310-316. [PMID: 10922420]   One factor that has made the management of patients with  GI bleeding more difficult in recent years is the increased use  of medications that alter coagulation. These include older  anticoagulant medications, such as warfarin and heparin, as  well as the newer antiplatelet agents, which are widely used in  patients with cardiovascular diseases, especially after coro-  nary stent placement. Unfortunately, few data are available to  guide management of these patients. In general, anticoagula-  tion is held if possible and the international normalized ratio  (INR) is reduced or normalized in these patients.   In a retrospective study of 233 patients with nonvariceal  upper GI bleeding receiving endoscopic therapy, the presence  of mild to moderate anticoagulation did not appear to alter   the outcomes of endoscopic therapy. This suggests that upper  endoscopy with endoscopic therapy is effective in patients who  are mild to moderately anticoagulated. However, more studies  are needed in patients who are on antiplatelet agents.   Wolf AT, Wasan SK, Saltzman JR. Impact of anticoagulation on  rebleeding following endoscopic therapy for non-variceal upper  gastrointestinal hemorrhage. Am } Gastroenterol. 2007;102:  290-296. [PMID: 17100959]   This section discusses the diagnosis and treatment of com-  mon (Table 30-4) and uncommon (Table 30-5) sources of  upper GI bleeding, including several specific causes of upper  GI bleeding, both nonvariceal and variceal in origin.   ► Peptic ulcers are the most common cause of upper GI  bleeding.   ► Most ulcers are caused by H pylori infection or NSAID use.   The most common cause of acute upper GI bleeding is pep-  tic ulcer disease, which accounts for up to 50% of cases and  over 100,000 hospital admissions per year in the United  States. The annual incidence of peptic ulcer disease in  patients infected with H pylori is about 1% per year, which is  six to ten times higher than in patients who are uninfected.   Table 30-4. Common sources and prevalence of upper  gastrointestinal bleeding. 3   frequency >5% in American Society for Gastrointestinal Endoscopy  bleeding survey of 2225 patients.   A variety of conditions can lead to development of erosive or  ulcerative diseases of the upper GI tract. In addition to peptic  ulcer disease, which develops from an imbalance of protective  and disruptive factors of the GI mucosa, medications such as  NSAIDs and aspirin, Zollinger-Ellison syndrome, erosive  esophagitis, stress-induced gastric erosions and ulcers, and  infections can cause erosions or ulcers. Disruptive factors that  can damage the mucosa of the GI tract include acid, pepsin,  bile salts, ischemia, and H pylori. Exogenous causes are pre-  dominately medications (NSAIDs and aspirin). Stress-  induced ulcers are a common cause of bleeding in patients  hospitalized for other severe illnesses. Risk factors for stress-  induced ulcers include respiratory failure and coagulopathy.  The defensive forces of the upper GI tract include esophageal  motility with clearance of refluxed materials, the lower  esophageal sphincter to prevent reflux, and salivary secretions  that contain bicarbonate. The gastric protective factors  include the mucous layer as well as tissue mediators.   Clinical manifestations of peptic ulcer disease range from  silent, asymptomatic disease to severe abdominal pain with  bleeding. Peptic ulcers classically cause dyspepsia with epigas-  tric burning pain, and are relieved with anti-acid therapies.  Classic duodenal ulcer symptoms occur when acid is secreted  without a food buffer, typically 2-5 hours after meals or on an  empty stomach (such as nocturnally). Although symptoms are  typically in the epigastric area, they may localize to either the  left or right upper quadrants or the hypochondrium. In  patients with ulcer symptoms, symptomatic periods may be  followed by symptom-free periods of weeks or months. Other  symptoms that have been associated with ulcers include belch-  ing, anorexia, early satiety, nausea, vomiting, and weight loss.  Only 30-40% of patients with severe bleeding from peptic  ulcer disease have symptoms from their ulcers prior to the GI  bleeding.   The laboratory findings for bleeding peptic ulcer disease are  nonspecific and include anemia with a decrease in hemoglo-  bin (which, if acute, will be normocytic) and an elevated  ratio of blood urea nitrogen to creatinine of greater than 30:1  in some patients. Helicobacter pylori serology may be indica-  tive of current or prior infection. In the rare patient with  Zollinger-Ellison syndrome, the serum gastrin level will be  elevated, although more commonly an elevated gastrin level  is due to PPI use.   Upper endoscopy is the primary modality to detect peptic  ulcers, due to its combination of both high sensitivity and  specificity, as well as its capability of providing endoscopic  therapy. Barium studies, although capable of detecting peptic  ulcers, should be avoided in the acute setting, as barium inter-  feres with further endoscopic treatments and other imaging  modalities. In patients with ongoing upper GI bleeding with-  out an identifiable cause on upper endoscopy, or who have  recurrent bleeding uncontrolled by upper endoscopy, angiog-  raphy may define the source of the bleeding and provide treat-  ment (either with placement of a coil or embolization of the  involved artery).   As the symptoms of peptic ulcer disease are nonspecific, other  causes of upper abdominal pain should be considered, includ-  ing gastroesophageal reflux disease, nonulcer dyspepsia,  cholelithiasis, choledocholithiasis, pancreatic disease, and  malignancy. These conditions, however, are not typically asso-  ciated with GI bleeding. The differential diagnosis of lesions  seen at endoscopy that appear as peptic ulcers includes NSAID-  induced damage, infectious etiologies, and malignant disease,   including adenocarcinoma and lymphoma. Ischemic disease as  a cause of bleeding in the upper GI tract is unusual.   Complications of peptic ulcer disease include bleeding, per-  foration, and obstruction. However, most patients with pep-  tic ulcers do not develop these complications. Patients with  bleeding peptic ulcers may develop aspiration pneumonia or  complications of endoscopic therapy, such as respiratory  depression and perforation. The tissue damage associated  with ulcers may worsen with endoscopic treatment, particu-  larly with thermal methods of cautery. This is a potential  advantage of endoclip use, which will not further damage an  already compromised mucosa.   The principles of treatment of peptic ulcer disease are those  outlined previously for treatment of upper GI bleeding and  are detailed in Figure 30-4. Patients initially must be ade-  quately resuscitated and stabilized. Decisions on whether to  admit patients and how to optimally manage them depend  on the clinical presentation and initial bleeding severity.  Patients should be kept NPO and evaluated with an early  upper endoscopy.   In patients requiring endoscopic therapy, use of adjuvant  medical therapy with PPIs is routinely administered. In  patients who do not have high-risk endoscopic stigmata of  hemorrhage and who do not require endoscopic therapy,  medical treatment can be initiated with H 2 -receptor antago-  nists or PPIs, to begin the healing process. The presence of  H pylori should be sought by endoscopic biopsy, serology, or  breath testing, and patients who have H pylori should  undergo eradication therapy to decrease the risk of recurrent  bleeding and peptic ulcer disease. If other identifiable factors  are present such as medications, including NSAIDS and  aspirin, these should be discontinued if possible.   Endoscopic therapy should be performed in patients with  high-risk endoscopic stigmata of recent hemorrhage, which  include active bleeding and presence of a nonbleeding visible  vessel. Optimal treatment is combination therapy consisting  of injection combined with a thermal coagulation method or  with endoclip therapy. Although the approach is controver-  sial, patients who have an adherent clot over an ulcer should  be considered for endoscopic therapy and aggressively  treated medically.   Patients who have large ulcers (> 2 cm) or ulcers in loca-  tions associated with large arteries (eg, the high lesser curva-  ture of the stomach near the left gastric artery or the  posterior inferior wall of the duodenal bulb near the gastro-  duodenal artery) should be aggressively treated and consid-  ered for early surgery, especially with a hemodynamically  significant bleed. However, surgery usually can be avoided  with optimal medical and endoscopic therapy, and reserved  for use in patients who have persistent or recurrent upper   ▲ Figure 30-4. Algorithm for the management of ulcers and acute gastrointestinal bleeding. ICU, intensive care unit. (Adapted, with permission, from  Eisen GM, Dominitz JA, Faigel DO, et al; American Society for Gastroenterology. Standards of Practice Committee. An annotated algorithmic approach to upper  gastrointestinal bleeding. Gastrointest Endosc. 2001;53:853-858.)   GI bleeding, those with large ulcers, or those with perfo-  ration. Surgery is directed at control of bleeding, such as lig-  ation of the bleeding artery and oversewing of the ulcer.  Surgery can also be performed for other complications of  peptic ulcers, including perforation and nonhealing or giant  ulcers. Whether surgical treatment to reduce acid production  such as a vagotomy is needed is unclear due to the availabil-  ity of effective antisecretory medications.   The natural history of patients with bleeding peptic ulcers is  that the majority will spontaneously stop bleeding and will not  require emergency treatments. In patients who have bleeding  requiring endoscopic therapy, the majority can be controlled  with endoscopic measures. Surgery is needed only in a small  number of patients who have ongoing or severe upper GI  bleeding, not controllable by endoscopic and medical thera-  pies. Mortality, typically from comorbid illnesses and in  patients who were already hospitalized, remains significant in  patients who have upper GI bleeding in peptic ulcer disease.  After discharge from the hospital, it is unusual for patients to  require readmission for recurrent bleeding if the previously  described management measures have been instituted and if  the patient does not have further need for anticoagulation. A  comprehensive approach to the management of patients with  bleeding peptic ulcers results in optimal outcomes.   Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper  gastrointestinal bleeding in patients with Helicobacter pylori  infection who are taking low-dose aspirin or naproxen. N Engl J  Med. 2001;344:967-973. [PMID: 11274623]   Hawkey CJ. Risk of ulcer bleeding in patients infected with  Helicobacter pylori taking non-steroidal anti-inflammatory  drugs. Gut. 2000;46:310-311. [PMID: 10573289]   Lai KC, Hui WM, Wong WM, et al. Treatment of Helicobacter  pylori in patients with duodenal ulcer hemorrhage — a long-  term randomized, controlled study. Am J Gastroenterol.  2000;95:2225-2232. [PMID: 1107222]   A Mallory-Weiss tear is a common cause of upper GI bleeding,  accounting for approximately 5% of all cases. As the tears are  relatively superficial, most heal within 24-48 hours. Mallory-  Weiss tears may not be visualized on upper endoscopy, espe-  cially if the procedure is not performed prompdy. Although in  most patients the tears resolve spontaneously, massive bleeding   can occur from Mallory-Weiss tears in patients who have por-  tal hypertension, especially if esophageal varices are present.   Mallory-Weiss tears occur at the gastroesophageal junction  in the distal esophagus or proximal stomach. Typically, these  tears form after repeated and severe vomiting or retching.  The tears may extend into the underlying venous or arterial  plexuses.   The typical presentation of a Mallory-Weiss tear is acute upper  GI bleeding in a young to middle-aged man, following repeated  vomiting or retching after drinking alcohol. The antecedent  history of retching and vomiting may not always be obtained.  If there are other systemic signs, such as fever, chest pain, and  shortness of breath, the Boerhaave syndrome (esophageal per-  foration) should be considered.   The laboratory findings for a Mallory-Weiss tear are nonspe-  cific and are similar to those for peptic ulcer disease.   Upper endoscopy, performed promptly, is the diagnostic  (and therapeutic procedure) of choice. The tears can be seen  as single or multiple longitudinal disruptions of the mucosa  of the distal esophagus, at the gastroesophageal junction,  within a hiatal hernia, or in the stomach just below the gas-  troesophageal junction with associated bleeding (Plate 55).  As the injury of a Mallory-Weiss tear is relatively superficial  and subtle, upper GI radiographs are typically nondiagnostic  and not indicated.   The differential diagnosis of Mallory-Weiss tears includes other  lesions of the gastroesophageal junction, including reflux  esophagitis, infectious esophagitis, pill-induced esophagitis,  Cameron lesion, and Dieulafoy lesion. Mallory-Weiss tears are  focal lesions within an otherwise normal-appearing region of  mucosa, which distinguishes them from reflux or infectious  esophagitis. Patients with pill-induced esophagitis often have  injury higher up the esophagus, and this etiology may be  suspected by history. A Dieulafoy lesion is associated with a  normal-appearing adjacent mucosa and the presence of an  artery several centimeters below the gastroesophageal junction.   Although the natural history of Mallory-Weiss tears is that  they are self-healing, patients may have ongoing bleeding  or rebleeding. This is more likely with deeper tears or in   anticoagulated patients. It is also possible to have a perfora-  tion (Boerhaave syndrome) either spontaneously, due to  repeated vomiting, or after endoscopic therapy leading to  mediastinitis.   Endoscopic treatment of patients with Mallory- Weiss tears is  indicated if there is active bleeding or a nonbleeding visible  vessel at the time of endoscopy. Combination therapy with  injection initially to slow or stop the bleeding followed by  cautery is effective in most patients. However, because the  injury is a tear of the lining (and the esophagus lacks a  serosa), overinjection and overcauterization should be  avoided. Endoclips have been used for this indication, are  effective, and should not cause additional damage to the tis-  sue. In cases of associated portal hypertension or esophageal  varices, endoscopic therapy must be cautiously performed  and cautery therapy should be avoided. These patients can be  treated with sclerotherapy, band ligation, or endoclip place-  ment. Medical therapy should be initiated in patients with  Mallory- Weiss tears, but has not been shown to alter the nat-  ural history of the acute bleeding. Surgical intervention, with  oversewing of a vessel, is rarely needed in patients with  Mallory- Weiss tears.   GI tract, including the esophagus, duodenum, and colon.  The cause of a Dieulafoy lesion is unknown, although the  lesion may be congenital. When a Dieulafoy lesion bleeds,  massive arterial bleeding will occur. The typical patient with  a Dieulafoy lesion is a man, with multiple comorbidities,  already hospitalized for other problems.   A patient with a Dieulafoy lesion often presents with a mas-  sive acute upper GI bleed. However, the bleeding may be self-  limited in nature. In active bleeding, the diagnosis is  confirmed by finding a visible vessel with active arterial  pumping, without an associated ulcer or mass. The diagnosis  can be difficult, as bleeding is often so massive that the area  may be covered with blood and the source may not be visu-  alized. In the absence of active bleeding, the lesion is even  more difficult to see, as it may appear as a small and subtle raised  area, such as a nipple or visible vessel without an associated  ulcer. In patients with massive bleeding and no obvious cause,  the lesser curvature within 6 cm of the gastroesophageal  junction should be carefully inspected for evidence of a  Dieulafoy lesion.   The natural history of Mallory- Weiss tears is that bleeding  will stop spontaneously and healing will start to occur within  24-48 hours in the majority of patients. Rebleeding is  unusual once bleeding has ceased.   A Dieulafoy lesion is a dilated, aberrant submucosal vessel  that erodes through otherwise normal surrounding epithe-  lium not associated with an ulcer. Although originally  described in 1884 by Gallard, the French surgeon Georges  Dieulafoy 14 years later designated the lesion "exulceratio  simplex." The arteries are 1-2 mm in size, which is approxi-  mately ten times the caliber of mucosal capillaries. The typi-  cal location is in the upper stomach along the high lesser  curvature, within 6 cm of the gastroesophageal junction.  Dieulafoy lesions have been reported in areas throughout the   Upper endoscopy is the primary modality to detect a  Dieulafoy lesion. If bleeding has stopped and there is doubt  about the nature of the lesion, endoscopic ultrasound may be  helpful to confirm the diagnosis.   Endoscopic treatment is the primary modality for bleeding  control of a Dieulafoy lesion. Combination therapy with  injections of epinephrine followed by cautery may be used,  or endoclips may be placed. There are also reports of band  ligation over a Dieulafoy lesion. The risk of recurrent bleed-  ing following endoscopic treatment is relatively high due to  the size of the underlying artery. It may be helpful to tattoo  the area with ink to help localize the area for subsequent  endoscopic therapy or future operative treatment. In patients  with recurrent bleeding, repeat endoscopic therapy is rea-  sonable; however, surgical therapy may be necessary. Surgical  treatment of a Dieulafoy lesion is typically a wedge resection,  as simple oversewing has a high rebleeding rate.   McGrath K, Mergener K, Branch S. Endoscopic band ligation  of Dieulafoy 's lesion: report of two cases and review of the  literature. Am J Gastroenterol. 1999;94:1087-1090. [PMID:  10201488]   Schmulewitz N, Baillie J. Dieulafoy lesions: a review of 6 years of  experience at a tertiary referral center. Am ] Gastroenterol.  2001;96:1688-1694. [PMID: 11419815]   Various terms are used to describe vascular malformations of  the upper GI tract, including arteriovenous malformations,  vascular ectasia, angiodysplasia, and telangiectasia. Although  these lesions can present as acute, overt upper GI bleeding,  they are frequently a source of chronic occult GI bleeding  and iron deficiency anemia. Vascular malformations of the  upper GI tract may be associated with small bowel angioec-  tasias (also of obscure origin).   Vascular malformations of the upper GI tract maybe arterial or  venous in origin. The majority are idiopathic with unknown  causes. The spectrum of vascular malformations includes  Dieulafoy lesions, as previously discussed, watermelon stomach  (gastric antral vascular ectasia), Osier- Weber- Rendu syndrome  (hereditary hemorrhagic telangiectasia), blue rubber bleb  nevus syndrome, and radiation-induced telangiectasias.   Bleeding from upper GI vascular malformations is typically  intermittent and low-grade in nature, although it can be  acute and overt. The endoscopic appearance can be variable,  but includes a superficial collection or tuft of blood vessels  (Plate 56). These also can be detected by angiography, with  findings including an early filling vein, a vascular tuft, and a  late draining vein.   The primary treatment of vascular malformations is endo-  scopic therapy. Endoscopic therapy with thermal coagulation  is the treatment of choice, with cautery applied initially to  the periphery and then at the center of the lesion. There  should be whitening of the mucosa and ablation of all visible  vascular tissue. Argon plasma coagulation has been applied  to the treatment of vascular malformations and is an effec-  tive therapy. It is important to avoid overdistention of the  stomach or small intestine during therapy, as well as to avoid  contact with tissue when using argon plasma coagulation  therapy. Repeat therapy should not be applied to the same  location due to the risk of transmural injury and perforation.   Various medications have been used in an attempt to treat  vascular malformations in the upper GI tract. Combination  estrogen-progesterone therapy has been widely used, but  overall has yielded inconsistent results. Surgery can be  offered for failures of endoscopic and medical therapy, but is  rarely necessary.   ► Characteristic endoscopic appearance of radiating rows  of vascular malformations extending outward from the  pylorus.   Watermelon stomach or gastric antral vascular ectasia  (GAVE) is a relatively unusual cause of upper GI bleeding.  This condition can occur along with, or be confused with,  portal hypertensive gastropathy. In this condition vascular  malformations occur in rows of reddish stripes that radiate  outward from the pylorus, in a pattern that resembles the  stripes on a watermelon. These stripes represent rows of vas-  cular malformations and the entity is easy to recognize in the  classic form. However, watermelon stomach may have a less  organized appearance, with more scattered erythema and vas-  cular malformations, making it more difficult to recognize.   The cause of watermelon stomach is idiopathic; however,  it may be due to gastroduodenal prolapse and has been noted  to occur in patients with cirrhosis, portal hypertension, and  systemic sclerosis. Patients with concomitant portal hyper-  tension have bleeding that is more difficult to control, requir-  ing treatment of the underlying portal hypertension.   The diagnosis of watermelon stomach is based on the classic  endoscopic appearance of radiating rows of vascular malfor-  mations originating from the pyloric area (Plate 57). Although  the diagnosis is endoscopic, it can be confirmed by histology  from endoscopic biopsy. Biopsies of watermelon stomach show  areas of vascular ectasia associated with spindle cell prolifera-  tion and fibrohyalinosis. The bleeding that occurs is typically  chronic and low grade, often associated with iron deficiency  anemia and occult bleeding. It is unusual to have acute or mas-  sive upper GI bleeding from watermelon stomach.   Endoscopic therapy is effective at treating watermelon  stomach, especially in the absence of concomitant portal   hypertension. This may be done with multipolar electrocoag-  ulation or argon plasma coagulation. Several courses of treat-  ment are required to obliterate the vascular ectasias and  decrease or stop bleeding. Although most patients respond to  endoscopic therapy, surgery may be needed for patients who  have persistent bleeding despite endoscopic management.  Surgical management with antrectomy prevents further  bleeding.   Sebastian S, O'Morain CA, Buckley MJ. Review article: current  therapeutic options for gastric antral vascular ectasia. Aliment  Pharmacol Ther. 2003;18:157-165. [PMID: 12869075]   directly. Diagnostic tests need to be done in an expeditious  manner along with surgical evaluation.   The management of an aortoenteric fistula is surgical. The  mortality rate of an unrecognized fistula is 100%, whereas the  mortality for a recognized fistula is 30%. Treatment consists  of surgical repair of the aortoenteric fistula.   Lemos DW, Raffetto JD, Moore TC, et al. Primary aortoduodenal  fistula: a case report and review of the literature. ] Vase Surg.  2003;37:686-689. [PMID: 12618713]   Aortoenteric fistulas occur when there is a direct communi-  cation between the aorta and the GI tract. These typically  occur in patients who have had a prosthetic aortic graft that  erodes into the intestine. They also can occur from aortic  aneurysms, after radiation therapy, or from postinfectious  aortitis (eg, from syphilis or tuberculosis), trauma, or tumor  invasion.   The third or fourth portion of the duodenum is the most  common site of aortoenteric fistulas, followed by the  jejunum and the ileum. Patients may have a "herald" bleed  with initial hematemesis or hematochezia, which may spon-  taneously remit. This may then be followed by massive bleed-  ing, including exsanguination, making it important to  diagnose this condition as early as possible. Intermittent  bleeding can occur if a blood clot temporarily seals a fistu-  lous connection. Abdominal or back pain occurs in about  half of patients. Signs of fever or infection may be present.  On physical examination, a bruit may be heard or a pulsatile  mass may be palpable.   A high index of suspicion is needed to properly diagnose  a patient with an aortoenteric fistula while there is still time  for successful management. In a patient who has a known  risk factor, such as previous aortic grafting, this diagnosis  should be considered early in the course. It should also be  suspected in patients with bleeding from the third or fourth  portion of the duodenum, particularly with massive bleed-  ing. Aortic graft material may occasionally be seen at  endoscopy protruding into the bowel lumen. The diagnosis  can be confirmed by CT with angiography or angiography   Hemobilia, bleeding that occurs from the hepatobiliary tract,  is a rare cause of acute upper GI bleeding. Hemobilia should  be considered in patients who have had a recent history of  hepatic or biliary tract injury. This includes trauma to the  area and percutaneous (or transjugular) liver biopsies, and  percutaneous transhepatic cholangiograms or biopsies.  Hemobilia can also occur from gallstones, cholecystitis,  hepatobiliary tumors, hepatic abscesses, and aneurysms.   The classic triad of hemobilia is biliary colic, obstructive  jaundice, and GI bleeding. Obstructive jaundice may be asso-  ciated with biliary sepsis. Patients with this triad should be  considered as potentially having hemobilia.   The diagnosis of hemobilia can be difficult by upper  endoscopy. A side-viewing duodenoscope is very helpful to  look at the ampulla directly or to perform endoscopic retro-  grade cholangiopancreatography (ERCP) (Plate 58). A  tagged red blood cell scan or angiography can be done to  localize the source of bleeding.   Treatment is directed at the primary cause of bleeding.  Although occasionally treatment can be carried out endo-  scopically, it usually needs to be done angiographically (such  as by arterial embolization) or surgically.   Hemosuccus pancreaticus occurs when there is bleeding  from the pancreatic duct. This is a rare cause of upper GI  bleeding that can be due to chronic pancreatitis, pancreatic   pseudocysts, and pancreatic tumors. Bleeding occurs when  there is erosion into a vessel, forming a direct communica-  tion with the pancreatic duct. It can also occur after a thera-  peutic endoscopy of the pancreas, including pancreatic  sphincterotomy or stone removal.   The diagnosis of hemosuccus pancreaticus should be sus-  pected when upper GI bleeding occurs in the setting of pan-  creatic disease. Although it can be difficult to detect by  routine endoscopy, a side-viewing duodenoscope and ERCP  may reveal the source of the bleeding. The diagnosis can be  confirmed by abdominal CT scan, angiography, or intra-  abdominal exploration. Mesenteric angiography is an impor-  tant adjunct for diagnosis and treatment, often with coil  embolization to control the acute bleeding. For persistent or  massive bleeding, surgery with resection of the bleeding area  or ligation of the bleeding vessel may be required.   Benz CA, Jakob P, Jakobs R, et al. Hemosuccus pancreaticus — a  rare cause of GI bleeding: diagnosis and interventional radio-  logical therapy. Endoscopy. 2000;32:428-431. [PMID: 10817187]   Cameron lesions are erosions or ulcers that occur in the dis-  tal aspect of a hiatal hernia. Although this may be an inci-  dental finding, a Cameron lesion can be responsible for  acute or chronic upper GI bleeding and iron deficiency ane-  mia. The mechanism of formation of a Cameron lesion is  incompletely understood, although potential causative fac-  tors include gastroesophageal reflux and mechanical trauma  of the area.   Management of a Cameron lesion depends on the clinical  situation. Patients with acute bleeding can be treated by  endoscopic methods. Patients who do not have acute bleed-  ing, but have chronic blood loss may be treated with medical  therapy, such as PPI therapy and iron repletion. Surgical  repair of the hiatal hernia is curative, but rarely needed.   Neoplasms of the upper GI tract account for less than 3% of  cases of upper GI bleeding. These tumors may be malignant  tumors (primary or metastatic) such as adenocarcinomas or  lymphomas, or can be benign, such as leiomyomas or GI  stromal tumors.   The symptoms that suggest bleeding may be from a GI  tumor include those that may be attributable to the primary  tumor, such as dysphagia from esophageal cancer or gastric  outlet obstruction due to carcinoma of the stomach. Other  symptoms are nonspecific, including cachexia, weight loss,  and early satiety.   Bleeding from an upper GI tumor can be from diffuse  mucosal erosions or ulcerations, or from erosion of the tumor  into an underlying vessel (Plates 59 and 60). The bleeding may  be slow or may be massive. If the diagnosis of a tumor is not  previously known, it may be detected at the time of endoscopy  and confirmed by brushings or biopsies. Endoscopic ultra-  sound may be needed to evaluate submucosal masses.   Endoscopic treatment of patients with upper GI bleeding  can be offered, but is less effective in the setting of tumors.  Typically endoscopic treatments, although they may be effec-  tive, should be used as a temporizing measure prior to more  definitive measures such as surgery, because rebleeding will  frequently occur after endoscopic control of bleeding, thus  requiring a more durable approach. Medical therapy is inef-  fective in this setting, although palliative measures may be  provided, including chemotherapy and radiation of the pri-  mary tumor.   Patients who have bleeding due to an upper GI malignancy  have a very poor prognosis. The majority of patients will die  within 3 months. However, patients who have a benign upper  GI tumor that bleeds should be cured by surgical resection.   Esophageal and gastric varices may occur without any clini-  cal symptoms. In patients with cirrhosis, particularly in more  advanced stages, screening measures are performed to detect  varices in an attempt to decrease the risk of initial bleeding.  Acute variceal bleeding is different from nonvariceal bleed-  ing in many respects. Only 50% of patients with a variceal  hemorrhage stop bleeding spontaneously (compared with   approximately 80-90% of patients with nonvariceal upper  GI bleeding). Following cessation of active variceal bleeding,  there is a high risk of recurrent bleeding within 6 weeks. The  time of greatest risk is within the first 48-72 hours, and over  50% of all rebleeding episodes occur within the first 10 days.  Recurrent variceal bleeding may occur in up to 70% of  patients within 6 weeks of the index bleed. Survival during  the 6 weeks following the index bleed is directly related to  rebleeding. Risk factors for rebleeding include age greater  than 60 years, large varices, severe initial bleed (hemoglobin  < 8 g/dL on admission), and renal failure. Mortality is between  15% and 50% for each bleeding episode, and 70-80% in those  with continuous bleeding. Variceal hemorrhage is responsible  for one third of all deaths due to cirrhosis.   Esophageal and gastric varices develop as a result of portal  hypertension. Portal hypertension can be from prehepatic  causes (eg, portal vein thrombosis and schistosomiasis),  from hepatic disease (cirrhosis most commonly), and from  posthepatic disease (eg, hepatic vein thrombosis, cardiac fail-  ure, and constrictive pericarditis). Varices are dilated venous  collaterals with a weak wall that have a tendency to rupture  and can bleed massively. Varices may be isolated to the stom-  ach if they are due to splenic vein thrombosis, acute pancre-  atitis, or a pancreatic tumor.   The symptoms of variceal bleeding are nonspecific and  include hematemesis, melena, and hematochezia. Patients  may feel lightheaded and dizzy, and those with severe liver  disease may have hepatic encephalopathy. Other associated  signs and symptoms are manifestations of cirrhosis, includ-  ing jaundice, spider telangiectasia, palmar erythema, ascites,  and Dupuytren contractures.   Abnormalities of the liver enzymes (alanine aminotrans-  ferase and aspartate aminotransferase) are seen in patients  with active hepatocellular damage. Patients may have hyper-  bilirubinemia and poor synthetic function, with hypoalbu-  minemia and an elevated INR. Patients with bone marrow  suppression from alcohol may have pancytopenia; those with  hypersplenism may have low platelets. In patients with liver  failure, hypoglycemia may occur, and in those with hepa-  torenal syndrome, blood urea nitrogen and creatinine are  elevated.   Upper endoscopy is the primary diagnostic modality and  allows for endoscopic therapy. The Japanese Research Society   for Portal Hypertension criteria includes a size (or form)  classification. Small straight varices are classified as Fl,  enlarged tortuous varices occupying less than one third of  the esophageal lumen are F2, and large coil-shaped varices  that occupy more than one third of the esophageal lumen are  F3. Barium radiographs may be suggestive of large varices;  however, they are not sensitive to small varices, and the use  of barium impedes further diagnostic or therapeutic  attempts. Abdominal CT or abdominal ultrasound may show  the presence of collateral vessels. Portal vein angiography  may also demonstrate the presence of collaterals or recanal-  ization of the umbilical vein. Hepatic venous pressure gradi-  ents of more than 12 mm Hg are a predictor of bleeding.   The differential diagnosis includes all the nonvariceal causes  of upper GI bleeding. Patients with cirrhosis and upper GI  bleeding are found to have a variceal source of bleeding in  50-90% of cases. Patients with cirrhosis can also bleed from  esophagitis, peptic ulcer disease, Mallory-Weiss tears, and  other nonvariceal sources.   Bleeding from esophageal or gastric varices may be massive  and uncontrollable, resulting in severe hemorrhage and  death. Acute variceal bleeding in a patient with cirrhosis may  precipitate further worsening of liver disease, with increasing  hepatic encephalopathy and development of the hepatorenal  syndrome. Bacterial infections are present in up to 20% of  cirrhotic patients with GI bleeding, and subsequently  develop in an additional 50% of patients during hospitaliza-  tion for variceal bleeds. The use of prophylactic antibiotics in  patients with acute variceal bleeding has been shown to  decrease the rates of subsequent infection, spontaneous bac-  terial peritonitis, bacteremia, and death.   Patients with acute variceal bleeding are typically treated  with multiple modalities simultaneously, including medical  therapies and endoscopic management. Over-resuscitation  should be avoided, as overvigorous volume repletion has  been associated with precipitation of further bleeding. In  addition radiologic and surgical treatments may be needed.   In patients with suspected variceal bleeding, medical therapy  to reduce bleeding should be initiated prior to endoscopic  evaluation. The use of prophylactic antibiotics given before  endoscopy in cirrhotic patients reduces infectious complica-  tions and decreases mortality.   Medications have been shown to decrease active variceal  bleeding. In the past, intravenous vasopressin was given to  constrict the mesenteric vasculature and decrease portal   venous blood flow. A systemic vasodilator, such as intravenous  nitroglycerin, was concurrently administered to reduce the  adverse effects related to the systemic vasoconstriction, which  include myocardial, cerebral, bowel, and extremity ischemia.  However, this combination of vasopressin and nitroglycerin is  rarely used now because of the availability of other medica-  tions with fewer side effects.   Terlipressin is a synthetic analog of vasopressin that is  released in a sustained and slow manner. It appears to have a  similar ability to control bleeding and reduce mortality as  vasopressin, without many of the systemic side effects.  Terlipressin is not currently available in the United States, but  is used in other countries.   Somatostatin and its analog, octreotide, have been exten-  sively studied in patients with bleeding esophageal and gas-  tric varices. These drugs indirectly cause vasoconstriction  and decrease portal blood flow. Octreotide is given as a bolus  injection of 25-50 meg followed by a continuous infusion of  25-50 meg/h intravenously. Octreotide and somatostatin  have been found to be useful in achieving hemostasis and  preventing early rebleeding. Once patients are stabilized  from the acute variceal bleeding episode, f3-blockers are  given to prevent rebleeding. (See Chapter 47 for additional  discussion of portal hypertension.)   The treatment of choice for bleeding esophageal varices is  endoscopic hemostasis (Plates 61 and 62). The objective of  endoscopic therapy is to find the source of the bleeding and to  treat it. Varices are evaluated for signs of either active bleeding  or markers of recent bleeding. These markers include large  tortuous varices with red wale marks (longitudinal red streaks  on varices that resemble red, corduroy wales), cherry red spots  (discrete cherry red spots that are flat on a varix), and hemo-  cystic spots (raised discrete red spots that overlie varices that  appear as "blood blisters"). Platelet or fibrin plugs are white  nipple-like projections that project from a varix indicative of a  site with recent bleeding and with a very high risk of bleeding.   Endoscopic therapies are initially applied to the distal  esophagus at the gastroesophageal junction and then extended  proximally. Most variceal bleeding is from the distal 5-10 cm  of the esophagus. Gastric varices are poorly responsive to  endoscopic therapy and do not respond to typical endoscopic  treatments (Plate 63). Recent reports of the use of cyanoacry-  late injections for bleeding gastric varices are promising,  although not approved for use in the United States.   Endoscopic injection sclerotherapy is an established  method of injecting varices directly using a freehand tech-  nique with 1-3 mL of a sclerosing agent (sodium morrhuate  or ethanolamine) at each site. Numerous techniques and  agents have been used to sclerose varices. Although this tech-  nique is effective, esophageal variceal band ligation is more  effective, associated with less rebleeding, fewer complica-  tions, and a lower mortality rate, and requiring fewer treat-  ment sessions to obliterate the varices.   Endoscopic variceal band ligation therapy is a method of  placing elastic bands over varices, similar to the technique of  banding hemorrhoids. This is typically performed within the  distal 5 cm of the esophagus. Varices are suctioned into a  banding device, and the bands are released around the base  of the varices. Esophageal variceal band ligation controls  acute bleeding in 90% of patients, with a rebleeding rate of  30%. Endoscopic variceal ligation is the treatment of choice  for controlling acute variceal hemorrhage. A drawback of the  banding technique is that it can be difficult to perform in the  setting of active bleeding; it may be hard to localize the exact  source of bleeding with the restricted endoscopic view  afforded by the banding device, and blood may pool within  the banding mechanism. In addition, it is not feasible to per-  form banding in the retroflexed position in the stomach due  to the nature of the device.   Balloon tamponade is an effective way to achieve short-term  hemostasis but should be reserved for patients whose bleeding  cannot be controlled by endoscopic therapy or who are having  massive bleeding that prohibits an endoscopic attempt. A  commonly used device is the Sengstaken-Blakemore tube,  which has a large 250-mL gastric balloon and an esophageal  balloon, as well as a gastric suctioning port. In patients with  massive bleeding uncontrollable by other measures, this tube  can be placed with the gastric balloon first inflated after radi-  ographic confirmation of proper position. If necessary, the  esophageal balloon can be carefully inflated. However, the use  of the esophageal balloon is associated with esophageal rup-  ture, a lethal complication. If definitive therapy is not per-  formed, recurrent bleeding likely will occur when the balloon  is deflated. In general, balloon tamponade should be used in  an effort to temporarily stabilize a patient prior to the per-  formance of a more definitive treatment.   The main radiologic therapy is transjugular intrahepatic por-  tosystemic shunt (TIPS). TIPS is a radiologic procedure that  creates a portosystemic shunt via a transjugular approach. In  this procedure, a connection is made between the portal and  hepatic veins and a stent is placed between the two veins.  Complications include encephalopathy due to the shunting,  shunt occlusion with rebleeding, and shunt migration. In  general TIPS is reserved for patients who have persistent  variceal bleeding despite endoscopic and medical attempts to  control.   Various surgical therapies can be performed to control  esophageal and gastric variceal bleeding. These include cre-  ation of a portosystemic shunt, which may be a portal caval  shunt (nonselective) or a distal splenorenal shunt (selective).  Alternately, esophageal transection can be performed, in   which the distal esophagus is transected and then stapled  back together after ligation of varices, with devascularization  of the gastroesophageal junction (Sugiura procedure). The  ultimate operation to control variceal bleeding is liver trans-  plantation. This is an option in patients who already are  planned to have a liver transplantation due to poor liver  function. In general, the patients who have the best outcomes  with surgical shunt therapy have relatively well-preserved  liver function (Child-Turcotte-Pugh class A), but have failed  endoscopic treatment.   Variceal bleeding is a significant cause of rebleeding and  mortality. Variceal bleeding will stop in approximately 50%  of patients, but those who have continued bleeding have a  mortality that approaches 80%. Patients have a high risk of  rebleeding (up to 70%) until gastroesophageal varices are  obliterated. If a patient survives the initial bleeding episode,  repeated courses of band ligation are performed approxi-  mately every 2 weeks until the varices are obliterated. This  technique is combined with medical therapy using p-blockade.  The prognosis for patients with bleeding gastroesophageal  varices is poor, even with control of bleeding varices, as this is  indicative of progressive liver disease. Patients die from hepatic  decompensation, rebleeding, infections, renal failure, and other  complications.   Portal hypertensive gastropathy, also called congestive gas-  tropathy, occurs with edema and capillary venous dilation in  the submucosa and mucosa of the stomach. This causes fri-  ability and can result in bleeding with rupture of the ectatic  vessels. Endoscopically, the appearance is a reticular, mosaic-  like pattern of pink mucosa, with a characteristic "snakeskin"  appearance. In patients with cirrhosis and portal hypertension,   gastric mucosal blood flow is increased, leading to conges-  tion and hyperemia of the stomach.   Portal hypertensive gastropathy may develop after treat-  ment of esophageal varices by either endoscopic sclerother-  apy or band ligation therapy. It is postulated that treatment  of the esophageal varices increases backpressure into the  stomach, leading to the development of gastric congestion.  Overall this is a relatively rare cause of acute upper GI bleed-  ing, although it may be a source of chronic blood loss in cir-  rhotic patients.   The goal of treatment of portal hypertensive gastropathy is to  decrease portal pressures and therefore stop bleeding.  Endoscopic treatments are not effective in this disorder. The  affected area is diffuse, and pharmacologic agents that  decrease blood flow, such as octreotide, can be used acutely.  Low-dose propranolol (20-40 mg/day) is often given ini-  tially, with the dose then increased and adjusted until bleed-  ing stops or side effects occur. Patients with uncontrolled  bleeding may need TIPS therapy or shunt surgery. In patients  with decompensated liver disease, liver transplantation is  indicated.   Bafiares R, Albillos A, Rincon D, et al. Endoscopic treatment versus  endoscopic plus pharmacologic treatment for acute variceal  bleeding: a meta-analysis. Hepatology. 2002;35:609-615. [PMID:  11870374]   Bernard B, Grange ID, Khac EN, et al. Antibiotic prophylaxis for  the prevention of bacterial infection in cirrhotic patients with  gastrointestinal bleeding. Hepatology. 1999;29:1655-1661.  [PMID: 10347104]   Corley DA, Cello JP, Adkisson W, et al. Octreotide for acute  esophageal variceal bleeding: a meta-analysis. Gastroenterology.  2001;120:946-954. [PMID: 11231948]   DAmico G, De Franchis R. Cooperative Study Group. Upper  digestive bleeding in cirrhosis. Post-therapeutic outcome and  prognostic indicators. Hepatology. 2003;38:599-612. [PMID:  12939586]   Grace ND. Diagnosis and treatment of gastrointestinal bleeding  secondary to portal hypertension. American College of  Gastroenterology Practice Parameters Committee. Am J  Gastroenterol. 1997;92:1081-1091. [PMID: 9219775]   Monescillo A, Martinez-Lagares F, Ruiz-del- Arbol L, et al. Influence  of portal hypertension and its early decompression by TIPS  placement on the outcome of variceal bleeding. Hepatology.  2004;40:793-801. [PMID: 15382120]   Diverticulosis, arteriovenous malformations, and  ischemic colitis are the most common causes of lower  Gl bleeding.   Endoscopic and radiologic tests can provide both diag-  nosis and therapy.   Urgent colonoscopy may have increased diagnostic  yield but does not clearly lead to decreased rates of  rebleeding.   Lower gastrointestinal (GI) bleeding is defined as bleeding  that occurs from a source distal to the ligament of Treitz. This  chapter discusses only colonic sources of bleeding; upper GI  bleeding is explored elsewhere (see Chapter 30).   Lower GI bleeding accounts for about 20% of major GI  bleeding and is less common and generally less severe than  upper GI bleeding. There are 20-27 hospitalizations per  100,000 adults in the United States due to lower GI bleeding.  It generally occurs in older adults with a mean age between  63 and 77 years old. Nearly 80% of lower GI bleeding stops  spontaneously, similar to upper GI bleeding. The overall  mortality rate of lower GI bleeding is 2-4%. Similar to upper  GI bleeding, patients who begin lower GI bleeding as outpa-  tients have a significantly lower mortality rate (3.6%) than  those who develop lower GI bleeding as inpatients (23%).   Longstreth G. Epidemiology and outcome of patients hospitalized  with acute lower gastrointestinal hemorrhage: a population-based  study. Am } Gastroenterol. 1997;92:419-424. [PMID: 9068461 ]   Hematochezia is defined as bright red blood per rectum and  usually implies a left colonic source, although it can be  caused by a more brisk, proximal source of bleeding. Maroon  stools are maroon-colored blood mixed with stool and are  often associated with a right colonic source of bleeding; how-  ever, they also can result from a more brisk, proximal source  of bleeding. Melena refers to black, tarry, foul-smelling stool  that results from the bacterial degradation of hemoglobin  over a period of at least 14 hours. It usually implies an upper  GI source of bleeding although it may be associated with  right colonic bleeding in cases of slow motility. Ingestion of  iron, bismuth, charcoal, and licorice should be excluded as  they all can turn stool black. Occult blood refers to the pres-  ence of small quantities of blood in the stool that does not  change its color and can only be detected by performing a  stool guaiac card test. Blood loss of at least 5-10 mL/day can  be detected by stool guaiac card tests. The GI tract normally  loses about 0.5-1.5 mL of blood per day, which is not usually  detected by guaiac tests.   When patients initially present with lower GI bleeding, they  should be triaged and managed based on the severity of the  hemorrhage (Figure 31-1).   Patients who have minor bleeding with scant hema-  tochezia represent 75-90% of all patients with lower GI bleed-  ing and may be evaluated as outpatients. For patients over the  age of 50 years, colonoscopy should be performed to evaluate  the source and to screen for colon cancer. In younger patients  with rectal bleeding, there is debate regarding the necessity of  a colonoscopy versus flexible sigmoidoscopy. Several studies  demonstrate that 10-30% of patients with rectal bleeding had   A Figure 31-1. Algorithm for the management of patients with suspected lower gastrointestinal (Gl) bleeding.  NG, nasogastric; UGI, upper gastrointestinal.   proximal lesions, which would have been missed by flexible  sigmoidoscopy. Other studies found that no cancers and only  a very few polyps would have been missed by flexible sigmoi-  doscopy in patients with "outlet-type bleeding," defined as  blood seen during or after defecation on the toilet paper or in  the toilet bowl without symptoms or special risk factors for  colorectal neoplasia.   Physicians are unable to reliably predict based on history  alone, which patients with rectal bleeding will have significant  pathology. As patients grow older, it becomes cost-effective to  perform a full colonoscopy. Patients in their mid- 30s or older  should likely be evaluated with a colonoscopy, whereas patients  in their 20s with outlet-type bleeding may undergo flexible sig-  moidoscopy. If no lesion is discovered to explain the hema-  tochezia, those patients should then undergo a full colonoscopy.   Another category of patients presents with chronic inter-  mittent bleeding that manifests as guaiac-positive stool or  anemia, or both. Evaluation of these patients can usually  occur in the outpatient setting; however, if the patients are  severely anemic with cardiopulmonary symptoms or disease,  inpatient admission should be considered for further moni-  toring, evaluation, and management. All of these patients  must be evaluated with colonoscopy. About 25-41% of these   patients will have abnormalities on upper endoscopy.  Therefore, if no source is identified on colonoscopy and the  patient has upper gastrointestinal symptoms, an upper  endoscopy should be performed. Asymptomatic patients  may also harbor upper Gl abnormalities, and those with iron  deficiency anemia should undergo an upper endoscopy.   Other patients with lower Gl bleeding include those with  episodic severe bleeding and continuous active bleeding who  must be evaluated in the hospital. It is important to be aware  that about 10-15% of cases initially thought to represent  lower Gl bleeding ultimately have an upper gastrointestinal  source. Clues to the presence of a possible upper Gl source  include hematochezia with hemodynamic instability, melena,  and a history of upper Gl bleeding. Placement of a nasogas-  tric tube or obtaining a prompt upper endoscopy examina-  tion may be helpful to rule out an upper Gl source in patients  with severe lower Gl bleeding.   Bond IH. Rectal bleeding: is it always an indication for colonoscopy?   Am J Gastroenterol. 2002;97:223-225. [PMID: 11866253]  Davila RE, Rajan E, Adler DG, et al. Standards of Practice   Farrell JJ, Friedman LS. Review article: the management of lower  gastrointestinal bleeding. Aliment Pharmacol Titer. 2005;21:  1281-1298. [PMID: 15932359]   Lewis JD, Brown A, Localio AR, et al. Initial evaluation of rectal  bleeding in young persons: a cost-effectiveness analysis. Ann  Intern Med. 2002;136:99-110. [PMID: 11790061]   During the initial clinical evaluation of patients with sus-  pected acute lower GI bleeding, resuscitation should proceed  simultaneously with the placement of two large-bore periph-  eral catheters or a central line followed by administration of  intravenous fluids, including normal saline or packed red  blood cells (RBCs), or both.   1. History — The history in these patients should focus on  factors that could be associated with potential causes: blood  coating the stool suggests hemorrhoidal bleeding while  blood mixed in the stool implies a more proximal source;  bloody diarrhea and tenesmus is associated with inflamma-  tory bowel disease while bloody diarrhea with fever and  abdominal pain especially with recent travel history suggests  infectious colitis; pain with defecation occurs with hemor-  rhoids and anal fissure; change in stool caliber and weight  loss is concerning for colon cancer; abdominal pain can be  associated with inflammatory bowel disease, infectious coli-  tis, or ischemic colitis; painless bleeding is characteristic of  diverticular bleeding, arteriovenous malformation (AVM),  and radiation proctitis; nonsteroidal anti-inflammatory drug  (NSAID) use is a risk factor for diverticular bleeding and  NSAID-induced colonic ulcer; and recent colonoscopy with  polypectomy suggests postpolypectomy bleeding.   Patients should be asked about symptoms of hemodynamic  compromise, including dyspnea, chest pain, lightheadedness,  and fatigue.   2. Physical findings — The physical examination should  focus on the following areas:   A. Vital signs — Orthostatic hypotension implies at least a  15% loss of blood volume.   C. Rectal examination — Key elements include inspection  of the anus, palpation for masses, characterization of the stool  color, and stool guaiac card test.   Among the blood tests that should be performed are a com-  plete blood count, prothrombin time, partial thromboplastin  time, electrolytes, and typing and cross-matching for blood  products.   Coagulopathy and thrombocytopenia should be immedi-  ately corrected if possible. Platelets should be maintained  above 50,000/mL and coagulopathy should be corrected with  vitamin K or fresh frozen plasma. Vitamin K should be taken  orally unless the patient has cirrhosis or biliary obstruction,  in which case it should be administered subcutaneously. The  full effect of vitamin K is not obtained for 12-24 hours,  unlike fresh frozen plasma which immediately reverses coag-  ulopathy. The intravenous formulation of vitamin K reverses  coagulopathy more quickly and may be used in cases of  severe bleeding, however, patients should be monitored for  anaphylaxis. The effects of fresh frozen plasma last about 3-5  hours and large volumes (> 2-3 L) may be required to com-  pletely reverse coagulopathy, depending on the initial pro-  thrombin time. Recombinant activated factor VII has been  approved for use in patients with hemophilia A and B with  factor VIII and IX inhibitors. Evidence of possible benefit in  patients with cirrhosis and GI bleeding has been demon-  strated, although the optimal dose is unclear and recombi-  nant activated factor VII is very expensive.   Diagnostic evaluation must be performed after patients have  been adequately resuscitated. If an upper GI source is sus-  pected, an upper endoscopy should be performed first.  Lower GI evaluation can be performed with anoscopy, flexi-  ble sigmoidoscopy, colonoscopy, rarely barium enema, and  various radiologic studies.   1 . Anoscopy — Anoscopy is useful only for diagnosing bleeding  sources from the anorectal junction and anal canal, including  internal hemorrhoids and anal fissures. It is superior to flexible  sigmoidoscopy for detecting hemorrhoids in an outpatient set-  ting and can be performed quickly in the office or at the bed-  side as an adjunct to flexible sigmoidoscopy and colonoscopy.   2. Flexible sigmoidoscopy — Flexible sigmoidoscopy uses a  65-cm long sigmoidoscope that visualizes the left colon. It  can be performed without sedation and only minimal prepa-  ration with enemas. However, the diagnostic yield of flexible  sigmoidoscopy in acute lower GI bleeding is only 9%. The  role of anoscopy and flexible sigmoidoscopy in inpatients  with acute lower GI bleeding is limited, as most patients  should undergo colonoscopy.   3. Colonoscopy — Colonoscopy is the test of choice in the  majority of patients with acute lower GI bleeding as it can be  both diagnostic and therapeutic. The diagnostic accuracy of  colonoscopy in lower GI bleeding ranges from 48% to 90%,  and urgent colonoscopy appears to increase diagnostic yield.  This wide range in yield is partially explained by different  criteria for diagnosis, as often if no active bleeding, non-  bleeding visible vessel, or adherent clot is found, bleeding is  attributed to a lesion if blood is present in the area. The pres-  ence of fresh blood in the terminal ileum is presumed to  indicate a noncolonic source of bleeding.   The overall complication rate of colonoscopy in acute lower  GI bleeding is 1.3%. Bowel preparation is safe and well-tolerated  in most patients. The complication rate of colonoscopy in an  unprepped colon may be higher. About 2-6% of colonoscopy  preparations in acute lower GI bleeding are poor. Between  4 and 8 L of Golytely should be administered orally or via  nasogastric tube until the effluence is clear.   4. Urgent colonoscopy — Multiple validated scoring systems  exist to predict the probability of rebleeding, surgery, and mor-  tality in upper GI bleeding. This enables appropriate triage and  aggressive management of high-risk patients and potentially  early discharge of low-risk patients. Few studies have stratified  patients by severity of lower GI bleeding. Risk factors identified  for increased severity of lower GI bleeding are heart rate greater  than 100 beats per minute, systolic blood pressure less than  115 mm Hg, syncope, nontender abdomen, rectal bleeding  within 4 hours of presentation, aspirin use, and more than two  comorbidities. Patients with none of these risk factors have a  low risk of severe bleeding, those with one to three of these fac-  tors have a moderate risk, and those with more than three risk  factors have a high risk of severe bleeding.   It is not clear that aggressive treatment with urgent  colonoscopy improves the outcome in patients with severe  lower GI bleeding. There has been one randomized trial to  date of patients with significant lower GI bleeding who were  randomized to standard care or urgent colonoscopy with  mean follow-up of 55 months. Patients in the standard care  arm underwent elective colonoscopy within 4 days of  admission. If they experienced ongoing bleeding, they  underwent tagged RBC scan followed by angiography or  colonoscopy. Patients undergoing urgent colonoscopy were  administered 4-6 L of Golytely orally or via a nasogastric  tube over 3-4 hours and underwent colonoscopy within  8 hours of hospitalization or diagnosis of hematochezia.  More sources of bleeding were identified in the urgent  colonoscopy group, but there was no difference in early or  late rebleeding, length of hospital stay, surgery, mortality, or  complications. Therefore, it is unclear if urgent colonoscopy  influences patient outcome despite the increased identifica-  tion and treatment of a source of bleeding, and further larger  studies are needed.   Green BT, Rockey DC, Portwood G, et al. Urgent colonoscopy for  evaluation and management of acute lower gastrointestinal  hemorrhage: a randomized controlled trial. Am J Gastroenterol.  2005;100:2395-2402. [PMID: 16279891]   Strate LL, Orav EJ, Syngal S. Early predictors of severity in acute  lower intestinal tract bleeding. Arch Intern Med. 2003;163:  838-843. [PMID: 12695275]   Strate LL, Saltzman JR, Ookubo R, et al. Validation of a clinical  prediction rule for severe acute lower intestinal bleeding. Am J  Gastroenterol. 2005;100:1821-1827. [PMID: 16086720]   Velayos FS, Williamson A, Sousa KH, et al. Early predictors of  severe lower gastrointestinal bleeding and adverse outcomes: a  prospective study. Clin Gastroenterol Hepatol. 2004;2:485-490.  [PMID: 15181617]   5. Barium enema — There is no role for barium enema in  the evaluation of acute lower GI bleeding. It may impede the  performance of a colonoscopy or subsequent angiography  due to the presence of barium in the colon. In young patients  with minor hematochezia who have a negative flexible sig-  moidoscopy, barium enema can be an alternative to  colonoscopy.   6. Tagged red blood cell scan— Tagged RBC scan and  angiography may be the tests of choice in patients with mas-  sive lower GI bleeding that prevents colonoscopy and in  those with ongoing bleeding and a negative colonoscopy.  Although tagged RBC scan is solely a diagnostic examina-  tion, angiography, like colonoscopy, can be both diagnostic  and therapeutic.   A bleeding rate of at least 0.1-0.5 mL/min is required for  detection by tagged RBC scan. An injected radiotracer cir-  culates in the blood and extravasation of blood into the GI  lumen can be identified on a series of static images cap-  tured after injection or on multiple sequential dynamic  images obtained at 15- or 30-second intervals (Figure 31-2A  and 31-2B). Two radiotracers have been used for tagged RBC  scan: technetium 99m ( 99m Tc) sulfur colloid and ""re-  labeled RBC, which involves labeling the patient's RBCs in  vitro and then reinjecting them into the patient. Sulfur col-  loid is rapidly cleared by the reticuloendothelial system and,  therefore, leaves the blood pool within minutes, which pro-  vides approximately a 10-minute window to detect extrava-  sation. RBC labeling is superior because the red cells persist  for at least 24 hours in the circulation. This allows for longer  and repeated imaging if the patient rebleeds during this time  window. Typically a 90-minute imaging period is used as the  diagnostic yield plateaus at this time.   About 45% of tagged RBC scans for lower GI bleeding are  positive. Accuracy of localization of the bleeding site ranges  from 24% to 91%. Scans that are positive within 2 hours were  95-100% accurate in localizing the bleeding site compared  with 57-67% accurate for scans positive after 2 hours.  Because of the relatively high rate of false localization, con-  firmatory studies are required before proceeding to surgery.   Tagged RBC scan is most useful before angiography  because it selects patients who are bleeding sufficiently for  an angiogram and it may allow more targeted angiography  with decreased contrast load. A positive tagged RBC scan  increases the diagnostic yield of angiography 2.4 times by  selecting out patients who are not actively bleeding at the  time of tagged RBC scan. It is important that following a pos-  itive tagged RBC scan, urgent angiography be performed  within 1 hour if feasible. Delaying angiography may lead to  increased negative results, as lower GI bleeding is often episodic  and intermittent.   7. Angiography — A more rapid rate of bleeding of at least  0.5-1.5 mL/min is necessary for detection during angiography  (Figure 31-3) compared with tagged RBC scan. Patients who  are massively bleeding and hemodynamically unstable should  be resuscitated and proceed directly to angiography without    A Figure 31-2. A. Baseline tagged red blood cell scan.  B. Tagged red blood cell scan with active bleeding from  the right colon.   tagged RBC scan. The diagnostic yield of angiography ranges  from 27% to 77% with a mean of 47%; sensitivity and speci-  ficity are 47% and 100%, respectively. Complications of  angiography occur in 10-20% of patients and include renal  failure, hematoma, ischemia, and infarction. Provocative test-  ing using anticoagulants (eg, intravenous heparin and intra-  arterial tissue plasminogen activator) and vasodilators  (intra-arterial tolazoline) can increase diagnostic yield with-  out significant complications. Further studies are necessary to  optimize the efficacy and prove the safety of this approach.   Anderson CM. GI magnetic resonance angiography. Gastrointest  Endosc. 2002;55:S42-S48. [PMID: 12024121]    A Figure 31-3. Angiography with active bleeding from  the right colon.   advances in the technology of computed tomography (CT)  may lead to a future role for CT scan in lower GI bleeding.  Multidetector-row CT (MDCT) incorporates several  improvements, which allow enhanced delineation of mesen-  teric vessels: faster scanning time, more accurate acquisition  of images in arterial and venous phases, and improved three-  dimensional display. Patients do not ingest any water or con-  trast material orally and, after an initial unenhanced CT  scan, images are obtained during the arterial phase to iden-  tify extravasation of contrast into the bowel lumen.  Preliminary studies using angiography as the gold standard  demonstrate sensitivity and specificity of 90.9% and 99% for  detecting acute GI bleeding with MDCT and 100% accuracy  in localization of bleeding site. Single-detector CT scan can  detect bleeding rates of 0.3 mL/min, and MDCT may  approach the detection ability of tagged RBC scans.   Yoon W, Jeong YY, Kim JK. Acute gastrointestinal bleeding:  contrast-enhanced MDCT. Abdom Imaging. 2006;31:1-8. [PMID:  16333701]   9. Magnetic resonance angiography— Magnetic reso-  nance angiography is not typically used in acute lower GI  bleeding because it lacks the resolution to detect hemorrhage  from small blood vessels. A new blood pool contrast agent  may help localize the bleeding to a bowel segment. This con-  trast agent remains in the intravascular space for many  hours, and subsequent imaging could identify extravascular  contrast.   Data from Longstreth GF. Epidemiology and outcome of patients  hospitalized with acute lower gastrointestinal hemorrhage: a  population-based study. Am J Gastroenterol. 1997;92:419; Strate LL,  Orav EJ, Syngal S. Early predictors of severity in acute lower intestinal  tract bleeding. Arch Intern Med. 2003;1 63:838; and Zuccaro G Jr.  Management of the adult patient with acute lower gastrointestinal  bleeding. American College of Gastroenterology Practice Parameters  Committee. Am J Gastroenterol. 1998;93:1202.   The differential diagnosis of acute lower GI bleeding is  broad, although the vast majority of such bleeding is due to  diverticulosis, ischemic colitis, AVMs, neoplasia, and hemor-  rhoids (Table 31-1). Following evaluation, the cause of lower  GI bleeding remains uncertain in about 12% of cases.   Diverticulosis is the most common cause of lower GI bleed-  ing. It is more prevalent in developed countries and older  patients. Although 5-10% of people under the age of 40 have  diverticulosis, nearly two thirds of people older than 80 years  are affected. A detailed discussion of diverticular disease  appears in Chapter 21.   About 75-80% of people with diverticulosis are asympto-  matic; however, 3-20% experience diverticular bleeding.  Massive bleeding occurs in 3-5% of patients. Risk factors for  diverticular bleeding include the use of NSAIDs, advanced  age, and right colon location. Bleeding occurs at the site of  penetration of the vasa recta, with the vasa recta stretched  over the dome of the diverticula, resulting in segmental wall  weakness and predisposing to rupture. Abrupt painless  bleeding characterizes diverticular bleeding; mild lower  abdominal cramping may occur before passage of bright red  or maroon blood due to the cathartic nature of blood in the   intestines. Melena is unusual for arterial bleeding from diver-  ticulosis. Guaiac-positive stool alone and iron deficiency  anemia are not consistent with diverticular bleeding.   Over 75% of diverticula are located in the left colon.  Bleeding diverticula detected during angiography usually  occur in the right colon whereas 60% of bleeding diverticula  diagnosed at colonoscopy are located in the left colon. The  vast majority of diverticular bleeding stops spontaneously.  Colonoscopy is often the initial diagnostic procedure per-  formed to rule out other lesions and determine the bleeding  site, which is found in less than 22% of cases. Urgent  colonoscopy increases the chance of detecting a bleeding site.  If bleeding without a clear source persists or recurs, tagged  RBC scan can be performed followed by immediate angiog-  raphy, if positive, or by possible repeat colonoscopy, if nega-  tive. An algorithm for management of diverticular bleeding  is included in Chapter 21 (see Figure 21-4).   There are multiple endoscopic options if a bleeding diver-  ticulum is identified, including epinephrine injection, bipo-  lar coagulation, combination therapy, and mechanical  therapy. Epinephrine injection in four quadrants can control  bleeding or close the mouth of the diverticulum by tampon-  ade. The majority of bleeding vessels or nonbleeding visible  vessels identified during endoscopy are located on the neck  of the diverticulum. Thermal therapy should be avoided at  the dome of the diverticulum. Bipolar coagulation should be  performed with 10-15 watts of power, moderate pressure,  and short 1 -second pulses. Clots can be removed using the  cold guillotine technique (similar to the technique for upper  GI bleeding) and any underlying lesion should be treated  appropriately. A small study suggested that endoscopic  treatment is successful long term: none of the patients  treated endoscopically had recurrent bleeding over a median  of 30 months compared with 53% of patients treated  medically who rebled. There are case reports of successful  treatment of bleeding diverticula using mechanical therapy  with endoclips or endoscopic band ligation (Plates 64 and 65).   Angiography offers another treatment option. Continuous,  selective intra-arterial vasopressin infusion stops bleeding  in about 90% of cases, with up to 50% rebleeding after  discontinuing the infusion. Despite this temporary effect  in many patients, vasopressin infusion can be helpful to  allow bowel preparation before a semi-elective definitive  surgical procedure. However, it can cause abdominal pain  and should be avoided in patients with known coronary  artery disease.   Superselective embolization with microcatheters uses  2.5-3 French microcatheters, which are advanced through  conventional 5 French catheters to access smaller, more  distal vessels. Various embolic agents are used, including  gel foam, polyvinyl alcohol, and microcoils. Treatment  success ranges from 44% to 91%, with rates of rebleeding  from 6% to 34%. Recurrent bleeding 1 month after  embolization occurs in less than 15% of patients with  diverticular hemorrhage compared with over 40% with  nondiverticular causes such as AVM. Major ischemic   complications requiring surgery appear to occur in less than  6% of cases.   Persistent massive hemorrhage, transfusion requirement  over 4 units in 24 hours, and recurrent diverticular bleeding  are potential indications for surgery, which is needed in  18-25% of people requiring transfusions. Mortality rate is  still relatively high at 10% even with directed segmental  resection, and the rebleeding rate is 14% at 1-year follow-up.  Blind segmental resection should be avoided due to rebleed-  ing rates as high as 33% and mortality rates ranging from  20% to 57%. Rebleeding rates as low as 0% but mortality  rates ranging from 0% to 33% have been reported for blind  subtotal colectomy. Therefore, aggressive efforts should be  made to localize a bleeding site preoperatively.   Repeat diverticular bleeding occurs in 25-35% of  patients, and 50% of these people experience a third episode  of diverticular hemorrhage. NSAID use is a potential risk  factor; however, whether avoiding NSAIDs reduces the  chance of rebleeding is unclear.   progress toward the central vessel (Plates 66 and 67). Argon  plasma coagulation has become a popular noncontact method,  with a reported 77-83% success rate. Nonbleeding AVMs  without evidence of GI bleeding should not be treated.  However, if there is a history of guaiac-positive stool or iron  deficiency anemia, AVMs should be treated even if not  actively bleeding.   There is a potential role for medical treatment of AVMs.  A small study of patients who failed previous endoscopic or  angiographic treatment and were administered octreotide  (100 meg subcutaneously three times daily for 6 months)  found 14 of 17 patients stopped bleeding, and 4 patients  required ongoing octreotide treatment. Long-term estrogen-  progesterone treatment for 1 year did not decrease rebleeding  from AVMs in a randomized trial. Another study that sug-  gested benefit from hormone therapy had a study population  containing 50% of patients with Osler-Weber-Rendu disease.  Therefore, this subset of patients may experience decreased  bleeding from AVMs with hormone therapy.   Bloomfeld RS, Rockey DC, Shetzline MA. Endoscopic therapy of  acute diverticular hemorrhage. Am J Gastroenterol. 2001;96:  2367-2372. [PMID: 11513176]   Funaki B. Superselective embolization of lower gastrointestinal  hemorrhage: a new paradigm. Abdom Imaging. 2004;29:  434-438. [PMID: 15024510]   lensen DM, Machicado GA, Jutabha R, et al. Urgent colonoscopy  for the diagnosis and treatment of severe diverticular hemor-  rhage. N Engl J Med. 2000;342:78-82. [PMID: 10631275]   AVMs are the reported source of lower GI bleeding in 3-40%  of patients. They are usually congenital and occur in 1-2% of  colon autopsy specimens. AVMs are ectatic mucosal and sub-  mucosal blood vessels that have a direct communication  between the arteries and veins without intervening capillar-  ies. Over half are located in the right colon, and 47% of  patients experience painless hematochezia similar to diver-  ticular hemorrhage. Patients with bleeding AVMs can pres-  ent with chronic, intermittent bleeding. Risk factors for  bleeding include advanced age (older than 60 years), right-  sided location, and possibly certain conditions (aortic steno-  sis and chronic renal failure).   Angiography is considered the gold standard in diagnos-  ing AVMs. Findings include ectatic slowly emptying veins,  vascular tufts, or early filling veins. The diagnostic sensitivity  of colonoscopy is 80-90% with the characteristic finding of  a 2- to 10-mm, red, fernlike flat lesion with ectatic vessels  radiating from a central vessel. Poor bowel preparation and  use of meperidine, which transiently decreases mucosal  blood flow, could potentially hinder the identification of  AVMs. Use of naloxone may enhance colonic vasculature and  AVM identification.   Bleeding AVMs discovered during colonoscopy can be  treated with a variety of thermal therapies. Contact electro-  cautery should begin with the outer feeder vessels and   Junquera F, Feu F, Papo M, et al. A multicenter, randomized, clin-  ical trial of hormonal therapy in the prevention of rebleeding  from gastrointestinal angiodysplasia. Gastroenterology. 2001;121:  1073-1079. [PMID: 11677198]   Kwan V, Bourke MJ, Williams SJ, et al. Argon plasma coagula-  tion in the management of symptomatic gastrointestinal vas-  cular lesions: experience in 100 consecutive patients with  long-term follow-up. Am /Gasfroentero/. 2006;101:58-63. [PMID:  16405534]   Nardone G, Rocco A, Balzano T, et al. The efficacy of octreotide  therapy in chronic bleeding due to vascular abnormalities of the  gastrointestinal tract. Aliment Pharmacol Ther. 1999; 13:  1429-1436. [PMID: 10571598]   The diagnosis of colonic ischemia is established by a combina-  tion of clinical setting, physical diagnosis, and diagnostic stud-  ies. The differential diagnosis includes infectious colitis,  inflammatory bowel disease, diverticulitis, radiation enteritis,  and colon cancer. In hospitalized patients Clostridium difficile  infection must be excluded. Although there are no specific  blood tests for colonic ischemia, elevations may be noted in the  white blood cell count and in amylase, creatine phosphokinase,  and serum lactate levels. Most plain radiographs in colonic  ischemia have nonspecific findings, although thumbprinting  due to submucosal edema and pneumatosis may be seen typi-  cally in patients with more advanced disease.   Diagnostic testing with CT scans may reveal segmental  thickening of the involved colon. Endoscopic evaluation with  sigmoidoscopy or colonoscopy may be used to confirm the  diagnosis in patients whose diagnosis is unclear and who do  not have signs of peritonitis or perforation. Care must be  taken to avoid overdistention with air during the examina-  tion to prevent worsening of ischemic damage. Endoscopic  findings typically occur in a segmental distribution and vary  depending on the degree of damage, ranging from pale   mucosa with petechial bleeding to cyanotic, necrotic bowel.  Angiography is usually not indicated in colonic ischemia as  the blood flow to the colon returns to normal by the time of  clinical presentation.   Neoplasms of the colon may present with GI bleeding. In  patients over the age of 50 years, rectal bleeding is due to a  neoplasm in about 10% of cases; however, neoplasms are an  uncommon source of rectal bleeding in persons younger  than age 50. Although most bleeding from colonic neo-  plasms tends to be low grade and occult, bleeding may be  brisk and overt at times. Bleeding occurs due to erosion or  ulceration of the lesion. Distal lesions (left side and rectum)  are more likely to present with bright red blood per rectum  whereas more proximal lesions tend to present with maroon  stool, melena, or occult blood.   The diagnosis of a neoplasm as the source of lower GI  bleeding is typically done by colonoscopy, with biopsies per-  formed to confirm the diagnosis. Larger neoplasms may be  detected on CT scans. The therapeutic options for those  patients with bleeding neoplasms are limited. Standard  endoscopic therapies have marginal effectiveness. The use of  fibrin glue has been reported to be effective in small studies  (Plates 68 and 69). The treatment for most patients with  bleeding colonic neoplasms is surgical resection.   Hemorrhoids and other anorectal disorders (solitary rectal  ulcers and anal fissures) are an important source of lower GI  bleeding. Hemorrhoids are dilated submucosal vessels in the  anus, which are considered internal if above the dentate line  (Plate 70) and external if below. Hemorrhoids are extremely  common and usually asymptomatic but can present with  pruritus, thrombosis, or hematochezia. Bleeding from hem-  orrhoids occurs when there is rupture of a blood vessel.   The clinical manifestations of bleeding hemorrhoids  include painless hematochezia with the stool being coated  with bright red blood. Further bleeding may occur, with  blood dripping into the toilet bowl or staining underwear.  Although bleeding from hemorrhoids is usually low grade,  high volume or massive bleeding may occur rarely. Severe  bleeding from hemorrhoids may occur in patients with a  coagulopathy. Acute treatment for most patients with bleed-  ing hemorrhoids is not needed as most episodes are mild and  resolve spontaneously. Topical medical treatments help  decrease inflammation, and surgery is rarely needed for  those with persistent or massive bleeding.   Postpolypectomy bleeding occurs after 1-6% of polypec-  tomies and is the leading major complication following  colonoscopy with polypectomy. Acute hemorrhage occurring   at the time of polypectomy accounts for less than 50% of  cases. Therapeutic options include resnaring the stalk of the  polypectomy site to apply pressure, injection therapy with  epinephrine, contact or noncontact thermal treatment with  bipolar coagulation or argon plasma coagulation, and endo-  clip application (Plates 71 and 72). Although bleeding usu-  ally occurs within 7 days, delayed bleeding can occur within  20 days following polypectomy when the eschar falls off the  site. Polypectomy bleeding is usually self-limited and over  70% of cases resolve with supportive care.   Risk factors for postpolypectomy bleeding include  removal of large polyps, platelet dysfunction, and coagulopa-  thy. Multiple studies have tried to identify techniques to  reduce the risk of postpolypectomy bleeding. Only submu-  cosal injection of saline has proven useful in large polyps,  and it is unclear whether the type of electrical current  (blended vs cutting), placement of prophylactic endoclips, or  use of an endoloop decreases the risk of bleeding.   Sorbi D, Norton I, Conio M, et al. Postpolypectomy lower GI  bleeding: descriptive analysis. Gastrointest Endosc. 2000;51:  690-696. [PMID: 10840301]   While it is well known that NSAIDs are among the most  common causes of peptic ulcer disease, it is less appreciated  that NSAIDs can damage the large intestine and cause lower  GI bleeding. Characteristic endoscopic findings include sin-  gle or multiple well-defined ulcers with normal intervening  mucosa that are classically found in the terminal ileum and  proximal colon and a single or multiple diaphragm-like  strictures with normal intervening mucosa. Only 21% of  patients with colonic ulcers have simultaneous gastric ulcers.  Clinical presentation is variable and includes guaiac-positive  stool, iron deficiency anemia, hematochezia, crampy abdom-  inal pain, weight loss, and change in bowel habits. NSAID-  induced colonic ulcers may also be an incidental finding in  asymptomatic patients. Because pathology from NSAID-  induced colonic ulcers is nonspecific, diagnosis is made after  excluding other potential causes of colonic ulcers including  infectious, ischemic, and inflammatory. Symptomatic  patients usually respond within a few days after cessation of  NSAIDs. If NSAIDs cannot be discontinued, concomitant  therapy with misoprostol, sulfasalazine, or metronidazole  may protect the mucosa from damage and help heal ulcers.   Kurahara K, Matsumoto T, Iida M, et al. Clinical and endoscopic  features of nonsteroidal anti-inflammatory drug-induced colonic  ulcerations. Am J Gastroenterol. 2001;96:473-480. [PMID:  11232693]   Pelvic radiation can cause both acute and chronic radiation  proctitis. Acute damage presents within 3 months of radiation   therapy with diarrhea, tenesmus, and, rarely, bleeding.  Chronic radiation proctitis typically occurs 9-14 months fol-  lowing radiation in up to 20% of patients but can occur years  later (Plate 73). Bleeding is a prominent symptom caused by  mucosal atrophy and fibrosis, which result in chronic  mucosal ischemia.   There are no standardized recommendations for treat-  ment of bleeding from radiation proctitis. Endoscopic ther-  apy appears superior to medical treatment in reducing severe  bleeding, with nearly 75% success following endoscopic  treatment compared with 33% for medical therapy. Multiple  oral and topical therapies have been investigated (mainly in  small clinical trials or case series), and a few may be effective,  including sucralfate enema, short-chain fatty acid enema,  and topical formalin therapy.   Endoscopic management with heater probe and bipolar  coagulation has proved effective in controlling bleeding dur-  ing a mean of four treatment sessions performed every 4-6  weeks. Argon plasma coagulation has received more atten-  tion recently, with 85-100% success in reducing or stopping  bleeding over a mean of two to three treatments every 1-2  months. All visible telangiectasias are obliterated at each ses-  sion, while rectal ulcers resulting from previous treatments  are avoided. Short-term complications occur in 7% of  patients and include rectal pain and fever. Rare major com-  plications include rectovaginal fistula, anal or rectal stricture,   and perforation, presumed secondary to accumulation of  combustible gas. A full bowel preparation is safest, as there  have been rare reports of explosions of gas during argon  plasma coagulation when an enema preparation was used.  During long-term follow-up over 1-5 years, recurrent bleed-  ing occurred in 0-8% of patients.   Hyperbaric oxygen may represent another therapeutic  option and is believed to promote angiogenesis and collagen  formation, leading to reepithelialization. The few recent case  series selected patients who had failed previous medical or  endoscopic therapy for hyperbaric oxygen treatment, and  report a 75-100% decrease or cessation of bleeding. The  treatment regimen is rigorous; for example, one study placed  patients in a hyperbaric chamber at a pressure of 2.4 atmos-  pheres with 100% oxygen for 90 minutes 5-7 days per week  for an average of 36 sessions. Hyperbaric oxygen therapy may  be considered before proceeding to surgery in patients who  are refractory to standard medical and endoscopic treatment.   Denton AS, Andreyev HJ, Forbes A, et al. Systematic review for  non-surgical interventions for the management of late radia-  tion proctitis. Br J Cancer. 2002;87:134-143. [PMID: 12107832]   Jensen DM, Machicado GA, Cheng S, et al. A randomized prospec-  tive study of endoscopic bipolar electrocoagulation and heater  probe treatment of chronic rectal bleeding from radiation telang-  iectasia. Gastrointest Endosc. 1997;45:20-25. [PMID: 9013165]   Since the introduction of endoscopic retrograde cholan-  giopancreatoscopy (ERCP) in 1968 and endoscopic sphinc-  terotomy in 1974, the management of various biliary and  pancreatic illnesses has evolved from surgical to endoscopic  methods with substantial improvements in patient outcomes.  Additionally, development of custom accessories has improved  procedural efficiency and success rates; these include balloons  and baskets for stone extraction, lithotripsy devices, stents,  drains, and duodenoscope-assisted cholangiopancreatoscopy.  In expert centers success rates for many endoscopic interven-  tions exceed 90%.   Several acute biliary and pancreatic conditions are amenable  to endoscopic diagnosis and therapy. ERCP has been shown to  have better outcomes than surgery when dealing with most duc-  tal obstructions and leaks. Additionally, ERCP may have a lim-  ited role in the diagnosis of bleeding conditions and the  treatment of associated complications. This chapter details  endoscopic treatment options for these conditions.   ► Diagnosis of acute biliary obstruction with cholangitis  relies on clinical findings, blood counts, blood chemistries,  biochemical profile, and imaging studies such as MRI with  MRCR   ► Endoscopic biliary drainage is the standard of care, with  emergent drainage for patients not responding to antibi-  otics and supportive measures or showing signs of clini-  cal deterioration (ie, hypotension, altered mental states,  and signs of continuing infection such as persistent  fever).   Acute cholangitis is characterized by biliary stasis and infec-  tion of the bile ducts. In 1877, Charcot defined the clinical  triad of fever, right upper quadrant pain, and jaundice that is  present in up to 70% of patients with acute cholangitis. The  spectrum of clinical presentation ranges from mild pain and  low-grade fever, to a fulminate course with hypotensive  sepsis. In 1959, the Charcot triad was modified to include  hypotension and mental status changes, subsequently known  as the Reynolds pentad. Clinical presentation is, however, not  useful in differentiating between suppurative and nonsuppu-  rative cholangitis, which can only be determined at the time  of therapy. In the latter form, bacteria are still present in bile,  but without the formation of pus. Suppurative cholangitis  has a more acute course and is less likely to respond to antibi-  otics; however, either form is potentially life threatening, and  when acute cholangitis is suspected urgent diagnosis and  treatment are critical.   Bile duct obstruction and infection are requisite for the  development of cholangitis. Over 90% of cases are attributed  to common bile duct stones. Other causes of obstruction  include iatrogenic biliary instrumentation and endoprosthe-  ses. Less common causes include malignant biliary obstruc-  tion, benign bile duct strictures, ampullary adenomas,  periductal adenopathy, choledochal cysts, parasites, and  blood clots.   Following bile duct obstruction and biliary stasis, infec-  tion may occur either by direct ascent from the bowel, or via  the lymphatics or portal vein. The latter assumes transloca-  tion of bacteria from the bowel into the portal circulation  and subsequent clearance of bacteria by the reticuloendothe-  lial system with excretion into bile. Although the origin of  infecting organisms is questionable, the most common  organisms are enteric and often polymicrobial. Escherichia  coli, Klebsiella, Enterobacter, and Proteus are most common,  while enterococcus and anaerobes are less frequent. Positive   bile cultures are seen in approximately one third of patients  with bacteremia.   Initial studies include blood cultures, a complete blood  count, and a full biochemical profile. Several noninvasive  imaging studies are available to diagnose biliary obstruction.  Abdominal ultrasound is sensitive for intrahepatic biliary  dilation; however, it is poor at identifying choledocholithia-  sis, with a sensitivity of less than 30%. Additionally, up to one  third of patients with choledocholithiasis do not have evi-  dence of biliary dilation, and cholangitis can occur before the  bile duct becomes dilated. Nuclear hepatobiliary imaging can  detect biliary obstruction earlier than ultrasound, with  higher sensitivity. However, magnetic resonance imaging  (MRI) with magnetic resonance cholangiopancreatography  (MRCP) is most accurate, with a sensitivity of 97%. ERCP is  no longer viewed as an initial diagnostic option and is  reserved for therapy.   Supportive care with restoration of fluid and electrolyte  balance and broad-spectrum antibiotics, including gram-  negative coverage, should be promptly instituted. Additionally,  anaerobic coverage should be included if there is a history of  prior instrumentation. Up to 85% of patients will respond to  these conservative measures allowing for semi-elective bil-  iary drainage within 48 hours. Emergent drainage is indi-  cated in those patients who do not respond to conservative  measures or when clinical deterioration occurs, particularly  with the development of hypotension or alteration of mental  status.   Endoscopic biliary drainage is the standard of care for most  causes of cholangitis. Definitive therapy typically involves  endoscopic sphincterotomy with removal of stones or other  obstructions. This has proven to be safer than surgical  options. Complete clearance of gallstones is possible in up to  90% of cases on the initial procedure, with morbidity and  mortality rates of 6% and near 0%, respectively.   It is important to avoid excess contrast injection as this  may precipitate cholangiovenous reflux and sepsis. Bile  should initially be aspirated to decompress the collecting sys-  tem, with samples sent for culture. The amount of contrast  injected should be half that of the bile removed.   If the patient is particularly ill or on anticoagulation, a  two-step approach may be preferred, consisting of ERCP  with stent placement alone followed by definitive endoscopic  sphincterotomy and stone removal when the patient is more  appropriately prepared. Additionally, when stones are too   large to remove, stents may be placed as a temporizing meas-  ure to ensure adequate drainage.   Mechanical or electrohydraulic lithotripsy may be neces-  sary for the complete removal of large common duct stones.  This should not be attempted during the initial treatment of  acute cholangitis.   When endoscopic drainage is not possible, percutaneous  transhepatic cholangiography (PTC) with drainage is indi-  cated. The degree of urgency similarly depends on the clini-  cal situation; however, emergent drainage should be  performed if partial injection occurred on attempted ERCP.  Since its introduction in 1974, PTC has evolved into numer-  ous therapeutic interventions including stenting, stone  removal, and in rare cases, even sphincterotomy. In the set-  ting of acute cholangitis, the initial procedure is limited to  drainage of the obstructed system. Definitive therapy with  stone removal can be achieved on subsequent procedures. A  wire may be placed through the transhepatic access and into  the duodenum allowing for endoscopic stone removal; this is  referred to as a rendezvous procedure. If endoscopic access to  the biliary system is not possible, a series of procedures is  typically required involving upsizing of drains and various  methods of lithotripsy.   Endoscopic ultrasound (EUS) may also be used to access  the biliary system and perform a rendezvous procedure.  Although only small case series have been reported, early  results are encouraging. In this procedure a 19-gauge EUS  needle is used for fine needle aspiration of the bile duct via a  transduodenal or transgastric route. Following drainage,  contrast may be injected and a wire passed. If the wire is  placed successfully through the papilla and into the duode-  num, it may be used to guide retrograde access and perform  a rendezvous procedure. If the wire is unable to pass from the  duct and into the duodenum, a stent may be placed ante-  grade into the bile duct as a temporary measure.   Gupta K, Maallery S, Hunter D, et al. Endoscopic ultrasound and  percutaneous access for endoscopic biliary and pancreatic  drainage after initially failed ERCP. Rev Gastroenterol Disord.  2007;7:22-37. [PMID: 17392627]   Mallery S, Matlock J, Freeman ML. EUS-guided rendezvous  drainage of obstructed biliary and pancreatic ducts: report of 6  cases. Gastrointest Endosc. 2004;59:100-107. [PMID: 14722561]   Shami VM, Kahaleh M. Endoscopic ultrasound (EUS)-guided  access and therapy of pancreatico-biliary disorders: EUS-guided  cholangio and pancreatic drainage. Gastointest Endosc Clin N  Am. 2007;27:581-593. [PMID: 17640584]   Surgical biliary drainage carries significant risk of morbidity  and a mortality rate as high as 40%. This is reserved for cases  in which endoscopic and percutaneous methods fail.   Lipsett PA, Pitt HA. Cholangitis. In: Blumgart LH, Fong Y (editors) .  Surgery of the Liver and Biliary Tract. Saunders, 2000;  917-926.   ► Diagnosis is guided by clinical picture and imaging stud-  ies (eg, MRCP).   ► Endoscopic drainage and papillotomy is reserved for  suspected ascending cholangitis, established choledo-  cholithiasis, or deteriorating course.   Gallstone pancreatitis is defined as acute pancreatitis with  clinical evidence of gallstones, in the absence of other causes  of pancreatitis. A clinical definition is needed for this condi-  tion as calculi are often challenging to demonstrate by  abdominal imaging during an acute attack, and frequently  pass spontaneously into the bowel. Although this is the most  common cause of acute pancreatitis, the exact pathogenesis  remains unclear, and in up to 30% of patients with acute  pancreatitis, the cause is considered idiopathic.   Several theories have been proposed to explain the develop-  ment of gallstone pancreatitis.   Gallstones can be identified in the stool of up to 94% of  patients with acute gallstone pancreatitis compared with  only 10% in patients with symptomatic cholelithiasis and no  history of pancreatitis. The bile reflux theory, first postu-  lated by Lancereaux in 1899, suggests that as stones pass  through the ampulla it is disrupted allowing reflux of bile,  and other duodenal contents, into the pancreatic duct with  subsequent intraglandular pancreatic enzyme activation.   The association of an impacted gallstone at the ampulla  of Vater and fatal acute pancreatitis, first described by Opie  in 1901, prompted the development of the common channel  theory. This theory suggests that impaction of a stone at the  ampulla of Vater leads to increased biliary pressures that  exceed pancreatic duct pressure, with secondary reflux of bile  into the pancreatic duct. This theory is weakened by the fact  that some patients do not have common channels, and by  studies that have shown sterile bile does not activate prote-  olytic enzymes. Nevertheless, infected bile is a potent stimu-  lator of these enzymes due to the presence of bacterial  amidase and the theory remains popular.   A third theory, the obstructive theory, suggests an  increase in pancreatic duct pressure alone due to complete  pancreatic duct obstruction is sufficient to trigger gallstone   pancreatitis. This has been suggested by various animal mod-  els and remains a favored concept.   The exact pathogenesis is likely multifactorial, and  depending on patient anatomy and stone size any one of  these theories may be more applicable.   Although the diagnosis of acute gallstone pancreatitis is a  clinical one, there are no signs or symptoms that are specific  for the condition. A thorough history excluding other poten-  tial causes of pancreatitis is essential. Alcohol, lipid levels,  infectious agents, and medications should be considered.   Once other etiologies have been excluded, the likelihood of  gallstone pancreatitis must be determined. Several biochem-  ical parameters have been evaluated with conflicting results.  Various studies have shown aspartate aminotransferase  (AST), bilirubin, alkaline phosphatase, or y-glutamyl transpep-  tidase (GGTP) to be most sensitive at predicting gallstone  pancreatitis; however, there is no consensus and none of these  parameters is specific.   Several abdominal imaging modalities are available and some  are more useful than others at helping make the diagnosis.   Abdominal ultrasound is good at identifying gallstones,  with 92% accuracy, and has the advantages of being widely  available, inexpensive, and noninvasive. However, as 10% of  the adult population have gallstones, this is not adequate for  the diagnosis of gallstone pancreatitis. Ultrasonography has  a sensitivity of between 55% and 91% for identifying bile  duct dilation, which is associated with a higher prevalence of  choledocholithiasis; however, this is highly operator depen-  dant and is not sensitive at detecting common duct stones.   CT is good at identifying cholelithiasis and can be used to  measure common bile duct diameter. Additionally, helical  CT cholangiography is an evolving technique that has sensi-  tivities as high as 95% in diagnosing choledocholithiasis;  however, the contrast agents required cause significant nau-  sea, and the technique is not highly utilized.   MRCP is an accurate and noninvasive modality, with a  sensitivity and specificity for detecting choledocholithiasis of  81-100% and 92-100%, respectively. Although MRCP is  expensive and may miss stones smaller than 5 mm, the tech-  nique is comparable to diagnostic ERCP and intraoperative  cholangiography and has emerged as the noninvasive diag-  nostic modality of choice.   EUS also has sensitivity and specificity of 88-97% and  96-100%, respectively; however, the technique is invasive   and requires sedation. Thus, the role of EUS is not well estab-  lished in most centers where MRCP is available.   ERCP was historically the diagnostic procedure of choice  with accuracy similar to MRCP; however, it is associated with  complication rates as high as 15% that include cholangitis,  pancreatitis, perforation, and bleeding. With improved accu-  racy and increased availability of less invasive modalities, ERCP  is no longer considered to be a first-line diagnostic procedure.   The management of acute gallstone pancreatitis has been  controversial. Supportive care with aggressive intravenous  hydration, nothing by mouth, and pain control is similar to  the management of pancreatitis due to other etiologies; how-  ever, timing and method of common bile duct exploration  for possible gallstone removal have been the focus of many  studies. It is clear that ERCP is favored over surgery due to  significantly better patient outcomes, with lower morbidity  and mortality (Figure 32-1). The exact timing of ERCP has  been more difficult to establish and depends on severity of  illness. What appears to be consistent is that in patients with  biliary pancreatitis and associated cholangitis, early drainage  is indicated, typically within 48 hours of onset and after ini-  tial stabilization. Additionally, patients with clinical deterio-  ration, as indicated by fever, increasing pain, and confusion,  are likely to benefit from urgent ERCP. In patients without  obstructive jaundice, early ERCP does not appear to be ben-  eficial. Also, in patients with a mild course of biliary pancre-  atitis, up to 80% will have already passed the culprit stone  and urgent ERCP is not recommended.   Although endoscopic sphincterotomy has been shown to  be protective regarding future episodes, cholecystectomy is  the standard of care. More than 25% of patients who do not  undergo cholecystectomy will have a recurrent episode, or  related biliary complication, in the following 6 weeks. Early  cholecystectomy is safe, and the preferred timing is upon  resolution of pancreatitis and prior to hospital discharge.   Acosta JM, Katkhouda N, Debian KA. Early ductal decompression  versus conservative management for gallstone pancreatitis with  ampullary obstruction. Ann Surg. 2006;243:33-40. [PMID:  16371734]   Freitas ML, Bell RL, Duffy AJ. Choledocholithiasis: evolving stan-  dards for diagnosis and management. World } Gastroenterol.  2006;12:3162-3167. [PMID: 16718834]   Hernandez V, Pascual I, Almela P, et al. Recurrence of acute gall-  stone pancreatitis and relationship with cholecystectomy or  endoscopic sphincterotomy. Am J Gastroenterol. 2004;99:  2417-2423. [PMID: 15571590]   Bile duct leaks, transection, and occlusion from ligature  or strictures occur most often after cholecystectomy.   Diagnosis can be established by imaging, including  ultrasound to identify fluid accumulations and HIDA  scan to detect occlusion or active leakage.   A Figure 32-1. A: Common bile duct stones in a patient with cholangitis. B: Stent placement adjacent to stones for  temporary drainage.   Types of bile duct injuries include leaks, transection, occlu-  sion (ligation or stricture), or a combination. The majority of  bile duct injuries are iatrogenic, most commonly following  laparoscopic cholecystectomy, with an incidence of 0.3-2%.  Common reasons for injury include aberrant anatomy, inad-  equate exposure, and otherwise difficult cases. Additional  causes of bile duct injury include other biliary surgery, liver  biopsy, penetrating or blunt abdominal trauma, and, rarely,  spontaneous perforation.   Patients usually present with abdominal pain that may be  diffused or localized. Nausea, anorexia, and abdominal disten-  tion due to ileus may also be seen. Clinically apparent ascites  and bile peritonitis are less common. Fever is often absent,  and laboratory evaluation typically reveals leukocytosis and  nonspecific liver function test abnormalities. Initial imaging  studies should involve abdominal ultrasound to assess for  fluid collections or abnormalities in the biliary tree such as  focal dilation, and radionuclide biliary scintigraphy to assess  for ongoing leakage. Technetium-99m-labeled hepato-  iminodiacetic acid derivative (HIDA) scanning is most accu-  rate, approaching 100%.    A Figure 32-2. Type A bile duct injury with extravasation  of contrast from the cystic duct.   Bile duct injuries were historically managed surgically, but  with significant morbidity and mortality. Endoscopic inter-  vention has replaced surgery in the majority of cases. The  flow of bile is pressure dependent, and it will follow the path  of least resistance. The objective of endoscopic therapy is to  make the path to the duodenum that of lowest resistance.  This requires stenting the sphincter of Oddi or sphinctero-  tomy. The procedure reduces the leakage of bile and allows  healing of the defect. Additionally, drainage of large fluid col-  lections either surgically or percutaneously is important for  prompt resolution of pain and prevention of infection.   The Bergman classification system is useful for grading  severity and prognosticating response to therapy. Type A  injuries are leaks from the cystic duct or the ducts of  Luschka. They are typically mild and have a near- 100%  response rate to ERCP with sphincterotomy or stent place-  ment (Figure 32-2). Type B lesions are high-grade leaks of  the common bile duct or main hepatic ducts with or without  stricturing. These may be amenable to endoscopic therapy,  with a 71% response rate to stenting. Bridging the defect  with the stent is important for resolution of type B defects.  Type C injuries consist of strictures without leak. Endoscopic  stent placement is now considered the standard of care for  these lesions. Costamagna and others have shown that upsiz-  ing and the use of multiple stents are critical to success.  Type D injuries are complete transections of the biliary system.  Diagnosis is best made by MRCP, and surgical hepaticoje-  junostomy is standard of care.   Aduna M, Larena JA, Martin D, et al. Bile duct leaks after laparo-  scopic cholecystectomy: value of contrast-enhanced MRCP.  Abdom Imaging. 2005;30:480-487. [PMID: 15688109]   Bridges A, Wilcox CM, Varadarajulu S. Endoscopic management  of traumatic bile leaks. Gastrointest Endosc. 2007;65:1081-1085.  [PMID: 17531646]   Costamagna G, Shah SK, Tringali A. Current management of post-  operative complications and benign biliary strictures. Gastrointest  Endosc Clin N Am. 2003;13:635-648. [PMID: 14986791]   Demetriades D, Salim A, Berne TV. Liver and bile duct injury. In:  Blugmart LH, Fong Y (editors). Surgery of the Liver and Biliary  Tract. Saunders, 2000;1035-1056.   Sandha GS, Bourke MI, Haber GB. Endoscopic therapy for bile  leak based on a new classification: results in 207 patients.  Gastrointest Endosc. 2004;60:567-574. [PMID: 15472680]   Shah IN. Endoscopic treatment of bile leaks: current standards and  recent innovations. Gastrointest Endosc. 2007;65:1069-1072.  [PMID: 17531644]   Zyromski NJ, Lillemoe KD. Current management of biliary leaks.  AdvSurg. 2006;40:21-46. [PMID: 17163093]   ► Pancreatic duct injuries may be iatrogenic or occur after  trauma or necrotizing pancreatitis.   ► Diagnosis may be suspected on computed tomographic  (CT) examination; however, MRCP is more specific.   The reported incidence of pancreatic injury is relatively low,  ranging from 0.2% to 6% following abdominal trauma.  However, the exact incidence is difficult to determine as  many patients with significant abdominal trauma never have  a laparotomy. Additionally, while the retroperitoneal location  affords some degree of protection to the gland, it can also  mask signs of significant injury.   The majority of affected patients are men under 40 years  of age. Penetrating trauma is responsible for over 70% of  traumatic injuries, with gunshot wounds and stabbings being  most common. Location of injury following penetrating  trauma is uniform among head and neck, body, and tail, with  less than 5% having an injury at multiple sites. Blunt trauma  is responsible for roughly 20% of injuries, with motor vehicle  accidents accounting for the majority of cases. The distribu-  tion is similar to that of penetrating trauma, with a slight pre-  ponderance for pancreatic body injuries due to compression  of the gland against the underlying spine at this location.  Iatrogenic causes are also notable and are more commonly  seen after pancreatic surgery, splenectomy, and ERCP.   Irrespective of the method of injury, the degree of injury  ranges from simple contusion to complete transection, and  typically results in local inflammation and fluid collections.  Additionally, associated injury is typical and varies depend-  ing on location of injury. Penetrating injuries to the head are  associated with major vascular injury in over 50% of cases.  Hollow viscus injuries are also common, occurring nearly in  40% of cases, with liver and spleen injuries in less than 20%  of cases. Overall mortality rates are between 10% and 31%,  with over 50% of deaths occurring within 48 hours of pres-  entation. Early mortality is typically due to associated  injuries, with less than 10% due to pancreatic injury.   The majority of patients managed nonoperatively will  develop a complication related to the pancreatic injury.  Pseudocysts occur in up to 75% of patients who survive  beyond 48 hours. Pancreatic fistula, pancreatitis, and peripan-  creatic abscess are also seen in roughly 30%. Although several  organ injury grading systems exist, the most important factor  in predicting clinical course and guiding therapy is the  integrity of the main pancreatic duct. This is a key element of  the diagnostic and management strategy.   Presenting symptoms vary from minimal pain or nausea to  frank peritonitis and hemodynamic instability. With severe pre-  sentations and penetrating wounds, imaging or laparotomy is  requisite and diagnosis is relatively straightforward. Diagnosis is  more challenging and often delayed with more subtie presenta-  tions or when other injuries serve as confounders.   followed by escalation over the subsequent 6-8 hours.  Physical examination is neither sensitive nor specific, and  even profound pancreatic injury may not be detected on ini-  tial examination. If pain is present, it is often out of propor-  tion to tenderness, and guarding is unusual.   No single laboratory test is adequate for early detection.  Serum amylase at time of admission is unreliable. Elevation  of serum amylase may be seen due to causes other than pan-  creatic trauma, including bowel injury, head trauma, alcohol  ingestion, profound hypotension, and salivary gland dam-  age. Early reports showed that only 8% of patients with ele-  vated serum amylase at the time of admission were found to  have pancreatic injury. In other series, only 14% of patients  with confirmed pancreatic gland injury had elevated amy-  lase at the time of admission. Additionally, isoenzymes were  not found to significantly improve diagnostic accuracy in  this setting. Serial amylase levels have, however, been found  to be useful in identifying pancreatic injury and guiding  management. As such, consistently normal serum amylase  levels have a negative predictive value of 93-98%, and per-  sistently abnormal or rising levels have sensitivity as high as  89%. Nevertheless, additional diagnostic modalities are typ-  ically needed.   Plain film radiographs and ultrasound are of limited value.  Loss of a distinct psoas margin or a halo of air surrounding  the kidney or psoas may suggest a retroperitoneal process,  however, this is nonspecific.   Abdominal CT scan is useful and may have findings spe-  cific to the diagnosis, including pancreatic transaction,  local hematoma, fluid separating the pancreas and splenic  vein, pancreatic enlargement, and increased attenuation of  the peripancreatic fat. In lieu of these, the admission CT  scan may hold signs suggestive of pancreatic injury, includ-  ing fluid in the lesser sac, thickening of the anterior renal  fascia, and associated injuries to local structures. CT rarely  shows ductal disruption. Sensitivity for detecting pancre-  atic injury by initial CT scan alone ranges from 60% to  80%, and repeat imaging may be helpful. Specificity is high,  ranging from 80% to 100%, although CT tends to underes-  timate degree of injury.   MRCP is particularly good at identifying pancreatic injury  and at characterizing type and degree of damage. Complete  visualization of normal size main ducts occurs in 97% of  patients. MRCP is excellent at clarifying ductal status and at  detailing parenchymal injury. ERCP is no longer considered a  first-line diagnostic option, due to its invasive nature.   Epigastric pain is the most common symptom following  blunt pancreatic trauma, with a pattern of initial abatement   Management is dependant on type and degree of injury.  Severe cases with associated injury to local structures usually   require emergent surgery. In such cases, the first priority is  control of hemorrhage followed by complete pancreatic eval-  uation. This requires significant tissue dissection and  mobilization. If parenchymal damage is seen, the integrity of  the main pancreatic duct must be assessed. Intraoperative  pancreatography may be performed in a variety of ways and  is effective at identifying ductal disruption. If ductal injury is  not present, typical management involves debridement and  wide external drainage. If ductal injury is identified, choice of  procedure depends on location of the injury. For distal  injuries, distal pancreatectomy is preferred. The surgical  approach to proximal ductal injuries is more varied and duo-  denal diversion may be necessary.   ERCP with pancreatic stent placement is a less invasive  alternative that should be considered when emergent sur-  gery is not required and when disruption is suggested on  imaging (Figure 32-3). Stent insertion is technically possi-  ble in 95% of cases, and outcomes appear to vary depend-  ing on the degree and location of disruption. Partial  disruptions in the body and head appear to have the high-  est response rates. Additionally, placement of a stent that  bridges the disruption is associated with better outcomes.  In a recent series of 43 patients described by Telford and  colleagues, multivariable analysis found that only bridging  stent position was correlated with successful outcome. In  this series bridging position was associated with a 92% suc-  cess rate, compared with a 44% success rate for stents that  merely cross the papilla. This is unlike the treatment of bile  duct leaks, where elimination of the biliary duodenal pres-  sure gradient by stenting across the papilla is sufficient.   Patients with complete duct disruptions do not fare as well  with endoscopic treatment; however, data are limited.  Pancreatic duct stent placement is relatively safe and com-  plications are well defined, including occlusion, migration,  stricture formation, infection, and duodenal erosion. In a  study by Varadarajulu and associates, a complication rate of  7.1% was seen for stent placement in the treatment of pan-  creatic duct disruption. Finally, pancreatic cyst drainage  may be required and may be performed via a transgastric  approach; however, fluid collection encapsulation takes sev-  eral weeks and must occur before it is safe to proceed with  endoscopic therapy.   Telford JJ> Farrell JJ, Saltzman JR, et al. Pancreatic stent placement  for duct disruption. Gastrointest Endosc. 2002;56:18-24. [PMID:  12085030]   Varadarajulu S, Noone TC, Tutuian R, et al. Predictors of outcome  in pancreatic duct disruption managed by endoscopic transpap-  illary stent placement. Gastrointest Endosc. 2005;61:568-575.  [PMID: 15812410]   Hemobilia and hemosuccus pancreaticus are rare and poten-  tially life-threatening conditions that are typically considered  late in the diagnostic evaluation of the bleeding patient. Each  condition has specific etiologies, requiring a unique approach  to diagnosis and management.   ▲ Figure 32-3. A: Pancreatic duct disruption at genu. B: Stent bridging disruption.   Hemobilia can occur after trauma, gallstones, tumor,  and vascular disorders and should be suspected in  patients with hemorrhage, biliary colic, and jaundice.   Diagnosis may be suggested by MRI with MRCP; how-  ever, selective arteriography is most accurate.   Hemobilia is an abnormal communication between blood  vessels and bile ducts either within the liver or the extrahep-  atic biliary tree. Clinical manifestations are due to blood loss  and biliary obstruction due to blood clots. Symptoms  include melena in 90% and hematemesis in 60%, biliary colic  in 70%, and jaundice in 60%. These three cardinal symptoms  when together are known as the Quincke triad. The spec-  trum of hemobilia spans massive exsanguination causing  shock and minor recurrent hemobilia resulting in chronic  anemia. Whenever biliary symptoms are present in the set-  ting of gastrointestinal bleeding or anemia, the diagnosis  should be considered.   Common causes of biliary- vascular fistula that lead to hemo-  bilia include blunt or penetrating trauma, iatrogenic etiolo-  gies, gallstones, tumors, and vascular disorders. Presentation  may be immediate or several months after the inciting event.  Additionally, parasites, choledochal cysts, portal hypertension,  and blood coagulation defects may be implicated. Of these,  iatrogenic causes are most common, with liver biopsy and  PTC the most frequent.   When a communication is formed by one of these mecha-  nisms, blood follows the path of least resistance and results in  hemobilia. Blood clots may form leading to symptoms of bil-  iary obstruction; however, bile has fibrinolytic properties  which serve to dissolve clots and clear the duct of fibrin  deposits. Clots are more likely to cause obstruction when they  are sheltered from the bile stream as is the case with T-tubes or  other biliary drains. Additionally, continuous hemorrhage with  clot formation may exceed the rate of fibrinolysis leading to  jaundice. The clots typically take the form of a luminal cast, and  the consistency may vary from soft to well defined and firm.   In rare cases where the pressure in the biliary tree is  greater than that of the vascular system, bilhemia occurs.  This is typically seen with distal bile duct obstruction and  low hepatic vein pressure. Symptoms include rapidly wors-  ening jaundice and elevated direct bilirubin without increase  in liver transaminases. Mortality rates in this rare condition  are as high as 50%. ERCP with drainage is the initial therapy  of choice, with surgery reserved for failed cases.   The diagnosis of hemobilia is typically easy to make if it is  considered in the differential. Upper endoscopy is essential to  rule out other sources of bleeding, and use of a side-viewing  duodenoscope for proper evaluation of the papilla is recom-  mended. Biliary imaging to evaluate for clotted blood is also  helpful. Ultrasonography has been used with success; how-  ever, MRI with MRCP is more sensitive and can show active  bleeding. Selective arteriography is most accurate for verify-  ing suspected hemobilia and specifically identifying the  source. Blood clots may be seen at ERCP; however, endo-  scopic therapy is not a long-term solution for hemostasis.   Treatment of hemobilia is dependant on the cause.  Transarterial embolization is the preferred method for hepatic  artery sources. Surgical ligature or resection is reserved for  embolization failure and hemorrhage from the gallbladder.  Liver resection may also be required for central liver rupture  and some tumors. At the present time, ERCP is not an  accepted therapeutic option for the treatment of hemobilia;  however, ERCP is the preferred alternative for restoring bil-  iary patentcy when the bile duct is obstructed with clots  (Figure 32-4). If bleeding stops spontaneously and treatment  of obstruction is required prior definitive bleeding therapy,  stent placement may be preferable to sphincterotomy and clot  extraction as the latter may lead to recurrent hemorrhage.    ▲ Figure 32-4. Blood clot in bile duct seen in a patient  with hemobilia.   Sandblom JP. Hemobilia and bilhemia. In: Blumgart LH, Fong Y  (editors). Surgery of the Liver and Biliary Tract. Saunders,  2000;1319-1342.   Hemosuccus pancreaticus, or hemorrhage from the pancre-  atic duct, is also rare and management depends on the under-  lying cause. Episodic bleeding and sharp epigastric pain are  the most common presenting symptoms. Anemia may be the  only sign in up to 10% of patients. Endoscopy to look for a   clot at the papilla is unreliable for diagnosis, and there is no  endoscopic therapeutic option. Common etiologies include  splenic artery aneurysm and chronic pancreatitis with  pseudoaneurysm. Other less common causes include malig-  nancy, acute pancreatitis, and pseudocyst. CT angiography is  the diagnostic modality of choice and can make the diagnosis  with high accuracy even in patients without active bleeding.  Data on MRCP are limited. Transarterial embolization is the  suggested treatment for primary splenic artery aneurysms,  whereas surgical arterial ligation and targeted pancreatec-  tomy is preferred in the setting of chronic pancreatitis.   The first human ingestion of a video capsule endoscope  occurred in 1999, and high-quality images from healthy  human volunteers were described in 2000. A commercially  available capsule was approved by the U.S. Food and Drug  Administration (FDA) for use in the United States in August  2001, having been approved for use in Europe earlier that  year. Between 2001 and 2007, more than a half million cap-  sule endoscopy studies were performed.   Currently, three video capsules are available for use in the  United States. Two are made by Given Imaging (Yoqneam,  Israel). One capsule, the PillCam SB2, images the small  bowel, while the other, the PillCam ES02, is designed for  imaging of the esophagus. Olympus Medical Systems  Corporation (Tokyo, Japan) has also released a small bowel  capsule, the EndoCapsule. The PillCam SB2 is composed of  a complementary metal oxide silicon (CMOS) chip camera,  a short focal length lens, six white light- emitting diode  (LED) illumination sources, two silver oxide batteries, and a  UHF band radio telemetry transmitter. Improvements in  the design of CMOS image sensors, application-specific  integrated circuits (ASICS) and white LED illumination,  along with the development of nontoxic batteries made  from silver oxide, allowed for the development of video cap-  sules. The PillCam SB2 and the PillCam ES02 capsules  are 11x26 mm and weigh 3.7 g. The images acquired by the  capsules have a field of view of 156 degrees, with eightfold  magnification and a 1-30 mm depth of view. The capsules  have a resolution of 0.1 mm that allows for the visualization  of individual villi. The small bowel capsule transmits two  256 x 256 pixel color images per second for a total of 8 hours  (-55,000 images), and the esophageal capsule transmits  nine images per second from each of its two lenses, for a  total of 18 images per second over the course of 20 minutes  (-22,000 images).   Arnott ID, Lo SK. The clinical utility of wireless capsule endoscopy.   DigDis Sci. 2004;49:893-901. [PMID: 15309874]  Cave DR. Technology insight: current status of video capsule   158-164. [PMID: 16511550]  Mishkin DS, Chuttani R, Croffie I, et al; Technology Assessment   The indications for small bowel and esophageal capsule  endoscopy are summarized in Table 33-1.   Obscure gastrointestinal bleeding refers to bleeding that per-  sists or recurs, without a source identified, after standard endo-  scopic evaluation with upper endoscopy and colonoscopy.  Obscure gastrointestinal hemorrhage can be subdivided into  obscure-overt and obscure-occult gastrointestinal bleeding.  Patients with obscure-overt gastrointestinal bleeding present  with visual evidence of bleeding, such as hematemesis, melena,  or hematochezia. Obscure-occult bleeding is manifested by  stool that is positive for occult blood, frequently with iron defi-  ciency anemia. Obscure bleeding accounts for approximately  5% of patients with gastrointestinal bleeding, and the source of  bleeding is frequently from the small bowel, between the liga-  ment of Treitz and the ileocecal valve.   Common causes of small bowel bleeding include vascular  ectasias, small bowel tumors, Crohn disease, and nonsteroidal  anti-inflammatory drug (NSAID) enteropathy (Table 33-2;  see also Plates 74 and 75). Vascular ectasias are the most com-  mon cause of obscure gastrointestinal bleeding, accounting  for 30-40% overall, and are responsible for the majority of   Evaluation of disease activity in established Crohn disease  Small bowel tumors  Diagnosis of celiac disease  Evaluation of refractory celiac disease  Polyp surveillance in polyposis syndromes  Surveillance for graft rejection after small bowel transplant  Detection of graft-versus-host disease  Indications for esophageal capsule endoscopy  Screening for esophageal varices  Screening for Barrett esophagus  Detection of esophagitis   obscure gastrointestinal bleeds in older patients. Patients  between the ages of 30 and 50 years are more likely to have a  small bowel tumor as the source of their bleeding. Finally,  young patients often are found to have an ulcerated Meckel  diverticulum as the source, although it should be remembered  that bleeding from a Meckel diverticulum may occur at any age.   Scleroderma with CREST syndrome (calcinosis cutis, Raynaud  phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias)   Metastatic cancer (eg, melanoma)  Crohn disease  NSAID enteropathy  Pelvic radiotherapy  Dieulafoy lesions  Aortoenteric fistulas  Meckel diverticula  Small bowel polyps  Small bowel varices  Hemosuccus pancreaticus  Stwngyloides stercoralis  Pseudoxanthoma elasticum   Leighton JA, Goldstein J, Hirota W, et al. Obscure gastrointestinal  bleeding. Gastrointest Endosc. 2003;58:650-655. [PMID:  14595294]   In patients with Crohn disease limited to the small bowel,  or in those with indeterminate colitis, arriving at a correct  diagnosis can be difficult. Capsule endoscopy can help  diagnose small bowel Crohn disease by providing  mucosal detail that is not available radiologically (Plate 76).  It also provides the opportunity to visualize areas of the  bowel not accessible by standard endoscopy. Because cap-  sule endoscopy has a resolution of 0.1 mm, it is able to  detect small, superficial defects, such as aphthoid ulcers. It  is important to note, however, that not all mucosal ulcera-  tions occur as a result of Crohn disease (Table 33-3). Ten to  23% of normal volunteers who are not taking NSAIDs will  have mucosal breaks and other lesions seen on capsule  endoscopy, and 50-71% of NSAID users will have evidence  of small bowel injury (red spots, erosions, and ulcerations).  Therefore, it is important to use capsule endoscopy findings  in combination with other clinical information to arrive at  the correct diagnosis.   Benign and malignant small bowel tumors are found in  approximately 6-8% of people and can be seen on capsule  endoscopy (Plate 77). Capsule endoscopy may be able to  detect tumors years before they would be detected by other  imaging modalities, potentially increasing the chance to  remove them while still localized.   Capsule endoscopy can also detect of small bowel polyps  in patients with hereditary polyposis syndromes. Peutz-  Jeghers syndrome and familial adenomatous polyposis  (FAP) are two of the hereditary polyposis syndromes that are  associated with small bowel polyps and malignancies.  Patients with Peutz-Jeghers syndrome form hamartomatous  polyps within the gastrointestinal tract, along with mucocu-  taneous pigmentation. The polyps have a predilection for the  small bowel and will develop in more than 90% of patients  (Plate 78). Complications from the polyps include gastroin-  testinal bleeding, anemia, intestinal obstruction, intussus-  ception, and development of cancer. Patients with  Peutz-Jeghers syndrome have a 13% lifetime risk of develop-  ing small bowel cancer, so surveillance of the small intestine  is recommended. Traditionally, patients have undergone  radiographic imaging with a small bowel series or entero-  clysis every 2 years, starting at age 10. This approach exposes  a patient to significant amounts of ionizing radiation. In  addition, radiologic evaluation with small bowel follow-  through, computed tomography (CT) enteroclysis, or mag-  netic resonance enteroclysis lacks sensitivity for detecting   Anisakiasis  Neoplastic  Adenocarcinoma  Carcinoid tumor  tymphoma  tymphosarcoma  Metastatic disease  Collagen vascular disease  Churg-Strauss syndrome  Dermatomyositis  Giant cell arteritis  Henoch-Schonlein purpura  tymphomatoid granulomatosis  Mixed connective tissue disease  Polyarteritis nodosum  Polymyositis   Rheumatoid arthritis vasculitis  Systemic lupus erythematosus  Takayasu arteritis  Thromboangiitis obliterans  Thrombotic thrombocytopenic purpura  Wegener granulomatosis  Trauma  Intussusception  Foreign body  Incarcerated hernia   Table 33-3. Differential diagnosis of small bowel  erosions and ulcerations, (continued)   small polyps. Push enteroscopy has also been employed, but  is only able to visualize a portion of the upper small bowel.  Capsule endoscopy on the other hand, is capable of detecting  small polyps throughout the small bowel.   Celiac disease affects up to 0.3-1% of Caucasians. Celiac dis-  ease has traditionally been diagnosed by detection of anti-  bodies (eg, antiendomysial and tissue transglutaminase  antibodies), followed by endoscopy with biopsies of the  small bowel to confirm the diagnosis. Capsule endoscopy has  been proposed as a possible alternative to endoscopy for the  diagnosis of celiac disease. Capsule endoscopy findings of  celiac disease include scalloping, a mosaic mucosal pattern,  loss of mucosal folds, visible vessels, and micronodularity  (Plates 79 and 80) . An advantage of capsule endoscopy is that  it allows for visualization of the entire small bowel, and  symptom severity in celiac disease is more closely related to  the length of small bowel involved and not to the severity of  the villous atrophy seen on biopsy.   Capsule endoscopy may have an even more important  role in the evaluation of refractory celiac disease. Celiac dis-  ease can be complicated by small bowel adenocarcinoma,  lymphoma (including enteropathy-associated T-cell lym-  phoma), and ulcerative jejunitis. In patients who fail to  respond to a gluten-free diet or who have a recurrence of  symptoms while on a gluten-free diet, further evaluation is  needed to differentiate between refractory celiac disease (ie,  celiac disease that does not respond to a gluten-free diet),  ongoing gluten ingestion (intentional or unintentional), and  a complication of celiac disease.   Capsule endoscopy has also been used to evaluate for evi-  dence of small bowel graft-versus-host disease in patients   following bone marrow transplantation, to look for evidence  of rejection following small intestinal transplantation, and to  evaluate for radiation enteritis. However, in the case of  suspected radiation enteritis, the risk for capsule retention is  increased. In addition, capsule endoscopy may detect small  intestinal varices or portal hypertensive enteropathy in  patients with portal hypertension.   The PillCam ES02 was designed to visualize the esopha-  gus and can be used to detect findings such as esophageal  varices, erosive esophagitis, and Barrett esophagus.   Capsule endoscopy is contraindicated in some patients.  Because cooperation is required, demented patients are not  good candidates for capsule endoscopy. Capsule endoscopy  is also contraindicated in patients with cardiac pacemakers  or defibrillators (due to concerns that the capsule could  interfere with the cardiac device) and in pregnant women  (due to a lack of data on the effects of capsule endoscopy in  pregnancy). Many centers, however, perform capsule  endoscopy in patients with pacemakers or defibrillators, and  studies have suggested that the capsules may not interfere  with the devices. In addition, the cardiac devices have not  been shown to disrupt the capsule study (with the exception  of one instance of images being lost as a capsule passed the  pulse generator of an abdominally implanted pacemaker).  Finally, there have been no reports of a cardiac device mal-  functioning due to a capsule study. Patients should be  instructed not to undergo magnetic resonance imaging until  passage of the capsule has been confirmed, which can be  done with a plain abdominal radiograph if the capsule was  not noted to pass naturally. Patients with gastrointestinal  tract obstructions, strictures, or fistulas (either suspected or  demonstrated on imaging studies) should not undergo cap-  sule endoscopy, because of an increased risk of capsule reten-  tion or obstruction.   In patients with swallowing disorders, such as achalasia,  esophageal strictures, esophageal diverticula, or gastropare-  sis, the capsule may need to be delivered using a special  delivery device to ensure that it enters and traverses the  small bowel during its recording time. The AdvanCE device  (US Endoscopy, Mentor, Ohio) is composed of a catheter  that is passed through the channel of a gastroscope. A cap  that holds the capsule is then screwed onto the end of the  catheter. The scope is then advanced blindly into the esoph-  agus (the cap obscures visualization). Once in the esopha-  gus, the catheter can be advanced slightly to allow for  limited visualization. The scope is then advanced to the  small bowel, where the capsule is deployed. A standard  upper endoscopy examination should be carried out before  using the device to detect any abnormalities that could  complicate capsule delivery. Alternative delivery methods  include placing the capsule in the stomach by inserting it  through an over-tube and then advancing it to the small  bowel using snares or nets.   1 . Patient preparation — Studies can be performed on both  inpatients and outpatients. For a small bowel study, a patient  fasts for 8-12 hours before the examination. Some centers  also have the patient consume only clear liquids for up to  24 hours prior to the examination. Data are conflicting,  but some studies suggest that preparing the small bowel with  2-4 L of a polyethylene glycol solution may improve visuali-  zation (oral phosphosoda should not be used, as it has been  shown to increase gastric emptying time). A consensus panel  at the 2005 International Conference on Capsule Endoscopy  (ICCE), however, did not recommend a bowel preparation  other than fasting prior to the study. In cases where there is  concern for slowed gastric transit, such as in diabetic  patients, a prokinetic agent such as metoclopramide or  erythromycin is given approximately 30-60 minutes prior to  the study. The ICCE consensus panel, however, did not rec-  ommend routine use of prokinetic agents. Some centers give  patients simethicone prior to the study in an attempt to  decrease air bubbles that can obscure the view of the mucosa,  although this, too, was not recommended by the ICCE con-  sensus panel.   2. Techniques — Prior to capsule ingestion, an eight-element  sensor array is attached to the patient's abdomen. Removing  the magnet that is packaged with the capsule activates the  capsule. The patient then swallows the capsule in an upright  position, or the capsule is placed endoscopically (see preced-  ing text), and images are transmitted to a recording device  worn about the patient's waist. During the study, patients are  instructed to avoid activities that could lead to sensor detach-  ment, such as exercise. After 2 hours, the patient is allowed to  have clear liquids, and a light meal can be consumed  after 4 hours. At the end of the study, the images are down-  loaded to a computer workstation equipped with proprietary  software (either the RAPID Application, version 5, Given  Imaging Ltd, Norcross, GA, or the Endo Capsule Software,  Olympus, Tokyo, Japan). A physician can then read the study  and generate a report, a process that takes on average 40-60  minutes. To aid in reading the study, the software has fea-  tures such as a blood indicator that marks areas with sus-  pected bleeding. In addition, the RAPID Application can  triangulate the location of the capsule relative to the three  closest sensors. The capsule can theoretically be located  within 3 cm, but localization by the software should not be  relied upon in determining the location of a lesion.   To allow real-time viewing of the images, hand-held  devices have been developed. A possible disadvantage is that  reading a study in real time takes significantly longer than  reviewing downloaded images (the average small bowel tran-  sit time is ~4 hours). However, in certain situations, real-time  imaging may have a role. For example, the capsule could be  administered in the emergency department with immediate  viewing to help guide further evaluation and management.   1. Patient preparation — For the esophageal examination,  patients need to fast only for 2 hours prior to ingesting the  capsule.   2. Techniques — A three-element sensor array is attached to  the patient's chest, and the patient consumes 100 mL of water  with simethicone while standing. The patient then lies supine  and the capsule is swallowed with a 10-mL sip of water. The  patient remains supine for 2 minutes, and then progressively  moves into an upright position (30 degrees for 2 minutes,  60 degrees for 1 minute, then upright for the remainder of  the study). The images are then downloaded to the workstation  and reviewed.   Due to difficulty with adherence to the ingestion protocol,  an alternative simplified ingestion protocol has been devel-  oped for the esophageal examination. The patient lies in the  right lateral decubitus position with his or her head on a pil-  low. The patient then swallows the capsule with a sip (approx-  imately 15 mL) of water. The patient remains on the right side  and takes an additional sip of water every 30 seconds for a  total of 7 minutes. After 7 minutes, the patient sits upright  and takes an additional sip of water. The patient may then get  up and walk for the remainder of the study. The images are  then downloaded to the computer workstation for review.   Obscure gastrointestinal bleeding is the most common indi-  cation for performing a capsule endoscopy. The overall yield  of capsule endoscopy is 55-70%, and leads to alterations in  management in approximately one third of patients (range,  25-71%). However, the yield is highly dependent on the indi-  cation for the study. In a 2004 study of 100 patients, if active  bleeding was suspected, the yield was 92%, but the yield  dropped to only 13% for patients with a previous overt gas-  trointestinal bleed (time between the bleed and capsule  endoscopy ranged from 10 days to 1 year). For patients with  occult gastrointestinal hemorrhage, the yield was intermedi-  ate at 44%. A second study of 47 patients from 2005, how-  ever, showed a yield of 100% for patients with ongoing  bleeding, 67% for patients with prior overt bleeding (time  between the bleed and capsule endoscopy ranged from 7 to  90 days), and 67% for occult gastrointestinal bleeding.   The difference in these two studies when it comes to patients  with previous overt gastrointestinal bleeding may relate to the  amount of time elapsed between the bleed and the capsule  endoscopy. In the first study, 25 of the 31 patients had their cap-  sule endoscopy studies at least 2 months after the bleeding  episode, and the study found that the yield for capsule  endoscopy dropped off in parallel with the length of time  between the bleed and the capsule endoscopy. In patients who  had an interval of 10-14 days, the yield was 67%, compared  with 6% for those with an interval of 4-12 months. In the   second study, the average time between the bleed and the cap-  sule endoscopy was only 16 days, which may explain the much  higher yield in this group. In the second study, when capsule  endoscopy was compared with the gold standard of intraopera-  tive enteroscopy, capsule endoscopy had a sensitivity of 95%, a  specificity of 75%, a positive predictive value of 95%, and a neg-  ative predictive value of 86% for detecting a bleeding source.   Capsule endoscopy has also been compared with push  enteroscopy, small bowel barium radiography (small bowel  follow- through or enteroclysis), CT angiography, and mesen-  teric angiography in the evaluation of obscure gastrointesti-  nal bleeding. A pooled analysis of seven prospective studies  that compared capsule endoscopy with push enteroscopy  demonstrated that capsule endoscopy had a yield of 71%,  compared with 29% for push enteroscopy (although other  studies have estimated the yield of push enteroscopy to be  higher, at 40-65%). In a meta-analysis of 14 studies, the yield  of capsule endoscopy in detecting clinically significant find-  ings for obscure gastrointestinal bleeding was 56%, compared  with 26% for push enteroscopy (P < .001). In that same meta-  analysis, three studies that compared capsule endoscopy with  small bowel barium radiography were analyzed. Capsule  endoscopy had a 42% yield for detecting clinically significant  lesions, compared with 6% for small bowel barium radiogra-  phy (P < .001). A prospective study that compared capsule  endoscopy with both CT angiography and mesenteric  angiography in 25 patients who were able to complete all  three studies found that capsule endoscopy was superior to  CT angiography, detecting a bleeding source in 72% of  patients compared with CT angiography, which detected a  bleeding source in only 24% (P = .005). Capsule endoscopy  also had a higher yield than mesenteric angiography, which  had a yield of 56%, although the difference between the two  studies did not reach statistical significance (P = .29).   Whether capsule endoscopy should be repeated in a  patient with a negative examination has been examined. One  small study found that 18 of 24 patients (75%) undergoing  repeat capsule endoscopy for the evaluation of obscure-overt  or obscure-occult gastrointestinal bleeding had new findings,  and in 15 (62.5%), the findings resulted in a change in man-  agement. However, a second study with a median follow-up of  19 months found that in 18 patients with obscure-overt gas-  trointestinal bleeding who had negative capsule endoscopies,  only one rebled (5.6%), compared with 15 of 31 patients  (48.4%) who had positive capsule studies. Therefore, it is rea-  sonable to wait for evidence of rebleeding before repeating a  capsule endoscopy, since a large percentage of patients with a  negative capsule endoscopy will not have further bleeding.   Capsule endoscopy has also been used in the evaluation  of acute gastrointestinal bleeding in the emergency depart-  ment. A study of 24 patients presenting with nonhe-  matemesis gastrointestinal bleeding found that if capsule  endoscopy was performed within 24 hours of presentation,  the yield for identifying a bleeding source was 63% (10/16).  In addition, capsule endoscopy demonstrated active bleeding  in 54% (13/24) of the study patients.   Cave DR. Obscure gastrointestinal bleeding: the role of the tagged  red blood cell scan, enteroscopy and capsule endoscopy. Clin  Gastroenterol Hepatol 2005;3:959-963. [PMID: 16234039]   Hartmann D, Schmidt H, Bolz G, et al. A prospective two-center  study comparing wireless capsule endoscopy with intraopera-  tive enteroscopy in patients with obscure GI bleeding.  Gastrointest Endosc. 2005;61:826-832. [PMID: 15933683]   Pennazio M, Santucci R, Rondonotti E, et al. Outcome of patients  with obscure gastrointestinal bleeding after capsule endoscopy:  report of 100 consecutive cases. Gastroenterology. 2004;126:  643-653. [PMID: 14988816]   Sachdev RM, Hibbert PL, Pearlmutter M, et al. Capsule endoscopy  in the emergency room for acute non hematemesis gastroin-  testinal bleeding. Am J Gastroenterol. 2004;99:S295-296   Saperas E, Dot J, Videla S, et al. Capsule endoscopy versus com-  puted tomographic or standard angiography for the diagnosis  of obscure gastrointestinal bleeding. Am J Gastroenterol.  2007;102:731-737. [PMID: 17397406]   Triester SL, Leighton JA, Leontiadis GI, et al. A meta-analysis of the  yield of capsule endoscopy compared to other diagnostic  modalities in patients with obscure gastrointestinal bleeding.  Am J Gastroenterol. 2005;100:2407-2418. [PMID: 16279893]   by capsule endoscopy in only 6% of those with abdominal  pain alone, and in 13% of those with abdominal pain and  diarrhea. Capsule endoscopy can also help in the evaluation  of indeterminate colitis. In patients with indeterminate coli-  tis, two retrospective studies of capsule endoscopy have  demonstrated small bowel ulcerations in 33-49% of  patients, suggesting (but not proving) a diagnosis of Crohn  disease.   In addition to detecting small bowel Crohn disease, cap-  sule endoscopy can help in defining the extent of disease,  diagnosing a Crohn flare, or detecting a postoperative recur-  rence in patients with established disease. In one study,  patients who were suspected of having a Crohn flare under-  went capsule endoscopy. In 20% there was no active disease,  suggesting that the symptoms may have been due to other  causes, including a superimposed functional disorder.   Kornbluth A, Legnani P, Lewis BS. Video capsule endoscopy in  inflammatory bowel disease: past, present, and future. Inflamm  Bowel Dis. 2004;10:278-285. [PMID: 15290925]   Capsule endoscopy is superior to other diagnostic modalities  in detecting small bowel disease when the suspicion for  Crohn disease is high (Table 33-4). A meta-analysis demon-  strated that capsule endoscopy is superior to small bowel  radiography, colonoscopy with ileoscopy, CT enterography  or enteroclysis, and push enteroscopy for the detection of  nonstricturing small bowel Crohn disease (incremental  yields of 40%, 15%, 38%, and 38%, respectively). Overall,  capsule endoscopy had a yield of 46-72% for detecting small  bowel Crohn disease. It had a yield of 33-70% in patients  with suspected Crohn disease, and a yield of 68-86% in  patients with established Crohn disease. It is possible, how-  ever, that the yield of capsule endoscopy for suspected Crohn  disease is significantly lower in practice, as patients being  evaluated for possible Crohn disease do not always fulfill the  selection criteria used in studies. In a study of patients being  evaluated for abdominal pain who had undergone previous  endoscopic or radiographic evaluations, a cause was detected   Table 33-4. Factors associated with positive capsule  endoscopy studies in patients with suspected small  bowel Crohn disease.   Capsule endoscopy is capable of detecting tumors and polyps  of all sizes throughout the small bowel; however, because  many of the tumors are submucosal, it can be difficult at  times to differentiate a tumor from the transient bulges that  are frequently seen during capsule endoscopy. In addition, a  tumor may only be seen tangentially on one frame of the  study, making characterization of the mass difficult, espe-  cially when it comes to size. Because capsule endoscopy lacks  biopsy capability, arriving at a definitive diagnosis is rarely  possible using capsule endoscopy alone. However, a presump-  tive diagnosis can be made in some cases, such as in a patient  with a small bowel mass and known metastatic melanoma (see  Plate 77).   In a study of patients with polyposis syndromes, capsule  endoscopy detected polyps in 10 of 11 patients (91%) with  Peutz-Jeghers syndrome. That study also examined patients  with FAR It found that 24% of FAP patients (5 of 12  patients) with duodenal adenomas had distal jejunal or ileal  polyps detected on capsule endoscopy. In patients without  duodenal adenomas, however, more distal polyps occurred  in only 12%. Of note, capsule endoscopy often failed to  achieve adequate visualization of the ampulla of Vater, an  area of frequent polyp and adenocarcinoma development in  patients with FAP. Therefore, capsule endoscopy is not a sub-  stitute for standard surveillance using a side-viewing duo-  denoscope with ampullary biopsies.   Schulmann K, Hollerbach S, Kraus K, et al. Feasibility and  diagnostic utility of video capsule endoscopy for the detec-  tion of small bowel polyps in patients with hereditary poly-  posis syndromes. Am J Gastroenterol. 2005;100:27-37. [PMID:  15654777]   In a small, blinded study of 20 patients (10 with celiac disease  and 10 with controls), capsule endoscopy had a sensitivity of  70%, a specificity of 100%, a positive predictive value of 100%,  and a negative predictive value of 77% for the diagnosis of  celiac disease. Interobserver agreement for experienced capsule  endoscopists was perfect (k = 1.0). Patients with extensive  small bowel involvement were more likely to have classic celiac  disease symptoms, including diarrhea and weight loss, whereas  those with only proximal involvement had mild, nonspecific  symptoms.   Studies have also looked at using capsule endoscopy in  patients with refractory celiac disease. In a study of 47 celiac  disease patients with persistent abdominal pain, occult blood  loss, or refractory iron deficiency anemia, capsule endoscopy  identified lesions in 87% (41 of 47 patients). The capsule  endoscopy studies detected findings consistent with celiac  disease in a majority of patients (32 with villous atrophy,  29 with scalloping and Assuring, and 9 with a mosaic pat-  tern). Additional findings included ulcerations (21 patients),  nodularity (6 patients), an adenocarcinoma (1 patient), a  polyp (1 patient), a stricture (1 patient), an intussusception  (1 patient), and a submucosal mass (1 patient). This study  suggests that in patients with ongoing symptoms, despite the  report of adherence to a gluten-free diet, capsule endoscopy  has a high yield for identifying abnormalities.   Culliford A, Daly J, Diamond B, et al. The value of wireless  capsule endoscopy in patients with complicated celiac disease.  Gastrointest Endosc. 2005;62:55-61. [PMID: 15990820]   Petroniene R, Dubcenco E, Baker JP, et al. Given capsule endoscopy  in celiac disease: evaluation of diagnostic accuracy and interob-  server agreement. Am J Gastroenterol. 2005;100: 685-694. [PMID:  15743369]   The PillCam ES02 was designed to visualize the esophagus  and can be used to detect findings such as esophageal varices,  erosive esophagitis, and Barrett esophagus. In a study of  32 patients, there was 97% concordance between capsule  endoscopy and upper endoscopy for the detection of varices,  and 91% concordance for the diagnosis of portal hyperten-  sive gastropathy.   An advantage of capsule endoscopy is that it has the poten-  tial to image the entire length of the small bowel. However, in  many instances there is poor visualization of areas of mucosa  due to quick passage, inability to insufflate, tangential views,  and debris. Additionally, in approximately 15% of cases, the  capsule does not reach the colon prior to the battery running  out (currently about 8 hours). A significant limitation is that  capsule endoscopy lacks biopsy capability. This can be a   problem because findings such as erythema, aphthous ulcer-  ations, or frank ulcerations are seen in multiple disorders  (see Table 33-3). In addition, nodules cannot be biopsied to  determine if there is an underlying malignancy. Some of  these limitations can now be addressed using double-balloon  enteroscopy if an abnormality is found on capsule endoscopy  (see "Double-Balloon Enteroscopy," later in this chapter).   The most important complication related to capsule  endoscopy is capsule retention. Overall, the risk of retention  is 1-2%. Many of the disorders for which capsule endoscopy  is being employed, such as Crohn disease or radiation enteri-  tis, can increase the risk of retention. Patients with Crohn  disease are at increased risk because of possible small bowel  strictures (which may be missed on conventional imaging).  In the setting of established Crohn disease, the risk or reten-  tion increases to 4-13%. In patients with established Crohn  disease, small bowel radiographic imaging (small bowel  follow-through or CT enteroclysis) should be performed  prior to capsule endoscopy to decrease the risk of retention.  The use of a patency capsule (Agile Patency System, Given  Imaging Ltd, Yoqneam, Israel) can also decrease the risk of  retention. A patency capsule is composed of a dissolving  body and a small transponder, and is the same size and shape  as the video capsule. Prior to disintegration, which will occur  in about 40 hours if the capsule is in a moist environment, a  scanner is used to determine if the capsule has passed. If the  patency capsule passes, it is safe to proceed with capsule  endoscopy. If the patency capsule is not able to pass, it will  subsequently dissolve into small fragments that can then  easily pass.   Capsule retention is often associated with the identification  of significant pathologic findings that often require further  surgical or endoscopic intervention. In a study of 733 cases,  capsule retention occurred in 1.9% (14 patients). Of these, all  occurred at a site of pathology (Crohn disease [5] , small bowel  stenosis [5], small bowel neoplasm [3], and mesenteric  ischemia [1]). Eleven patients underwent surgery for capsule  removal, two had the capsule removed endoscopically, and one  (with mesenteric ischemia) did not have the capsule removed.  Double-balloon enteroscopy is one option for retrieving cap-  sules that are retained in the mid or distal small bowel and are  thus out of reach of a standard enteroscopy (see the later sec-  tion on "Double-Balloon Enteroscopy").   Uncommon complications of capsule endoscopy include  aspiration of the capsule, impaction at the cricopharyngeus,  or retention in a Zenker or Meckel diverticulum. A case of  aspiration was noted in a patient who was part of the study  of 733 capsule endoscopy examinations. In that case, the  patient was able to expel the capsule by coughing. These  complications reinforce the need to evaluate patients care-  fully for swallowing disorders prior to performing a capsule  endoscopy study.   Cheifetz AS, Kornbluth AA, Legnani P, et al. The risk of retention  of the capsule endoscope in patients with known or suspected  Crohn's disease. Am J Gastroenterol. 2006;101:2218-2222.  [PMID: 16848804]   Rondonotti E, Herrerias JM, Pennazio M, et al. Complications,  limitations, and failures of capsule endoscopy: a review of 733  cases. Gastrointest Endosc. 2005;62:712-716. [PMID: 16246685]   The small bowel is on average 430 cm (14 feet) long. Push  enteroscopy with an over-tube, however, can at most be  advanced to 160 cm beyond the ligament of Treitz. With the  advent of wireless capsule endoscopy, it is now possible to  visualize the entire length of the small bowel, but capsule  endoscopy lacks biopsy and therapeutic capability. Lesions  detected by capsule endoscopy that are beyond the reach of a  push enteroscope can now be evaluated using double-balloon  enteroscopy. Total enteroscopy is possible with double-balloon  enteroscopy and has the advantage of allowing for biopsies  and for therapeutic interventions. Yamamoto and colleagues  first described double-balloon enteroscopy in 2001, and it was  FDA approved for use in the United States in the fall of 2004.   Jonnalagadda S. Double-balloon enteroscopy: wired technology  meets wireless. Gastroenterology. 2006;131:327-329. [PMID:  16831620]   Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a non-  surgical steerable double-balloon method. Gastrointest Endosc.  2001;53:216-220. [PMID: 1174299]   Double-balloon enteroscopy is used most often for the eval-  uation of obscure gastrointestinal bleeding, small bowel radi-  ographic abnormalities, abnormalities identified on capsule  endoscopy, chronic diarrhea, and malabsorption, and in poly-  posis syndromes to detect and remove polyps (Table 33-5). It  has also been used to biopsy and dilate small bowel strictures,  to screen for disease recurrence in patients with a history of  small bowel malignancies, and to evaluate patients with  refractory celiac disease. In patients who have undergone  roux-en-Y gastric bypass, it can visualize the defunctional-  ized stomach and gain access to the bile and pancreatic ducts.  Undoubtedly, as familiarity with the procedure grows, addi-  tional applications will continue to emerge.   Di Caro S, May A, Heine DG, et al. DBE European Study Group. The  European experience with double-balloon enteroscopy: indica-  tions, methodology, safety and clinical impact. Gastrointest  Endosc. 2005;62:545-50. [PMID: 16185969]   Gerson LB. Double-balloon enteroscopy: the new gold standard  for small-bowel imaging? Gastrointest Endosc. 2005;62:71-75.  [PMID: 15990822]   bypass  Access to the bile and pancreatic ducts after Roux-en-Y gastric bypass   Patients who are undergoing an antegrade (per os) study fast  for 8-12 hours prior to the study. For a retrograde (per anus)  study, a standard colonoscopy preparation is employed.   The system is composed of an enteroscope, an over- tube, and  a balloon pump controller. The system uses two latex bal-  loons, one on the end of the enteroscope and one on the end  of the over-tube (Figure 33-1). Through a combination of  antegrade and retrograde approaches, the entire small bowel  can be examined in 42-86% of patients.   The examination can be carried out using conscious  sedation or propofol, although some centers prefer general  anesthesia due to the length of the study and the potential for  patient discomfort. During an antegrade study, the scope and   over-tube are advanced until both are within the duodenum.  The balloon on the end of the over-tube is then inflated to  anchor the small bowel. The scope is then advanced. When  the scope can no longer be advanced, the balloon at the tip of  the scope is inflated, again anchoring the small bowel. The  balloon on the over-tube is then deflated and the over-tube is  advanced until it reaches the end of the scope. At this point,  the balloon on the end of the over-tube is again inflated.  With both balloons inflated, the scope and the over-tube  are gently withdrawn until resistance is met. In so doing,  the small bowel is pleated onto the over-tube and loops are  reduced. The balloon on the scope is then deflated and the  scope is again advanced. This sequence is repeated until  the lesion of interest is reached or until the scope can no  longer be advanced. Fluoroscopic guidance may be used to aid  with scope advancement and reductions. When a retrograde  approach is employed, the scope and over-tube are advanced  until they are both within the terminal ileum, and the same  sequence is carried out.   Using the antegrade approach, an average of 240-270 cm  of small bowel can be examined. With the retrograde  approach, an average of 140-150 cm of small bowel can be  visualized. The current therapeutic double-balloon entero-  scope (Fujinon EN-450T5; Fujinon Inc, Saitama, Japan) has  140-degree field of view and a working length of 200 cm. It  has a forceps channel diameter of 2.8 mm, which will accom-  modate biopsy forceps, argon plasma coagulation probes,  bipolar hemostasis probes, cytology brushes, Roth nets,  snares, and injection needles. The over-tube is 135 cm with  an outer diameter of 13.2 mm.   In a 2005 study of 1 37 patients by May and colleagues, double-  balloon enteroscopy had a diagnostic yield of 80%. The  majority of the patients were being evaluated for obscure  gastrointestinal bleeding (67%). Other indications included  polyposis syndromes (10%), abdominal pain (8%), sub ileus  or severe abdominal pain in the setting of Crohn disease  (4%), chronic diarrhea or malabsorption (2%), non-  Hodgkin lymphoma of the small bowel (2%), and intestinal  obstruction by a foreign body (2%). A new diagnosis was  made in 34% of patients and a diagnosis was confirmed in  30%. In 12% of the patients, the study determined the  extent of a previously known diagnosis, and in 10% of the  patients a previously made diagnosis was excluded. Findings  included ulcerations, polyps, tumors, angiodysplasias, small  bowel diverticula, foreign bodies (video capsules and den-  tures), hypertensive enteropathy, and bleeding sources out-  side of the small bowel. Endoscopic therapy was employed  in 41.5% of the patients (argon plasma coagulation, polypec-  tomy, foreign body extraction, dilation, and injection of dilute  epinephrine). Medical treatments were started or changed in  17% (mainly in patients with Crohn disease of the small  bowel). Surgical therapy was recommended as a result of the   study in 17.5% of patients. Double-balloon enteroscopy  had no treatment implications in only 14.5% of the patients  studied.   In a second study of 353 patients from 2007, May and  associates found a similar diagnostic yield of 75% for small  bowel lesions. Sixty percent of the patients were being evalu-  ated for suspected small bowel bleeding, 10% had chronic  abdominal pain, 9% had a polyposis syndrome, 8% had  Crohn disease, and 13% underwent the study for other indi-  cations, including foreign body extraction. The findings  influenced subsequent therapy in 67%. Endoscopic therapy  was performed in 59%, and medical therapy was initiated or  changed in 19%. Twenty- two percent of the patients required  surgery. Not surprisingly, the majority of patients who  received endoscopic therapy suffered from small bowel  bleeding (74%).   May A, Nachbar L, Ell C. Double-balloon enteroscopy (push-  and-pull enteroscopy) of the small bowel: feasibility and diag-  nostic and therapeutic yield in patients with suspected small  bowel disease. Gastrointest Endosc. 2005;62:62-70. [PMID:  15990821]   May A, Nachbar L, Pohl J, et al. Endoscopic interventions in the  small bowel using double-balloon enteroscopy: feasibility and  limitations. Am ] Gastroenterol. 2007;102:527-535. [PMID:  17222315]   The primary limitation of double-balloon enteroscopy is  incomplete mucosal visualization. Although the entire small  bowel can be examined in 42-86% of patients using a com-  bined antegrade and retrograde approach, a significant per-  centage of patients are left with incomplete small bowel  visualization. Most commonly this occurs due to inability to  advance the scope through the entire length of small bowel.  Double-balloon enteroscopy is also limited by the fact that it  requires two operators (at least one of whom is a physician),  and it is very time consuming, with an average procedure  time of 73-115 minutes. In addition, because of potential  patient discomfort, some centers use general anesthesia,  which can make procedures logistically more difficult to  arrange.   The most common adverse event is abdominal pain the day  of or the day after the procedure. This occurs in up to 20% of  patients. Patients also may report a sore throat. Perforations  have been reported, including multiple perforations follow-  ing chemotherapy for lymphoma and following small bowel  polypectomy. Post-procedure paralytic ileus and pancreati-  tis have also been reported. Bleeding has been seen follow-  ing polypectomies. The overall major complication rate in  May's study of 353 patients, cited earlier, was 3.4%. Bleeding  occurred in 1.1%, perforation in 1.7%, and enteritis in 0.6%.   This, however, underestimates the risk associated with indi-  vidual interventions. Of the 46 patients who underwent  polypectomies, 5 (10.8%) suffered complications. Bleeding  occurred in 2 (4.3%), and perforation occurred in 3 (6.5%).  All of the complications in patients undergoing polypec-  tomy occurred after the removal of polyps that were larger  than 3 cm. Argon plasma coagulation had a lower complica-  tion rate of 1 in 108 (0.9%). Thus, while the overall rate of   complications is low, patients undergoing polypectomy  should be advised that there is a significant complication  rate associated with the removal of large polyps, as are often  seen in Peutz-Jeghers syndrome. However, given that the  alternative in these patients is intraoperative enteroscopy,  which has a morbidity rate up to 30% and a mortality rate  of 2%, double-balloon enteroscopy is still an attractive  option.   Plain films should be the initial diagnostic study; obtain  both lateral and posteroanterior films of the neck,  chest, and abdomen as indicated.   Endoscopic evaluation may be required for objects that  are potentially radiolucent in patients with a compelling  history but negative imaging findings.   Impacted meat is typically radiolucent and is the most  common esophageal foreign body in adults; perform  endoscopy promptly in all cases with clinical evidence  of obstruction and failure to pass on initial medical  management.   Many foreign bodies pass spontaneously, but certain  objects (eg, sharp objects and batteries) need urgent  intervention.   Gastrointestinal foreign bodies occur in all age groups and  are commonly seen by the gastroenterologist, as well as by  those in various surgical disciplines. The endoscopic removal  of foreign bodies dates back to the early 1900s, with more  widespread adoption following the advent of the fiberscope  in 1957. Methods of diagnosis and treatment have continued  to evolve since that time with the development of specialized  accessories and improved procedural efficacy.   Foreign body ingestion, including dietary foreign bodies  or food bolus impaction, currently represents the second  most common indication for emergent gastrointestinal  endoscopy, after gastrointestinal hemorrhage. Patients with  foreign body ingestion typically present to their primary  care physician or the emergency department, and the major-  ity of foreign bodies pass spontaneously. Nevertheless, signif-  icant complications may arise resulting in approximately   1500-1600 deaths in the United States annually. Therefore, it  is essential for the endoscopist to efficiently determine which  patients require therapeutic intervention, and to be comfort-  able with proper methods of extraction. This chapter reviews  indications for foreign body removal, the typical diagnostic  evaluation, and endoscopic techniques for foreign body  management.   Following foreign body ingestion patients may present in a  variety of ways, ranging from asymptomatic to having signs  and symptoms of complete esophageal obstruction or frank  perforation. In the majority of cases a careful clinical history  provides the correct diagnosis. Clinical history may be less  reliable in children younger than age 5 years, the mentally ill,  and in otherwise uncooperative patients. In such popula-  tions, symptoms and diagnostic studies are more critical to  clarifying the diagnosis.   Most true foreign body ingestions are seen in children  between the ages of 1 and 5 years who swallow small house-  hold items or toys. Fortunately, most of these objects are  small and blunt, and they typically pass spontaneously.  Adults who ingest true foreign bodies often have psychi-  atric disturbance, mental retardation, alcoholism, or iden-  tifiable reasons for secondary gain, such as prisoners.  Dietary foreign bodies and food bolus impactions typically  occur in older adults, denture wearers, and those with under-  lying esophageal disorders.   Presenting symptoms are determined by the type of for-  eign body ingested and its location.   1. Esophageal foreign bodies — Esophageal foreign bodies  may result in symptoms of dysphagia, odynophagia, or signs  of complete esophageal obstruction, including inability to  swallow secretions, drooling, and regurgitation. Sudden  onset of odynophagia following eating suggests impaction of   a bone, sharp food fragment, toothpick, or similar objects in  the esophagus. Respiratory symptoms such as coughing and  stridor are common in younger children as their compliant  tracheal rings are more easily compressed by an adjacent  esophageal foreign body. Upper airway obstruction is a rare  presentation for adults with an esophageal foreign body;  however, meat bolus impaction at the level of the cricopha-  ryngeus can result in respiratory obstruction, which has been  referred to as "steak house syndrome." Subcutaneous emphy-  sema in the supraclavicular area or the neck suggests perfo-  ration of the esophagus or hypopharynx. Esophageal  perforation by sharp objects at the level of the aortic arch  may also result in an aortoesophageal fistula. This typically  presents with a herald bleed, followed by massive hemor-  rhage. Fortunately these presentations are rare.   2. Gastric foreign bodies — Gastric foreign bodies are gen-  erally asymptomatic, except when they are large enough to be  associated with postprandial emesis and early satiety. Long-  standing foreign bodies or those that are sharp and pointed  may become impacted in the gastric wall and result in  inflammation, ulceration, hemorrhage, or perforation. These  patients often present with pain or bleeding.   3. Small bowel foreign bodies— Foreign bodies that have  made their way to the small bowel typically remain asympto-  matic. Symptoms of small bowel foreign bodies are typically  those of perforation or obstruction.   Physical examination may yield important clues to identify-  ing complications due to ingested foreign bodies. Crepitus in  the supraclavicular and cervical areas suggests perforation of  the hypopharynx or esophagus. Large gastric foreign bodies  may occasionally be palpable on abdominal examination.  Peritoneal signs often suggest gastric or intestinal perfora-  tion, and physical findings typical of bowel obstruction may  occur with small bowel foreign bodies.   The plain film radiograph should be the initial diagnostic  study. Both lateral and posteroanterior films should be  obtained of the neck, chest, and abdomen. This is important  in identifying small or flat objects that may overlie the spine,  and in determining the exact location of a foreign body. The  lateral film is often essential in differentiating between tra-  cheobronchial and esophageal locations. Perforation may  also be identified if the object is seen extending beyond the  lumen wall, or if a soft tissue mass is seen adjacent to the  object. Plain films should also be obtained to evaluate food  bolus impactions, as the presence of bone fragments may  alter the endoscopic management.   Objects that are relatively radiolucent, such as plastic,  wood, most glass, and small bones, may not be seen on  plain film, in which case Xeroradiography or computed  tomography may be helpful in making the diagnosis.   Contrast studies should be avoided. Gastrografin is con-  traindicated as it is very hypertonic and can result in a severe  chemical pneumonitis if aspirated, and barium can obscure  endoscopic visualization, thereby complicating therapy.   Endoscopic evaluation may also be required, even in the  absence of imaging findings, for a possible radiolucent object  and compelling history. Additionally, endoscopy is often the  therapeutic method of choice.   Although the majority of foreign bodies pass spontaneously,  certain objects need urgent intervention. The type of foreign  body and its location determine management. In general, all  esophageal foreign bodies, elongated and sharp gastric for-  eign bodies, and blunt objects should be removed from the  stomach after persisting 2 weeks. Endoscopic removal may be  technically challenging depending on the object shape and  material, and several accessories are available to enhance pro-  cedural success. Details of management follow.   A wide variety of ingested foreign bodies may be encoun-  tered by the gastrointestinal endoscopist. Roughly 75% of all  foreign bodies pass spontaneously, with 1% resulting in serious  complication or surgery.   Foreign bodies may be broadly classified as true foreign  bodies or dietary foreign bodies. They may be further cate-  gorized as dull or sharp, blunt or pointed, long or short, toxic  or nontoxic, and as food bolus impactions. These features are  associated with prognosis, and depending on anatomic loca-  tion may indicate when urgent removal is necessary.   1. Sharp and pointed objects — The most common sharp  objects include fish or chicken bones and toothpicks; how-  ever, razor blades, hat pins, nails, and fragments of glass may  also be seen (Figure 34-1 and Plate 81). Although the major-  ity of such objects can pass safely through the gastrointesti-  nal tract, perforation rates are as high as 35%. Thus,  endoscopic removal is necessary if the object is within reach  of the endoscope. When the object is above the cricopharyn-  geus, referral to an otolaryngologist for direct laryngoscopy  is indicated. Otherwise, urgent flexible endoscopy should be  considered. If the object has passed beyond the duodenum,  daily radiographs should be obtained to determine its loca-  tion and detect free air or other evidence of complications. If  the object fails to progress for 3 consecutive days, then surgi-  cal intervention should be considered.   2. Long objects — Long and narrow foreign bodies such as  toothbrushes and stiff wires are associated with a high inci-  dence of perforation as they have difficulty passing the fixed  curves of the duodenum. Objects 6 cm in length or longer  are particularly problematic, and early endoscopic interven-  tion is recommended.    A Figure 34-1. Plain film radiographs. A: Posteroanterior film showing nails. B: Lateral film showing a razor blade.   3. Blunt foreign bodies — This is perhaps the most diverse  class of ingested foreign bodies and is the most common in  the pediatric population. In a review describing the manage-  ment of 242 foreign bodies, coins were the most common  foreign body ingested by children. Other objects in this class  include marbles, small toys, and disc batteries. Conservative  outpatient management is indicated for the vast majority of  blunt foreign bodies that have passed into the stomach.  Rounded objects larger than 2.5 cm are less likely to pass  the pylorus, and endoscopic removal should be considered if  the object fails to pass the stomach within 2-3 weeks. If the  object successfully passes through the stomach, a radiograph  should be obtained every 3-4 days to assess passage. Surgical  removal should be considered if the object remains in the  same location for more than 1 week.   Button batteries or disc batteries require special consid-  eration. The most common disc battery systems include  silver oxide, manganese dioxide, and mercuric oxide. These  typically contain alkaline solutions of either sodium hydrox-  ide or potassium, which can cause direct corrosive effects or  low-voltage burns. Liquefaction necrosis of the esophagus  and perforation can also occur. Urgent endoscopic evalua-  tion with battery removal is thus indicated. If battery disrup-  tion is noted, heavy metal levels should be monitored in the  blood and urine. Mercury poisoning is a rare complication of   battery disruption. Copper, nickel, and lead poisoning have  also been reported after prolonged retention of various  metallic foreign objects. If a disc battery successfully passes  into the stomach, it will typically pass the gastrointestinal  tract without consequence. Forceps should be avoided if  endoscopic removal is attempted as they can lead to battery  disruption. Cathartics and acid suppression have no proven  role and should also be avoided.   4. Toxic foreign bodies— Internal concealment of illicit  drugs wrapped in plastic or latex packages, also known as  "body packing," is seen with higher frequency in regions of  drug trafficking. Package rupture or leakage can be fatal, and  such foreign bodies require special consideration. Endoscopic  removal should not be attempted.   Drug packages can be subdivided into three types. Type 1  includes condoms and balloons. These typically appear as a  density with surrounding halo of gas on radiography. Each  condom can contain 3-5 g of cocaine, and ingestion of 1-3 g  may be lethal. As these packages are very susceptible to  breakage, surgical removal should be considered early.   Type 2 and type 3 packages consist of layers of tubular latex  or plastic, with or without aluminum foil. Type 2 packages  may appear similar to type 1 on radiography. Type 3 packages  are typically smaller and may not be seen on radiographs.   These packages are less susceptible to breakage and, if identi-  fied, they may be followed with daily radiographs.  Indications for surgery include failure of the package to  progress on the daily radiograph, evidence of intestinal  obstruction, visualization of broken packages on radiograph,  passage of broken packages, or development of consequen-  tial symptoms.   5. Food bolus impaction — Impacted meat is the most com-  mon esophageal foreign body in adults. Total esophageal  obstruction is implied by drooling and inability to swallow  secretions. This is an indication for urgent endoscopic inter-  vention. Ideally all meat boluses should be extracted or  advanced into the stomach urgently (within a few hours of  ingestion) as patients are at risk for aspiration. Additionally,  with prolonged bolus impaction there is risk for local  esophageal ischemia and pressure ulceration, and with time  the bolus may be partially digested, requiring piecemeal  removal. The administration of glucagon (1.0 mg intra-  venously) may also be attempted prior to endoscopy to  encourage spontaneous passage. Papain and other meat ten-  derizers should be avoided. Many impactions occur in the  proximal esophagus and careful attention must be paid to  this area on initial esophageal intubation. Additionally, many  patients with food bolus impactions have underlying  esophageal disease, such as peptic stricture, Schatzki ring, or  eosinophilic esophagitis. Local trauma and edema often pre-  clude an accurate diagnosis of such conditions at the initial  endoscopic evaluation, and subsequent studies are typically  required. This may include repeat upper endoscopy with  biopsy several weeks after the food bolus impaction.   The removal of esophageal foreign bodies dates back to the  early 1900s with Chevalier )ackson, who published a series of  over 3000 cases in 1936; however, foreign body extraction  using the flexible fiberoptic endoscope was not reported  until 1972. Throughout the 1980s and 1990s endoscopes  evolved and several accessories were developed to assist in  the removal of ingested foreign bodies. Methods of removal  in current use are detailed in this section.   Prior to removal, a complete history and physical exami-  nation are essential to determine the need for removal and to  assess the safety of the procedure. This will also help in selec-  tion of the correct instruments based on the type of foreign  body and its location.   1. Sedation — When planning foreign body extraction, the  first decision involves determining the type of sedation  that is most appropriate for the patient. Many patients who  have ingested foreign material are poor candidates for con-  scious sedation. History of alcoholism, drug abuse, or cer-  tain psychiatric conditions may render them difficult to  sedate and increase associated procedural risk. General anes-  thesia with endotracheal intubation provides deeper sedation   and additional airway protection that may be desirable in cer-  tain circumstances.   2. Choice of endoscope — The second decision involves  which type of endoscope to use. Forward-viewing (single-  channel or double-channel) or side-viewing endoscopes may  each have a role, and selection should not be arbitrary. The  forward-viewing endoscopes have an advantage over side-  viewing endoscopes in visualizing the esophagus and most  parts of the stomach and small bowel. Double-channel endo-  scopes are also particularly useful for removing elongated  objects as accessories may be passed through both channels,  which may be helpful in positioning the object for capture or  holding it in a straight position for extraction. The double-  channel endoscope, however, is larger in diameter than the  single-channel endoscope and may not be useable with all  accessories, such as a hood or some overtubes. Additionally,  the double-channel endoscope may be too large for use in  infants or small children due to concern for tracheal com-  pression. The side-viewing endoscope provides better visual-  ization of the medial aspect of the lesser curve and the  periampullary area in the small bowel, and may be useful in  addressing foreign bodies lodged in these areas.   3. Choice of accessories — Several accessories may facilitate  the endoscopic management of foreign bodies. Various  devices are available to protect the gastrointestinal tract or  airway during extraction, and to grasp objects of different  sizes and shapes.   A. Forceps and snares — Different types of forceps or  graspers are available, and certain varieties may be more or  less useful for specific materials. Rat-toothed forceps and  alligator forceps are more effective than standard biopsy for-  ceps at grasping various foreign materials, including plastics  and metal (Figure 34-2). Snares, biliary stone retrieval bas-  kets, and snares fitted with netting may also be useful for  contending with certain objects. Netted snares are particu-  larly useful for dealing with objects that are prone to crum-  bling and button batteries.   The way the objects are grasped is also important. For  elongated objects it is important to grasp them at one end  and keep the long axis in line with the esophagus. For sharp  objects it is critical to grasp the object such that the sharp end  is trailing. Additionally, when planning a procedure it is rec-  ommended that various instruments be tested on a similar  object, as this will reduce procedure time and could lead to  improved outcomes.   B. Overtubes — An overtube is a plastic sheath with an inner  diameter large enough to accommodate an endoscope, and  several varieties are available (Figure 34-3). Use of an over-  tube should be considered if multiple intubations are antici-  pated, additional if airway protection is desired, or sharp  objects have been ingested.   Overtubes come in various lengths and may extend to the  midesophagus or into the proximal stomach. There are two   methods for placing overtubes. Reusable overtubes may be  introduced over a snug fitting wire-guided Savary dilator,  and single-use overtubes may be preloaded over the endo-  scope with the matching tapered-tip introducer. It is not  acceptable to place a reusable overtube by preloading it over  an endoscope as the resulting gap between the endoscope and  the overtube could result in perforation of the hypopharynx.  The inner diameter of the overtube varies depending on the  specific product but is typically less than 14 mm in diameter.  This feature can be limiting when dealing with large objects.   C. Hoods — The foreign body hood is an alternative to the  overtube and is particularly useful when dealing with  sharp foreign objects (Figure 34-4). The protective hood  is attached to the bending segment of the endoscope and  is folded back to avoid compromising endoscopic visuali-  zation. After the object is grasped using the appropriate    endoscopic accessories, the endoscope is withdrawn. As the  hood passes through the lower esophageal sphincter it is  folded forward, covering the object and protecting the gas-  tric cardia and esophagus from contact with the object.  Unlike the overtube, the hood does not provide additional  airway protection.   ▲ Figure 34-4. Foreign body hood protector. A: Open  configuration. B: Closed hood, following acquisition of a  foreign body and withdrawal of the endoscope.   For food bolus impactions, it may be safer to push the object  into the stomach rather than attempt removal. This must be  done with care. It is essential to first evaluate the area beyond  the foreign body, to make certain there is no stricture, or  other anatomic defect. Gentle pressure may then be applied  to the object to facilitate passage. This is typically not accept-  able for large true foreign bodies.   Athanassiadi K, Gerazounis M, Metaxas E, et al. Management  of esophageal foreign bodies: a retrospective review of 400  cases. Eur J Cardiothorac Surg. 2002;21:653-656. [PMID:  11932163]   Ciriza C, Garcia L, Suarez P, et al. What predictive parameters best  indicate the need for emergent gastrointestinal endoscopy after  foreign body ingestion? / Clin Gastroenterol. 2000;31:23-28.  [PMID: 10914771]   Lin HH, Lee SC, Chu HC, et al. Emergency endoscopic manage-  ment of dietary foreign bodies in the esophagus. Am J Emerg  Med. 2007;25:662-665. [PMID: 17606092]   Yong PT, Teh CH, Look M, et al. Removal of a dinner fork from the  stomach by double-snare endoscopic extraction. Hong Kong  Med]. 2000;6:319-21. [PMID: 11025854]   Endoscopic retrograde cholangiopancreatography (ERCP)  (Figure 35-1 ) is a combined endoscopic and fluoroscopic pro-  cedure that was introduced in the early 1970s to allow access  to the biliary and pancreatic ductal systems and their openings  at the major and minor duodenal papillae. ERCP has evolved  from a purely diagnostic technique, performed by a few, into a  complex set of procedures offered in all major medical centers  integrating diagnosis and therapy for a wide variety of pancre-  atobiliary disorders. For many of these, ERCP has become the  minimally invasive treatment of choice when supported by  prospective studies comparing it with the standard alternatives  which, in the past, often involved open surgery. ERCP requires  dedicated training in order to acquire the range of techniques  that include endoscopic papillectomy, sphincter of Oddi  manometry, biliary sphincterotomy, pancreatic sphinctero-  tomy, stone removal, tissue sampling, placement of plastic and  metallic stents, and drainage of pancreatic fluid collections.  Although it has become a highly successful therapeutic modal-  ity, ERCP also carries a risk of adverse events of 7% or less that  includes pancreatitis (4%), hemorrhage (1%), cholangitis  (1%), perforation (0.5%) and death (0.1%). Since the advent  of magnetic resonance cholangiopancreatography (MRCP)  (Figure 35-2) in the last few years, with its ability to image the  pancreatic and biliary tracts noninvasively and without risk,  the need for purely diagnostic ERCP has appropriately dimin-  ished considerably and the demands for therapy have grown.   Telford J, Carr-Locke DL. Infections of the biliary tract. In: Clinical GI   Small intestinal tumors represent 2.4% of all gastrointestinal  malignancies and more than half of these are found in the   duodenum. Duodenal adenomas occur in 50-100% of patients  with familial adenomatous polyposis (FAP) and are most com-  monly in the periampullary location. Sporadic adenomas of the  papilla also occur; like their genetic counterpart, they may be  detected as an incidental finding during upper endoscopy per-  formed for another indication or may manifest with recurrent  pancreatitis, weight loss, or biliary obstruction. The frequency of  carcinoma in papillary adenomas ranges from 30% to 65%.   Adenomas of the papilla follow the adenoma-carcinoma  sequence similar to that seen in the colon; thus, resection of  these lesions is recommended. Traditionally, the approach  was wide radical resection by pancreaticoduodenectomy,  because the presence of malignancy could not be completely  excluded based on evaluation of preoperative biopsies. This  resection was accompanied by a significant morbidity and,  even with improvements in surgery, local resection is cur-  rently the method of choice. Since the first reports of endo-  scopic resection of the papilla in the early 1990s, endoscopic  papillectomy or ampullectomy has gained wider acceptance  as a less invasive treatment modality, particularly for patients  with adenomas, small neuroendocrine tumors, and Tl can-  cers in poor operative candidates.   The technique involves inspection of the papilla with a  side-viewing duodenoscope, and ERCP to define any intra-  ductal tumor extension and to opacify the ducts with con-  trast to aid in identifying the ductal orifices after the  procedure is completed. Most experts resect the papilla and  some surrounding normal mucosa en bloc with an electro-  cautery polypectomy snare and retrieve the specimen for  histopathologic examination. Residual adenomatous tissue  at the margins of the resection site can be ablated with con-  tact thermal or noncontact argon plasma coagulation. After  resection, a short polyethylene pancreatic stent is placed to  minimize the risk of post-procedural pancreatitis, and many  endoscopists also place a biliary stent if a sphincterotomy has  not been performed (Plates 82, 83, and 84). The stents are  endoscopically removed about 1 month later, and the site is  inspected for residual adenoma. Surveillance endoscopy with  a duodenoscope is offered every 6-12 months.   Accurate preoperative diagnosis and staging of papillary  malignancies is essential. ERCP with biopsies and endoscopic  ultrasound is the current accepted approach for diagnosis and  staging of local invasion and assessment of lymph node status.    ▲ Figure 35-2. MRCP image showing small distal  common bile duct stones during late pregnancy.   Inoperable ampullary cancer causing biliary obstruction is  best treated by sphincterotomy into the unaffected bile duct if  feasible, or by placement of a self-expanding metal stent.   Kahaleh M, Shami VM, Brock A, et al. Factors predictive of malig-  nancy and endoscopic resectability in ampullary neoplasia. Am  J Gastroenterol. 2004;99:2335-2339. [PMID: 15571579]   The sphincter of Oddi is a complex muscular structure that  surrounds the distal pancreatic duct, bile duct, and ampulla of  Vater. This sphincter mechanism lies mostly within the duo-  denal wall and measures 6-10 mm in length. Functionally, the  sphincter of Oddi is independent from the duodenal smooth  muscle system. It serves to prevent reflux of duodenal con-  tents into the ductal system and controls the flow of bile and  pancreatic juice into the duodenum.   Sphincter of Oddi dysfunction (SOD) describes an abnor-  mality within the sphincter, either motility related (dyskinesia  or spasm) or structural (stenosis), and can involve the biliary  sphincter, the pancreatic sphincter, or both. Patients typically  present with episodic pancreatic-type epigastric pain radiating  to the back and associated with hepatic or pancreatic enzyme  abnormalities or frank acute pancreatitis (pancreatic-type  SOD) or, more commonly, are postcholecystectomy and expe-  rience abdominal pain similar to the preoperative pain of sus-  pected biliary origin (biliary-type SOD). Each type of SOD  has three subtypes:   • Biliary-I patients have biliary-type pain, abnormal liver  enzymes (alanine aminotransferase and aspartate amino-  transferase values greater than twice normal) documented  on two or more occasions, delayed drainage of ERCP con-  trast greater than 45 minutes, and dilated common bile duct  greater than 12 mm diameter.   ' Biliary-II patients have biliary-type pain but only one or  two of the preceding criteria.   ' Biliary-III patients have only biliary-type pain and no  other abnormalities.   • Pancreatic-I patients have recurrent pancreatitis or typical  pancreatic pain, elevated pancreatic enzymes 1.5-2 times  the upper limit, dilated pancreatic duct greater than 6 mm  in the head and 5 mm in the body, and delayed contrast  during ERCP more than 9 minutes.   Pancreatic-II patients have pancreatic pain and one or  two of the above criteria.   Sphincter function can be evaluated by noninvasive meth-  ods that include hepatobiliary scintigraphy, ultrasound  assessment of pancreatic and bile duct after secretin or chole-  cystokinin stimulation, and secretin-stimulated MRCP. The  gold standard diagnostic test for SOD, however, is manomet-  ric assessment of basal sphincter pressure by sphincter of  Oddi manometry (SOM), which involves the use of solid state   or perfusion low-compliance catheters that can measure the  biliary and pancreatic sphincter pressures through ports  located at the distal end. Multiple station pull-throughs are  performed and graphic recording of the pressures are dis-  played on a dedicated workstation. The patient must be  sedated for the procedure but narcotics and smooth muscle  relaxants are usually avoided as they may interfere with the  recordings. A basal sphincter pressure greater than 40 mm Hg  above duodenal pressure is considered abnormal, and sphinc-  terotomy is the current standard treatment of choice for SOD  in the appropriate clinical setting.   Symptomatic patients with type I SOD benefit from  sphincterotomy (90-100%) irrespective of the manometry  findings. Thus, manometry is not required for this group of  patients. In type II SOD, 85-95% of patients with elevated  basal sphincter pressure will benefit from sphincterotomy.  Patients with type III SOD and elevated basal sphincter pres-  sure on SOM may benefit form sphincter ablation in 55-65%  of cases.   The rate of complications is high in patients undergoing  endoscopic sphincterotomy for SOD and can vary between  10% and 22%, with pancreatitis as the most common. The  risk of pancreatitis is minimized by temporary stenting of  the pancreatic duct.   Bile duct stones occur in up to 15% of symptomatic patients  with cholelithiasis and in up to 2% of cholecystectomies per-  formed for acalculous biliary disease. Patients may present   with abdominal pain of biliary origin (erroneously termed bil-  iary colic), cholangitis, jaundice, pancreatitis, transient eleva-  tion of transaminases, or filling defect with or without biliary  ductal dilation on imaging studies such as transabdominal  ultrasound, computed tomography (CT), and MRCP. When  choledocholithiasis is suspected, therapy is directed toward  extraction of the stones from the biliary tree to minimize seri-  ous complications such as severe pancreatitis, sepsis, and  death. Stone extraction can be achieved endoscopically, surgi-  cally, or by the transhepatic approach radiologically.   Endoscopic removal of bile duct stones is the first-line  therapy of choice in centers that have expertise in this tech-  nique (Figure 35-3). Since the first descriptions of endo-  scopic sphincterotomy in 1974, the role of ERCP in the  management of bile duct stones has undergone tremendous  growth. The standard techniques of stone extraction can  achieve success in up to 90% of bile duct stones. The remain-  ing 10% of cases require more advanced techniques. Patients  receive moderate sedation or monitored anesthesia prior to  therapeutic ERCP and, in some high-risk patients, full gen-  eral anesthesia with endotracheal intubation will be neces-  sary. Access to the bile duct by deep cannulation is  mandatory in order to achieve endoscopic therapy. When  biliary access is difficult there are several technical options to  gain entry to the bile duct, including access papillotomy.  Once stones are identified on a cholangiogram, a biliary  sphincterotomy (incision of the intraduodenal portion of  the common bile duct sphincter muscle) is usually per-  formed to the maximum extent of endoscopic landmarks  and under direct endoscopic guidance and is achieved with a  bow-type sphincterotome, a catheter carrying a cutting elec-  trosurgical wire at its distal end.   ▲ Figure 35-3. ERCP images showing (A) bile duct stones being extracted by (B) basket.   Multivariate analysis of large series of sphincterotomies  has shown that five risk factors for complications are significant:  suspected SOD, cirrhosis, difficult bile duct cannulation, precut  (access) papillotomy, and use of a combined percutaneous-  endoscopic procedure. The rate of complications was highest  when the indication for the procedure was suspected SOD  (22%) and lowest when the indication was removal of bile  duct stones within 30 days of laparoscopic cholecystectomy  (5%). Endoscopists who performed more than one sphinc-  terotomy per week had lower rates of all complications (8.4%  vs 11.1%, P= 0.03) and severe complications (0.9% vs 2.3%,  P = 0.01) than those who did less then one per week.   As an alternative to sphincterotomy, endoscopic balloon  dilation of the papilla was introduced in the 1980s. This  involves the use of a hydrostatic balloon positioned across  the papilla and inflated under high pressure while dilation is  monitored fluoroscopically. The potential advantages over  endoscopic sphincterotomy are preservation of the sphincter  and possible reduction of long-term complications.   When comparing endoscopic balloon dilation with sphinc-  terotomy in the treatment of bile duct stones, there are similar  outcomes in overall complications and success rates but higher  rates of post-procedural pancreatitis with balloon dilation  (7.4% vs 4.3%) and some mortality. Mechanical lithotripsy is  also required more frequently after balloon dilation (20.9% vs  14.8%, P= 0.014). This technique is used regularly in Southeast  Asia without high morbidity, but because there seems to be an  increased incidence of adverse events in Western populations,  balloon dilation of papilla cannot be recommended as the rou-  tine first-line option in the management of bile duct stones.  Balloon dilation of a prior sphincterotomy may, however, be  safer than repeated sphincterotomy.   Unless temporary drainage, only, is considered expedient,  an attempt at stone extraction should always be made after a  biliary sphincterotomy. The most commonly used acces-  sories for this purpose are balloon catheters and metal wire  baskets (see Figure 35-3). Stones larger than 15 mm present  a challenge and often require additional endoscopic tech-  niques such as mechanical, electrohydraulic, or laser  lithotripsy. When complete stone removal fails, insertion of a  biliary stent provides temporary drainage, minimizing the  risk of biliary sepsis before further endoscopic attempts at  duct clearance can be made. Long-term biliary drainage in  the old or frail patient has now been questioned as a safe  alternative to clearance because the cholangitis and cholecys-  titis rates are unacceptably high.   Hepatolithiasis, the presence of stones in the intrahepatic  biliary tree above the hepatic duct confluence, is difficult to  treat and poses a major challenge to the endoscopist in coun-  tries where is this is common. Surgery is often required but  rarely solves the problem as stone recurrence is high.   Disario JA, Freeman ML, Bjorkman DJ, et al. Endoscopic balloon  dilation compared with sphincterotomy for extraction of bile  duct stones. Gastroenterology. 2004;127:1291-1299. [PMID:  15520997]   When patients present with the combined problem of gall-  stones in the gallbladder and bile duct simultaneously, there  are two questions to answer: (1) what is the best method for  clearing the bile duct, and (2) what should be done with the  gallbladder? The sequential options are (1) laparoscopic  cholecystectomy with laparoscopic bile duct exploration,  (2) laparoscopic or open cholecystectomy followed by postop-  erative ERCP, (3) preoperative ERCP followed by cholecys-  tectomy (laparoscopic or open), (4) open cholecystectomy  with open exploration of the bile duct, (5) ERCP and no  cholecystectomy, and, in special circumstances, (6) a range of  additional and much less commonly used surgical and non-  surgical techniques such as percutaneous cholecystostomy,  percutaneous access to the bile duct (including percutaneous  cholangioscopy), techniques for Mirizzi syndrome, manage-  ment of hepatolithiasis, and approaches to recurrent stones  after biliary and nonbiliary upper gastrointestinal surgery. It  is unlikely that one option will be appropriate for all clinical  circumstances in all centers in all countries because the vari-  ables of disease states, patient demographics, and risk strati-  fications; available endoscopic, radiologic, and surgical  expertise; patient preferences; and health care economics will  all have significant influences on practice.   In patients with contemporaneous cholelithiasis and  choledocholithiasis, it is usually the latter that dominates the  acute clinical presentation and leads to intervention for pain,  obstructive jaundice, cholangitis, pancreatitis, or any combi-  nation thereof. Less commonly, asymptomatic bile duct  stones are discovered incidentally on noninvasive imaging for  nonbiliary indications, during evaluation of symptomatic  cholelithiasis, or intraoperatively during cholecystectomy.  Since the universal adoption of laparoscopic cholecystectomy  as the primary method for treating cholelithiasis in the early  1990s, only a minority of surgeons have mastered the tech-  niques required for laparoscopic transcystic or direct chole-  dochal exploration to treat choledocholithiasis and there has  been some reluctance to convert to open bile duct exploration  for this indication. Since ERCP has become the standard  approach for acute presentations of choledocholithiasis in the  1980s and with the overall success of endoscopic bile duct  clearance, the question of treating choledocholithiasis surgi-  cally has become a secondary issue.   Although there is evidence that elective and emergent  clearance of the bile duct by ERCP had advantages over open  bile duct exploration, the comparison of ERCP therapy with  laparoscopic bile duct clearance is much more equivalent for  most stones in the elective setting. Unfortunately, this surgi-  cal option is not always available and the evidence is there-  fore tempered by local expertise. Following endoscopic bile  duct clearance, the decision to leave the gallbladder in situ  and follow the patient expectantly (option 5, earlier) com-  pared with routine laparoscopic cholecystectomy has been  questioned as there is an unacceptably high incidence of  cholecystitis unless the gallbladder is empty. Where the   expertise is available, elective management of cholelithiasis  and choledocholithiasis by the laparoscopic approach is opti-  mal. The role for ERCP in acute calculous disease remains  central to the management of biliary disease.   Carr-Locke DL. Cholelithiasis plus choledocholithiasis: ERCP  first, what next? Gastroenterology. 2006;130:270-272. [PMID:  16401489]   First described by Mirizzi in 1948, this syndrome is a rare  complication of gallstone disease and refers to stone  impaction in the neck of the gallbladder or the cystic duct,  with subsequent inflammation and extrinsic compression of  the main bile duct leading to obstructive jaundice and  cholangitis (Figure 35-4). Type I refers to extrinsic compres-  sion of the main bile duct secondary to a stone in the cystic  duct or gallbladder, and type II occurs when there is chole-  cystocholedochal fistula.   Treatment of Mirizzi syndrome has traditionally been  surgical. Endoscopic management consists of drainage and  decompression of the bile duct or gallbladder, or both, prior  to surgical intervention but can be definitive if the impacted  stone can be fragmented and removed.   Benign biliary strictures have many causes, with the most  common being anastomosis, operative injury, and chronic  pancreatitis. Patients present with cholestasis, cholangitis, or,  rarely, secondary biliary cirrhosis. In the past, surgical man-  agement was the standard approach, with an associated mor-  bidity and mortality, but currently endoscopic therapy with   ▲ Figure 35-5. ERCP sequence showing (A) benign biliary  stricture and (B) placement of multiple plastic stents.   dilation and stenting offers a less invasive and an effective  line of therapy (Figure 35-5). The insertion of multiple bil-  iary stents, to achieve maximum dilation for the diameter of  the bile duct distal to the stricture, has gained increasing  acceptance and carries a 90% success rate in the short term  with a less than 10% complication rate. The use of self-  expanding metal stents in benign bile duct strictures has not  been advocated until the recent availability of covered stents,  which are potentially removable.   Catalano MF, Linder JD, George S, et al. Treatment of symptomatic  distal common bile duct stenosis secondary to chronic pancre-  atitis: comparison of single vs. multiple simultaneous stents.  Gastrointest Endosc. 2004;60:945-952. [PMID: 15605010]   Costamagna G, Pandolfi M, Mutignani M, et al. Long-term results  of endoscopic management of postoperative bile duct strictures  with increasing numbers of stents. Gastrointest Endosc.  2001;54:162-168. [PMID: 11474384]   Biliary obstruction secondary to malignant bile duct stricture  of pancreatic, biliary, or metastatic origin is now usually palli-  ated by stent placement. Polyethylene plastic stents are placed  into the bile duct of patients with tumors that may be surgi-  cally resectable, and during initial evaluation when histologic  or cytologic findings are not yet available. Patients with locally  advanced and metastatic tumors of biliopancreatic origin and  those who are poor surgical candidates are suitable candidates  for metal stents (Figure 35-6). Self-expandable metal stents  (SEMS) are commonly used for their ease of deployment, high  patency rate, and cost- effectiveness despite the high cost of  individual stents, because the reintervention rate is drastically  reduced compared with plastic stents. Metal stents remain  patent twice as long as polyethylene stents, a median of about  270 days versus 125 days. Unlike plastic stents, SEMS occlude  not from a bacterial biofilm but from tumor ingrowth or over-  growth, tissue hyperplasia at the ends of the stent, and migra-  tion. Uncovered SEMS have a higher occlusion rate but lower  migration rate compared with covered ones.   Tissue sampling of bile duct strictures is important in  defining their nature (benign vs malignant) and can be  achieved by forceps biopsy, brush cytology, and needle aspira-  tion. Biliary brush cytology is the most common method of  sampling and has low sensitivity of 30-60% but a specificity of  over 90%. The sensitivity for brush cytology is higher for pri-  mary bile duct tumors (80-86%) and when combined with   biopsies of the stricture (63%). Additional molecular tech-  niques such as fluorescence in situ hybridization, digital image  analysis, and flow cytometry may improve accuracy.   Arguedas MR, Heudebert GH, Stinnett AA, et al. Biliary stents in  malignant obstructive jaundice due to pancreatic carcinoma: a  cost-effectiveness analysis. Am } Gastroenterol. 2002;97:898-904.  [PMID: 12003425]   Baron TH, Harewood GC, Rumalla A, et al. A prospective compar-  ison of digital image analysis and routine cytology for the iden-  tification of malignancy in biliary tract strictures. Clin  Gastroenterol Hepatol. 2004;2:214-219. [PMID: 15017605]   Carr- Locke DL. Metal stents for distal biliary malignancy: have we  got you covered? Gastrointest Endosc. 2005;61:534-536. [PMID:  15812405]   Injury to the bile duct is a well-recognized complication of  cholecystectomy. Postoperative bile leak occurs in up to 0.5%  of patients after open cholecystectomy and up to 1% after  laparoscopic cholecystectomy, and cystic duct leaks are the  most common type. Patients may present with abdominal  pain, abdominal tenderness, fever, and continued drainage  through a drain when present. ERCP is the most accurate  technique in defining the biliary anatomy, delineating the site  of the leak, and providing definitive therapy (Figure 35-7),  which is highly successful. Endoscopic therapy is most com-  monly achieved by stent placement to decrease the pressure  gradient between the bile duct and duodenum, allowing  preferential flow of bile through the transpapillary route and  sealing of the leak site. The stent does not have to cross the  leak site unless there is a major bile duct injury.   A Figure 35-6. ERCP images showing (A) malignant biliary obstruction and (B) placement of a self-expanding  metallic stent.   Choledochal cysts are congenital anomalies typically seen in  children and young adults but can be diagnosed at any age.  They may affect the intrahepatic biliary tree, extrahepatic bil-  iary tree, or both. They occur in 1 in 13,000 to 1 in 2,000,000  live births and are three times more common in females than  in males.   The cysts are commonly classified into five types, with  type I the most common and type V the least. Type I  (80-90%) involves the extrahepatic bile duct and is subclas-  sified into IA (common type), IB (segmental dilation), and  IC (diffuse dilation). Type II (2%) is a diverticulum in the  main bile duct. Type III cysts (1.4-5%) involve the intraduo-  denal portion of the bile duct and are also referred to as  choledochoceles. Type IV (13%) is the second most common  type and more frequently seen in adults. It is subclassified  into IVA (multiple intrahepatic and extrahepatic cysts) and  IVB (multiple extrahepatic cysts). Type V (< 1%), or Caroli  disease, refers to single or multiple dilations of intrahepatic  bile ducts (Figure 35-8).   Anomalous pancreatobiliary union (APBU) is frequently  associated with a long common channel (> 15 mm). The  risk of biliary malignancy (gallbladder and bile duct) is  increased when APBU is present, with an overall risk of 14%  in patients with choledochal cysts and 50% in those with-  out. The classic presenting symptoms and signs of jaundice,  abdominal mass, and pain are more common in children  than adults (82% vs 25%, respectively). Adults often present  with vague abdominal pain, cholecystitis, cholangitis, and  pancreatitis.   Many choledochal cysts are detected on imaging studies  such as abdominal ultrasonography and CT scan done for  other reasons. ERCP usually establishes the diagnosis, classi-  fies bile duct cysts, and detects the presence of APBU, but  MRCP is increasingly being used as a noninvasive imaging  modality as it has an accuracy rate of 96% for choledochal  cyst detection.   Surgical management (cyst excision and biliary recon-  struction) is the recommended approach for all except  type III cysts to avoid the risk of biliary tract malignancy.  Management of choledochocele by biliary sphincterotomy  has been recommended.   ▲ Figure 35-7. ERCP images showing (A) bile leak  after partial left hepatectomy, (B) treatment by a short  10-French plastic stent, and (C) no leak present at the  time of stent removal.   The goal of therapeutic ERCP in the setting of acute gallstone  pancreatitis is to clear the bile duct of stones that, if left in  place, may worsen the severity of pancreatitis and increase the  risk of further attacks. The role of urgent ERCP and sphinc-  terotomy in gallstone pancreatitis has clearly been shown to  improve morbidity and mortality in patients with severe  attacks but has little or no benefit in patients with mild  pancreatitis as the majority of these patients pass the stones   ▲ Figure 35-8. ERCP images of choledochal cysts. A: Type 1 with anomalous union of the bile and pancreatic ducts.  B: Type 5 with a single large intrahepatic cyst.   spontaneously and recover with supportive care. Meta-analyses  of all randomized prospective studies have shown that ERCP  with endoscopic sphincterotomy reduces morbidity and mor-  tality of patients with acute biliary pancreatitis, and treating  26 such patients is predicted to save one life. Tables 35-1 and  35-2 summarize the results. Cholecystectomy should be  planned for the same admission, if possible, but can be   Acosta JM, Katkhouda N, Debian KA, et al. Early ductal decom-  pression versus conservative management for gallstone pancre-  atitis with ampullary obstruction: a prospective randomized  clinical trial. Ann Surg. 2006;243:33-40. [PMID: 16371734]    a Data from Neoptolemos JP, Carr-Locke DL, London NJ, et al. Controlled trial of urgent endoscopic retrograde  cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis  due to gallstones. Lancet. 1988;2:979-983.   b Data from Fan ST, Lai EC, Mok FP, et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy.  N Engl J Med. 1993;328:228-232.   c Data from Nowak A, Marek TA, Nowakowska-Dulawa E, et al. Biliary pancreatitis needs endoscopic retrograde  cholangiopancreatography with endoscopic sphincterotomy for cure. Endoscopy. 1998;30:A256-A259.  d Data from Folsch UR, Nitsche R, Ludtke R, et al. Early ERCP and papillotomy compared with conservative treat-  ment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. N Engl J Med.  1997;336:237-242.  e P < .05 compared with conventional treatment.   a Data from Neoptolemos JP, Carr-Locke DL, London NJ, et al. Controlled trial of urgent endoscopic retrograde  cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis  due to gallstones. Lancet. 1988;2:979-983.   b Data from Fan ST, Lai EC, Mok FP, et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy.  N Engl J Med. 1993,328:228-232.   c Data from Nowak A, Marek TA, Nowakowska-Dulawa E, et al. Biliary pancreatitis needs endoscopic retrograde  cholangiopancreatography with endoscopic sphincterotomy for cure. Endoscopy. 1998;30:A256-A259.  d Data from Folsch UR, Nilsche R, Ludtke R, et al. Early ERCP and papillotomy compared with conservative treat-  ment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. N Engl J Med.  1997;336:237-242.  e P < .05 compared with conventional treatment.   ERCP plays a role in delineating and treating those patients  with pancreatic-type SOD presenting with unexplained pan-  creatitis and other rarer causes of pancreatitis, such as  ampullary adenoma, pancreas divisum, autoimmune disease,  rare tumors, and helminths if not detected by noninvasive  imaging.   Chronic pancreatitis is a progressive disease characterized by  persistent inflammation, fibrosis, atrophy of the gland, and  ductal abnormalities. Chronic pancreatitis causes significant  morbidity related to chronic abdominal pain, loss of  exocrine and endocrine function, and complications such as  pancreatic stones, strictures, and fluid collections.   Pancreatic duct pressure may be elevated secondary to  strictures, stones, or outflow obstruction at the level of the  major papilla. The goal of therapeutic ERCP is to decom-  press the pancreatic ductal system and relieve the obstruc-  tion with the hope of minimizing attacks of recurrent  pancreatitis and alleviating chronic abdominal pain.   Benign strictures and stone disease of the main pancreatic  duct (Figure 35-9) can result in ductal hypertension, which  may be the basis of relapsing pain and recurrent pancreatitis.  Strictures are treated by balloon or catheter dilation and inser-  tion of one or more plastic stents that are exchanged every 2-4  months for up to 1 year. Stone extraction is technically feasible   if the stones are small, few in number, located in the head of  the pancreas, and not impacted. A pancreatic sphincterotomy  is usually required, and the stones are removed with a basket  or balloon. Stones located in the upstream duct proximal to a    ▲ Figure 35-9. ERCP showing chronic pancreatitis with  narrowed main duct in the head, ectatic side branches,  and an irregular dilated main pancreatic duct in the body  and tail. A transgastric stent is in place.   stricture require stricture dilation prior to extraction. Direct  pancreatoscopy and electrohydraulic lithotripsy of pancreatic  duct stones has been advocated as an additional option, and  extracorporeal shock wave lithotripsy in treatment of refrac-  tory stones has also been used successfully. Most studies have  shown an overall long-term improvement in about 67% of  patients who undergo endoscopic therapy.   Rosch T, Daniel S, Scholz M, et al. Endoscopic treatment of  chronic pancreatitis: a multicenter study of 1000 patients with  long-term follow-up. Endoscopy. 2002;34:765-771. [PMID:  12244496]   Pancreatic duct disruption and fluid collections can be the  result of acute or chronic pancreatitis. A pseudocyst is a  collection of amylase-rich pancreatic juice enclosed by a  wall of nonepithelialized, fibrous, or granulation tissue.  Symptomatic pseudocysts may be drained percutaneously  (radiologically), surgically, or endoscopically. Endoscopic  drainage of pancreatic pseudocysts and pancreatic necrosis  can be performed by using transpapillary or transmural  (transgastric, transduodenal) placement of endoprostheses.  The transpapillary approach is utilized for pseudocysts com-  municating with the main pancreatic duct, with the tip of the  stent positioned in the cyst cavity after a pancreatic sphinc-  terotomy. Fluid collections not clearly communicating with  the pancreatic duct are drained using the transmural  approach. The goal is to establish a communication between  the cyst cavity and gastric or duodenal lumen for continuous  drainage of pancreatic juice. The major prerequisite for such  a procedure is a distance between the cyst and gastrointesti-  nal tract of 10 mm or less and an obvious bulge on  endoscopy or a "window" for needle puncture demonstrated  on endoscopic ultrasound (Figure 35-10, Plates 85 and 86),  which also permits detection of varices or other vascular  structures (eg, pseudoaneurysm) that may impede access or  create a complication.   Hookey LC, Debroux S, Delhaye M, et al. Endoscopic drainage of  pancreatic-fluid collections in 1 16 patients: a comparison of eti-  ologies, drainage techniques, and outcomes. Gastrointest  Endosc. 2006;63:635-43. [PMID: 16564865]   Pancreas divisum, the failure of fusion of dorsal and ventral  pancreatic ductal systems during embryogenesis, is the most  common variant of pancreatic ductal anatomy and occurs in  about 10% of individuals (Plates 87, 88, and 89). The rela-  tionship between pancreas divisum and pancreatitis remains  controversial, but endoscopic therapy in patients with recur-  rent pancreatitis and a normal dorsal duct aims at decom-  pressing the dorsal pancreatic duct by minor papillotomy  and temporary stent insertion with greater than 80%   long-term success. These patients were the first group shown  to develop ductal changes resulting from stent therapy, and  care must be taken to avoid this complication by not leaving  stents in place longer than necessary.   Gerke H, Byrne MF, Stiffler HL, et al. Outcome of endoscopic  minor papillotomy in patients with symptomatic pancreas divi-  sum. SOP. 2004;5:122-131. [PMID: 15138333]   The first case of chronic inflammatory sclerosis of the pan-  creas with possible underlying autoimmune mechanism was  reported in 1961, but the terminology of "autoimmune pan-  creatitis" (AIP) was not proposed until 1995. The epidemiol-  ogy of AIP is not well known but a prevalence of 5% has been  reported among patients with chronic pancreatitis. The dis-  ease is more common in men in their late 50s. The coexistence  and association of AIP with other autoimmune diseases,  such as primary sclerosing cholangitis, Sjogren syndrome,  and diabetes mellitus, has been reported (see Chapter 27).  Diagnostic criteria include (1) pancreatic imaging studies  showing diffuse narrowing of the main pancreatic duct with  irregular walls and diffuse enlargement of the pancreas,  (2) laboratory data demonstrating abnormally elevated  levels of serum y-glcbulin, or immunoglobulin G, or the  presence of autoantibodies, and (3) histopathologic examination  of the pancreas showing fibrotic changes with lymphocyte  and plasma cell infiltration. For diagnosis of AIP, criterion 1 must  be present along with 2 or 3. There is currently no therapeu-  tic role for ERCP in this condition unless there is concomi-  tant biliary obstruction.   Nakazawa T, Ohara H, Sano H, et al. Cholangiography can dis-  criminate sclerosing cholangitis with autoimmune pancreatitis  from primary sclerosing cholangitis. Gastrointest Endosc.  2004;60:937-944. [PMID: 15605009]   Intraductal papillary mucinous neoplasm (IPMN) is a cystic  neoplasm of the pancreas that involves the main pancreatic  duct, side branches, or both. It is characterized by intraductal  growth of mucin-producing epithelium, segmental or diffuse  ductal dilation, and, when the tumor is in the head of the pan-  creas, a gaping or "fish-mouth" papilla from which large  amounts of mucus flow (Figure 35-1 1). Approximately 75%  of IPMNs arise from the main pancreatic duct in the head of  the pancreas, whereas the branch duct type most commonly  arises from the uncinate process or, less commonly, from the  tail of the pancreas. IPMN occurs more commonly in elderly  men who may present with recurrent pancreatitis and/or dia-  betes, laundice and weight loss can be the presenting symp-  toms in cases with malignant transformation.   Several imaging modalities are used to diagnose IPMN,  including CT, endoscopic ultrasound, magnetic resonance  imaging, and ERCP. A pancreatogram is usually remarkable    ▲ Figure 35-10. Sequence of pseudocyst drainage: (A) computed tomographic (CT) scan showing retrogastric  pseudocyst, (B) endoscopic ultrasound image with needle inside cyst, (C) balloon dilation of the cystgastrostomy  track, (D) double pigtail stents across cystgastrostomy stoma, and (E) follow-up CT scan showing resolution.  See also Plates 85 and 86.    ▲ Figure 35-11. ERCP in a patient with IPMN showing (A) a dilated main pancreatic duct with a mucus filling defect,  and (B) direct pancreatoscopy, which demonstrated the ductal tumor.   for dilated pancreatic ducts, intraluminal filling defects, and  mural nodules. During ERCP, pancreatic juice can be aspirated  for cytology, and transpapillary brushings and biopsies can be  obtained from suspicious lesions seen on pancreatography.  Direct pancreatoscopy involves the use of an ultrathin endo-  scope of 10-French diameter or less introduced through the  working channel of a duodenoscope and advanced into the  pancreatic duct through the major papilla. The ductal epithe-  lium can be examined, and directed biopsies of suspicious  mural nodules or masses can be performed. Pancreatoscopy   has been increasingly used as an adjunct to other imaging  modalities for diagnosis and determining the extent of IPMN,  because the tumor is easily seen as a "cluster of eggs" appear-  ance when it affects the main duct and surgical resection cur-  rently aims to be as conservative as possible.   Yasuda K, Sakata M, Ueda M, et al. The use of pancreatoscopy in  the diagnosis of intraductal papillary mucinous tumor lesions  of the pancreas. Clin Gastroenterol Hepatol. 2005;3:S53-S57.  [PMID: 16012998]   ► Endoscopic ultrasound (EUS) is a critical tool in cancer  staging and is superior to computed tomography (CT)  and positron emission tomography (PET), in esophageal  cancer staging.   ► EUS-guided fine needle aspiration (EUS-FNA) is the most  sensitive method for diagnosing pancreatic cancer; accu-  racy of EUS is similar to CT for assessing vascular invasion.   ► EUS helps evaluate submucosal lesions, although the  yield of EUS-FNA is lower for submucosal than for extra-  luminal lesions.   ► EUS is emerging as an important tool in diagnosing  chronic pancreatitis.   ► Diagnostic yield for EUS is similar to MRCP in detecting  choledocholithiasis, but initial EUS has the greatest  cost-utility.   Endoscopic ultrasound (EUS) has emerged as the premier  tool for staging cancers and has revolutionized the role of  gastrointestinal endoscopy in diagnostic imaging inside and  outside the gastrointestinal tract. EUS merges endoscopy,  which is limited to visualizing the lumen of the gastrointesti-  nal tract, with ultrasonography, which allows imaging of the  layers of the gastrointestinal wall and surrounding struc-  tures. Tissue diagnosis can be obtained with EUS-guided fine  needle aspiration (EUS-FNA), which uses a catheter with a  retractable needle that can be advanced into visualized tissue.  Exciting advances in the therapeutic application of EUS have  begun with this technique, including the well-established  endoscopic pseudocyst drainage and rendezvous techniques  with endoscopic retrograde cholangiopancreatography (ERCP)  as well as possibilities of EUS-guided fine needle injection  (EUS-FNI) therapy.   Radial scanning echoendoscopes were the first instruments  used with the advent of EUS in the 1980s (Figure 36-1). The  ultrasound transducer is mounted on the tip of the endoscope  and rotates 360 degrees to provide cross-sectional images per-  pendicular to the long axis of the endoscope (Figure 36-2).  The endoscopic viewing optic is mounted proximal to the  ultrasound transducer and provides an oblique view of the  lumen. To overcome the problem of ultrasound waves travel-  ing through an air-filled lumen, a balloon that can be filled  with water surrounds the ultrasound transducer. Various  ultrasonic frequencies between 5 and 20 MHz are used.   Linear array echoendoscopes provide ultrasound images  along the long axis of the endoscope usually in an 80- to  105-degree arc (Figures 36-2 and 36-3). This is critical to  allow simultaneous imaging of the needle and target lesion  during EUS-FNA. A variety of needles, including 19-, 22-, and  25-gauge, can be passed through the endoscopic working  channel.   In high-frequency ultrasound probe sonography, a  catheter with a tiny mechanically rotating ultrasound trans-  ducer at the tip is inserted through the endoscopic working  channel (Figure 36-4). The probe images with frequencies  between 12 and 30 MHz, and higher resolution allows for  more detailed imaging but with decreased depth of penetra-  tion. Newer generation probes include wire-guided probes  that can be introduced into the biliary and pancreatic ducts  to perform intraductal ultrasound.   Typically a standard upper endoscopy or flexible sigmoi-  doscopy for a rectal EUS is performed before the EUS to  identify the area of interest and to ensure the echoendoscope  can be passed safely in the gastrointestinal tract. The echoen-  doscope is passed in a "blind" manner similar to the duo-  denoscope. Once the echoendoscope has been advanced to  the area to be imaged, a water interface is established between    ▲ Figure 36-1. A: Radial echoendoscope. B:  echoendoscope with balloon inflated.   the ultrasound transducer and the gastrointestinal wall. This  can be done by inflating the balloon on the tip of the trans-  ducer or by filling the gastrointestinal lumen with water, or  both. Once a sufficient water interface has been established,  EUS images should be obtained perpendicular to the lesion  of interest as oblique images commonly distort the gastroin-  testinal wall and lead to false interpretations.   EUS-FNA is performed with the linear echoendoscope.  The needle is advanced under endosonographic guidance  into the lesion of interest, the stylet is withdrawn, and suc-  tion may be applied using a 10- to 25-cc syringe while  advancing the needle back and forth within the lesion.   EUS imaging of the gastrointestinal wall layer typically reveals  five layers alternating in bright and dark bands (Figure 36-5).  The first bright or hyperechoic layer closest to the probe repre-  sents the superficial mucosa; the second dark or hypoechoic  layer corresponds to the deep mucosa or muscularis mucosa;  the third hyperechoic layer is the submucosa; the fourth hypoe-  choic layer is the muscularis propria; and the fifth hyperechoic  layer represents the serosa or adventitia. The normal thickness  of the gastrointestinal wall varies from 2 to 4 mm.   ▲ Figure 36-2. Imaging planes for radial and linear  echoendoscopes. The radial echoendoscope provides  images in a plane perpendicular to the long axis. The linear  echoendoscope provides images along the long axis in an  80-105-degree arc with fine needle aspiration capability.   Most cancers are staged according to the TNM system of the  American Joint Commission on Cancer. Depth or extent of  tumor invasion (T), presence or absence of locoregional  lymph nodes (N), and presence or absence of distant metas-  tases (M) are captured by the TNM system (Table 36-1).   As with many cancers, the prognosis of esophageal cancer  correlates with stage at diagnosis. Although the optimal  management of patients with locally advanced esophageal  cancer remains controversial, preoperative chemoradiation  appears to improve survival compared with surgery alone in  patients with stage lib or stage III cancer and possibly stage  Ha (Table 36-2). Thus, accurate staging is important to select   the appropriate patients for preoperative treatment. Multiple  studies have confirmed the superiority of EUS over CT in  T and N staging of esophageal cancer (Figure 36-6 and  Table 36-3). Both CT and fluorodeoxyglucose-positron  emission tomography (FDG-PET) identify more distant  metastases than EUS, and FDG-PET appears superior to CT.   Carcinoma in situ (Tis) is often not visible on EUS. With  the high-frequency ultrasound probes, Tl stage can be sepa-  rated into Tim (tumor confined to mucosa) and Tlsm  (tumor invading submucosa). About 8-35% of Tlsm tumors  have local lymph node metastases. Patients with stage Tlsm  cancer have a lower 5-year overall survival rate of 58% com-  pared with 91% for Tim; therefore, local endoscopic therapy  should not be performed for Tlsm lesions.   For each T stage, positive nodes increase the overall  tumor stage and predict a worse prognosis. EUS characteris-  tics suggestive of a malignant lymph node include size  greater than 1 cm, round, well defined, and hypoechoic.  Presence of all four features predicts malignancy in 80-100%  of cases, but only 20-40% of all malignant lymph nodes have  all four findings. FNA of lymph nodes improves accuracy of  nodal staging compared with EUS alone. If FNA is not pos-  sible, a recent study suggested the number of lymph nodes  might correlate with 5-year survival.   Metastasis to celiac axis lymph nodes portends a poor  prognosis and upstages the tumor to Ml. In one study celiac  axis lymph nodes greater than 1 cm were all malignant.  Nonetheless, FNA of these nodes should be performed given  their impact on management and survival.   Restaging of esophageal cancer following chemoradiation  with EUS is significantly less accurate than pretreatment  staging. Accuracy of T staging is about 37-60%, and the  majority of tumors are overstaged presumably due to peritu-  mor inflammation and fibrosis being mistaken for tumor.  Reduction in the cross-sectional area or thickness of the  tumor by more than 50% has been associated with response  to treatment and possibly improved survival.   The clinical impact of EUS on management of esophageal  cancer has been demonstrated in several studies. Treatment  strategy was changed in about 75% of patients following    Table 36-3. Accuracy of imaging modalities for T and N  staging of gastrointestinal cancers.   ▲ Figure 36-6. EUS images of esophageal cancer.  A: Stage T1. B: Stage T2. C: Stage T3.   CT, computed tomography; EUS, endoscopic ultrasound; FNA, fine  needle aspiration; MRI, magnetic resonance imaging; PET, positron  emission tomograph.   EUS-FNA, and performance of EUS was associated with  increased recurrence-free survival and overall survival. This  was attributed to greater use of chemoradiation following  more accurate preoperative staging with EUS.   Kelly S, Harris KM, Berry E, et at. A systematic review of the staging  performance of endoscopic ultrasound in gastro-oesophageal  carcinoma. Gut. 2001;49:534-539. [PMID: 11559651]   Liu L, Hofstetter WL, Rashid A, et al. Significance of the depth of  tumor invasion and lymph node metastasis in superficially  invasive (Tl) esophageal adenocarcinoma. Am ] Surg Pathol.  2005;29:1079-1085. [PMID: 16006804]   Pfau PR, Perlman SB, Stanko P, et al. The role and clinical value of  EUS in a multimodality esophageal carcinoma staging program  with CT and positron emission tomography. Gastrointest  Endosc. 2007;65:377-384. [PMID: 17321235]   Ribeiro A, Franceschi D, Parra J, et al. Endoscopic ultrasound  restaging after neoadjuvant chemotherapy in esophageal cancer.  Am J Gastroentrol. 2006;101:1216-1221. [PMID: 16771940]   With a recent study demonstrating improved survival in  patients who underwent perioperative chemotherapy with  at least stage II operable gastric adenocarcinoma, preopera-  tive staging for gastric adenocarcinoma assumes more   importance. EUS appears similar to multidetector-row CT  and magnetic resonance imaging (MRI) for T and N stag-  ing. EUS-FNA of lymph nodes should increase accuracy for  N staging. As with esophageal cancer, EUS can identify  superficial mucosal tumors, which may be amenable to  endoscopic mucosal resection.   EUS-staging of gastric mucosa-associated lymphoid  tissue (MALT) lymphomas is 95% accurate for T staging and  seems to predict response to Helicobacter pylori treatment.  Complete remission occurs in 78% of patients with Tim dis-  ease compared with 12.5% of patients with Tlsm tumor.  Therefore, EUS may allow early selection of patients with  higher T stage disease for consideration of other treatments.   GastrointestEndosc. 2002;56(Suppl4):21-26. [PMID: 12269963]  Yasuda K. EUS in the detection of early gastric cancer. Gastrointest   Local recurrence of rectal cancer occurs in 10-40% of cases  despite surgical excision. Preoperative chemoradiation fol-  lowed by radical resection for tumors that have extended into  the perirectal fat or have local lymph nodes (T3/T4, Nl, or  both) decreases local recurrence by about half and possibly  improves survival. There are limited data on the benefits of  adjuvant chemoradiation in patients with unfavorable Tl or  T2 tumors. Tumor size greater than 3 cm, poorly differenti-  ated histology, and lymphovascular invasion are associated  with increased risk of lymph node metastases. Local recur-  rence can be as high as 11-29% for Tl tumors and 25-62%  for T2 tumors, which most likely reflects lymph node  involvement occurring in 0-12% of Tl and 12-28% of T2  tumors. Therefore, local excision, which does not remove the  mesorectum containing lymph nodes, rather than radical  resection should be performed in only select patients with  favorable Tl tumors.   Accurate staging of rectal cancer is again critical for  correct patient selection for the appropriate preoperative  and operative treatment. EUS remains superior to CT  for both T and N staging; however, the accuracy of EUS  appears comparable to endorectal coil MRI for both T and  N staging.   The modest accuracy of EUS for staging rectal cancer is  attributed to several factors, including inflammation sur-  rounding the tumor, leading to overstaging; operator expe-  rience; and level of tumor in the rectum, with distal lesions  being staged less accurately. In contrast to its utility for  esophageal cancer, EUS-FNA of regional lymph nodes in  rectal cancer does not appear to significantly improve accu-  racy of N staging. The greatest impact of EUS-FNA may  reside in early T-stage tumors which, if node positive, would  necessitate preoperative treatment. A recent study suggested  that antibiotics are not necessary for transrectal EUS-FNA  procedures due to low rates of bacteremia.   EUS-FNA may offer a powerful method to survey for  local recurrence of rectal cancer, which often occurs extralu-  minally following surgical resection. Standard endoscopy is  inadequate for detecting these recurrences, and CT scan is  limited due to artifacts from surgical metal clips and the  inability to differentiate between postoperative changes and  recurrence. Sensitivity of EUS for detecting recurrence is  91-100% compared with 82-85% for CT scan, with limited  specificity for EUS of 57% that improves to 93% with EUS-  FNA. There is no standard recommendation for surveillance  with EUS following surgical resection; however, the patients  who may benefit most include those with more advanced  stage tumors at diagnosis. The greatest risk of recurrence  occurs in the first 2 years following surgery; therefore, EUS  may be performed every 3-6 months during this time.   Bianchi P, Ceriani C, Palmisano A, et al. A prospective comparison  of endorectal ultrasound and pelvic magnetic resonance in the  preoperative staging of rectal cancer. Ann Ital Chir. 2006;  77:41-46. [PMID: 15910358]   Savides Tl, Master SS. EUS in rectal cancer. Gastrointest Endosc.  2002;56(Suppl4):12-18. [PMID: 12297742]   The role of EUS in pancreatic cancer includes diagnosis  (Figure 36-7) and staging. Tissue diagnosis is important to  confirm malignancy and rule out metastatic lesions to the  pancreas, which comprised 11% of masses referred for EUS-  FNA in one study. EUS-FNA is the most accurate diagnostic  modality, with 80-95% sensitivity and 100% specificity com-  pared with CT- or ultrasound-guided FNA, which have  sensitivity ranging from 62% to 81%. Diagnostic sensitivity  diminishes to 73% in the setting of chronic pancreatitis.  Presence of an onsite cytopathologist increases diagnostic  accuracy while reducing procedure time, number of needles  used, and overall procedure cost. EUS-FNA is favored because  of its accurate detection of small lesions less than 1.5 cm, and  because the needle tract along which seeding can theoretically  occur is resected for lesions in the pancreatic head. Tumor  spread along the needle tract was suspected in one case report  of a patient who developed recurrent cancer within the gastric  wall 16 months after complete resection of a T1N0M0 pancre-  atic tumor located in the pancreatic tail. Therefore, for poten-  tially resectable tumors located in the pancreatic body or tail,  the options of proceeding directly to surgery without a tissue  diagnosis versus EUS-FNA should be carefully considered.   The best outcome in pancreatic cancer occurs in patients  without nodal, vascular, or systemic metastases (5-year sur-  vival up to 25%). More accurate patient selection could reduce  unnecessary surgeries in patients with unresectable tumors. A  recent review of studies comparing EUS and CT for preoper-  ative staging of pancreatic cancer concluded that it is unclear  which modality is superior for both tumor and nodal staging.   EUS criteria for vascular invasion include abnormal ves-  sel contour, loss of hyperechoic interface between the tumor  and blood vessel, tumor in the vessel lumen, and presence of   collateral vessels in the absence of a main vascular structure.  Presence of any one of these criteria indicates vascular inva-  sion. A recent meta-analysis examining the accuracy of these  EUS criteria for assessing vascular invasion demonstrated 73%  sensitivity and 90% specificity. EUS is more reliable for evalu-  ating invasion into the portal vein and splenic confluence than  the superior mesenteric artery or vein. With recent advances in  helical CT and MRI, these modalities will most likely surpass  EUS for vascular staging. Initial staging should be performed  with pancreatic protocol CT scan. EUS will still have a poten-  tially important impact on staging through identifying and  sampling lymph nodes, ascites, and hepatic lesions.   Pancreatic neuroendocrine tumors are notoriously difficult  to diagnose, and EUS is particularly helpful in evaluating these  tumors (Figure 36-8). Because most insulinomas occur in the  pancreas, sensitivity of EUS is highest for these neuroendocrine  tumors at 83%. Gastrinomas and glucagonomas more com-  monly occur in extrapancreatic sites leading to decreased diag-  nostic sensitivity for EUS and a more important role in  diagnosis for somatostatin receptor scintigraphy, CT, and MRI.   Horwhat JD, Paulson EK, McGrath K, et al. A randomized com-  parison of EUS-guided FNA versus CT or US-guided FNA for  the evaluation of pancreatic mass lesions. Gastrointest Enclose.  2006;63:966-975. [PMID: 16733111]   Early detection of small hepatocellular carcinomas remains  problematic, with over 70% of lesions smaller than 1 cm  missed by MRI. Preliminary study of EUS in detecting early  hepatocellular carcinoma reports promising results. In one  study, patients with cirrhosis and at high risk for hepatocellular   carcinoma because of elevated oc-fetoprotein levels or abnor-  mal radiologic findings underwent ultrasound, CT, MRI and  EUS or EUS-FNA; diagnostic accuracy was 38%, 69%, 92%,  and 94%, respectively. EUS alone had a lower accuracy of  65% mainly due to poor specificity. Complications following  EUS-FNA of hepatic lesions occurred in about 4% of patients  and included bleeding, fever, and abdominal pain, and death  in one patient with obstructive jaundice who developed  cholangitis. Further studies are necessary to define the role  and safety of EUS-FNA in hepatocellular carcinoma.   Cholangiocarcinoma also remains a difficult diagnostic  dilemma. Several small studies suggest EUS-FNA is safe and  useful in diagnosing biliary strictures following negative  ERCP brush cytology, with sensitivity ranging from 43% to  86% and 100% specificity based on surgical pathology. EUS  finding of bile duct wall thickness of 3 mm or greater was  found to have 79% sensitivity and specificity. Intraductal  ultrasound (IDUS) offers data about depth of tumor inva-  sion and invasion into the pancreas and portal vein, with  accuracies greater than 85%. Therefore, EUS, EUS-FNA, and  probably IDUS should be included in the armamentarium  for evaluating potentially malignant biliary strictures.   DeWitt J, Misra VL, LeBlanc JK, et al. EUS-guided FNA of proximal   Gastrointest Endosc. 2006;64:325-333. [PMID: 16923477]  Inui K, Miyoshi H, Yoshino J, Bile duct cancers: what can EUS   Endoscopy. 2006;38(Suppl l):47-49. [PMID: 16802223]  Thuluvath PJ. EUS-guided FNA could be another important tool   The scope of EUS is not limited to the gastrointestinal tract,  and it can have a major impact on staging in lung cancer,  which remains the leading cause of cancer-related mortality  in the United States. As with gastrointestinal cancers, accu-  rate staging is critical in determining prognosis and appro-  priate treatment for patients with lung cancer. Standard  staging methods include CT, PET, transbronchial FNA, medi-  astinoscopy, and thoracoscopy. EUS-FNA can access areas  complementary to the other techniques, and 16% of thoraco-  tomies can be avoided by performing EUS-FNA in addition  to mediastinoscopy.   Fickling W, Wallace MB. EUS in lung cancer. Gastrointest Endosc.  2002;56(Suppl4):18-21. [PMID: 12544191]   For submucosal lesions, accurate preoperative diagnosis can  prevent unnecessary surgical resection of benign lesions.  Before EUS, this was difficult because submucosal lesions  grow underneath the mucosa and cannot be readily diag-  nosed by endoscopy and biopsy. EUS appears most useful for  differentiating submucosal lesions from extrinsic compres-  sion and for characterizing the submucosal lesion. Extrinsic  compression from adjacent organs or blood vessels is cor-  rectly differentiated from a submucosal lesion in 94% of  cases. Using EUS, the size, layer of origin, margins, and echo-  pattern of the submucosal lesion are determined; the layer of  origin and echotexture are most useful in suggesting a diag-  nosis (Table 36-4). Malignancy can be inferred from larger   lesions (> 3 cm) with irregular margins. EUS-guided FNA  has limited diagnostic yield with lower diagnostic accuracy  for submucosal (61% sensitivity, 79% specificity) compared  with extraluminal lesions (88% sensitivity, 95% specificity).   The most common submucosal lesion is a gastrointestinal  stromal tumor (GIST), which has a mesenchymal cell of ori-  gin. On EUS, GISTs are hypoechoic and typically arise from  the fourth muscularis propria layer (Figure 36-9). Presence  of an irregular border, cystic spaces, echogenic foci, and size  greater than 3 cm are suggestive of malignancy.   Lipoma is the second most common submucosal lesion  and may be readily diagnosed during endoscopy by its yel-  lowish hue and soft texture. If the diagnosis is unclear, EUS  should be performed; it will reveal a hyperechoic lesion aris-  ing from the third submucosal layer (Figure 36-10 and  Plate 90). Cysts are also easily diagnosed by EUS as anechoic  structures lying within the second or third layer.   ▲ Figure 36-10. EUS image of a lipoma. (For an endoscopic  view, see Plate 90.)   Carcinoids are mildly hypoechoic, homogeneous and typ-  ically arise from the first, second, or third layer (Figure 36-1 1  and Plate 91). Size is usually predictive of malignancy, and  they are usually benign if less than 2 cm. Other malignant  submucosal tumors include metastases, which are rare, and    ▲ Figure 36-11. EUS image of a rectal carcinoid. (For an  endoscopic view, see Plate 91.)   lymphomas, which may appear as hypoechoic heterogeneous  masses within the gastrointestinal wall.   A few other benign submucosal lesions include pancre-  atic rests and granular cell tumors. Pancreatic rests are sub-  mucosal deposits of ectopic pancreatic tissue that typically  occur in the antrum and have a characteristic umbilicated  appearance on endoscopy. On EUS, they appear hypoechoic  or heterogeneous, arise from the second, third, or fourth  layer and may contain ductal structures (Figure 36-12 and  Plate 92). Granular cell tumors are believed to arise from  neural tissue and appear heterogeneous within the third  submucosal layer.   Management of these submucosal lesions is guided by  their diagnosis, size, location, and potential for malignancy.  GISTs with several EUS features raising concern for malig-  nancy should be removed surgically. Smaller benign-appearing  GISTs may be observed, although the appropriate follow-up  interval is unknown. Lipomas should only be removed if  symptomatic. Carcinoids smaller than 2 cm confined to the  first three layers can be removed endoscopically, whereas  larger lesions involving the fourth muscularis propria layer  should be surgically resected.   Chak A. EUS in submucosal tumors. Gastrointest Endosc.  2002;56(Suppl 4):43-48. [PMID: 12297748]   Large gastric folds present a diagnostic dilemma that often  necessitates multiple diagnostic studies. The differential   diagnosis is broad and includes malignant and benign  conditions (Table 36-5). Endoscopic appearance does not  usually enable differentiation between malignant and benign  conditions, and superficial mucosal biopsies may miss a malig-  nancy. Snare resection or cap-assisted endoscopic mucosal  resection increases diagnostic yield from 17% to 87% but  carries an increased risk of complications from bleeding and  potentially perforation.   Few studies exist examining the utility of EUS in evaluat-  ing a thickened gastric wall (Figure 36-13). The main pre-  dictor of malignancy is thickening of the deep gastric layers,  including submucosa, muscularis propria, and serosa,  whereas enlargement of the superficial mucosal layers is  associated with benign conditions or MALT lymphoma,  which is usually readily diagnosed with biopsies. Ascites and  lymph nodes are present in over 60% of patients with gastric  wall thickening from malignancy.   Gines A, Pellise M, Fernandez-Esparrach G, et al. Endoscopic  ultrasonography in patients with large gastric folds at  endoscopy and biopsies negative for malignancy: predictors of  malignant disease and clinical impact. Am J Gastroenterol.  2006;101:64-69. [PMID: 16405535]   Pancreatic cysts are increasingly discovered as abdominal  imaging studies have improved in quality and have become  more frequently utilized. These lesions are often of unclear  clinical significance and pose a diagnostic dilemma.  Pseudocysts account for the majority of pancreatic cysts  while an increasing minority is pancreatic cystic neoplasms,  which may be benign serous cystadenomas or premalignant  or malignant mucinous lesions that include mucinous cys-  tadenomas or intrapapillary mucinous neoplasm (IPMN).  Therefore, it is important to differentiate among these dif-  ferent cysts.   Serous cystadenomas occur anywhere throughout the  pancreas typically in women over the age of 60 years. On  radiology or EUS imaging, they usually appear microcystic    A Figure 36-13. EUS images of the gastric wall. A: Normal  gastric wall. B: Thickened gastric wall.   and less commonly macrocystic or solid due to the presence  of numerous microcysts that give the appearance of a  homogeneous hypoechoic mass. A central calcification is  pathognomonic but is only seen in about 10% of serous cys-  tadenomas. Malignant transformation is very rare, and these  cysts can typically be followed.   Mucinous cystadenomas are premalignant lesions that  generally occur in women between 40 and 50 years old.   They typically appear macrocystic in the body and tail of  the pancreas with a rare, but pathognomonic, peripheral  eccentric calcification. IPMN is also a mucinous cystic neo-  plasm that arises from the pancreatic ductal epithelium and  communicates with the main duct, side branches, or both  (Figure 36-14). It occurs more commonly in men between  the ages of 50 and 60 years. About 40% of main-duct IPMNs  contain malignancy at the time of diagnosis. Features sug-  gestive of malignancy in side-branch IPMNs include pres-  ence of a mass, mural nodules, dilated main pancreatic duct,  and cyst size greater than 3 cm, although a recent study  demonstrated presence of malignancy in smaller cysts.   Accurate preoperative diagnosis of serous cystadenoma,  mucinous cystadenoma, and mucinous cystadenocarcinoma  using CT scanning occurs in about 20-30% of cases. MRCP  may be more helpful than endoscopic retrograde pancre-  atography (ERP) in diagnosing IPMN by delineating the  main pancreatic duct, side branches, and communicating  cystic lesions. EUS imaging alone is not sufficient to diagnose  pancreatic cystic lesions. EUS-FNA probably improves diag-  nostic yield for pancreatic cystic lesions; however, the opti-  mal cyst fluid markers remain unknown. Current evidence  suggests that carcinoembryonic antigen (CEA), CA 72-4, and  molecular markers may be most useful while cytology has  poor sensitivity and accuracy in differentiating mucinous  from nonmucinous lesions as well as benign from malignant  or premalignant lesions (Table 36-6). Molecular analysis of  pancreatic cyst DNA for mutations, including early k-ras  mutation followed by allelic loss and detection of telomerase  activity in pancreatic juice from IPMNs, have appeared  promising in detecting malignancy.   Further work is necessary to discover new and more accu-  rate markers of malignancy and mucinous cystic lesions as  pancreatic cystic lesions are increasingly uncovered on inci-  dental imaging studies.   Noh KW, Pungpapong S, Raimondo M. Role of endosonography  in non-malignant pancreatic diseases. World J Gastroenterol.  2007;13:165-169. [PMID: 17226895]   Diagnosis of chronic pancreatitis remains challenging, espe-  cially because there is no defined gold standard. Histology  may be considered the true gold standard; however, it is avail-  able in a minority of patients, sampling error may occur if  only a core biopsy specimen is obtained, and there is no con-  sensus on a histologic grading scale for severity of chronic  pancreatitis. ERP is less attractive as a diagnostic modality  due to its potential complications and decreased sensitivity  for early-stage chronic pancreatitis. In addition, the  Cambridge classification for ERP changes in chronic pancre-  atitis was based on expert consensus and has not been vali-  dated. Only one study has compared secretin-stimulated  functional studies with histology; it found accuracy of the  functional test to be 81%.   EUS is an attractive alternative diagnostic possibility due  to its relatively low morbidity and ability to assess both  parenchymal and ductal features. EUS criteria for chronic  pancreatitis include the following parenchymal and ductal  changes: hyperechoic foci, hyperechoic strands, lobulation,  cysts, calcifications, main duct dilation, main duct irregu-  larity, hyperechoic walls of the main duct, and visible side  branches (Figure 36-15). A recent retrospective study  noted that the presence of three or more EUS criteria had  83% sensitivity and 80% specificity for diagnosing chronic   pancreatitis using histology as the gold standard. The thresh-  old for diagnosing chronic pancreatitis can be varied  depending on whether one is trying to establish or exclude  the diagnosis. In the previous study, presence of five or  more criteria had 100% specificity. In a population at low  to moderate risk of chronic pancreatitis, EUS is most accu-  rate when unambiguously normal with two or fewer crite-  ria or abnormal with five or more criteria present. This is  especially true in elderly patients, in whom up to three EUS  criteria for chronic pancreatitis may be present without  actual pancreatic disease. Certain features including calcifi-  cation and lobulation are more indicative of chronic pan-  creatitis, and recently a weighted scoring system accounting  for these factors has been proposed.   The clinical significance of the presence of three or four  EUS criteria for chronic pancreatitis is unclear. The addition  of FNA does not appear to increase diagnostic yield for  chronic pancreatitis. A recent study comparing EUS and  MRCP using the gold standards of ERP, histology, or long-  term clinical follow-up of median 15 months demonstrated  higher sensitivity of 93% for EUS compared with 65% sensi-  tivity for MRCP, and similar specificity of 90-93%. The com-  bination of both studies yielded higher sensitivity and  specificity of 98% and 83%. Therefore, the less invasive  modalities of EUS and MRCP have largely supplanted ERCP  in the diagnosis of chronic pancreatitis.   Sahai AV. EUS and chronic pancreatitis. Gastrointest Endosc.  2002;56(Suppl4):76-81. [PMID: 12297754]   EUS has similarly proven to be a powerfully accurate and  safe method for detecting choledocholithiasis. A recent  meta-analysis of randomized controlled blinded trials com-  paring EUS and MRCP with the gold standard of ERCP or  intraoperative cholangiography in patients with suspected  bile duct stones demonstrated sensitivity for EUS and MRCP  of 93% and 85%, with similar specificities of 96% and 93%,  respectively. A cost-analysis study indicated that initial EUS  rather than MRCP had the greatest cost-utility by reducing  unnecessary ERCP procedures.   Mattery S, Matlock J, Freeman ML. EUS-guided rendezvous drainage  of obstructed biliary and pancreatic ducts: report of 6 cases.  Gastrointest Endosc. 2004;59:100-107. [PMID: 14722561]   Palazzo L, O'Toole D. EUS in common bile duct stones. Gastrointest  Endosc. 2002;56(Suppl4):49-57. [PMID: 12297749]   With the advent of EUS-FNA, a new realm of diagnostic pos-  sibilities was discovered, followed more recently by various  innovative therapeutic techniques. The following sections  discuss both well-established and more experimental thera-  peutic uses of EUS-FNA.   Celiac plexus neurolysis (CPN) refers to the permanent  destruction of the celiac plexus using absolute ethanol.  Temporary block of the plexus with corticosteroid injection  is termed celiac plexus block (CPB). Pancreatic pain is pre-  dominantly controlled by the celiac plexus. CPN using surgi-  cal and transcutaneous approaches has been used for many  years; however, major complications including paralysis  occur in about 1% of cases, which makes the endoscopic  approach a potentially more attractive option.   The EUS technique involves first flushing a 22-gauge nee-  dle with normal saline to clear the needle of air followed by  insertion of the needle 1 cm cranial and anterior to the take-  off of the celiac artery and aspiration to ensure no blood  returns. For CPN, 10 mL of 0.25% bupivacaine is injected fol-  lowed by 20 mL of 98% absolute ethanol. For CPB, 20 mL of  0.25% bupivacaine is injected followed by 80 mg of triamci-  nolone. This is a safe technique without reported incidences  of paralysis. Minor complications include transient diarrhea  in 4-15% of patients, transient increase in pain in 9%, and  transient orthostasis in 1%. Normal saline is administered  during the procedure, and patients should be monitored for  2 hours post-procedure for orthostasis. Major complications  include retroperitoneal bleed and peripancreatic abscess.   EUS-CPN in pancreatic cancer reduces pain scores in  78% of patients, which is similar to the results with surgical  and transcutaneous neurolysis. The response rate and dura-  bility are lower for EUS-CPB in chronic pancreatitis, with   55% response rate at 8 weeks, which decreases to 10% at  24 weeks. Pain reduction lasts about 20 weeks following  EUS-CPN in pancreatic cancer compared with 2 weeks for  chronic pancreatitis with EUS-CPB.   Hoffman BJ. EUS-guided celiac plexus block/neurolysis. Gastrointest  Endosc. 2002;56(Suppl 4):26-28. [PMID: 12297745]   Pancreatic pseudocysts are the most common cyst in the pan-  creas, and studies suggest that even large pseudocysts greater  than 6 cm can be followed conservatively until symptoms  develop or the cyst increases in size. Surgical drainage had been  the standard of care but carries a 10% morbidity rate and a 1%  mortality rate; therefore, radiologic and endoscopic drainage  have replaced surgical drainage as initial treatment.  Complications of endoscopic pseudocyst drainage include  early bleeding, perforation of adjacent structures, and infec-  tion. Traditionally, endoscopic pseudocyst drainage was per-  formed by piercing the endoscopically visible bulge. Access to  the pseudocyst can be achieved by using a needle-knife with  electrocautery or the Seldinger technique, which advances a  guidewire through a 19-gauge needle. Retrospective studies  suggest that the rate of bleeding is reduced to 4.6% using the  Seldinger technique compared with 15.7% using the needle-  knife. After establishing access to the cavity, the opening is dilated  with a balloon followed by placement of several pigtail stents.   EUS allows drainage of pseudocysts that do not create a  visible bulge and has changed the management of about 25%  of patients undergoing endoscopic pseudocyst drainage. EUS is  helpful for several reasons, including detecting blood vessels in  the wall of the pseudocyst or path of drainage, confirming that  the distance between the wall of the pseudocyst and the gastric  wall is less than 1 cm, and characterizing the pseudocyst and its  contents. Presence of necrotic debris within the pseudocyst  necessitates either surgical debridement or endoscopic necro-  sectomy, which involves entering the cavity with the endoscope  and removing necrotic debris with a variety of accessories. This  technique is still evolving and needs to be compared with sur-  gical management. No randomized trials exist comparing EUS-  guided pseudocyst drainage with non-EUS-guided techniques,  and the debate continues over whether EUS is essential for  safe endoscopic pseudocyst drainage.   Fockens P. EUS in drainage of pancreatic pseudocysts. Gastrointest  Endosc. 2002;56(Suppl4):93-97. [PMID: 12297758]   Endoscopic decompression of biliary and pancreatic  obstruction has been traditionally performed via ERCP,  with greater than 90% success in biliary drainage by skilled  endoscopists. Unsuccessful endoscopic drainage results from  surgically altered anatomy, tumor invasion, periampullary  diverticulum, endoscopist inexperience, or other causes.   Alternative therapeutic options include percutaneous tran-  shepatic drainage or surgery. Morbidity from percutaneous  transhepatic drainage is not insignificant, ranging from 4%  to 32% with a mortality rate up to 5.6%. Therefore, EUS-  guided decompression offers a potentially attractive endo-  scopic alternative for failed ERCP procedures.   To date there have been only small case series detailing the  technique of EUS-guided biliary and pancreatic drainage,  which involves either a rendezvous procedure with ERCP or  the creation of an EUS-guided enterobiliary or enteropancre-  atic fistula. During a rendezvous procedure, a 19- or 22-gauge  needle is used to access the pancreatic duct or the bile duct via  an intrahepatic or extrahepatic approach under EUS guidance.  A guidewire is then advanced into the duodenum, followed by  exchange of the echoendoscope for a duodenoscope to com-  plete the procedure. One study suggested that puncture of the  bile duct closest to the point of obstruction may increase tech-  nical success whereas another suggested that entering the  extrahepatic bile duct may lead to greater complications.   Another EUS-guided technique involves creating an enter-  obiliary or enteropancreatic fistula. The intrahepatic bile duct  or pancreatic duct is punctured with a 19-gauge needle fol-  lowed by guidewire placement, dilation of the puncture tract  to 4-6 mm, and placement of metal or plastic pigtail stents.  Small studies have reported a 90% success rate with the EUS-  approach and complications in 10-17%, including cholangi-  tis, bile leak, and self-limited pneumoperitoneum.   EUS-FNI encompasses injection of any material through the  needle. Biweekly EUS-guided injection of cyanoacrylate into  gastric varices until they are obliterated may reduce rebleed-  ing rates compared with non-EUS-guided injections admin-  istered only during episodes of bleeding. Additional larger  studies are necessary to determine the efficacy and complica-  tions of this technique.   EUS has revolutionized staging of many cancers, and it may  allow more directed and potentially more efficacious anti-  cancer treatments such as brachytherapy and local injection of  antitumor therapy. A few small case series have demonstrated  the feasibility of placing radioactive seeds into head and neck  cancer, lymph nodes, and pancreatic cancer. The technique  involves withdrawing the stylet about 1 cm and backloading  the radioactive seed into a 19-gauge needle. Similarly, inactive  radiographic markers, termed fiducials, which serve as targets  for CyberKnife radiation therapy, can be placed under EUS  guidance. The CyberKnife system delivers high doses of pre-  cisely targeted, small beams of radiation using real-time image  guidance. This revolutionary technique reduces radiation  exposure of surrounding organs, the total time of radiation  treatment, and side effects compared with conventional radio-  therapy. Fiducials have traditionally been placed surgically or  percutaneously; however, safe EUS-guided delivery of fiducials  into abdominal (predominantly pancreatic cancer) and medi-  astinal tumors has recently been demonstrated in a small study.   Targeted local injection of anti-tumor therapy under EUS-  guidance is feasible. EUS has been used to deliver allogenic mixed  lymphocyte culture (cytoimplant) and antitumor viral therapy  into pancreatic adenocarcinoma and a novel gene therapy agent,  TNFerade, which is a replication-deficient adenovector contain-  ing human tumor necrosis factor-a gene, into pancreatic and  esophageal adenocarcinoma. A phase I trial using cytoimplant in  patients with pancreatic cancer was halted early because patients  in the control arm receiving gemcitabine therapy had better out-  comes. Another trial using the antitumor viral therapy was also  stopped early due to poor response and a high rate of complica-  tions, including sepsis and duodenal perforation.   Chang KJ. EUS-guided fine needle injection (FNI) and anti-tumor  therapy. Endoscopy. 2006;38(Suppl l):88-93. [PMID: 16802235]   EUS continues to grow as a diagnostic and therapeutic  modality. In the future, EUS will be coupled with other imag-  ing modalities to allow more accurate diagnosis of both  benign and malignant lesions. The realm of therapeutic EUS  will require the development of innovative devices and acces-  sories and perhaps new echoendoscopes to allow many  potential procedures to become a reality.   Recent development of three-dimensional (3D) software to  allow rendering of two-dimensional (2D) EUS images into 3D  images may allow more accurate tumor staging. A study of rec-  tal cancer staging using 2D and 3D radial EUS demonstrated  no difference in staging for Tl and T2 tumors. However, 40%  of patients with tumors identified as T3N0 by 2D EUS were  upstaged to T3N1 using 3D EUS. Overall accuracy of staging  for 2D and 3D EUS was 71.4% and 88.6%, respectively.   Combining EUS with CT images and a real-time guid-  ance system called the image-registered gastroscopic ultra-  sound (IRGUS) system may improve the diagnostic  capability of EUS. The system uses a miniaturized tracking  sensor that is attached to the tip of an echoendoscope and  allows real-time displays of the position of the echoendo-  scope within a previously obtained CT scan. In a porcine  model, endosonographers were more efficient and effective,  identifying 25% more basic structures in a timed trial using  the IRGUS system compared with standard EUS, and 90% of  the users preferred the IRGUS system.   Techniques using contrast agents, elastography, and digi-  tal image analysis (DIA) with fluorescence in situ hybridiza-  tion (FISH) appear promising in their ability to detect  malignancies (Table 36-7). Several different contrast agents  have been used, including Levovist, Albunex, Optison, and  Sonovue. Following contrast injection, benign lesions such as  inflammatory changes from chronic pancreatitis enhance  and appear hyperechoic whereas malignant tumors are  underperfused and hypoechoic.   Elastography is based on the principle that cancer  changes the elastic properties or the hardness of tissue. Slight  compression of tissue by an ultrasound transducer displaces  the tissue, and the elasticity distribution of the tissue before  and after compression can be compared. In addition to  enhancing the different tissue properties of malignant com-  pared with normal tissue, the search for new molecular  markers of malignancy continues. The techniques of DIA  and FISH assess the nuclear DNA content and presence of  aneuploidy to diagnose malignancy.   Finally, the horizons of EUS may be expanding with a  recent study exploring the application of EUS-FNA and the  heart. Six animals survived for 2 weeks following introduc-  tion of an EUS needle into the left atrium and coronary  artery. In a separate study in humans, three patients under-  went successful aspiration of pericardial fluid and puncture  of a left atrial mass using EUS-FNA.   The realm of therapeutic EUS is in its infancy and may be  slow to develop given a relatively limited number of  endosonographers and the lack of incentive for instrument  manufacturers to invest time and resources in this area.  There have been a few animal studies using a new EUS-  guided suturing system to create gastrojejunal anastomoses,  perform posterior gastropexy for gastroesophageal reflux,  and remove lymph nodes.   Expanding on the premise of EUS-FNI, experimental pig  models have demonstrated the feasibility of EUS-guided  radiofrequency ablation, photodynamic therapy, and emboliza-  tion of the portal vein using ethylene vinyl alcohol co-polymer  (Enteryx). There are a few case reports of successful treatment  of splenic and superior mesenteric artery pseudoaneurysms  using thrombin injected into the vessels under EUS guidance. In  addition, the safety of EUS-guided ethanol ablation of pancre-  atic cysts was demonstrated in a small pilot study.   Endoscopy. 2006;38(S1):S95-S99. [PMID: 16802237]  Giovannini M. Endosonography: new developments in 2006.    ▲ Plate 1. Rectal mucosal biopsy specimen from a  patient with dysentery caused by shigellosis. There is  considerable mucosal inflammation caused by infiltration  with polymorphonuclear leukocytes and mononuclear  cells, as well as substantial damage to surface epithelial  cells. However, mucosal architecture is generally  preserved with straight, closely adjacent crypts. A crypt  microabscess is seen on the right.    ▲ Plate 2. Rectal mucosal biopsy specimen from a  patient with dysenteric stools caused by a flare of  chronic ulcerative colitis. The mucosa is heavily infiltrated  with polymorphonuclear leukocytes and mononuclear  cells. In contrast to Plate 1, mucosal architecture is  markedly distorted, with substantial reduction in crypts  and distortion of those that remain.    ▲ Plate 4. Esophageal carcinoma. Fused PET-CT image  shows a "hot spot" (black arrow) at the level of the distal  esophagus corresponding to squamous cell carcinoma.  Note the hepatic metastasis (white arrowhead).    ▲ Plate 5. Colonic polyp. Three-dimensional endoluminal  reconstructed image confirms the presence of a colonic  polyp (arrow). (For corresponding axial MDCT image, see  Figure 9-17 in the text.)   ▲ Plate 11. Histopathologic findings of low-grade  dysplasia in Barrett esophagus. The surface epithelium  displays nuclear stratification, limited to the lower half  of the cytoplasm. (Courtesy of Jason Hornick, MD, PhD,  Brigham and Women's Hospital.)    ▲ Plate 10. Histopathologic findings in nondysplastic  Barrett esophagus. Note the glandular epithelium  containing goblet cells. (Courtesy of Jason Hornick, MD, PhD,  Brigham and Women's Hospital.)    ▲ Plate 12. Histopathologic findings of high-grade  dysplasia in Barrett esophagus. There is full-thickness  nuclear stratification and the mucosa has a villous  appearance. (Courtesy of Jason Hornick, MD, PhD, Brigham  and Women's Hospital.)    ▲ Plate 15. Barrett esophagus with high-grade dysplasia  and intramucosal adenocarcinoma.    A Plate 21. The upper panel shows a characteristic  severe lesion from a patient with untreated celiac sprue.  Villi are absent, crypts are hyperplastic, and the lamina  propria is infiltrated with many mononuclear cells. For  comparison, the lower panel shows a biopsy sample  from a normal volunteer showing normal mucosal  architecture with tall villi and shallow crypts and just a  few mononuclear cells in the lamina propria.   ▲ Plate 20. Histologic findings in eosinophilic esophagitis.  Note increased eosinophils in the squamous mucosa.   ▲ Plate 22. The left panel shows at higher magnification  the absorptive surface of the biopsy sample from the  patient with celiac sprue shown in the upper panel of  Plate 21. The surface absorptive cells are decreased in  height and vacuolated, and the nuclei have lost their  polarity. Numerous intraepithelial lymphocytes (lELs) can  be seen between adjacent epithelial cells. The underlying  lamina propria is heavily infiltrated with lymphocytes  and plasma cells. For comparison, in the panel on the  right is the tip of a villus from the biopsy sample shown  in lower panel of Plate 23 from a normal individual. In  contrast to the panel on the left, the absorptive cells are  tall and have a well-developed brush border, with only  occasional lELs evident between epithelial cells.   A Plate 23. Upper panel shows a biopsy sample obtained  from a normal volunteer and stained with periodic acid-  Schiff (PAS) stain. The glycoprotein-rich epithelial cell  brush border and the goblet cell mucous is PAS-positive.  The biopsy sample in the lower panel was obtained from  a patient with untreated Whipple disease. The villus  architecture is markedly distorted and the lamina propria  is packed with large PAS-positive macrophages that virtu-  ally replace the lymphocytes and plasma cells that would  normally be seen. Additionally, profiles of dilated lymphatics  are evident in the lamina propria.   ▲ Plate 25. Endoscopic view of a diminutive  adenomatous polyp before cold snare excision (narrow  band imaging mode).    ▲ Plate 26. Diminutive adenomatous polyp after cold  snare excision. Same patient as in Plate 25.   A Plate 28. Sessile adenomatous polyp undergoing hot  snare polypectomy without mucosal injection. Same  patient as in Plate 27.   ▲ Plate 31. Snare polypectomy for a large pedunculated  polyp, with endoloop in place prior to snare resection.   A Plate 32. Hemostatic clips applied after polypectomy  for hemostasis and suspected perforation. Same patient  as in Plate 27.   A Plate 30. Endoscopic view of a standard snare  polypectomy for a pedunculated polyp.   ▲ Plate 36. Barrett nodule after snare resection. Same  patient as in Plate 35. (Courtesy of Dr John R. Saltzman,  Brigham and Women's Hospital.)   ▲ Plate 41. Endoscopic mucosal resection: closure of  the mucosal defect with clips.   sessile polyp. (Courtesy of Professor Yutaka Saito, National  Cancer Center Hospital, Tokyo, Japan.)   ▲ Plate 46. Mucosal defect after endoscopic submucosal  dissection. Same patient as in Plate 44. (Courtesy of  Professor Yutaka Saito, National Cancer Center Hospital,  Tokyo, Japan.)   patient as in Plate 44. (Courtesy of Professor Yutaka Saito,  National Cancer Center Hospital, Tokyo, Japan.)   ▲ Plate 48. Nonbleeding visible vessels. Giant duodenal A Plate 50. Adherent clot on a gastric ulcer,  ulcer occupying the entire duodenal bulb, with a non-  bleeding visible vessel at bottom right (arrow).    ▲ Plate 49. Nonbleeding visible vessels. A pyloric  channel ulcer with a pigmented, nonbleeding visible  vessel (arrow).    A Plate 54. Duodenal ulcer controlled by placement of  two hemoclips.   A Plate 55. Linear Mallory-Weiss tear just below the  gastroesophageal junction.   ▲ Plate 66. Arteriovenous malformation in a patient  with lower gastrointestinal bleeding.   A Plate 88. Endoscopic therapy for pancreas divisum  showing minor papillotomy.   ► Jaundice is most often caused by decompensation of  preexisting chronic liver disease, alcoholic hepatitis, and  gallstone disease.   ► Careful history, physical examination, and routine labo-  ratory tests lead to accurate diagnosis in 85% of  patients with jaundice.   ► Cirrhosis can be diagnosed on the basis of two physical  findings (asterixis, ascites) and two laboratory findings  (decreased serum albumin [< 2.8 g/dL], prolonged pro-  thrombin time [INR > 1.6]).   ► Dilated intrahepatic bile ducts indicate obstruction from  extrahepatic causes (stone, structure, tumor).   ► Absence of dilated ducts in jaundiced patients with serum  bilirubin > 10 mg/dL suggests intrahepatic cholestasis.   ► Sepsis, drugs, sickle cell disease, and chronic hepatitis are  the most common causes of intrahepatic cholestasis.   Jaundice refers to the yellowish discoloration of tissue  resulting from the deposition of bilirubin in tissues; this  indicates that the serum bilirubin is likely 3.0 mg/dL or  higher. Jaundice most often is the result of acute or chronic  liver disease, or biliary tract disease, and less commonly the  result of hemolytic disorders. The differential diagnosis of  jaundice has changed significantly in the past decade due  largely to a sharp decline in the incidence of viral hepatitis  types A and B as a result of immunization. The most com-  mon causes of jaundice in the adult population now are  decompensation of preexisting chronic liver disease, alco-  holic hepatitis, sepsis and abnormal hemodynamic condi-  tions, and gallstone disease.   Jaundice can occur as a result of acute or chronic parenchy-  mal liver disease, extrahepatic biliary tract obstruction (due  to stone, stricture, or tumor), intrahepatic cholestasis (having  several causes, as detailed below), and hemolytic anemia.  Serum bilirubin derives from the degradation of senescent  red cells in the reticuloendothelial system. Each day a normal  individual destroys 50 mL of red blood cells, which gives rise  to 7.5 g of hemoglobin. Each gram of hemoglobin that is  degraded results in production of 35 mg of bilirubin.  Unconjugated bilirubin is liquid soluble, water insoluble, and  hence circulates bound to albumin. The hepatic processing  of bilirubin involves uptake of unconjugated bilirubin, con-  jugation with uridine diphosphate glucuronyl transferase,  transfer to the bile canaliculus, and excretion into the intra-  hepatic biliary tree (Figure 37-1). Bilirubin is excreted in the  bile primarily as bilirubin diglucuronide (80%), bilirubin  monoglucuronide (20%), and unconjugated bilirubin (< 1%).  Any disease process that results in an increased load of  unconjugated bilirubin presented to the liver, impaired con-  jugation, or impaired excretion of conjugated bilirubin,  either intrahepatic or extrahepatic, can lead to accumulation  of bilirubin in the blood, resulting in jaundice.   On the basis of a detailed history and a carefully conducted  physical examination, along with the routine liver tests sum-  marized below, the examiner should be able to formulate a  differential diagnosis and be correct in over 85% of the  patients who present with jaundice and evidence of liver dis-  ease. The importance of a careful history and physical exam-  ination along with critical evaluation of the standard liver  tests cannot be overemphasized.   system. (Reproduced, with permission, from Sherlock S,  Dooley J. Diseases of the Liver and Biliary System, 10th ed.  Blackwell Science, 1997:218.)   Table 37-1 summarizes the specific information to be  obtained from patients with jaundice or liver disease. The  information is grouped into that relating to viral hepatitis,  especially hepatitis A, medications, alcohol use, and miscella-  neous relevant information.   Table 37-2 summarizes characteristic findings on physical  examination in patients with jaundice. Attention should be   Table 37-1. Specific information to obtain from patients  with jaundice or liver disease.   Ask about:  Blood transfusion (especially if before 1990)  Intravenous drug use  Sexual practices:   • Intercourse with persons infected with hepatitis B or C  Contact with persons with jaundice   in which exposure to users of IV drugs may occur  Shared razors or toothbrushes  Body piercing (ears, nose)  Tattoos   • Exposure in settings where clusters of hepatitis may occur  (eg, institutions, restaurants, preschool nurseries)   Any foods, herbal preparations, or home remedies purchased  in a health food store   alcohol use from patient and family members  Ask whether patient has experienced withdrawal symptoms,   extrahepatic)  Evaluation of jaundice (dark urine, light stools)  Recent changes in menstrual cycle (amenorrhea suggests   chronic liver disease, often cirrhosis)  Review:  History of anemia, sickle cell disease, known hemoglobinopathy,   artificial heart valves  Symptoms suggestive of biliary colic, chronic cholecystitis  Family history of liver disease, gallbladder disease   Adapted, with permission, from Greenberger NJ. History taking and  physical examination for the patient with liver disease. In: Schiff ER,  Sorrell MF, MaddreyWC (editors). Schiff's Diseases of the Liver, 1 oth   • Behavioral alterations (confusion, disorientation, failure  to complete simple mental tasks)   Adapted, with permission, from Greenberger NJ. History taking and  physical examination for the patient with liver disease. In: Schiff ER,  Sorrel I MF, Maddrey WC (editors). Schiff's Diseases of the Liver, 10th  ed, vol 1. Lippincott Williams & Wilkins, 2007:6.   paid to the peripheral stigmata of liver disease, including spi-  der angioma, which characteristically occurs above the clavi-  cles in the distribution of the superior vena cava. More than  15 spider angiomata indicate the presence of significant liver  disease and likely portal hypertension. The triad of gyneco-  mastia, Dupuytren contracture, and parotid enlargement is a  clear indication that alcohol is the most likely cause of the  patient's liver disease. Splenomegaly, ascites, and prominent  abdominal collateral veins indicate the presence of portal  hypertension and in all likelihood the presence of esophageal  or gastric varices, or both. Hepatic encephalopathy is suggested  by the presence of asterixis and behavioral alterations.   The following point bears special emphasis. A clinician  can make a firm diagnosis of cirrhosis on the basis of two  physical findings and two laboratory findings. These four  features — the presence of asterixis and ascites, along with  decreased serum albumin (< 2.8 g/dL) and a prolonged pro-  thrombin time — clearly indicate cirrhosis. This statement is  based on an older Mayo Clinic study in which over 500  patients with chronic liver disease were evaluated; the preced-  ing compilation of clinical features was present in approxi-  mately 98% of patients with proven cirrhosis of the liver.   Liver tests that are useful in the differential diagnosis of jaun-  dice are summarized in Table 37-3. Four altered liver test find-  ings point to a diagnosis of chronic liver disease (eg, cirrhosis):  (1) decreased serum albumin, (2) elevated serum globulins,  (3) prolonged prothrombin time, and (4) decreased cholesterol.   The serum bilirubin level exceeds 20 mg/dL rarely in  patients with acute viral hepatitis, infrequently in patients with  cirrhosis, and rarely in those with obstructive jaundice due to  a common duct stone or pancreatic cancer. The highest serum  bilirubin levels are seen in cirrhosis with accompanying olig-  uric hepatic failure (ie, hepatorenal syndrome). The reason is  that if extrahepatic obstruction is present, the serum bilirubin  level will rise to about 15 mg/dL but the compensatory mech-  anism is the kidney and the excess bilirubin will be excreted,  resulting in bilirubinuria. In oliguric hepatic failure this com-  pensatory mechanism is lost, which explains why the highest  serum bilirubin levels are seen in advanced cirrhotic liver dis-  ease with hepatorenal syndrome.   Serum aminotransferases are characteristically increased  to values above 400 IU/L in acute viral hepatitis and are usu-  ally less than 400 IU/L in cirrhosis and less than 400 IU/L in  over 90% of patients with obstructive jaundice. Of note, in  patients with choledocholithiasis with or without cholangi-  tis, serum aminotransferases may be in the hepatitis range  (ie, 800-1000 IU/L); however, within 2-3 days elevated val-  ues will fall abruptly.   Serum alkaline phosphatase is disproportionately elevated  in obstructive jaundice, with values four- to tenfold or greater  than normal, whereas these values usually are normal or min-  imally elevated in acute viral hepatitis or cirrhosis. Serum  albumin and globulin levels are very helpful in that both are  usually normal in acute viral hepatitis and usually normal with  obstructive jaundice of brief duration. The serum albumin  level is frequently decreased in cirrhosis whereas globulins are  increased, and the finding of hypergammaglobulinemia and  hypoalbuminemia in someone with liver disease almost always  means that the patient has chronic liver disease.   The prothrombin time and partial thromboplastin time are  usually both normal in acute viral hepatitis. However, in a  patient with acute viral hepatitis, a prolonged prothrombin  time and an international normalized ratio (INR) greater than  1.8 may be the harbinger of submassive necrosis of the liver and  impending liver failure. The prothrombin time and partial   Table 37-3. Differential test results in patients with acute, chronic, and obstructive  hepatobiliary disease.    May be helpful 93% sensitivity and 95%  specificity if bilirubin > 10  mg/dL for 10 days   ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBD, common bile duct; CMV, cytomegalovirus;  EBV, Epstein-Barr virus; NL, normal limits; PT, prothrombin time; PTT, partial thromboplastin time; I decreased;  t increased.  ^Special circumstances may apply.   thromboplaslin time are prolonged in chronic liver disease and  cirrhosis. The prothrombin time may be prolonged in patients  with prolonged obstructive jaundice because of failure to  absorb vitamin K. In this setting, however, the prothrombin  time will normalize with administration of vitamin K.   Serum cholesterol is frequently low in patients with  chronic liver disease. The usual serologies to obtain in patients  with jaundice include tests for hepatitis A, B, and C as well as  Epstein-Barr virus and cytomegalovirus.   Abdominal ultrasound is a very helpful examination in  patients with jaundice and obstructive-type chemistries. In a  patient with serum bilirubin of 10 mg/dL or higher and in  whom the elevation has persisted for more than 2 weeks,  ultrasound has a sensitivity and specificity of approximately  95%. The presence of dilated ducts indicates that the process  is extrahepatic. If dilated ducts are not demonstrated, it may  indicate that the patient has a disorder causing intrahepatic  cholestasis (Table 37-4).   As previously noted, the differential diagnosis of jaundice  has changed significantly since the advent of immunization   Table 37-4. Spectrum of disorders and causes resulting  in intrahepatic cholestasis.    Viral hepatitis (especially type A)  Alcoholic liver disease  Chronic hepatitis  a, -Antitrypsin deficiency   Parenteral nutrition  Hodgkin disease  Sickle cell disease  Toxic shock syndrome  Amyloidosis   for hepatitis A and B. Prior to 2000, viral hepatitis was the cause  of jaundice in 85-90% of patients younger than age 30 years.  In patients presenting with jaundice who were between the  ages of 40-60 years, alcoholic liver disease was the most com-  mon diagnosis, occurring in 50-70%. In patients 60-80 years  of age without a history of blood transfusion, excessive alco-  holic use, contact with a person with jaundice, or use of  putative medicines, the diagnosis in over 80% was either gall-  stones and their complications or cancer of the pancreas.  Chronic hepatitis was the cause of jaundice in 5% of patients  across the age spectrum. Drug-induced jaundice occurred in  less than 5% of individuals (Table 37-5).   Recent studies call attention to changing trends in the dif-  ferential diagnose of jaundice (Table 37-6). In a review of  732 patients with serum bilirubin levels greater than 3 mg/dL,  the most common cause was decompensation of chronic  liver disease, occurring in 20.5% of the patients. Alcoholic  hepatitis was present in 16.5%. Acute viral hepatitis was less  frequently a cause of acute onset jaundice in 8.8% of the  patients, a decline in incidence that is attributed to increased  immunization of children and pregnant women against hep-  atitis A and B. Other hepatic causes of jaundice included  acute autoimmune hepatitis and drug-induced jaundice. An  extrahepatic etiology was evident in nearly half the patients,  with sepsis, gallstone disease, hemolysis, and malignancy  accounting for the bulk of cases.   Sepsis is a cause of jaundice due to intrahepatic cholesta-  sis (see Table 37-4). Sickle cell anemia, which is common  among African Americans, also may be characterized by  intrahepatic cholestasis (see Table 37-4).   Gilbert syndrome, or chronic idiopathic unconjugated  hyperbilirubinemia, occurs in 2-7% of the population and is  associated with entirely normal liver tests and absence of  bilirubinuria. The importance of making this diagnosis is  that patients are so identified and unnecessary testing is  avoided.   Primary biliary cirrhosis and primary sclerosing cholan-  gitis are being increasingly recognized as important causes of  jaundice, although in both of these disorders the diagnosis is  being made earlier with the use of biochemical tests and  imaging studies.   The spectrum of disorders causing intrahepatic cholestasis is  summarized in Table 37-4. At every site in the intrahepatic  biliary tree, there are disorders associated with jaundice.  Thus, hepatocellular causes, including viral hepatitis (espe-  cially type A), alcoholic liver disease, chronic hepatitis, and  CXj-antitrypsin deficiency can be associated with intrahepatic  cholestasis. Canalicular cholestasis may be drug induced   HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus;   (eg, caused by phenothiazines or alkylated steroids), or asso-  ciated with the postoperative state, sepsis, parenteral nutri-  tion, Hodgkin disease, sickle cell disease, toxic shock  syndrome, or amyloidosis. The ductules are the source of  jaundice in primary biliary cirrhosis and sarcoidosis; the  larger ducts in primary sclerosing cholangitis, Caroli disease,  and intrahepatic biliary atresia. Recurrent jaundice occurs   with recurrent cholestasis of pregnancy, benign recurrent  intrahepatic cholestasis and Dubin-Johnson syndrome.  Jaundice can occur in patients with sepsis, especially gram-  negative sepsis, because gram-negative bacilli elaborate toxins  that interfere with canalicular function (ie, canalicular mem-  brane ATPases). It should also be remembered that patients  with intrathoracic or intra-abdominal bleeding may develop  jaundice because of the large bilirubin pigment load. Every  50 mL of blood loss produces up to 250 mg of bilirubin; thus,  a patient who has experienced a 5-unit intraperitoneal or  intrathoracic bleed may have 2500 mg of bilirubin presented  for excretion, overwhelming the body's uptake, conjugation,  and excretion mechanisms for handling bilirubin.   The differential diagnosis of chronic hepatitis is depicted  using a mnemonic device in Table 37-7. The letters in the left-  hand column — A, B, C, Dl, D2, El, E2, F, and H — correspond  to the categories of possible causes of chronic hepatitis.   Chronic hepatitis may be due to autoimmune disease in  which the subtypes are anti-nuclear body smooth muscle  positive, anti-actin positive, anti-LKM-1 positive, and  anti-liver surface antigen positive. The most common entity  in the United States is anti-nuclear and smooth muscle  (F-actin)-positive disease. Approximately 5% of patients  with acute hepatitis B develop chronic hepatitis. Approximately  70% of patients with acute hepatitis C develop chronic hep-  atitis. Hepatitis D occurs only with hepatitis B. Various  drugs, including oc-methyldopa, isoniazid, and nitrofuran-  toin, are associated with jaundice. In the United States, the  drug most frequently associated with jaundice is amoxicillin  and its various derivatives. Wilson disease is a rare cause of  jaundice but needs to be considered because it is eminently  treatable. a t -Antitrypsin deficiency also needs to be consid-  ered. Nonalcoholic fatty liver disease (NAFLD) is the most  common cause of liver test abnormalities and is discussed in   detail in Chapter 43. Hemochromatosis is another important  cause of liver disease and is detailed in Chapter 41.   An elevation in aminotransferase in asymptomatic individuals  is common, occurring in over 8% of the U.S. population.  Recent surveys by the National Health and Nutrition  Examination Survey (NHANES) have provided important  information on aminotransferase elevations in asymptomatic  individuals in the United States. The third annual NHANES  survey reported on 15,676 adults over the age of 17 years.  Aminotransferase elevation was defined by an aspartate  aminotransferase (AST) value greater than 37, and an alanine  aminotransferase (ALT) value greater than 42 and was classi-  fied as explained if there was (1) evidence of hepatitis B,  (2) hepatitis C, (3) iron overload (ie, transferrin saturation  > 50%), or (4) alcohol consumption greater than two drinks  per day for men and greater than one drink per day for  women. Aminotransferase elevation was classified as unex-  plained if any of the preceding four factors were absent.   Prevalence of aminotransferase elevation in the United  States was 7.9%. Aminotransferase elevations were more com-  mon in men (9.3%) compared with women (6.6%), and in  Mexican Americans (14.9%) and non-Hispanic blacks 8.1%  compared with non-Hispanic whites (7.1%). Known causes  occurred in 31% of the patients, with the most common   causes being alcohol, hepatitis C virus, hemochromatosis, and  hepatitis B virus. The cause was unexplained in two thirds of  cases but was associated with higher body mass index, dyslipi-  demia, diabetes, hypertension, and insulin resistance. Among  patients with a body mass index greater than 40, over half had  NAFLD. Many patients with these findings have the metabolic  syndrome. Fifteen percent of such patients may already have  cirrhosis.   Uncommon but important causes of asymptomatic amino-  transferase elevations included chronic acetaminophen use  greater than 4 g/day, celiac sprue, and use of statins. Elevations  in aminotransferase values in statin users ranged from 0.5% to  3% and were dependent in large part on the dose of statin. It  bears emphasizing that despite the aminotransferase elevations  noted in users of statins, only rare cases of significant liver dis-  ease have been reported in such patients, and in those cases  another cause was usually identified.   Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of  elevated aminotransferase levels in the United States. Am f  Gastroenterol. 2003;98:960-967. [PMID: 12809815]   Greenberger NJ. History taking and physical examination for the  patient with liver disease. In: Schiff ER, Sorrell MF, Maddrey WC  (editors). Schiff's Diseases of the Liver, 10th ed. Lippincott  Williams & Wilkins, 2007:3-18.   Vuppalanchi R, Liangpunsakul S, Chalasani N. New onset jaun-  dice: how often is it caused by idiosyncratic drug-induced liver  injury in the United States. Am J Gastroenterol. 2007;  102:558-562. [PMID: 17156142]   Drugs, toxins, and viral hepatitis are the most common  causes of acute liver failure (ALF).   Consider acetaminophen toxicity in all patients, even  without a history of toxic ingestion, particularly when  serum aminotransferase levels are very high (> 1000  units).   Depending on timing of ingestion, acetaminophen lev-  els may not be elevated even in cases of overdose.   Acute liver failure (ALF) affects approximately 2000 people  in the United States each year. The most widely accepted  definition of ALF includes evidence of coagulation abnor-  mality (international normalized ratio [INR] > 1.5), and  encephalopathy in a patient without preexisting cirrhosis  and with a hepatic illness manifested by hyperbilirubinemia  of less than 26 weeks' duration.   The U.S. Acute Liver Failure Study Group (ALFSG) was  formed in 1997 as a consortium of centers aimed at cap-  turing nationwide data on ALF. Preliminary results  released in 2002 with 308 patients enrolled over a 41-  month period found that the most common causes of ALF  were acetaminophen overdose (39%), indeterminate (17%),  idiosyncratic drug reactions (13%), and viral hepatitis A or B  (12%). More recent data from the ALFSG indicate that  nearly 50% of ALF in the United States is attributable to  acetaminophen.   Larson AM, Poison J, Fontana RJ, et al. Acute Liver Failure Study  Group. Acetaminophen-induced acute liver failure: results of a  United States multicenter, prospective study. Hepatology.  2005;42:1364-1372. [PMID: 16317692]   Lee WM. Acute liver failure in the United States. Semin Liver Dis.  2003;23:217-226. [PMID: 14624381]   Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospec-  tive study of acute liver failure at 17 tertiary care centers in the  United States. Ann Intern Med. 2002;137:947-954. [PMID:  12484709]   The constellation of clinical findings in ALF includes jaundice  in a previously healthy person, often preceded by malaise or  nausea, and the rapid onset of altered mental status and  coma accompanied by laboratory evidence of coagulopathy  and acute hepatic injury.   History-taking should include a review of all possible expo-  sures to viral infection, drugs, and toxic ingestions, as well as  risk factors for underlying chronic liver disease. If the patient  shows evidence of severe encephalopathy, a history should be  obtained from family members.   Jaundice and right upper quadrant tenderness may or  may not be present. An enlarged liver may be seen early in  viral hepatitis, malignant infiltration, congestive heart fail-  ure, or acute Budd-Chiari syndrome. Alternatively, there may  be decreased hepatic dullness to percussion, indicating  diminished hepatic mass. The most critical part of the phys-  ical examination is the assessment of mental status.   Initial laboratory analysis should aim to determine the cause  of ALF, the severity of presentation, and the need for treat-  ment of associated complications (Table 38-1).   Arterial lactate  Complete blood count  Blood type and screen  Acetaminophen level  Toxicology screen  Viral hepatitis serologies   ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody;  ALT, alanine aminotransferase; AST, aspartate aminotransferase;  GGT, y-glutamyl transferase; HAV, hepatitis A virus; HBc, hepatitis  core antigen; HCV, hepatitis C virus; HEV, hepatitis E virus; HBsAg,  hepatitis B surface antigen; IgM, immunoglobulin M; INR, interna-  tional normalized ratio.   a Done to recognize potential underlying infection.  b Done only if Wilson disease is a consideration (eg, in patients  younger than 40 years without another obvious explanation for  acute liver failure); in this case uric acid level and bilirubin to alka-  line phosphatase ratio may be helpful as well.  Reproduced, with permission, from Poison J, Lee WM; American  Association for the Study of Liver Diseases. AASLD position paper: the  management of acute liver failure. Hepatology. 2005;41:1179-1197.   Liver biopsy, usually done via the transjugular route  because of coagulopathy, may be indicated when certain con-  ditions such as autoimmune hepatitis, metastatic liver dis-  ease, lymphoma, or herpes simplex virus are suspected.   Significant neurologic, cardiopulmonary, and renal sequelae  are associated with ALF. Cerebral edema and intracranial  hypertension are the most serious of these complications.  Mortality is related to neurologic status and infection, which   require careful monitoring (see next section). Acute renal  failure complicates ALF in approximately 30-50% of patients  and can be a sign of poor prognosis.   Because ALF often involves the rapid deterioration of mental  status and the potential for multiorgan failure, patients  should be managed in the intensive care unit. Table 38-2  outlines general treatment recommendations for intensive  care management of patients with ALF. For patients not at a  transplant center, the possibility of rapid progression of ALF  makes early consultation with a transplant facility critical.  Accordingly, plans for transfer to a transplant center should  begin in patients with any abnormal mentation.   Early institution of antidotes or specific therapy may pre-  vent the need for liver transplantation and reduce the likeli-  hood of poor outcome. Measures appropriate for specific  causes of ALF are described in detail later in this chapter.   Taian R. Acute liver failure: current management and future  prospects. / Hepatol. 2005;42(Suppl):S115-S123. [PMID:  15777566]   Poison T, Lee WM. American Association for tlie Study of Liver  Diseases. AASLD position paper: the management of acute liver  failure. Hepatology. 2005;41:1179-1197. [PMID: 15841455]   1. Neurologic complications— Patients with grade I— II  encephalopathy (Table 38-3) should be transferred to a liver  transplant facility and listed for transplantation. Consider a  brain computed tomography (CT) scan to rule out other  causes of decreased mental status. Stimulation and overhy-  dration can cause elevations in intracranial pressure (ICP)  and should be avoided. Unmanageable agitation may be  treated with short-acting benzodiazepines in small doses.  Lactulose can be considered at this stage. A preliminary  report from the ALFSG on 117 patients suggests that use of  lactulose in the first 7 days after diagnosis is associated with  a small increase in survival time, but with no difference in  severity of encephalopathy or in overall outcome.   For patients who progress to grade III— IV encephalopa-  thy, intubation for airway protection is generally required.  Many centers use propofol for sedation because it may  reduce cerebral blood. The head of the bed should be ele-  vated to 30 degrees, and electrolytes, blood gases, glucose,  and neurologic status monitored frequently.   The cause of intracranial hypertension in ALF is probably  multifactorial, combining cytotoxic brain edema due to an  increase in cerebral blood volume and cerebral blood flow  due to inflammation and toxic products of the diseased liver.  Cerebral edema inside the cranial vault raises ICP and  decreases cerebral perfusion assessed by cerebral perfusion   • Consider transfer to liver transplant facility and listing for transplantation   • Brain CT— rule out other causes of decreased mental status; little utility to iden-  tify cerebral edema    Surveillance for and prompt antimicrobial treatment of infection required  Antibiotic prophylaxis possibly helpful but not proven   ALF, acute liver failure; CT, computed tomography; FFP, fresh frozen plasma; ICP, intracranial pressure; NAC,  W-acetylcysteine; PPI, proton pump inhibitor.   Adapted, with permission, from Poison J, Lee WM; American Association for the Study of Liver Diseases. AASLD  position paper: the management of acute liver failure. Hepatology. 2005;41:1179-1197.   Evidence of increased ICP includes unequal pupil size and  lack of pupillary reaction to light. Patients with cerebral edema  may have systemic hypertension and bradycardia (Cushing  reflex), increased muscle tone followed by decerebrate rigidity  and posturing, abnormal papillary reflexes (usually dilation),  and finally brainstem respiratory patterns and apnea. Brain  herniation from elevated ICP is the immediate cause of death  in 35% of patients with ALF, and 15-20% of patients listed for  transplantation die from increased ICP. Cerebral edema is  rarely seen in patients with grade I — II encephalopathy but   increases to 65-75% in patients with grade IV coma and is the  leading cause of death in these patients.   Seizure is common in patients with ALF, although pres-  entation is often subclinical and likely due to use of sedatives  and paralytics in intubated patients. Seizures aggravate  intracranial hypertension and should therefore be promptly  controlled with phenytoin. Small clinical trials using pro-  phylactic phenytoin have shown no mortality benefit and  unclear impact on cerebral edema or prevention of seizures.   The use of ICP monitoring in patients with ALF is com-  mon but not universal. Clinical signs of elevated ICP are  not always present and neurologic changes such as papillary    Marked confusion, incoherent speech, sleeping most  of the time but arousable to vocal stimuli   Reproduced, with permission, from Poison J, Lee WM; American  Association for the Study of Liver Diseases. AA5LD position paper: the  management of acute liver failure. Hepatology. 2005;41:1179-1197.   dilation or decerebrate posturing are often present only late  in the course. The risks of ICP monitoring in ALF patients  include bleeding and infection, with subdural and intra-  parenchymal monitors demonstrating greater reliability but  increased rates of complications when compared with  epidural catheters. A survival benefit with the use of ICP  monitoring has not been shown.   The goal is to maintain ICP below 20 mm Hg and CPP  above 70 mm Hg. Evidence of elevated ICP such as pupillary  abnormalities, decerebrate posturing, or monitoring suggest-  ing ICP above 20-25 mm Hg and CPP below 50-60 mm Hg,  should prompt intervention.   Interventions may include support of systemic blood pres-  sure to maintain adequate CPP or the use of mannitol, which in  doses of 0.5-1 g/kg has been demonstrated to decrease cerebral  edema and improve survival. The efficacy of mannitol in  patients with ICP may be affected by acute renal failure and olig-  uria. In order to be able to use mannitol repeatedly, fluid can be  taken off with hemofiltration, which by itself reduces ICP.   Hyperventilation has also been shown to cause quick  reductions in ICP, but the effect is short-lived and therefore  may be of therapeutic benefit only in situations of life-  threatening intracranial hypertension to prevent herniation.  Table 38-2 summarizes these and other strategies in the ICU  management of ALF patients.   Barbiturate agents such as thiopental or pentobarbital  may be considered when severe intracranial hypertension  does not respond to other measures.   Other therapies are being explored but currently lack  adequate supporting data to recommend use, including  indomethacin, hypothermia, and hypertonic saline.   Detry O, De Roover A, Honore P, et al. Brain edema and intracra-  nial hypertension in fulminant hepatic failure: pathophysiology  and management. World J Gastroenterol. 2006;12:7405-7412.  [PMID: 17167826]   lalan R. Intracranial hypertension in acute liver failure: pathophys-  iological basis of rational management. Semin Liver Dis.  2003;23:271-282. [PMID: 14523680]   lalan R, Olde Daminck SW, Deutz NE, et al. Moderate hypother-  mia prevents cerebral hyperemia and increase in intracranial  pressure in patients undergoing liver transplantation for acute  liver failure. Transplantation. 2003;75:2034-2039. [PMID:  12829907]   lalan R, Olde Daminck SW, Deutz NE, et al. Moderate hypothermia  in patients with acute liver failure and uncontrolled intracranial  hypertension. Gastroenterology. 2004;127:1338-1346. [PMID:  15521003]   Murphy N, Auzinger G, Bernal W, et al. The effect of hypertonic  sodium chloride on intracranial pressure in patients with acute  liver failure. Hepatology. 2002;39:464-470. [PMID: 14767999]   Wijdicks EF, Nyberg SL. Propofol to control intracranial pressure  in fulminant hepatic failure. Transplant Proc. 2002;34:1220-1222.  [PMID: 12072321]   2. Cardiovascular complications— Increased cardiac out-  put and low systemic vascular resistance are characteristic of  ALF. Pulmonary artery catheterization should be considered.  Hypotension should be treated preferentially with fluids, but  systemic vasopressor support with agents such as epineph-  rine, norepinephrine, or dopamine should be used if fluid  replacement fails to maintain mean arterial pressure of  50-60 mm Hg. Vasoconstrictive agents (especially vasopressin)  should be avoided.   3. Pulmonary complications— Pulmonary edema and pul-  monary infections are commonly seen in patients with ALF.  Mechanical ventilation may be required. However, positive  end-expiratory pressure can worsen cerebral edema.   4. Coagulopathy and gastrointestinal bleeding-  Impaired hepatic synthesis of clotting factors, low-grade fib-  rinolysis, and intravascular coagulation are typical of ALF.  Thrombocytopenia is common and may also be dysfunc-  tional. Replacement therapy is recommended only in the  setting of hemorrhage or prior to invasive procedure.  Vitamin K can be given to treat an abnormal prothrombin  time, regardless of whether there is poor nutritional status.  Administration of recombinant factor Vila has shown prom-  ise; however, this treatment approach requires further study.  The use of gastrointestinal hemorrhage prophylaxis with a  histamine-2 (H,) blocker, proton pump inhibitor, or sucral-  fate is recommended.   Shami VM, Caldwell SH, Hespenheide EE, et al. Recombinant acti-  vated factor VII for coagulopathy in fulminant hepatic failure  compared with conventional therapy. Liver Transpl. 2003;9:  138-143. [PMID: 12548507]   5. Renal failure — Prevention of renal failure by ensuring ade-  quate systemic blood pressure, treating infections, and avoiding  nephrotoxic agents is important. Continuous renal replacement  therapies such as continuous venovenous or arteriovenous  hemofiltration should be used as they cause less fluctuation in  hemodynamics and ICP than intermittent hemodialysis.   In patients with grade I or II encephalopathy, enteral feeding  should be initiated early. Parenteral nutrition should be used  only if enteral feeding is contraindicated as it increases the  risk of infection. Severe restriction of protein is not beneficial;  60 g/day of protein is generally reasonable. Fluid replacement  with colloid (eg, albumin) is preferred rather than crystalloid  (eg, saline); all solutions should contain dextrose to maintain  euglycemia.   Multiple electrolyte abnormalities are common in ALE  Correction of hypokalemia is essential as hypokalemia  increases renal ammonia production, potentially exacerbat-  ing encephalopathy. Hypophosphatemia is especially com-  mon in patients with acetaminophen-induced ALF and in  those with intact renal function. Hypoglycemia occurs in  many patients with ALF and is often due to depletion of  hepatic glycogen stores and impaired gluconeogenesis.  Plasma glucose concentration should be monitored and  hypertonic glucose administered as needed.   7. Infection — Bacterial and fungal infections are common in  ALF, with one study demonstrating culture-proven infection  in 80% of ALF patients. Defective cellular and humoral  immunity as well as presence of indwelling catheters, coma,  broad-spectrum antibiotics, and medications that suppress  immunity all predispose to infection. Localizing symptoms  of infection such as fever and sputum production are fre-  quently absent and the only clues to an underlying infectious  process may be worsening of encephalopathy or renal func-  tion. There must be a low threshold for obtaining frequent  cultures (blood, urine, and sputum), chest radiographs, and  paracentesis. Bacteria that enter through the skin, such as  streptococci and staphylococci, tend to predominate.  Aggressive surveillance is essential as prophylactic antibiotics  have shown little benefit. Fungal infections, particularly in  the setting of broad-spectrum antibiotics, are also common,  and disseminated fungemia is a poor prognostic sign.   The advent of transplantation has changed survival from as  low as 15% in the pretransplant era to more than 60% today.  Liver transplantation is indicated for many patients with  ALF, and survival rates of 56-90% can be achieved. In addi-  tion to transplantation, better critical care and the trend  toward more benign causes, such as acetaminophen, all con-  tribute to improved survival rates. Spontaneous survival is  now around 40%.   The application of transplantation among patients with  ALF remains low, suggesting that the full potential of this  modality may not be realized. Timely availability of an allo-  graft is one of the major factors determining transplant out-  comes. In the largest U.S. study, only 29% of patients received  a liver graft, while 10% of the overall group (one fourth of  patients listed for transplantation) died on the waiting list.  Other series have reported death rates of those listed for  transplant as high as 40%.   In the ALFSG, the transplantation rate was higher in the  groups with lower short-term spontaneous survival, mak-  ing overall survival similar in all groups: acetaminophen,  73%; drug induced, 70%; indeterminate group, 64%; and  other causes, 61%. Causes of death for the 101 patients who  died within the 3 -week period included cerebral edema,  multiorgan failure, sepsis, cardiac arrhythmia or arrest, and  respiratory failure. The median time to death after admis-  sion was 5 days.   Brown RS Jr, Russo MW, Lai M, et al. A survey of liver transplan-  tation from living adult donors in the United States. N Engl J  Med. 2003;348:818-825. [PMID: 12606737]   Farmer DG, Anselmo DM, Ghobrial RM, et al. Liver transplanta-  tion for fulminant hepatic failure: experience with more than  200 patients over a 17-year period. Ann Surg. 2003;237:666-675.  [PMID: 12724633]   Clinical experience with bioartificial systems is mostly con-  fined to small numbers of patients in uncontrolled trials.  One systematic review of 12 randomized trials (with a total  483 patients) assessing artificial and bioartificial support sys-  tems for acute or acute-on-chronic liver failure as a "bridge"  to transplantation showed no significant effect on mortality  compared with standard medical therapy. Currently, avail-  able liver support systems are not recommended for the  treatment of ALF.   Due to the scarcity of organs and the importance of the tim-  ing and decision regarding transplantation, the ability to  assess prognosis in ALF is critical. The most important deter-  minant of short-term (3 week) outcome appears to be the  cause of the ALF. In the ALFSG patients with acetaminophen  overdose, hepatitis A virus infection, shock liver, or preg-  nancy-related ALF, short-term survival without transplanta-  tion was 50% or greater. Patients with other etiologies had a  survival rate of less than 25% without transplantation. Age  and length of time between onset of illness and onset of  encephalopathy, previously reported as prognostic, were not  prognostic in the AFLSG.   The traditional King's College Hospital criteria  (Table 38-4) have been the most commonly used and most  frequently tested of the numerous proposed criteria for  determining prognosis in ALF. Several studies evaluating  these criteria have shown positive predictive values ranging  from 70% to nearly 100% and negative predictive values  from 25% to 94%. Fulfillment of these criteria suggests  that without transplantation, the patient has a very high  mortality risk.   For hepatitis A, the ALFSG demonstrated that the pres-  ence of two of four prognostic indicators (alanine amino-  transferase [ALT] > 2600 IU/L, creatinine > 2.0 mg/dL,  intubation, pressors) predicted transplantation or death in  89-100% of patients. Alternative criteria based on decreased   Table 38-4. Potentially helpful indicators 3 of poor  (transplant-free) prognosis in patients with acute  liver failure.   • Arterial pH < 7.3 (following adeguate  volume resuscitation) irrespective of coma  grade   • PT > 100 seconds (INR 6.5) + serum  creatinine > 300 mol/t (93.4 mg/dt) in  patients in grade lll/IV coma   -Drug toxicity, indeterminate cause of ALF  -Age <10 years or > 40 years  -Jaundice to coma interval > 7 days  -PT > 50 seconds (INR 3.5)  -Serum bilirubin > 300 mol/L (17.5 mg/dL)   ALF, acute liver failure; INR, international normalized ratio; PT,  prothrombin time.   a None of these factors, with the exception of Wilson disease and  possibly mushroom poisoning, are either necessary or sufficient to  indicate the need for immediate liver transplantation.  Adapted, with permission, from Poison J, Lee WM; American  Association for the Study of Liver Diseases. AASLD position paper: the  management of acute liver failure. Hepatology. 2005;41: 1179-1197.   levefs of factor V in patients with encephalopathy was shown  to have improved sensitivity in determining a poor progno-  sis in acute viral hepatitis.   Shakil AO. Predicting the outcome of fulminant hepatic failure.  Liver Transpl. 2005;11:1028-1030. [PMID: 16123964]   The ALFSG reports a rise in the annual percentage of  acetaminophen-related ALF from 28% in 1998 to 39% in  2003. These numbers may underestimate the contribution of  acetaminophen to ALF. In one study using a new acetaminophen  detection assay, 20% of ALF patients with indeterminate   etiology were found to have acetaminophen-containing pro-  tein adducts released from dying hepatocytes, suggesting that  unrecognized acetaminophen poisoning may have con-  tributed to ALF. Acetaminophen may also contribute to ALF  due to viral hepatitis, as patients may be taking acetamino-  phen products for relief of viral symptoms. A report from  France showed ALF in acute hepatitis A patients was signifi-  cantly associated with acetaminophen use.   Alcohol use, starvation, and acute illness may deplete glu-  tathione, predisposing to liver injury from acetaminophen.  In the ALFSG, participants who developed acetaminophen-  induced ALF after ingesting less than 4 g acetaminophen per  day before presentation more often used alcohol (65% vs  37%), more often reported unintentional overdose (74% vs  40%), and were older (median, 46 years vs 34 years) than  other study participants.   Acetaminophen toxicity should be considered in all patients  with ALF even without a history of toxic ingestion, particu-  larly in patients with very high aminotransferase values  (ie, > 1000 units/mL). Acetaminophen levels should be  drawn on initial evaluation; however, keep in mind that  depending on the timing of ingestion, acetaminophen levels  may not be elevated even in overdose.   If ingestion is suspected within a few hours of presentation,  activated charcoal (1 g/kg orally) may be useful up to 3-4  hours after ingestion and does not reduce the effectiveness of  oral N-acetylcysteine (NAC). The administration of NAC,  which replenishes glutathione stores, is recommended in any  patient with ALF in whom acetaminophen overdose is sus-  pected. Although early administration enhances efficacy,  some benefit has been shown even when NAC is given as late  as 36 hours, and possibly even 48 hours, after ingestion. A 20-  hour intravenous dosing regimen may be the therapy of  choice when oral administration is not possible. Allergic reac-  tions to NAC may be treated with antihistamines and epi-  nephrine for bronchospasm or discontinuation if necessary.   In the ALFSG, among 275 patients with acetaminophen-  induced ALF, 65% survived, 27% died without transplanta-  tion, and 8% underwent transplantation. However, nearly  one third of those reaching the threshold of encephalopa-  thy died. Extended acetaminophen dosing, delay in seeking  medical attention, and failure to institute NAC therapy are  associated with greater morbidity and mortality. Suicidal  intent, a history of previous suicide attempts, or evidence of  substance abuse may preclude transplant consideration.  Outcomes appear to be similar between patients with sui-  cidal intent and unintentional overdose once the patient  develops ALF.   Lee WM. Acetaminophen and the US Acute Liver Failure Study  Group: lowering the risks of hepatic failure. Hepatology.  2004;40:6-9. [PMID: 15239078]   Sato RL, Wong JJ, Sumida SM, et al. Efficacy of superactivated char-  coal administration late (3 hours) after acetaminophen over-  dose. Am J Emerg Med. 2003;21:189-191. [PMID: 12811710]   Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of  outcome in severe acetaminophen-induced hepatotoxicity.  Hepatology. 2002;36:659-665. [PMID: 12198658]   ALF is rare in hepatitis A (0.35%) but some studies suggest  that women, the elderly, and patients with underlying liver  disease may be at greater risk of morbidity and mortality  with acute hepatitis A infection. Since the introduction of  hepatitis A vaccines in 1995, reported cases of hepatitis A in  the United States have declined by more than 85%, and with  it, the incidence of hepatitis A-associated liver failure has  also declined. Patients with hepatitis A infection in whom  liver failure develops have a good prognosis (> 60% survival),  although some require liver transplantation. Recent recom-  mendations for routine early childhood immunization  beginning at age 12-23 months are expected to further reduce  the number of ALF cases due to hepatitis A.   Eisenbach C, Longerich T, Fickensher H, et al. Recurrence of clin-  ically significant hepatitis A following liver transplantation for  fulminant hepatitis A. / Clin Virol. 2006;35:109-112. [PMID:  16185915]   Rezende G, Roque-Afonso AM, Samuel D, et al. Viral and clinical  factors associated with the fulminant course of hepatitis A  infection. Hepatology. 2003;38:613-618. [PMID: 12939587]   Taylor RM, Davern T, Munoz S, et al. Fulminant hepatitis A virus  infection in the United States: incidence, prognosis, outcomes.  Hepatology. 2006;44:1589-1597. [PMID: 17133489]   Acute hepatitis B infection is the most common viral cause  of ALF, accounting for 8% of cases in the ALFSG. The inci-  dence of ALF caused by hepatitis B may be underestimated,  as some studies have shown evidence of hepatitis B infection  by polymerase chain reaction (PCR) in patients who under-  went transplantation for what was classified non-A, non-B  hepatitis. Precore or pre-S mutant hepatitis B viruses cause  infection but do not produce hepatitis B e antigen and may  be difficult to diagnose by routine serology. Because rapid  destruction of hepatocytes occurs in patients with fulminant  hepatitis, some patients have no detectable hepatitis B sur-  face antigen and lower hepatitis B virus DNA levels; how-  ever, high-titered immunoglobulin M anti-hepatitis B core  antigen may be present.   A study in the United states comparing two separate  cohorts of patients with hepatitis B-associated ALF versus  chronic infection demonstrated that patients with ALF were   more likely to be non-Asians and more likely to have genotype D  than patients with chronic hepatitis B. In general, the care of  patients with viral hepatitis B is supportive. Lamivudine,  entecavir, and adefovir, used to treat chronic hepatitis B, have  also been used in ALF, but this therapy has not been sub-  jected to a controlled trial.   Ozasa A, Tanaka Y, Orito E, et al. Influence of genotypes and pre-  core mutations on fulminant or chronic outcome of acute hep-  atitis B virus infection. Hepatology. 2006;44:326-334. [PMID:  16871568]   Wai CT, Fontana RJ, Poison J, et al. Clinical outcome and virolog-  ical characteristics of hepatitis B related acute liver failure in the  United States. / Viral Hepatol. 2005;12:192-198. [PMID:  15720535]   The role of hepatitis C infection in ALF is controversial.  Studies from Japan and India report the presence of  anti-hepatitis C virus antibody or hepatitis C virus RNA  among patients with ALF, but studies in France, the United  States, and the United Kingdom have not shown hepatitis C  to be a significant cause of ALF.   In the United States, infection with hepatitis D virus  accounts for fewer than 10% of all cases of acute hepatitis  related to hepatitis B virus. It has been suggested that a  majority of cases of ALF in patients positive for hepatitis B  are due to delta virus rather than to hepatitis B alone.   Hepatitis E occurs in epidemics in which a high incidence of  ALF is seen, particularly in pregnant women. In pregnancy,  the fatality rate approaches 40%. Hepatitis E has only rarely  been identified in the United States but should be considered  in anyone with recent travel to endemic areas such as Russia,  Pakistan, Mexico, or India.   Chau TN, Lai ST, Tse C, et al. Epidemiology and clinical features of  sporadic hepatitis E as compared with hepatitis A. Am ]  Gastroenterol. 2006;101:292-296. [PMID: 16454833]   Adenovirus-induced ALF is rare, but multiple cases have  been reported after allogeneic stem cell transplantation, liver  transplantation, chemotherapy, and renal transplantation. It  has an aggressive clinical course and poor prognosis.   Similarly, cytomegalovirus, Epstein-Barr virus, and her-  pesviruses 1, 2, and 6 are occasionally implicated as causes of  ALF. ALF related to herpesvirus infection is usually associated  with immunosuppressive therapy or pregnancy, although  occurrences of herpes virus-induced ALF have been  reported in healthy individuals. Skin lesions are present in  only about 50% of cases, and liver biopsy is often helpful in   establishing the diagnosis. Treatment should be initiated  with acyclovir for suspected or documented cases. Varicella  virus has been rarely implicated in hepatic failure and can  also be treated with acyclovir.   Nakazawa H, Ito T, Makishima H, et al. Adenovirus fulminant  hepatic failure: disseminated adenovirus disease after unrelated  allogeneic stem cell transplantation for acute lymphoblastic  leukemia. Intern Med. 2006;45:975-980. [PMID: 16974062]   Many drugs produce idiosyncratic liver failure (Table 38-5),  including halothane, sulfonamides, phenytoin, and isoniazid.  In the ALFSG, 13% of ALF cases were attributed to idiosyn-  cratic drug-induced hepatotoxicity.   Drugs most frequently associated with idiosyncratic  ALF, as reported by the ALFSG, were antibiotics (especially  isoniazid), nonsteroidal analgesics, antiseizure medications,  and herbal preparations. Two drugs prominently impli-  cated in this study, bromfenac and troglitazone, have been  withdrawn by the U.S. Food and Drug Administration.  Amoxicillin-clavulanate was the most common drug impli-  cated in another registry that included 461 patients with  drug-induced liver injury. The fluorinated hydrocarbons  trichloroethylene and tetrachloroethane also produce ALF,  often with associated renal failure, in people who sniff glue  or those exposed to industrial cleaning solvents.   Identification of drug-induced ALF requires careful history  taking, including all medications, over-the-counter prepara-  tions, vitamin supplements, herbal supplements, and health  foods. Peripheral eosinophilia, skin rash, and fever may be  seen when associated with hypersensitivity; however, many  cases of drug-induced hepatotoxicity are nonallergic and  idiosyncratic.   Initial treatment of drug-induced liver disease includes  supportive care, exclusion of other causes of liver injury,  and withdrawal of the offending agent. Corticosteroids are  not indicated unless there is evidence of a hypersensitivity  reaction.   Patients with non-acetaminophen drug-induced ALF  have a poor outcome overall, with only 25% recovering  spontaneously, and a 60-80% mortality rate without liver  transplantation. Variables such as female sex, hepatocellular  damage, total bilirubin, and aspartate aminotransferase  (AST) levels were associated with ALF and were strongly pre-  dictive of poor short-term outcome. Hyman Zimmerman, in  an observation known as "Hy's rule," noted that if both drug-  induced hepatocellular injury and jaundice were present  simultaneously without biliary obstruction (or hemolysis), a  mortality rate of at least 10% could be expected.   Table 38-5. Drugs that may cause idiosyncratic liver  injury leading to acute liver failure.   Adapted, with permission, from Poison J, Lee WM; American  Association for the Study of Liver Diseases. AASLD position paper:  the management of acute liver failure. Hepotology. 2005;41:   Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver  injury: an analysis of 461 incidences submitted to the Spanish  registry over a 10-year period. Gastroenterology. 2005;129:  512-521. [PMID: 16083708]   Andrade RJ, Robles M, Fernandez-Castaner A, et al. Assessment of  drug-induced hepatotoxicity in clinical practice: A challenge for  gastroenterologists. World ] Gastroenterol. 2007;13:329-340.  [PMID: 17230599]   Bernal W, Donaldson N, Wyncoll D, et al. Blood lactate as an early  predictor of outcome in paracetamoi-induced acute liver failure:  a cohort study. Lancet. 2002;359:558-563. [PMID: 11867109]   Bjornsson E, Olsson R. Outcome and prognostic markers in severe  drug-induced liver disease. Hepatology. 2005;42:481-489.  [PMID: 16025496]   Ohmori S, Shiraki K, Inoue H, et al. Clinical characteristics and  prognostic indicators of drug-induced fulminant hepatic fail-  ure. Hepatogastroenterology. 2003;50:1531-1534. [PMID:  14571779]   Ranganathan SS, Sathiades MJ, Sumanasena S, et al. Fulminant  hepatic failure and paracetamol overuse with therapeutic intent  in febrile children. Indian J Pediatr. 2006;73:871-875. [PMID:  17090896]   Mushroom poisoning is common in Western Europe, with  50-100 fatal cases reported yearly. Amanita phalloides is the most  common species implicated. Hepatic failure is preceded by  muscarinic effects such as profuse sweating, vomiting, and  diarrhea. Diagnosis should be suspected in patients with a his-  tory of severe vomiting, diarrhea, and abdominal cramping  within hours to a day of ingesting wild mushrooms. Gastric  lavage and activated charcoal via nasogastric tube to remove  stomach contents and to decrease the toxin in the enterohep-  atic circulation has been used although there are no definitive  studies of usefulness. The cholera-type diarrhea seen most  commonly as an effect of phalloidin during the first 24 hours  of illness can produce a profound metabolic alkalosis requir-  ing vigorous fluid resuscitation and electrolyte replacement.  Penicillin G, in doses of 250,000-1,000,000 units/kg/day, is  used as treatment and is believed to work by displacing aman-  itin from plasma protein-binding sites and allowing for  increased renal excretion. Sibilin (milk thistle) also has cyto-  protective abilities against amatoxin. Both antidotes are used  commonly despite no controlled trial demonstrating benefit.  Patients should be considered for transplantation as very low  rates of survival have been reported without it. Of note,  encephalopathy is not always present in severe cases and  should not be an absolute prerequisite for deciding on trans-  plantation. One study of 27 cases showed that an interval  between ingestion and diarrhea of less than 8 hours was a very  early predictor of fatal outcome. Later on, prothrombin index  and nonacetaminophen and acetaminophen King's College  criteria were more reliable indicators of prognosis.   Escudie L, Francoz C, Vinel IP, et al. Amanita phalloides poisoning:  reassessment of prognostic factors and indications for emer-  gency liver transplantation. / Hepatol. 2007;46: 466-473. [PMID:  17188393]   Soysal D, Cevik C, Saklamaz A, et al. Coagulation disorders sec-  ondary to acute liver failure in Amanita phalloides poisoning: A  case report. Turk J Gastroenterol. 2006;17:198-202. [PMID:  16941253]   Most patients with autoimmune hepatitis exhibit clinical fea-  tures of chronic hepatitis, but some present with ALF or an  acute-on-chronic presentation. Diagnosis of ALF due to   autoimmune hepatitis can be difficult and other causes need  to be ruled out. Autoantibodies may be absent and liver  biopsy is often needed to obtain a diagnosis. Corticosteroids  should be initiated (prednisone, 40-60 mg/day), but many  patients do not respond even to larger, pulsed doses of  steroids. Transplantation listing should therefore be consid-  ered in all patients with this presentation.   Czaja AJ. Treatment of autoimmune hepatitis. Semin Liver Dis.  2002;22:365-378. [PMID: 12447708]   Kotoh K, Enjoji M, Nakamuta M, et al. Arterial steroid injection  therapy can inhibit the progression of severe acute hepatic fail-  ure toward fulminant liver failure. World ] Gastroenterol.  2006;12:6678-6682. [PMID: 17075983]   ALF is rare in Wilson disease and appears to be more com-  mon in women. It is frequently associated with hemolytic  anemia as hepatocyte necrosis results in the massive release  of copper ions into the circulation. Clinical signs include  jaundice, hemoglobinuria, and renal failure. Diagnosis can  be difficult because ceruloplasmin, serum copper, urinary  copper, and even liver biopsy with copper staining can be  unreliable. As with autoimmune hepatitis, patients may have  evidence of cirrhosis and still present with signs of ALF  when rapid deterioration occurs. Kayser-Fleischer rings are  present in 50% of patients presenting with ALF due to  Wilson disease. Findings suggestive of the disease include  very high bilirubin level (> 20 mg/dL),markedly decreased  serum albumin and cholesterol levels, decreased serum alka-  line phosphatase, decreased uric acid, and a serum AST that  runs higher than ALT (over 4:1) due to hemolysis. A high  bilirubin (mg/dL) to alkaline phosphatase (IU/L) ratio (> 2)  is a reliable indicator of Wilson disease in this setting.   ALF due to Wilson disease is nearly always fatal without  transplantation, making early identification and immediate  listing for transplant critical. Treatment to acutely lower  serum copper and limit further hemolysis should include  continuous hemofiltration, plasmapheresis, or plasma  exchange. Penicillamine is not recommended in ALF as there  is a risk of hypersensitivity.   Roberts EA, Schilsky ML; American Association for the Study of  Liver Diseases. Diagnosis and treatment of Wilson disease: an  update. Hepatology. 2008;47:2089-2111. [PMID: 18506894]   Vascular causes of ALF include portal vein thrombosis,  hepatic vein thrombosis, veno-occlusive disease, and  ischemic hepatitis. Ischemic liver injury produces marked  aminotransferase elevations, centrilobular necrosis, and ALF  often with concurrent renal failure, myocardial infarction,  cardiac arrest, cardiomyopathy, congestive heart failure,  hypovolemia, and pulmonary embolism. Drug-induced   hypotension or hypoperfusion causing ALF can be observed  with long-acting niacin, cocaine, or methamphetamine.   Budd-Chiari syndrome or acute hepatic vein thrombosis  can also present as ALF and often is due to an underlying  prothrombotic problem. Abdominal pain, ascites, and  hepatomegaly are often present as well as lactic acidosis. The  diagnosis should be confirmed by imaging. Transjugular  intrahepatic portosystemic shunt, surgical decompression,  portacaval shunt, or thrombolysis may be beneficial in  patients with acute Budd-Chiari syndrome. Transplantation  may be required in patients who do not respond to venous  decompression or in whom significant liver failure has  occurred. It is important to rule out underlying cancer prior  to transplantation.   Malignant infiltration may cause ALF. Massive hepatic  enlargement may be seen. Diagnosis should be made by  imaging and biopsy, and treatment for the underlying disease  is indicated. Common causes include breast cancer, small cell  lung cancer, lymphoma, and melanoma. Transplantation is  not an option in these patients.   Kavanagh PM, Roberts J, Gibney R, et al. Acute Budd-Chiari syn-  drome with liver failure: the experience of a policy of initial  interventional radiological treatment using transjugular intra-  hepatic portosystemic shunt. / Gastroenterol Hepatol. 2004;19:  1135-1139. [PMID: 15377290]   Murad SD, Valla DC, de Groen PC, et al. Determinants of survival  and the effect of portosystemic shunting in patients with Budd-  Chiari syndrome. Hepatology. 2004;39:500-508. [PMID:  14768004]   Acute fatty liver of pregnancy (AFLP) occurs during the third  trimester and rarely presents as ALF. It is characterized by sud-  den onset of jaundice and coagulopathy, altered mental status,  hypoglycemia, and elevated transaminases but not to the extent  seen in acute viral or drug-related hepatitis. Alternatively,  HELLP syndrome, which involves very high aminotransferase  levels, hemolysis, thrombocytopenia, hypertension, proteinuria,  and preeclampsia, occurs in 0.1-0.6% of all pregnancies and in  4-12% of women with severe preeclampsia. Steatosis docu-  mented by imaging or biopsy supports the diagnosis of AFLP.  Rapid delivery is the treatment, but in 40% of cases the fetus  dies before delivery. Fatty liver of pregnancy can be treated with  transplantation if prompt recovery does not follow delivery.  Pregnancy can also increase the risk of ALF due to herpesvirus  infection, which should be treated with acyclovir.   Other rare causes of ALF include giant cell hepatitis or arteri-  tis, amebic abscesses, disseminated tuberculosis, sepsis, heat  stroke, and bone marrow transplantation. The cause of ALF  is indeterminate in nearly 20% of adult patients in the  United States. Indeterminate ALF carries a poor prognosis,  with a spontaneous survival rate of 20% or less. Several  reports have implicated a variety of viruses in indeterminate,  ALF including togaviruses, paramyxoviruses, herpes simplex  virus, SEN virus, and hepatitis C virus. The presence of many  of these viruses has been discovered later by PCR, after  results of routine serologic testing were negative.   ► Hepatitis A— E cause most recognized cases of acute  viral hepatitis; hepatitis B, C, and D cause most recog-  nized cases of chronic viral hepatitis.   ► Hepatitis A and E are transmitted by the fecal-oral  route; neither causes chronic infection.   ► Hepatitis B, C, and D are acquired percutaneously; all  can result in chronic infection.   ► Hepatitis D can occur only in a host already infected  with hepatitis B.   ► All five forms can cause fulminant hepatitis, but B, D,  and E are common causes, whereas A and C are very  rare causes.   ► Diagnostic tests appropriate to different clinical situa-  tions detect specific viral antigens and antibodies in  serum by sensitive enzyme immunoassay or radioim-  munoassay.   Although the hepatitis viruses have been characterized  extensively, the pathogenesis, diagnosis, and treatment of  chronic viral hepatitis continue to be the focus of research.  Sensitive and specific assays are available for all five forms  (A to E) of viral hepatitis (Table 39-1). Nevertheless, at least  5-20% of cases of acute and chronic hepatitis cannot be  attributed to any of the known forms of viral hepatitis and  do not appear to result from toxic, metabolic, or genetic con-  ditions. These include 5-20% of cases of acute viral hepati-  tis, 10-20% of cases of chronic hepatitis, and approximately  50% of cases of fulminant hepatitis. Whether additional  unidentified viruses cause acute or chronic liver disease  remains an unanswered question; to date, despite intense  investigation, no other hepatitis viruses have been identified.  This chapter focuses on clinical features of the five known   viruses that cause almost all recognized cases of acute and  chronic hepatitis (Table 39-2).   1. Symptoms and signs — Symptoms of acute viral hepati-  tis are usually nonspecific and include malaise, fatigue, nau-  sea, anorexia, and arthralgias. Fever, if present, is usually low  grade. With disease progression, pruritus, dark urine, scleral  icterus, and jaundice may occur.   2. Laboratory findings — In any acute viral hepatitis, serum  aminotransferase levels typically exceed 500 units/L and  often 1000 units/L, with the alanine aminotransferase (ALT)  characteristically higher than the aspartate aminotransferase  (AST). Elevation of aminotransferase levels begins in the  prodromal phase and precedes the rise in bilirubin level in  patients with icteric hepatitis. Serum alkaline phosphatase  may be normal or only mildly elevated. Serum bilirubin may  be normal (anicteric cases) or elevated (icteric cases), but  albumin and prothrombin time are generally normal unless  the acute hepatitis is sufficiently severe to impair hepatic syn-  thetic function. In most instances, bilirubin is divided  equally between conjugated and unconjugated fractions; val-  ues above 20 mg/dL that persist late into the course of viral  hepatitis are more likely to be associated with severe disease.  Prolongation of the prothrombin time (exceeding 3 seconds  above the control value or international normalized ratio  [INR] > 1.7) should raise concern and prompt close moni-  toring of the patient for worsening hepatic function and  impending hepatic failure. Neutropenia and lymphopenia  are transient and followed by a relative lymphocytosis.  Hypoglycemia occurs occasionally in severe acute hepatitis.  A mild and diffuse elevation of the y-globulin fraction is  common, especially in patients with acute hepatitis A.   3. Imaging findings — Radiologic imaging studies are rarely  necessary unless biliary tract disease is suspected. For example,   Anti-HAV, antibody to hepatitis A virus; anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen; anti-HBs, antibody to hepatitis B surface antigen;  anti-HCV, antibody to hepatitis C virus; anti-HDV, antibody to hepatitis D virus; anti-HEV, antibody to hepatitis E virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface anti-  gen; IgG, immunoglobulin G; IgM, immunoglobulin M.    Percutaneous, sexual, Percutaneous, (espe-  perinatal cially injection drug  use), sexual (rare),  perinatal (rare)    90% neonatal, 50% > 85%  infants, 20% children,  < 1% adults   for patients with profound cholestasis (such as occurs in  hepatitis A and even more commonly in hepatitis E), ultra-  sonography may be helpful in excluding extrahepatic biliary  tract obstruction.   4. Histologic evaluation — Liver biopsy is rarely necessary  in acute viral hepatitis except when the diagnosis is ques-  tionable or when chronic hepatitis is suspected.   1. Symptoms and signs — Chronic viral hepatitis may be  and is often asymptomatic; many patients are unaware of  their condition until the diagnosis is made incidentally or  until progression to advanced liver disease results in systemic  symptoms and clinical features of hepatic dysfunction.   2. Laboratory findings — The most telling laboratory mark-  ers are the aminotransferase levels, which may be elevated  continuously or may fluctuate; typically, ALT levels are  higher than AST levels until cirrhosis develops, when AST  levels tend to be higher. Otherwise, laboratory values that  reflect hepatic function (bilirubin, albumin, prothrombin  time) may be normal.   3. Imaging findings — Ultrasound, computed tomography  (CT), or magnetic resonance imaging (MRI) are useful to   evaluate liver parenchyma and to assess for the existence of  varices, reversal of portal hepatic flow, ascites, splenomegaly,  and other signs of portal hypertension; hepatic vein occlusion  and other vascular abnormalities; and focal mass lesions.   4. Histologic evaluation— Although its role is evolving,  liver biopsy is useful for grading the activity and for staging  the progression of disease, for identifying clinically relevant  histologic features (eg, steatosis, iron deposition, pathogno-  monic features of autoimmune liver injury, granulomatous  inflammation, etc), or for adding helpful information in  diagnostically challenging cases.   Infections with other viruses, such as cytomegalovirus,  Epstein-Barr virus, herpes simplex or zoster, and coxsack-  ieviruses, can result in an acute viral hepatitis syndrome  and elevated serum aminotransferase levels. Toxoplasmosis  and leptospirosis may also share clinical features with  acute hepatitis. If the results of serologic tests for the  known hepatitis viruses (discussed later) are negative, and  if clinical features are suggestive, serologic tests for these  agents should be considered.   Several drugs and anesthetic agents can produce a picture  similar to that of acute hepatitis; therefore, taking a careful  drug history is important. A past history of unexplained and  repeated episodes of hepatitis raises the possibility of under-  lying chronic hepatitis.   Alcoholic hepatitis is associated with a history of ethanol  abuse and usually with clinical stigmata of alcoholism. In  patients with alcoholic liver disease, serum aminotransferase  levels rarely rise above 300 units/L, and, typically, serum AST  levels exceed serum ALT levels.   When abdominal pain is prominent, acute viral hepatitis  may be confused with acute cholecystitis, choledocholithia-  sis, ascending cholangitis, pancreatitis, or other abdominal  disorders. Careful clinical and radiologic evaluation will  assist in making the correct diagnosis and thereby avoiding  unnecessary surgery. Cholestatic viral hepatitis may be con-  fused with obstructive jaundice resulting from pancreatic  carcinoma, common bile duct stone, other disorders that  obstruct the biliary tree, or hepatic infiltrative disorders (eg,  fatty infiltration, primary or metastatic tumor infiltration,  extramedullary hematopoiesis, granulomatous disorders).   Clinical features help to distinguish acute hepatitis from  congestive hepatopathy and acute ischemic injury, which tend  to be associated primarily with aminotransferase, not alkaline  phosphatase, elevations. Uncommonly, inherited metabolic  disorders, such as Wilson disease, mimic acute viral hepatitis.   In the differential diagnosis of chronic viral hepatitis are  autoimmune hepatitis, primary biliary cirrhosis, sclerosing  cholangitis, genetic disorders such as Wilson disease, hemochro-  matosis, c^-antitrypsin deficiency, alcoholic liver disease, nonal-  coholic fatty liver disease, and chronic drug hepatotoxicity.  Serology, biochemical testing, and liver histopafhology help in  arriving at the correct diagnosis in most instances.   ► Diagnosis of acute infection depends on the detection  of immunoglobulin M (IgM) antibodies to hepatitis A  virus (IgM anti-HAV).   ► IgM anti-HAV, the primary immune response, is  replaced by immunoglobulin G (IgG) anti-HAV, correlat-  ing with subsequent lifelong immunity.   ► Presence of IgG anti-HAV in a patient with acute hepa-  titis indicates that the illness is not caused by HAV.   Hepatitis A virus (HAV) is a 27-nm nonenveloped RNA virus  (genus Hepatovirus) that is transmitted by the fecal-oral   route through ingestion of contaminated food (eg, shellfish,  strawberries, onions) or water. The incubation period is 2-6  weeks, the duration of viremia is short (5-7 days), and  chronic infection does not occur; therefore, percutaneous  transmission is rare.   Infection is more prevalent in areas of low socioeconomic  status characterized by insufficient sanitation and poor  hygienic practices, which facilitate the spread of enteric  infections. In developing countries, hepatitis A is endemic,  infecting most children before the age of 5-10 years. In  developed countries, improved socioeconomic conditions  and sanitation have led to an increase in the mean age of  infection and a reduction in the prevalence of HAV exposure,  as reflected by serum antibodies to HAV (anti-HAV) in the  population.   As is true for all hepatitis viruses, viral replication of HAV  occurs primarily within hepatocytes. Except in extraordinary  circumstances, hepatitis viruses are not cytopathic; instead,  liver cell damage results from host cell-mediated cytotoxicity.  In hepatitis A, the necroinflammatory changes and mononu-  clear cell infiltrates are prominent in periportal areas, but lob-  ular focal necrosis, ballooning hepatocytes, and apoptosis are  regular features as well. In some cases, centrilobular cholesta-  sis may be severe, particularly in adults. Serum neutralizing  antibodies protect against HAV infection. HAV antigen can be  demonstrated by immunohistochemical staining as fine gran-  ules in the cytoplasm of hepatocytes and Kupffer cells.   Although more than 75% of adults infected with HAV have  symptoms, approximately 70% of infections in young chil-  dren are asymptomatic. When hepatitis A is clinically appar-  ent, patients present with fatigue, malaise, right upper  quadrant and epigastric discomfort, loss of appetite, and, in  icteric cases, jaundice. Less commonly, HAV infection maybe  profoundly cholestatic and accompanied clinically by  marked jaundice, acholic stools, and pruritus.   Hepatitis A results very rarely in fulminant hepatitis and  does not cause chronic liver disease, although extraordinarily  rare reports suggest that acute hepatitis A can trigger autoim-  mune hepatitis in susceptible persons. Approximately 10% of  cases can have a relapsing course lasting several months  (resumption of fecal viral excretion and aminotransferase  elevation after initial, apparent resolution) and invariably  culminating in eventual recovery. Systemic manifestations  are uncommon and include arthritis and, very rarely, trans-  verse myelitis, aplastic anemia, and leukocytoclastic vasculi-  tis, although reports of these complications are not linked  reliably to hepatitis A. Concomitant meningoencephalitis has  been reported rarely. Cholestatic hepatitis with protracted  cholestatic jaundice and pruritus can occur as a variant of  acute hepatitis A.   The diagnosis of acute HAV infection depends on the  detection of IgM antibodies to HAV (IgM anti-HAV). IgM  anti-HAV occurs as a primary immune response and per-  sists for approximately 3 months, sometimes extending to  6 months after acute HAV infection. It is replaced by  immunoglobulin G (IgG) anti-HAV, which correlates with  subsequent lifelong immunity. Thus, if a patient who pres-  ents with acute hepatitis has IgG anti-HAV, the acute illness  is not caused by HAV.   General measures to prevent the spread of HAV infection  include a safe water supply and proper environmental  hygiene (eg, sewage disposal, elimination of overcrowded  housing, etc). Killed HAV vaccines have a protective efficacy  of 94-100% after two doses, with negligible side effects. Two  such vaccines were licensed in the United States in  1995-1996 and are available worldwide. Their introduction  in the United States coincided with a decline in new, reported  cases of hepatitis A in the United States from an annual aver-  age of 28,000 in the 1980s and 1990s to 7600 cases in 2003.  In 2006, because of residual clusters of hepatitis A cases,  including severe and even fatal instances in otherwise healthy  adults, the Advisory Committee on Immunization Practices  recommended routine hepatitis A vaccination of children at  1 year of age. Recommendations for vaccination of other  persons in groups at increased risk for hepatitis A are listed  in Table 39-3.   Immunoglobulin has also been shown to be safe and  effective as both preexposure and postexposure prophylaxis  against HAV infection. For preexposure prophylaxis, if  immediate protection is required, travelers should receive  passive immunization with immunoglobulin and begin a  course of active immunization with vaccine; in this setting,  preexposure passive immunization requires a single intra-  muscular dose of immunoglobulin (0.02 mL/kg). For post-  exposure prophylaxis, the same dose, given within 10-14  days of exposure, has an efficacy of approximately 85% and  usually aborts or reduces the severity of, and renders clini-  cally inapparent, HAV infection (yielding a combination of  passive immunization and the durable immunity that fol-  lows acute infection). In the absence of such concomitant  active immunization, the passive protection offered by  immunoglobulin lasts only a few months.   Treatment is largely supportive and consists of discontinua-  tion of potentially hepatotoxic medications and restriction of  alcohol intake. Neither bed rest nor dietary restrictions are  effective. Most cases do not require hospitalization, which is  recommended for patients with advanced age, serious under-  lying medical conditions, chronic liver disease, malnutrition,   • Travelers to countries with high or intermediate endemicity of infec-  tion, including Africa, Asia (not Japan), the Mediterranean basin, east-  ern Europe, the Middle East, Mexico, Central and South America, and  parts of the Caribbean   • All children at age 1 year (12-23 months) as part of routine vaccinations   • Men who have sex with men and others with high risk sexual  behaviors   • Persons with occupational risk for infection (eg, food handlers, child  care workers, or people working with nonhuman primates)   • Persons with chronic liver disease, particularly hepatitis C, in whom  hepatitis A may be severe   • Susceptible persons who receive clotting factor concentrates,  especially solvent-detergent treated preparations   • Public safety workers with exposure to blood in the workplace   • Clients and staff of institutions for the developmental^ disabled, day  care centers, and schools   • Persons who have clotting factor disorders and who receive clotting  factor concentrates   • Household contacts and sexual partners of persons with chronic  hepatitis B   • International travelers spending > 6 months in endemic areas and who  may have close contact with local population or who are likely to have  blood exposure from or sexual exposure with the local population   • Sexually active heterosexual men or women who have recently  acguired other sexually transmitted diseases, who are sex workers, or  who have multiple sexual partners   pregnancy, immunosuppressive therapy, hepatotoxic med-  ications, severe vomiting that prevents adequate oral intake,  and clinical and laboratory findings that suggest fulminant  hepatitis. The occasional patient with fulminant hepatic fail-  ure, defined as the onset of encephalopathy within 8 weeks of  the onset of symptoms, should be referred for consideration  of liver transplantation.   The overall case fatality rate for HAV infection is very low  (~0.3-0.6%), although higher in adults older than age 50 years  (1.8%). In some reports, morbidity and mortality were  increased in the presence of a hepatitis A superinfection in  patients with underlying chronic liver disease.   Advisory Committee on Immunization Practices (ACIP), Fiore  AE, Wasley A, Bell B. Prevention of hepatitis A through active or  passive immunization: recommendations of the Advisory  Committee on Immunization Practices (ACIP). MMWR  RecommRep. 2006;55:1-23. [PMID: 16708058]   Craig AS, Schaffner W. Prevention of hepatitis A with the hepatitis A  vaccine. N Engl } Med. 2004;350:476-481. [PMID: 14749456]   Martin A, Lemon SM. Hepatitis A virus: from discovery to vac-  cines. Hepatology. 2006;43:S164-172. [PMID: 16447259]   Taylor RM, Davern T, Munoz S, et al. Fulminant hepatitis A virus  infection in the United States: incidence, prognosis and out-  comes. Hepatology. 2006;44:1589-1597. [PMID: 17133489]   Wasley A, Miller IT, Finelli L. Surveillance for acute viral  hepatitis— United States, 2005. MMWR Surveill Summ. 2007;  56:1-24. [PMID: 17363893]   ► Diagnosis relies on the presence of hepatitis B surface  antigen (HBsAg).   ► Presence of IgM versus IgG antibodies to hepatitis B  core antigen (anti-HBc) distinguishes acute from chronic  infection, and IgM anti-HBc indicates recent infection  (previous 6 months).   ► Hepatitis B e antigen (HBeAg) appears early in the  course of infection and in self-limited cases is replaced  within 2-3 months by antibody to HBeAg (anti-HBe).   ► During chronic hepatitis B in patients with wild-type  HBV infection, viral replication is rapid, infectivity is sub-  stantial, and liver injury is pronounced; this phase gives  way to one of lower viral replication, infectivity, and  liver injury in which patients become inactive carriers.   ► In patients with precore mutations (HBeAg-negative  chronic hepatitis B), HBV DNA levels fluctuate and anti-  HBe is detectable in serum.   ► Presence of isolated antibodies to HBsAg (anti-HBs) is  consistent with vaccine-induced immunity.   ► Antibodies to both surface and core proteins (anti-HBs,  anti-HBc, and anti-HBe) indicate prior HBV infection.   ► Interpretation of isolated IgG anti-HBc positivity is diffi-  cult and may represent ongoing, low-level HBV infec-  tion, prior HBV infection, or a false-positive test.   More than 400 million people worldwide — 5% of the world's  population — are currently HBsAg-reactive, indicating that  they are currently infected with hepatitis B virus (HBV), and  as many as 50% of the world's population have had HBV  infection, as reflected by the presence of anti-HBs. HBV is   endemic in areas containing 45% of the world's population.  In endemic areas, rates of current infection range from 8% to  25%, and exposure rates (based on the presence of anti-HBs)  range from 60% to 85%. In low prevalence areas such as the  United States, the prevalence of chronic HBV infection is  0.1-0.2% (1.25 million), and the annual incidence of new  HBV infections is 200,000-300,000.   HBV is transmitted primarily by perinatal, percutaneous,  and sexual routes. The virus can also be transmitted by inap-  parent percutaneous routes and close person-to-person con-  tact, presumably via open cuts and sores, especially among  children in endemic areas (eg, sub-Saharan Africa, which has a  prevalence of chronic HBV infection of just under 10%). In  the United States, most HBV infections occur in adolescence  and early adulthood, and the most common modes of trans-  mission are sexual and percutaneous (exposure to contami-  nated instruments and needles, eg, via injection drug use). In  contrast, in Asia, the most common mode is perinatal trans-  mission to infants of mothers with chronic HBV infection; in  sub-Saharan African countries in addition to perinatal spread,  another common mode of transmission is horizontal spread  between young children. Injection drug users are at high risk  of acquiring not only HBV infection but also other blood-  borne hepatitis agents, hepatitis C and D (see later sections).   HBV is a partially double-stranded, partially single-stranded  DNA virus (hepadnavirus type 1) that replicates via reverse  transcription through an RNA intermediate. Although HBV  is strongly hepatotrophic, viral sequences, including HBV  replicative intermediates, are present in extrahepatic tissues  (lymph nodes, peripheral blood mononuclear cells); how-  ever, the vast bulk of HBV replication is confined to the liver.  The HBV genome contains four open reading frames that  encode four major proteins: (1) the S gene, which codes for  the envelope protein, hepatitis B surface antigen (HBsAg);  (2) the C gene, which codes for the nucleocapsid proteins  hepatitis B core antigen (HBeAg) and hepatitis B e antigen  (HBeAg); (3) the P (or pol) gene, which codes for the DNA  polymerase, which, in turn, catalyzes transcription and  reverse transcription steps involved in viral replication; and  (4) the X gene, which codes for the X protein, a protein of  limited clinical relevance but which up-regulates the tran-  scription of host cellular and viral genes, including those of  other viruses such as HIV.   The envelope protein of the virus, HBsAg, in serum is the  primary marker of HBV infection. In the hepatocyte, HBsAg  is expressed in the cytoplasm and can be recognized histo-  logically by the presence of ground-glass hepatocytes. Eight  HBV genotypes (A to H) have been identified; the prevalence  of HBV genotype varies depending on geographic location.  In the United States the prevalences of genotypes A, B, C, D,  and others are 35%, 22%, 31%, 10%, and 2%, respectively.  Recent data suggest that HBV genotypes may play an impor-  tant role in progression of HBV-related liver disease as well as   in response to interferon therapy. Similar associations have  not been clarified definitively in patients treated with oral  agents (nucleoside and nucleotide analogs); therefore, the  testing of HBV genotype has not yet been adopted routinely  as a prelude to antiviral therapy (see later discussion).   The C region has two initiation codons and therefore two  gene transcripts (precore and core), the translation of which  result in two protein products (HBeAg and HBcAg). HBcAg,  the protein expressed on the 27-nm nucleocapsid core parti-  cles, is not secreted into serum but is localized predominantly  to the hepatocyte nucleus and is expressed also in smaller  quantities on the hepatocyte surface membrane. As such,  HBcAg is the target of the host immune response to infection,  playing an important role in the pathogenesis of HBV- induced  liver damage. The other nucleocapsid protein, HBeAg, a low-  molecular-weight nonparticulate protein, is encoded by the  precore plus core region of the C gene, enters the secretory  apparatus of the hepatocyte, and circulates in serum; the pres-  ence of HBeAg is indicative of active viral replication and cor-  relates with increased infectivity and liver injury. The products  of the same gene, HBcAg and HBeAg, have considerable  amino acid homology and immune cross-reactivity at the T-  cell level. Antibody to HBcAg (anti-HBc) appears at the onset  of clinical hepatitis, shortly after the appearance of HBsAg,  and may be the only marker detectable between the disap-  pearance of HBsAg and the appearance of anti-HBs (less likely  to be encountered now that the sensitivity of assays for HBsAg  and anti-HBs are so high). During acute hepatitis B, anti-HBe  appears as clinical symptoms and aminotransferase levels are  waning; its appearance marks a transition to lower viral repli-  cation, infectivity, and liver injury.   HBeAg-negative variants result from mutations in the  precore region of the C gene, with failure of HBeAg synthe-  sis (the serologic marker linked to active virus replication)  yet with continued high-level viral replication and liver  injury. "HBeAg-negative" mutant HBV has been associated  with fulminant hepatitis (rarely) and aggressive chronic hep-  atitis (commonly).   Liver injury associated with HBV infection is the product  of a combination of innate and adaptive immune responses,  the latter of which are effected by cytotoxic T cells directed at  liver membrane complexes of host histocompatibility antigens  and HBcAg. The clinical outcome of HBV infection depends  on the balance between viral activity and the host immune  response, as reflected by the robustness of the CD8 + cytotoxic  T-cell response and the release of antiviral T-cell cytokines;  however, other than certain clinical features (eg, age, infection  at birth, immunocompetence), what distinguishes those who  recover from those who progress to chronic infection remains  poorly defined. In perinatally acquired infection, immaturity  of the neonatal immune system and the presence of HBV on  hepatocytes shortly after birth combine to produce a level of  immunologic tolerance to HBV that limits the adequacy of the  host immune response to HBV. This state of immunologic tol-  erance can persist indefinitely. No robust cytotoxic T-cell  response occurs against HBV, no clinical illness ensues, but   chronic infection is almost invariable (> 90%). In contrast,  among young adults with acute hepatitis B, the cytotoxic T-cell  response to HBV expressed on hepatocyte membranes is sub-  stantial and efficient, leading to an acute hepatitis illness and,  typically, recovery; chronicity after clinically apparent acute  hepatitis B in healthy, immunocompetent young adults occurs  in fewer than 1% of cases.   Epidemiologically and clinically, chronic HBV infection is  linked strongly to the development of hepatocellular carci-  noma (HCC), which occurs in up to 50% of patients with  HBV- induced cirrhosis (see Chapter 49). The mechanism of  viral oncogenesis has been studied extensively; viral integra-  tion into the host genome is required, but no consistent sites  of integration have been identified (eg, adjacent to a host  tumor promotor or suppressor gene). Cell turnover associ-  ated with chronic inflammation likely contributes to the  pathogenesis of HCC, as do such cofactors such as alcohol  use and environmental anatoxin exposure.   A precore nucleotide mutation or core-promoter mutation  can lead to premature termination of the precore protein,  preventing production of HBeAg. HBeAg-negative HBV is  found more frequently in HBV genotypes other than geno-  type A, and its prevalence was concentrated initially in  Mediterranean countries. Currently, HBeAg-negative chronic  hepatitis B is the predominant form of chronic hepatitis B in  Europe and represents a growing proportion of chronic hep-  atitis B infections in the United States. Wild-type (HBeAg-  positive) chronic hepatitis B is associated with higher levels of  HBV replication (> 10 6 virions/mL) than HBeAg-negative  chronic hepatitis B (< 10 5 virions/mL), whereas HBeAg-  negative chronic hepatitis B is more likely to be associated  with fluctuating levels of HBV DNA and aminotransferase  activity. In addition, in HBeAg-negative chronic hepatitis B,  patients treated with antiviral therapy (see later discussion)  cannot experience treatment-induced HBeAg seroconversion,  which, in HBeAg-positive chronic hepatitis B, can be used as a  treatment end point. Therefore, the ideal duration of therapy  remains undefined in HBeAg-negative chronic hepatitis B.   2. S mutants — A mutation in the S gene has been reported  in infants who are born to HBV-infected mothers but acquire  HBV infection after vaccination and in liver transplant recip-  ients who acquire breakthrough HBV reinfection despite  treatment with hepatitis B immunoglobulin (HBIG). These  mutations alter the antigenicity of the HBV envelope, evad-  ing neutralizing anti-HBs. Fortunately, the frequency of such  mutations is limited.   3. P mutants — Mutations in the polymerase gene are asso-  ciated with resistance to HBV antiviral agents such as  lamivudine, adefovir, and telbivudine (see later discussion).   The incubation period of acute hepatitis B is between 4 weeks  and 6 months. Clinical symptoms are similar to those  described earlier for acute hepatitis A (eg, fatigue, anorexia,  jaundice), and aminotransferase elevations are the biochem-  ical hallmark of illness. In 5-10% of acute hepatitis B  patients, a serum sickness-like syndrome with arthralgias,  rash, angioedema, and, rarely, proteinuria and hematuria  may develop in the prodromal phase. In children, hepatitis B  may present rarely as anicteric hepatitis associated with a  nonpruritic papular rash on the face, buttocks, and limbs  (popular acrodermatitis of childhood).   Progression from acute to chronic hepatitis may be suggested  by the persistence of anorexia, weight loss, and fatigue,  although most patients with chronic hepatitis B are asymp-  tomatic. Physical findings may include hepatomegaly and  splenomegaly. Laboratory findings include persistence of  HBsAg, detectable HBeAg in HBeAg-positive hepatitis, and  elevations of aminotransferase, bilirubin, and globulin levels.  Histologic features include the presence of portal inflamma-  tion, bridging or, in severe cases, multilobular hepatic necro-  sis, and the presence of fibrosis.   Many patients with chronic HBV infection are inactive  carriers who have no symptoms, normal serum aminotrans-  ferase activity, low-level HBV DNA (< 10 3 virions/mL), cir-  culating anti-HBe, and normal or near-normal liver  histology.   Extrahepatic manifestations, when they occur, may  include arthralgias, arthritis, Henoch- Schonlein purpura,  generalized vasculitis (polyarteritis nodosa), glomeru-  lonephritis, pleural effusions, pericarditis, and aplastic anemia  (the latter not definitively linked to HBV infection, however).  Uncommon complications of HBV infection include pancre-  atitis, myocarditis, atypical pneumonia, transverse myelitis,  and peripheral neuropathy.   The diagnosis of HBV infection relies on the presence of  HBsAg. Acute and chronic infections are distinguished by the  presence of IgM versus IgG antibodies to HBcAg (anti-HBc).  The presence of IgM anti-HBc indicates recent infection,  generally within the previous 6 months. HBeAg appears dur-  ing early during acute hepatitis B, while viral replication is at  peak levels, and in self-limited cases is replaced within 2-3  months by antibody to HBeAg (anti-HBe).   During chronic hepatitis B, in patients with wild-type  HBV infection, the presence of HBeAg corresponds to a rela-  tively highly replicative period, during which levels of HBV  DNA exceed 10 6 virions/mL, infectivity is substantial, and liver  injury is pronounced. Over time, this highly replicative phase  gives way to a relatively low replicative phase, characterized by   low-level HBV DNA (< 10 3 virions/mL) and negligible infec-  tivity and liver injury. Patients in this phase are considered  inactive carriers.   In patients with precore mutations (HBeAg-negative  chronic hepatitis B), HBV DNA levels fluctuate between  undetectable and approximately 10 5 virions/mL, and anti-  HBe is detectable in serum. The presence of isolated anti-  HBs is consistent with vaccine-induced immunity.  Antibodies to both surface and core proteins (anti-HBs, anti-  HBc, and anti-HBe) indicate prior HBV infection.   Interpretation of isolated IgG anti-HBc positivity is diffi-  cult and may represent ongoing, low-level HBV infection,  prior HBV infection, or a false-positive test. Isolated anti-  HBc with ongoing low-level HBV infection is more common  in persons from high-prevalence areas, in persons with a his-  tory of injection drug use, and in patients with HIV or HCV  infection.   Hepatitis B vaccine is protective in over 90% of normal  adults and in almost 100% of newborns. Recombinant vac-  cines have largely supplanted the original plasma-derived  vaccine in most parts of the world. Common adverse effects  are local reactions at the injection site (soreness, tenderness,  pruritus, and swelling). The immunogenicity of hepatitis B  vaccines is reduced in adults older than 40 years; among  younger healthy adults, approximately 2.5-5% do not  acquire protective antibodies, and such nonresponsiveness  has been shown to be genetically determined.   Despite the availability of highly effective vaccines for  25 years, targeted vaccination programs for those at highest  risk of infection have failed to reduce the frequency of HBV  infection in the U.S. population. Currently, the U.S. Public  Health Service recommends universal vaccination of all  neonates and prepubertal teenagers. In addition, HBV vacci-  nation is currently recommended for immunocompromised  patients; hemodialysis patients; patients with coexisting  chronic liver disease of other causes, including chronic hep-  atitis C; health care workers; injection drug users; and those  with high-risk sexual exposures (see Table 39-3). Currently,  booster immunization is not recommended routinely,  although it may be useful in immunosuppressed persons  who have lost detectable anti-HBs or in immunocompetent  persons who sustain HBsAg inoculation after losing  detectable antibody (although this subgroup appears to be  protected even after loss of detectable anti-HBs).   In fulminant hepatitis, intensive care in a specialized unit  likely reduces mortality, which otherwise approaches 80%  (see Chapter 38). Protein intake should be restricted and  oral lactulose or rifaximin administered. Patients should be   supported by maintaining fluid and electrolyte balance and  cardiorespiratory function, controlling bleeding, treating pro-  phylactically with broad-spectrum antibiotics, and managing  other complications. Although antiviral treatment with inter-  feron has not been shown to be of benefit in fulminant hepa-  titis B, treatment with oral nucleoside or nucleotide agents  (described later) may be of benefit and would be recom-  mended in most specialized treatment centers.   Corticosteroid therapy is not only ineffective but harm-  ful, as demonstrated in clinical trials. Similarly, exchange  transfusions, plasma perfusion, human cross-circulation,  and porcine liver cross-perfusion have not proven effective.   Orthotopic liver transplantation is being performed with  increasing frequency, with excellent long-term results. Thus,  patients should be supported maximally until spontaneous  recovery or until prognostic factors indicate worsening out-  come necessitating transplantation; the threshold for refer-  ring to a liver transplantation center should be very low.  During and after transplantation, measures should be taken  to prevent HBV infection of the graft (see later discussion).   The objectives of treatment for chronic hepatitis B are to sup-  press HBV replication and reduce liver injury. Among the end  points of therapy are (1) profound reduction in circulating  HBV DNA, preferably to levels undetectable by highly sensitive  amplification assays; (2) in HBeAg-positive chronic hepatitis B,  HBeAg seroconversion (loss of HBsAg and acquisition of anti-  HBe); (3) normalization of ALT levels; (4) improvement in  liver histology (reduction in the grade of necroinflammatory  activity and limiting progression of, or even improving, the   stage of fibrosis). Although not proven conclusively, data sug-  gest that successful antiviral therapy has the potential to pre-  vent or delay progression to cirrhosis, hepatic decompensation,  and even HCC. Recommendations for patients with chronic  hepatitis B who are candidates for treatment are summarized  in Table 39-4; six therapies are approved and currently avail-  able for treatment of chronic hepatitis B (Table 39-5).   1. lnterferon-r/.2b — The first antiviral drug for hepatitis B,  interferon-oc2b (IFNa), was approved by the U.S. Food and  Drug Administration (FDA) in 1992. In patients with com-  pensated chronic hepatitis B (including those with early cir-  rhosis), detectable HBeAg, and elevated aminotransferase  activity, subcutaneous IFNa injections of 10 million units  three times per week or 5 million units daily for 16-24 weeks  resulted in HBeAg loss in approximately 30% (along with sup-  pression of HBV DNA to levels undetectable by relatively  insensitive hybridization assays) and HBeAg seroconversion in  approximately 18-20%. Patients with HBeAg-negative  chronic HBV should be treated for 12-24 months. In this early  experience with interferon, almost 10% of patients cleared  HBsAg after their initial course of therapy; however, such high  rates of HBsAg seroconversion have not been observed in  more recent experiences. The strongest predictor of response  to IFNa in HBeAg-positive patients is a high pretreatment  ALT level, but other factors favoring a response include a high  histologic activity index, low HBV DNA level, and HBV geno-  types A and B. Retreatment of nonresponders with a second  course of IFNa is unlikely to be of any clinical benefit.   In patients with HBeAg-negative hepatitis B, short  courses of IFNa are of little benefit and do not yield durable  suppression of HBV DNA and ALT; in this patient group,    Low efficacy of treatment  If ALI < ULN, observe  If ALT 1-2 x ULN:   • Consider biopsy for age > 40 y, family history of HCC    Treat with any of recommended agents  Lamivudine or telbivudine not first line  Liver biopsy optional   ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ULN, upper limit of normal.   Table 39-5. Approved antiviral therapy among treatment-naive patients with HBeAg-positive chronic hepatitis BJ   ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B; IFNoc, interferon a; NA, not available; PEG IFNa, pegylated   Data from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539.   long-term treatment (eg, 12-18 months) is preferable, but  the durability of treatment effect is degraded over time to less  than 20%, 5 years after therapy. Compensated cirrhotic  patients respond as do patients with precirrhotic chronic  hepatitis B; however, in decompensated cirrhosis, IFNa  may precipitate hepatic failure or be complicated by life-  threatening infection or psychiatric effects, and, therefore, is  not recommended.   Side effects of interferon, which, in addition to the need  for injection, are the major limitation to its use, include  (1) flulike symptoms of fever, myalgias, fatigue, and  headache; (2) marrow suppression (leukopenia, neutropenia,  and thrombocytopenia); (3) anxiety, emotional lability, or  depression; and (4) autoimmune disorders, primarily of the  thyroid. IFNa is accompanied by a flare in ALT in 30-40% of  patients, and although flares are considered to be predictive  of a favorable response, in patients with advanced or mar-  ginally compensated cirrhosis, an acute flare can precipitate  decompensation.   Contraindications to IFNa therapy include immune sup-  pression or autoimmune disease, and severe, uncontrolled  psychiatric disease or depression.   Before the availability of newer antiviral agents, IFNa was  considered a good therapeutic choice for patients with mild  liver disease, low levels of HBV replication, and high serum  aminotransferase levels. Some authorities recommend  interferon-based therapy for young persons, based on the  assumption that an approximately 30% chance of HBeAg loss  with a time-confined course of therapy might be preferable   for a young person to indefinite therapy with an oral agent  (see later discussion). An equally compelling argument  might be made to spare a young person the inconvenience  and side effects of IFNa therapy in favor of a side effect-free  oral agent, which might require an extra half year to a year to  achieve the same benefit as a course of IFNa.   For all practical purposes, IFNa as been supplanted by  long-acting, once-weekly pegylated interferon for those  favoring interferon therapy and by the several highly potent  polymerase inhibitors for those who favor oral agents. What  early studies of IFNa have shown is that successful antiviral  therapy can improve the natural history of chronic hepatitis  B, improving survival and complication-free survival.   2. Pegylated interferon alfa (PEG IFNa)— Pegylated  interferons are produced by binding of a large, inert polyeth-  ylene glycol moiety to the interferon molecule, thus increas-  ing the molecular weight of the compound, decreasing its  renal clearance, altering its metabolic degradation, and  increasing its half-life. Therefore, pegylated interferons can  be administered by subcutaneous injection once weekly.   PEG IFNa2a is the only pegylated interferon approved  for the treatment of chronic HBV in the United States.  Clinical trials have demonstrated that the efficacy of PEG  IFNa2a is similar to or slightly better than that of standard  IFNa, in addition to its more convenient administration. For  HBeAg-positive patients, the most definitive trial repre-  sented a comparison of 48 weeks of PEG IFNa2a alone, ver-  sus lamivudine alone, versus combination therapy. During   the 48 weeks of therapy, the level of HBV DNA suppression was  highest in the combination-treatment arm, and HBeAg sero-  conversion occurred in a similar percentage of the three  groups: 27%, 20%, and 24%, respectively. However, 24 weeks  after treatment was stopped, seroconversion was maintained in  32%, 19%, and 27%, indicating that 48 weeks of PEG IFNoc2a  monotherapy was superior to 48 weeks of lamivudine  monotherapy. In a study of HBeAg-negative patients, PEG  IFNa2a monotherapy was compared with lamivudine  monotherapy versus combination therapy for 48 weeks; a sus-  tained response, defined as suppression of HBV DNA to below  10 5 copies/mL or to undetectable by polymerase chain reaction  (PCR) amplification (10 2 copies/mL) and a return to normal of  ALT, was comparable in patients who received PEG IFNoc2a  alone or in combination with lamivudine (100 mg), which  were both better than lamivudine alone. In both HBeAg-reac-  tive and HBeAg-negative studies, a small proportion of PEG  IFNa2a-treated study subjects experienced HBsAg seroconver-  sion during (in the HBeAg-negative trial) or after (in the  HBeAg-positive trial) therapy. Side effects and predictors of  treatment response are similar to those of standard IFNoc  therapy, but PEG IFNoc2a is better tolerated by most subjects.  Although some patients may choose a year of PEG  IFNoc2a therapy, such therapy requires a year of weekly injec-  tions and willingness to accept interferon side effects. In  these trials of PEG IFNa2a, treatment was confined to a  finite, 48-week period, which is typical of the way PEG  IFNoc2a is used but not the way oral agents are used. Instead,  oral agents, very well tolerated, are administered for longer  periods (eg, until after HBeAg seroconversion or to maintain  responsiveness in HBeAg-negative patients). In fact, the same  HBeAg seroconversion rates achieved with 48 weeks of PEG  IFNoc2a injection therapy occur when oral agent therapy is  extended to 18-24 months. In addition, suppression of HBV  DNA and ALT after interferon-based therapy in HBeAg-  negative patients is lost gradually over time. Therefore, the  advantages of a year of PEG IFNoc2a therapy may be out-  weighed by the advantages of slightly longer treatment with  substantially better tolerated oral agents. The recommended  dose of PEG IFNoc2a is 180 meg weekly for 48 weeks.   3. Lamivudine — Lamivudine, an oral nucleoside analog that  inhibits viral DNA synthesis by blocking reverse transcriptase  and that is cleared renalfy, was approved by the FDA originally  for the treatment of HIV (150 mg daily) in 1995 and then for  the treatment of hepatitis B (100 mg daily) in 1998.   Several large, randomized controlled trials of HBeAg-  positive patients treated for 1 year documented HBeAg sero-  conversion (with suppression of HBV DNA to undetectable  levels as determined by insensitive hybridization assays) in  16-20% of treated patients (HBeAg loss in up to a third)  compared with 4-6% spontaneous seroconversion in con-  trol subjects. Furthermore, loss of detectable HBV DNA  occurs in the majority of patients, normalization of ALT in  50% of patients, and improvement in necroinfiammatory   histology scores in 49-56% of patients compared with  23-25% of control subjects. Recent studies in which lamivu-  dine was the comparator arm for new oral nucleoside  analogs demonstrated that lamivudine suppresses HBV DNA  by approximately 5.5 log 10 copies/mL. Reductions in the pro-  gression of fibrosis and progression to cirrhosis have also  been demonstrated. After achieving HBeAg seroconversion,  this serologic status is maintained in approximately 80% of  patients as long as a period of consolidation therapy follows  the seroconversion (at least 6 months in Western patients,  longer in Asian patients). For patients who do not achieve  HBeAg seroconversion during the first year of therapy,  HBeAg seroconversion rates increase with extended courses  of therapy, but the optimal duration of treatment with  lamivudine, as with other oral agents, remains to be defined.   In HBeAg-negative patients, lamivudine suppresses HBV  DNA by approximately 4.5 log 10 copies/mL, suppresses HBV  DNA to undetectable levels (as determined by sensitive  amplification assays) in approximately 70%, and reduces  ALT to normal in approximately 75%. When therapy is dis-  continued, however, generally, the therapeutic effect is lost as  HBV DNA and ALT return to baseline levels. Therefore,  almost all HBeAg-negative patients and the majority of  HBeAg-positive patients require extension of therapy indefi-  nitely beyond the first year.   Lamivudine is safe to use in patients with cirrhosis. Clinical  trials have demonstrated that lamivudine therapy for several  years can reverse cirrhosis and that, unlike interferon, this  drug can be used in patients with hepatic decompensation,  salvaging them from a further decline and leading to reversal  of decompensation. In addition, a prospective trial of lamivu-  dine versus placebo in compensated patients with advanced  fibrosis demonstrated the principle that such antiviral therapy  can prevent the incidence over time of hepatic decompensa-  tion; in this important study, a trend was apparent in the pre-  vention of, or delay in, the development of HCC.   Selection of lamivudine-resistant mutations is the main  concern with lamivudine monotherapy. Genotypic resistance  can be detected in 14-32% of patients after 1 year of lamivu-  dine treatment and increases to 60-70% after 5 years of treat-  ment. The most common mutation involves substitution of  methionine for valine or isoleucine in the tyrosine-methionine-  aspartate-aspartate (YMDD) motif of the HBV DNA poly-  merase. Factors associated with resistance include long  duration of treatment, high pretreatment serum HBV DNA,  and, most importantly, high levels of residual virus (> 10 3 -10 4  virions/mL) after initiation of treatment. Although in vitro  the YMDD mutation actually decreases replication fitness of  HBV, compensatory mutations restore the fitness of mutant  HBV, and clinical benefit is lost eventually after lamivudine  resistance emerges. Lamivudine resistance is usually detected  by virologic breakthrough followed by biochemical break-  through and, in some patients, can be associated with an  acute exacerbation of hepatitis or, in marginally compen-  sated cirrhotics, with hepatic decompensation.   Most patients with confirmed lamivudine resistance  should receive rescue therapy with antiviral agents, such as  adefovir or tenofovir, that are effective against lamivudine-  resistant HBV mutants. When adefovir or tenofovir is used to  treat patients with lamivudine resistance, the new drug  should be added to lamivudine therapy; for example, switch-  ing to adefovir monotherapy renders the patient susceptible  ultimately to adefovir resistance.   Because of the need for long treatment courses, lamivu-  dine is not an optimal first-line treatment for HBeAg-negative  chronic HBV, and now that more potent, less resistance-prone  antiviral agents are available, lamivudine, despite its estab-  lished safety, is being supplanted as an antiviral agent for  hepatitis B.   4. Adefovir dipivoxil— Adefovir is a nucleotide analog of  adenosine monophosphate that can inhibit both reverse  transcriptase and DNA polymerase activity and is incorpo-  rated into HBV DNA causing chain termination. Adefovir is  effective in suppressing wild-type HBV as well as lamivudine-  resistant HBV. The recommended dose for adults with nor-  mal renal function is 10 mg orally daily. Adefovir has been  shown to produce a histologic response in 53% of HBeAg-  positive patients versus 25% of placebo recipients after 48 weeks  of therapy, HBeAg seroconversion in 12% of patients versus  6% of placebo recipients, a 3.5 log 10 copies/mL decrease in  HBV DNA in patients versus 0.6 log 10 copies/mL in placebo  recipients, and normalization of ALT levels in 48% of patients  versus 16% of placebo recipients. Approximately 30% of  patients with no prior nucleotide analog treatment have a  primary nonresponse to adefovir (< 2 log 10 drop in HBV  DNA after 6 months of treatment), and alternative treatments  should be considered.   In HBeAg-negative patients, suppression of HBV DNA,  normalization of ALT, and histologic improvement occur as  well, but the therapeutic effect is lost once the drug is  stopped. Thus, as is the case for therapy with other oral  agents, in HBeAg-negative patients, continued treatment  is needed to maintain the antiviral response. In HBeAg-  negative patients who have completed 5 years of adefovir  treatment, HBV DNA was undetectable in 67% and ALT was  normal in 69%.   Adefovir has been shown to be effective in liver allograft  recipients and in HIV-HBV coinfected patients as well as in  lamivudine-resistant HBV. Adefovir resistance occurs at a  slower rate than with lamivudine treatment; the cumulative  probabilities of genotypic resistance to adefovir at 1,2, 3, 4,  and 5 years have been reported to be 0%, 3%, 1 1%, 18%, and  29%, respectively. As previously mentioned, in patients with  lamivudine-resistant HBV, lamivudine should not be  switched to adefovir; instead, adefovir should be added to  lamivudine therapy.   5. Entecavir — Entecavir, a carbocyclic analog of 2'-  deoxyguanosine, inhibits HBV replication at three steps:  priming of the HBV polymerase, reverse transcription of the   negative-strand HBV DNA from the pregenomic RNA, and  synthesis of the positive-strand HBV DNA. Entecavir, which  suppresses HBV DNA by almost 7 log 10 copies/mL in  HBeAg-positive patients (5.2 log 10 copies/mL in HBeAg-  negative patients), is more potent than lamivudine and ade-  fovir and, although cross-resistance occurs between entecavir  and other L-nucleosides, has such a low median effective  concentration in vitro that in vivo levels of drug are sufficient  to be effective against lamivudine-resistant HBV. Like other  L-nucleosides, entecavir is effective against adefovir-resistant  HBV mutants as well. The approved oral daily dose of ente-  cavir is 0.5 mg for treatment-naive patients but 1.0 mg for  lamivudine-resistant patients.   In HBeAg-positive patients, after 48 weeks of treatment,  when compared with lamivudine, entecavir had significantly  higher rates of histologic (72% vs 62%), virologic (67% vs  36% undetectable HBV DNA by highly sensitive amplifica-  tion assay), and biochemical (68% vs 60% with normal ALT)  responses. Among HBeAg-positive patients who underwent  HBeAg seroconversion during the first year (21%) and who  stopped treatment at 48 weeks, 70% remained HBeAg nega-  tive. In HBeAg-negative patients, similar rates of histologic,  virologic, and biochemical improvement have been seen;  however, the majority of patients relapse if treatment is  stopped after 1 year.   Entecavir has a very high barrier to resistance; in nucleoside-  na'ive patients, entecavir resistance has not been encountered  during the first 2 years of therapy and has emerged in less  than 1% of patients through year 4. In lamivudine-resistant  patients, however, entecavir resistance was observed in 7% of  patients at 1 year, 16% of patients at 2 years, 35% of patients  at 3 years, and 43% of patients at 4 years. Therefore, although  entecavir is favored above other L-nucleosides for treatment  of previously untreated patients, most authorities would  avoid entecavir as replacement therapy for lamivudine-  resistant hepatitis B, FDA approval for this indication  notwithstanding.   nucleoside analog that has been shown in clinical trials to be  more potent than lamivudine in suppressing HBV replication.  The approved dosage of telbivudine is 600 mg orally daily.   In HBeAg-positive patients, HBV DNA was undetectable  in 60% of telbivudine recipients versus 40% of lamivudine  recipients after 1 year and in 54% versus 8% after 2 years.  Patients taking telbivudine also had significantly higher rates  of normal ALT after 1 and 2 years of treatment compared  with those taking lamivudine; however, as was true for ente-  cavir, despite the substantially higher potency of telbivudine  over lamivudine in suppressing HBV DNA, no difference was  observed between telbivudine and lamivudine recipients in  the rate of HBeAg seroconversion at the end of 1 and 2 years  of treatment. In HBeAg-negative patients, telbivudine was  superior to lamivudine in treatment measures by the same  degree that entecavir exceeded lamivudine.   Unfortunately, telbivudine is associated with substantial  resistance, and telbivudine-resistant mutations are cross-  resistant with lamivudine. Like lamivudine, telbivudine  selects for YMDD mutations, and genotypic resistance was  observed in 4.4% and 21.6% of HBeAg-positive patients  after 1 and 2 years of therapy, respectively, and in 2.7% and  8.6% of HBeAg-negative patients after 1 and 2 years.  Although one of the more (albeit not the most) potent HBV  DNA inhibitors, telbivudine has a disappointing resistance  profile and, therefore, does not appear to have a role in  monotherapy for HBV infection.   7. Other therapies — Other therapies currently being con-  sidered for approval for the treatment of HBV infection  include emtricitabine (very similar to lamivudine in struc-  ture, potency/efficacy, and resistance profile) and tenofovir  (like adefovir, a nucleotide analog but more potent and with  an excellent resistance profile), both currently approved for  treatment of HIV infection. A combination of these two,  licensed for treatment of HIV infection, has the potential  advantage of combination, non-cross-resistant L- nucleoside  and nucleotide analog therapy. As patients begin to appear  with mutations to both classes of these oral antiviral agents,  interest in this combination and other combinations that can  preempt the emergence of antiviral resistance will grow. To  date, no advantage has been found for combinations of IFNoc  or PEG IFNa and oral agents. Just prior to publication of this  chapter, tenofovir was approved for treatment of Hepatitis B.  Shown to be far superior to adefovir, tenofovir should sup-  plant adefovir.   1. HBV-HIV coinfection— Response rates to standard IFNa  are reported to be lower in patients with HBV-HIV coinfection.  Lamivudine, emtricitabine, and tenofovir are all nucleoside  analogs with activity against both HIV and HBV; however, the  rate of HBV resistance to lamivudine in HBV-HIV coinfected  patients approaches 90% at 4 years. Given that antiretroviral  regimens may include drugs with activity against HBV, clini-  cians should base HBV treatment decisions on whether or not  HIV treatment is ongoing or planned. Lamivudine monother-  apy should never be used in HIV-positive patients in the  absence of highly active antiretroviral therapy (HAART).  Entecavir was thought initially to have no anti-HIV activity and  was considered a potential monotherapy for HBV-HIV coin-  fected patients not receiving HAART; however, recently, ente-  cavir was found to have modest activity against HIV,  contraindicating its use (because of the potential for early  emergence of HIV resistance) as monotherapy in patients with  HIV-HBV coinfection who are not receiving HAART.   3. HBV-HCV coinfection— Limited information is available  to guide treatment in this setting. Often, such patients have   relatively nonreplicative chronic hepatitis B and need to be  treated for hepatitis C. When both viruses need to be treated,  PEG IFNa (with ribavirin for hepatitis C) can be used to  address both infections; alternatively, both diseases can be  treated independently with PEG IFNa plus ribavirin for hep-  atitis C and one of the oral agents for hepatitis B. Generally,  antiviral therapy for hepatitis C in HCV-HBV coinfected  patients yields sustained virologic responses similar to those  achieved in patients being treated for HCV alone; however,  suppression of HCV replication has been reported, rarely, to  result in rebound replication of HBV.   Approximately 20-50% of patients with chronic hepatitis  B, including inactive carriers, have been reported to have  reactivation of HBV replication associated with immuno-  suppressive or cytotoxic chemotherapy, especially if the reg-  imen includes high-dose corticosteroids. This event occurs  primarily as chemotherapy is withdrawn and cytolytic  immune responsiveness recovers. Subclinical as well as clin-  ically severe, even fatal, reactivations can occur, reflected ini-  tially by increases in serum HBV DNA and ALT. Prophylactic  antiviral therapy should be administered to such patients  with chronic hepatitis B at the onset of chemotherapy and  should be maintained for at least 6 months afterward; in fact,  the duration of treatment is not known, and, in some cases,  discontinuing therapy proves difficult. Most of the experi-  ence in this setting involves lamivudine, but entecavir, similar  to lamivudine in its rapid onset of action and freedom from  nephrotoxicity, represents an appealing alternative.   Liver transplantation is currently a successful therapy for  end-stage chronic HBV-associated liver disease. Hepatitis B is  currently the seventh most common indication for liver  transplantation in the United States, comprising about 5% of  cases. Until the early 1990s, transplantation resulted in an  80% rate of reinfection in the absence of prophylaxis. The  resulting hepatitis could be severe and was almost invariably  chronic. The risk of reinfection was higher in patients with  chronic liver disease versus fulminant disease and lower in  those with HBD-HDV coinfection than in those with HBV  infection alone. The introduction in 1993 of high-dose hep-  atitis B immunoglobulin (HBIG) perioperatively and post-  operatively, combined with approval of lamivudine in 1998  for treatment of hepatitis B, has reduced graft infection rates  to less than 5% in patients who receive both HBIG and a  nucleoside analog post-transplantation. Given the need for  long-term therapy and both the risk and consequences of  lamivudine resistance in organ allograft recipients, newer drugs  with higher barriers to resistance (eg, entecavir or adefovir) and  especially those with potent antiviral activity and limited  nephrotoxicity (eg, entecavir) are favored first-line treatment to  prevent recurrent HBV infection post-transplantation.   Disadvantages of prolonged HBIG use include cost, patient  inconvenience, and intolerability. In some centers, switching  from intravenous HBIG to intramuscular HBIG has been  successful and associated with enhanced convenience and  tolerability. No clear guideline exists for the duration of HBIG  treatment post-transplantation; however, one recent study  showed that the risk of HBV reinfection is negligible if HBIG  is discontinued after 2 years and followed with continued use of  a maintenance nucleoside or nucleotide analog treatment.   Patients who have undergone liver transplantation for  HBV or HBV-HDV coinfection should have HBV DNA or  HDV RNA, or both, followed every 3 months. Studies of  combination nucleoside-nucleotide therapy after liver trans-  plantation are ongoing.   For neonates born to infected mothers and any person with  a percutaneous or sexual exposure, HBIG is available and is  helpful to achieve immediate high-level circulating anti-HBs  (passive immunization). Simultaneously, active immuniza-  tion with hepatitis B vaccine should be offered as well.   Ninety-five to 99% of healthy, immunocompetent young  adult patients with clinically apparent acute HBV infection  have a favorable course and recover completely. The case  fatality rate is low (0.1%) but increases with age and associ-  ated comorbid systemic illnesses (eg, diabetes mellitus and  congestive heart failure). The risk of chronicity is related to  the age of acquisition (> 90% in newborns, ~50% in young  children, and 1-5% in immunocompetent adults). In addi-  tion, chronicity is more likely (> 50%) in immunocompro-  mised adults such as transplant recipients, HIV-positive  persons, and patients undergoing cytotoxic chemotherapy.  Chronically infected patients may be inactive carriers or may  have chronic hepatitis with or without cirrhosis.   Hepatitis B accounts for approximately half of all cases of  fulminant viral hepatitis (see Chapter 38). The diagnosis is  suggested by rising bilirubin, an increasing prothrombin time  (INR), and signs of encephalopathy. Cerebral edema is com-  mon, and death usually results from a combination of brain-  stem compression, gastrointestinal bleeding, sepsis, respiratory  failure, cardiovascular collapse, and renal failure. Survivors  have complete biochemical and histologic recovery.   Patients with chronic hepatitis B, with or without HBeAg,  who have highly replicative HBV infection are likely to expe-  rience the negative consequences of chronic infection, cir-  rhosis, hepatic decompensation, and HCC; indeed, patients  with high-level HBV DNA are more likely to progress to cir-  rhosis and HCC than those with low-level HBV DNA, while  relatively nonreplicative inactive carriers are less likely to  progress to cirrhosis or to have HCC. In turn, patients with  high-level HBV replication tend to progress histologically,  and those with more advanced histologic stage have a worse   prognosis. In one prospective study, patients with cirrhosis  had a 5-year survival of only 55% and a 15-year survival of  only 40%.   Hepatitis B is a major risk factor for HCC. In HBV-  endemic regions, HCC is the leading cause of cancer-related  death. Cirrhosis is present in 70-80% of HBV-related HCC,  and the chronic inflammation and regenerative cellular pro-  liferation associated with cirrhosis may predispose to cellular  transformation and malignancy. A proportion of patients  with HBV-associated HCC, up to 20-30% in some series, do  not have cirrhosis, contrasting with hepatitis C-associated  HCC, almost all of which occurs in cirrhotic patients. In  otherwise healthy, inactive hepatitis B carriers, the HCC inci-  dence is 0.06-0.3% per year; in patients with chronic hepati-  tis, the annual incidence is 0.5-0.8%; and in those with  cirrhosis, the rate of HCC is 1.5-6.6% per year. The cumula-  tive risk of HCC almost doubles over 15 years in patients  with high-level HBV DNA compared with those who have  low-level HBV DNA. Furthermore, the risk of HCC is also  significantly higher among men and older patients as well as  in patients with a family history of HCC, a history of sero-  logic reversion from anti-HBe to HBeAg, HBV genotype C,  and coinfection with HCV Population- and clinic-based  screening programs that rely on serum a-fetoprotein (AFP)  and liver imaging (primarily ultrasound) have led to identi-  fication of patients with small and potentially resectable  tumors. Despite achieving earlier detection of HCC, however,  such screening programs have not been shown to reduce  mortality resulting from HCC (see Chapter 49). Furthermore,  because of the nonspecificity of AFP elevations in chronic  viral hepatitis, AFP screening is no longer recommended as  part of HCC surveillance.   Farrell G. Hepatitis B e antigen seroconversion: effects of lamivu-  dine alone or in combination with interferon alpha. ] Med Virol.  2000;61:374-379. [PMID: 10861649]   Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a,  lamivudine and the combination for HBeAg-positive chronic  hepatitis B. N Engl ] Med. 2005;352:2682-2695. [PMID:  14987917]   Lau DT, Khokhar MF, Doo E, et al. Long-term therapy of chronic  hepatitis B with lamivudine. Hepatology. 2000;32:828-834.  [PMID: 11003630]   Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology.  2007;45:507-539. [PMID: 17256718]   Ohata K, Hamasaki K, Toriyama K, et al. High viral load is a risk  factor for hepatocellular carcinoma in patients with chronic  hepatitis B virus infection. / Gastroenterol Hepatol 2004; 19:  670-675. [PMID: 15151623]   Tan I, Lok AS. Antiviral therapy for pre- and post-liver transplan-  tation patients with hepatitis B. Liver Transpl. 2007;13:323-326.  [PMID: 17318864]   Wong SN, Chu CI, Wai CT, et al. Low risk of hepatitis B virus  recurrence after withdrawal of long-term hepatitis B  immunoglobulin in patients receiving maintenance nucleos(t)ide  analogue therapy. Liver Transpl. 2007;13:374-381. [PMID:  17318855]   ► Enzyme immunoassay (EIA) for antibody to hepatitis C  virus (anti-HCV) indicates past exposure or ongoing  infection.   ► False-positive EIA tests occur most often in blood donors  and patients with rheumatoid factor; false-negative  tests occur most often in immunocompromised patients  (eg, hemodialysis patients, organ allograft recipients).   ► Recombinant immunoblot assay (RIBA) has been sup-  planted by testing for HCV RNA to confirm positive tests  for anti-HCV.   ► HCV RNA is usually detectable in serum 7-21 days after  exposure using one of the three available amplification  assays (PCR, transcription-mediated amplification  [TMA], and branched-chain DNA [bDNA]).   ► The clinically relevant threshold between high-level  and low-level HCV RNA is 800,000 lU/mL.   ► Liver biopsy permits accurate assessment of the degree  of inflammation and fibrosis but is not mandatory  before initiating therapy.   Based on serologic screening (NHANES, National Health  and Nutrition Examination Survey) between 1999 and 2002  of a representative cohort of the population, the U.S. Public  Health Service calculated that 4.1 million people in the  United States (1.6% of the population) have antibodies  to hepatitis C virus (anti-HCV) and that approximately  3.2 million (1.3%) have chronic hepatitis C virus (HCV)  infection. The peak prevalence observed was among persons  aged 40-49 years. When a similar survey was done earlier  during the 1990s, the peak prevalence of HCV infection  occurred among those aged 30-39 years. In fact, this shift  reflects the aging of the HCV-infected cohort who had been  infected in the remote past, during the 1960s and 1970s, during  an epidemic of experimentation with injection drugs.  Worldwide, approximately 3% of the population (170 million  people) are estimated to have chronic hepatitis C.   In the United States, HCV is the most common blood-  borne infection, the leading cause of chronic liver disease,  and the most common indication for liver transplantation.  The Centers for Disease Control and Prevention estimate  that the number of new cases of acute HCV infection has  fallen from approximately 230,000 per year in the 1980s to a  current level of less than 30,000 per year (< 0.3 cases annu-  ally per 100,000 population), indicating that new infections  are rare. The decline in new cases of acute hepatitis C paral-  lels directly the decline in cases among injection drug users,   which is thought to reflect the adoption of precautions in  this subpopulation to minimize the risk of acquiring HIV  infection. Almost all newly recognized cases of hepatitis C  occur among individuals who acquired their infections sev-  eral decades ago but who are just now coming to clinical  recognition as they seek health care for other reasons.   Groups at risk for HCV infection include transfusion  recipients (particularly those transfused before 1992, when  sensitive serologic screening of donor blood began, virtually  eliminating hepatitis C from the blood supply), injection  drug users, hemodialysis patients, Vietnam-era veterans, and  health care workers. Persons with hemophilia who received  factor VIII infusions before HCV screening was initiated  have a 74-90% prevalence of HCV infection. In intravenous  drug users, prevalence is 72-90%. Acquisition by health care  workers of hepatitis C as a result of a contaminated needle-  stick is inefficient, occurring in approximately 3% of those  exposed and accounting for a very small proportion of HCV  infections (~1%).   Sporadic HCV infection, in which the mode of transmis-  sion is unknown, is responsible for approximately 10% of  cases, but in many of these, long forgotten injection drug use  is the source.   Perinatal transmission is rare and inefficient, estimated to  occur in only approximately 5% of infants born to HCV-  infected mothers, independent of the route of delivery.   Sexual transmission of HCV can occur, but the risk is  extremely low (< 5% overall and closer to 1% in stable,  monogamous sexual partners), and HCV is much less effi-  ciently sexually transmitted than HBV In the rare instance  when both sexual partners are infected with HCV (0.4-3% of  the sexual partners of patients with HCV infection are also  infected), almost invariably, other risk factors are identified.  Because of the low risk of sexual transmission of hepatitis C,  the U.S. Public Health Service currently does not recommend  a change in sexual practices in stable sexual partners. In the  sexually promiscuous, those with sexually transmitted dis-  eases, and sex workers, however, the risk of sexual transmis-  sion can reach 10%. In the most recent NHANES data, the  risk of HCV infection was most strongly associated, inde-  pendently, with injection drug use. Anti-HCV was also asso-  ciated independently with Mexican-American ethnicity, birth  in the United States, low family income, noninjection illicit  drug use, and a lifetime total of 20 or more sexual partners.   Hepatitis C virus is a single-stranded, 9600 base-pair RNA  virus (genus Hepacivirus). Its genome encodes core and  envelope structural proteins at the 5' end and five nonstruc-  tural proteins (including a helicase, protease, and RNA poly-  merase) at the 3' end that are important in viral replication.  Six major HCV genotypes have been described, designated  1-6, which are divided further into subtypes (la, lb, 2a, etc)  of which over 50 have been described. Considerable variation  exists in the geographic distribution of HCV genotypes; in   the United States, approximately 70% of patients are geno-  type 1 and the other 30% are genotypes 2 and 3. Although  not predictive of the outcome of HCV infection, the geno-  type does predict the likelihood of treatment response and  also determines the duration of treatment and the dose of  ribavirin, one of the two drugs used to treat hepatitis C (see  later discussion). Genotypes 1 and 4 are more refractory to  interferon-based therapy compared with genotypes 2 and 3.  In addition to its genotype diversity, the heterogeneity of  HCV is exaggerated by the multiple quasispecies circulating  in serum, reflecting the hypervariability of regions of the  HCV envelope proteins that arise as a product of evolution-  ary changes in the virus as it evades host immunologic con-  tainment. This viral diversity accounts for the high likelihood  for HCV persistence after acute infection and the limited  ability of the host to mount durable neutralizing antibodies  against HCV. As a result, recovery from acute infection is  unusual (< 15%), and attempts to develop a protective vac-  cine have been frustratingly disappointing.   Levels of HCV in serum are lower (up to 10 5 -10 6 , rarely  10 7 , virions/mL) than levels of HBV (often exceeding 10 6 and  ranging to > 10 9 ), and HCV antigens are not detectable in  blood. The clinical features of acute and chronic hepatitis C  are similar to those of hepatitis B, except that acute hepatitis C  tends to be milder and progression to chronicity the rule,  rather than the exception. Several histologic features are  characteristic of chronic hepatitis C, including the presence  of microvesicular or macrovesicular steatosis, bile duct  injury, and lymphocytic follicles. As is true for the other viral  hepatitides, liver injury associated with HCV infection is  immunologically mediated; differences in the diversity and  robustness of cytolytic T-cell responses appear to be impor-  tant in distinguishing between the rare patients who recover  from acute hepatitis C and the vast majority of patients  who progress to chronic infection. A direct cytopathic effect  of HCV may also contribute to the damage in some situa-  tions (eg, in immunosuppressive states, such as after liver  transplantation).   immune-complex disorders as essential mixed cryoglobuline-  mia, membranoproliferative glomerulonephritis, and leuko-  cytoclastic vasculitis. Other extrahepatic disorders associated  with chronic hepatitis C include thyroiditis and porphyria  cutanea tarda.   The first step in the diagnosis of HCV infection is the EIA for  anti-HCV, which indicates past exposure or ongoing infec-  tion. The current, third-generation EIA is approximately  99% sensitive and specific. In hepatitis C, distinctions  between IgM and IgG anti-HCV are not helpful; therefore,  assays for IgM anti-HCV IgM are not available. False-positive  EIA tests are seen most often in populations with a low prior  probability of true infection, such as blood donors and  patients with rheumatoid factor, which can result in nonspe-  cific binding in the assay. False-negative tests are seen most  often in immunocompromised patients, including  hemodialysis patients and organ allograft recipients. In the  past, a recombinant immunoblot assay (RIBA) was used to  confirm positive tests for anti-HCV; however, RIBA has been  supplanted by testing for HCV RNA.   The next step in the diagnosis of HCV infection is detec-  tion of HCV RNA in serum. HCV RNA is generally  detectable 7-21 days following exposure. Currently, three  types of amplification assay are available for detecting HCV  RNA: PCR, transcription-mediated amplification (TMA),  and branched-chain DNA (bDNA). The most sensitive PCR  and TMA assays have a sensitivity of 5-50 IU/mL; bDNA is  less sensitive (10 3 copies/mL).   Quantitation of HCV RNA is based on World Health  Organization-standardized international units (IU) per  milliliter; the clinically relevant threshold between high-level  and low-level HCV RNA is 800,000 IU/mL. The HCV geno-  type is not necessary for the diagnosis of HCV infection but  provides valuable clinical information required for manage-  ment decisions about duration of therapy and drug doses.   Acute hepatitis C is asymptomatic in approximately 84% of  cases and is usually not recognized clinically. Jaundice,  fatigue, fever, nausea, vomiting, and right upper quadrant  discomfort can occur, usually within 2-12 weeks of exposure  and lasting from 2 to 12 weeks. The diagnosis is established  by demonstration of anti-HCV or HCV RNA, or both.   Chronic hepatitis C is also asymptomatic in most patients.  ALT values fluctuate in a substantial proportion of patients.  Extrahepatic manifestations, which develop in approxi-  mately 15% of patients with chronic infection, include such   Because the severity of liver damage cannot be determined  noninvasively with adequate reliability, a liver biopsy is neces-  sary to assess the degree of inflammation (histologic grade)  and fibrosis (histologic stage) accurately. According to the cur-  rent guidelines of the American Association for the Study of  Liver Diseases (AASLD), a liver biopsy should be done when  the results will influence whether treatment is recommended  or will provide information on prognosis, but a biopsy is not  mandatory in order to initiate therapy for hepatitis C.   Although some authorities have issued recommendations  against performing liver biopsies prior to therapy for chronic  hepatitis C, many clinicians, in weighing the risks, benefits,  and costs of biopsy versus those of treatment for hepatitis C,  choose to obtain a liver biopsy in patients with HCV genotype- 1  infection to inform treatment decisions. For patients with   genotypes 2 and 3, with a higher likelihood of response,  some authorities advocate treating all patients without liver  biopsy. For patients with little or no fibrosis (ie, Metavir  score < 2 or Ishak score < 3), in whom the prognosis for pro-  gression is relatively good and for whom, therefore, treat-  ment may be deferred, liver biopsy can be used to monitor  progression of disease; however, frequency of such histologic  monitoring has not been established.   Because the injection drug-using population represents the  largest reservoir of HCV, prevention of high-risk, drug-  related behaviors is the best way to prevent the majority of  new HCV infections in the United States. Even before screen-  ing of blood donors for hepatitis C began, transfusions never  accounted for more than a small proportion of all cases of  HCV infection in the United States. Since the advent of rou-  tine screening of the blood donor pool began in the 1990s,  the annual incidence of transfusion-related infection has  become negligible, and reduction in the frequency of post-  transfusion HCV infection is unlikely to have an impact on  the overall prevalence of disease.   Although success has been reported in case studies of post-  exposure interferon therapy, the efficacy of such an approach  has not been studied systematically, and the initiation of  antiviral therapy is not recommended until the diagnosis of  HCV infection is established. Standard immunoglobulin  administered after needlestick, sexual, or perinatal exposure  to HCV is ineffective and is not recommended. Currently,  an effective preventive vaccine is not available, and  prospects for a vaccine are dim (see the discussion of patho-  genesis, earlier).   The goal of treatment in patients with hepatitis C is to pre-  vent disease progression and the complications of infection,  which is achieved by eradication of HCV infection. HCV  infection is considered eradicated when there is a sustained  virologic response (SVR), defined as absence of HCV RNA in  serum, as demonstrated by the most sensitive amplification  assay, at the end of treatment as well as 6 months later. An  SVR is associated with improved histologic findings in up to  94% of patients, including both fibrosis and histologic activ-  ity index, and a reduced risk of progression to cirrhosis.   Patients who achieve an SVR almost always have a dra-  matic earlier reduction in the HCV RNA level, defined as a  2-log 10 or greater drop or loss of HCV RNA at 12 weeks into  therapy, referred to as an early virologic response (EVR). In  one study of 453 patients who underwent 12 weeks of ther-  apy, 86% had an EVR. Of those 86%, 65% went on to achieve  an SVR. Of the 14% who did not have an EVR, only 3%   achieved an SVR; in another, similar, large trial, none of the  subjects who failed to achieve an EVR experienced an SVR.   Currently, IFNa and PEG IFNoc are the backbone of  treatment for chronic hepatitis C. As discussed earlier, in the  section on hepatitis B, IFNa has direct antiviral activity as  well as immune-modulating activity (which may or may not  be involved in its activity against viral hepatitis). Pegylated  interferons are produced by binding an inert polyethylene  glycol moiety to interferon molecules, thereby increasing the  molecular weight of the molecule, decreasing its renal clear-  ance, and increasing its serum half-life.   In the 1990s, the sole treatment for hepatitis C was  monotherapy with interferon (3 million units 3 times weekly  initially for 24 weeks, then for 48 weeks), which produced  low SVR rates of 10% and 20%, respectively. Later in the  1990s ribavirin was added to interferon as combination ther-  apy for HCV infection. Ribavirin, a synthetic guanosine ana-  log, can inhibit several RNA and DNA viruses, including  flaviruses, to which HCV is similar. Ribavirin alone has no  more than a subtle antiviral effect on HCV replication; how-  ever, the combination of ribavirin with the standard inter-  feron regimen doubled SVRs to 38-43%. Although the  mechanism for ribavirin activity is not understood, ribavirin  reduces the relapse rate at the conclusion of therapy, thereby  increasing the SVR.   Standard interferon, administered by injection three  times a week in patients with hepatitis C, has been eclipsed  by PEG IFNa. Two types of pegylated interferon, which dif-  fer in their pharmacokinetics and chemical properties, were  approved by the FDA in 2001, PEG IFNa2a and PEG  IFNa2b. In large, randomized, controlled trials, the combi-  nation of weekly injections of PEG IFNa and twice-daily oral  ribavirin yielded higher SVR rates than either three injections  per week of standard IFNa together with oral ribavirin or  PEG IFNa monotherapy. In these trials, 12-kD PEG IFNa2b  was dosed by weight (1.5 mcg/kg) and coupled with 800 mg  of ribavirin; the larger, 40-kD PEG IFNa2a was given as a  fixed dose of 180 meg with a weight- adjusted, higher dose  of ribavirin (1000 mg if < 75 kg and 1200 mg if > 75 kg) for  48 weeks. In the initial two registration trials, genotype was  the strongest predictor of response. In patients with geno-  type- 1 infections, SVRs occurred in 42-46%, whereas the  SVR rate in those with genotype 2 or 3 was 76-82%. In a sub-  sequent registration trial of PEG IFNa2a, trial subjects were  randomized to receive either 24 or 48 weeks of PEG IFNa  plus ribavirin therapy and to receive either a fixed 800-mg  dose or standard 1000-1200-mg doses (based on weight < 75 kg  or > 75 kg) of ribavirin. In patients with genotype 1, the SVR  was highest (51%) in patients who underwent 48 weeks of  treatment with PEG IFNa and 1000-1200 mg of ribavirin;  patients treated for 24 weeks or with only 800 mg of ribavirin  had lower SVR rates. In contrast, among patients with HCV  genotypes 2 or 3, PEG IFNa plus a ribavirin dose of only  800 mg for 24 weeks was adequate to achieve an SVR rate of  just under 80%; extending therapy to 48 weeks or increasing  the ribavirin dose did not increase the frequency of SVR.   Several variables are associated with an increased likeli-  hood of achieving an SVR, among them HCV genotype  other than 1, low pretreatment HCV RNA levels (< 8 x 10 5  IU/mL), age < 40 years, body weight < 75 kg, absence of  bridging fibrosis or cirrhosis at baseline, non-African  American ethnicity, and the absence of hepatic steatosis  and insulin resistance. The presence of these poor predic-  tors of responsiveness, however, does not preclude respon-  siveness absolutely and should not be a reason to deny a  patient therapy.   Currently, based on the registration trials described  above, a full 48 weeks of PEG IFNa and 1000-1200 mg of  ribavirin are recommended for patients with HCV geno-  type 1 (and 4) but only 24 weeks of PEG IFNa and 800 mg  of ribavirin for patients with HCV genotypes 2 and 3.  Recognized more recently, tailoring therapy based on the  rapidity of a patient's response can increase the SVR or  shorten therapy, or both. The likelihood of an SVR is  increased if the level of HCV RNA falls to undetectable  within 4 weeks (a rapid virologic response, RVR). In  patients with genotype 2 or 3 who achieve an RVR, a 12-16-  week course of therapy may be as effective as one lasting  24 weeks. Conversely, in patients with genotype 2 or 3 who  have cirrhosis, some experts choose to treat a full 48 weeks;  however, in most cirrhotic patients with genotype 2, and  fewer with genotype 3, the recommended 24 weeks of ther-  apy will suffice to achieve an SVR. In patients with geno-  type 1, among those with an RVR, especially in the subset  with a low level of HCV RNA at baseline, 24 weeks of PEG  IFNoc plus ribavirin therapy may suffice to yield SVRs as  high as 90%. In the same vein, failure to achieve an RVR  signals refractoriness to therapy; for such patients with  genotype 1, extending therapy beyond 48 weeks to 72 weeks  increases the likelihood of an SVR. Clinical trials are in  progress as well to assess the efficacy of increasing PEG IFNoc  and ribavirin doses.   In patients who failed to respond during therapy with, or  who relapsed after, standard IFNa and ribavirin therapy,  retreatment with PEG IFNa and ribavirin can result in an  SVR in 25-40%. For relapsers or nonresponders to PEG  IFNa and ribavirin therapy, retreatment is unlikely to yield a  successful SVR. Occasionally, retreatment with longer dura-  tions of therapy, higher doses of ribavirin, or aggressive  attempts at maintaining adequate treatment doses with bone  marrow support (erythropoietin or filgrastim) may yield an  SVR in this setting, but none of these approaches has been  validated or recommended.   Although eradication of HCV RNA is the primary goal  for treatment of persons with chronic hepatitis C, evidence  suggests that maintenance interferon treatment may reduce  the progression of fibrosis and the emergence of hepatic  decompensation and its consequences, despite an absence of  virologic response to treatment. Studies are in progress, but  until they are completed and their results reported, no rec-  ommendation can be offered with regard to the value of  maintenance therapy.   Side effects of interferon and PEG IFNa were described ear-  lier in relation to treatment of hepatitis B. Additional side  effects are associated with combination therapy, specifically,  hemolytic anemia caused by ribavirin, which reduces hemo-  globin to less than 10 g/dL in 25% of patients. Red blood cell  counts recover typically within 4 weeks after treatment is  stopped. Because hemolytic anemia associated with ribavirin  may be severe and precipitous, ribavirin is contraindicated in  patients who cannot tolerate anemia, including those with  unstable coronary artery, cerebrovascular, pulmonary, or  renal disease, or baseline anemia. Ribavirin can cause pruri-  tus and rash (occasionally severe) and chest congestion or  cough. In addition, ribavirin is a documented teratogen; all  patients must be counseled on the danger of birth defects,  and both male and female patients and their sexual partners  of childbearing age should be required to use effective birth  control during treatment.   Once a patient is started on therapy, close follow-up is  essential. Monitoring of complete blood counts is necessary  every 2-4 weeks during the first 2 months, and then typically  every 4-8 weeks during treatment. Periodic thyroid tests at  the same frequency are also recommended. Virologic  response should be assessed at week 4 (RVR), week 12 (EVR),  end of therapy (end-treatment response), and 24 weeks after  completion of therapy (SVR); many clinicians check HCV  RNA levels more frequently, including at weeks 24 and 36 of  therapy and at weeks 4 and 12 after completion of therapy. If  an EVR is not present at 12 weeks, therapy can be stopped, if  the only goal of therapy is to achieve an SVR, especially in  patients who tolerate therapy poorly. If a patient achieves an  RVR, consideration may be given to shortening the duration  of therapy, and if a patient has not achieved an RVR, some  clinicians choose to prolong therapy beyond the recom-  mended treatment period.   1 . Acute HCV — In a small study of 60 patients with acute  hepatitis C, 85% of whom presented with symptomatic dis-  ease, treatment with interferon alone or in combination with  ribavirin was begun immediately upon diagnosis in 6 patients.  Of the 54 who were not treated, 37 (68%) cleared HCV  spontaneously within a mean of 8 weeks after diagnosis; 13  relapsed later, leaving 24 (44%) persistently HCV RNA-  negative. Although the numbers are small and should be  interpreted with caution, none of the nine patients with  asymptomatic acute hepatitis C cleared HCV RNA sponta-  neously, whereas 52% of those with symptomatic disease lost  virus spontaneously, all within 12 weeks. Treatment given to  those who did not recover spontaneously, beginning 3-6  months after onset of disease, led to SVR in 81%. Based on  these results, the authors recommended delaying treatment  2-4 months after acute onset of acute hepatitis C to allow for  spontaneous resolution. Others have presented evidence to   show that earlier treatment (within 8 weeks) is superior in  efficacy to treatment delayed thereafter. What is reassuring is  that most studies of antiviral therapy demonstrate a very high  frequency of viral clearance when therapy is administered  within the first 3 months after diagnosis; although earlier tri-  als involved high-dose interferon, subsequent trials suggest  that a 6-month course of PEG IFNoc plus ribavirin yields the  same high SVR rate. Additional studies are underway.   2. Renal disease — Historically, persons with renal disease  have been at increased risk of acquiring HCV, predomi-  nantly through blood transfusions and exposure to HCV-  contaminated equipment during hemodialysis. Ribavirin is  contraindicated in this population because the drug is not  removed during conventional dialysis, and its accumulation  causes a dose-dependent hemolytic anemia. Treatment of  patients with mild to moderate impairment in renal function  must be individualized; however, ribavirin is not recom-  mended in persons with creatinine clearance of less than  50 mL/min. Consequently, therapy for patients with sub-  stantial renal impairment or on hemodialysis should be PEG  IFNoc monotherapy at a reduced dose with close monitoring  for interferon toxicity.   3. Decompensated cirrhosis— Currently, interferon-based  antiviral therapy is not recommended for patients with  decompensated cirrhosis (ie, patients with one or more clin-  ical complications of chronic liver disease, such as ascites,  encephalopathy, variceal bleeding, coagulopathy, or hepa-  torenal syndrome). Instead, liver transplantation is the treat-  ment of choice for such patients.   In patients with decompensated cirrhosis, antiviral therapy  can be complicated by an increased risk of life-threatening  infections as well as accelerating hepatic decompensation.  Reinfection of the donor liver allograft with HCV is almost  assured, and progressive post-transplantation disease of the  allograft is common. Eradication of the virus prior to trans-  plantation is associated with a low likelihood of post-  transplantation infection, providing a strong incentive to  treat HCV infection before transplantation; however, treat-  ing someone with decompensated liver disease is not recom-  mended routinely, can be associated with substantial  treatment intolerability, and should be done only in special-  ized centers. In addition, even in patients with short-term  absence of HCV RNA post-transplantation, the virus is likely  to become apparent again after longer follow-up monitoring.  If such pretreatment antiviral therapy is initiated, low doses  should be used initially and only in patients with mild  degrees of hepatic compromise, with vigilant monitoring for  adverse events, preferably in those who have already been  accepted as candidates for liver transplantation.   Antiviral therapy for hepatitis C is indicated definitively  in patients with compensated HCV-related cirrhosis who  also have sufficient platelet and white blood cell counts to  tolerate therapy.   4. Post-solid organ transplantation— Immunosuppression  administered to prevent allograft rejection plays a role in the   accelerated liver disease observed in HCV-infected patients  following transplantation. Interferon has been reported to  precipitate rejection of kidney grafts; thus, the absence of  clear treatment benefit and the concern about precipitating  rejection mitigate against treating HCV infection in heart,  lung, or kidney allograft recipients. The risk of precipitating  rejection with interferon in liver allograft recipients appears  to be low. Because, typically, HCV-related liver disease is this  group is more progressive than that observed in immuno-  logically competent persons, in most liver transplantation  centers, antiviral therapy — its limitations and tolerability  issues notwithstanding — is instituted once recurrent disease  is established.   Newer treatments now being investigated include HCV pro-  tease and polymerase inhibitors, several of which have been  shown in early clinical trials to lower HCV RNA levels rap-  idly and profoundly. Early trials with oral protease inhibitors  specific for HCV administered together with PEG IFNoc and  ribavirin show promise for improving SVR rates and, poten-  tially, for shortening the duration of therapy. Patients inquire  frequently about and use herbal medicines; however, none of  the so-called complementary and alternative medications  improves HCV RNA or ALT levels, and they do not improve  the outcome of, or add to, standard antiviral therapy. Finally,  despite the very important and substantial improvements in  drug treatments, most patients are not benefited by these  therapies. First, for many patients, treatment is contraindi-  cated — specifically those with major, inadequately controlled  depression or risk for suicide; uncontrolled, severe autoim-  mune disorders; marked cytopenias; active cardiopul-  monary, cerebrovascular, or renal disease; or inadequately  treated and active substance abuse. Second, many patients  decline treatment because of their concern over side effects  or do not tolerate treatment. Third, approximately half of all  treated patients do not have a sustained response despite suc-  cessful completion of therapy.   Although most patients with hepatitis C are asymptomatic,  disease management goes well beyond the treatment possi-  bilities described earlier. Education and counseling com-  mand attention and resources in caring for patients with  hepatitis C. Because of the reported (but not universally  experienced) risk of increased morbidity and mortality asso-  ciated with acute hepatitis A superinfection, susceptible  patients (IgG anti-HAV-negative) should be vaccinated  against hepatitis A. Similarly, because of the risk of hepatitis B  when superimposed on chronic hepatitis C, patients who are  susceptible to HBV infection (eg, HBsAg, anti-HBs, anti-  HBc-negative) should be vaccinated against hepatitis B.  Excessive and frequent alcohol consumption promotes pro-  gression of chronic hepatitis C; therefore, avoidance of alco-  hol is recommended. Many patients inquire about diet, but   no dietary restrictions or supplements have been shown to  be beneficial. Finally, screening for HCC is recommended for  patients with cirrhosis or advanced fibrosis. Periodic radio-  logic imaging (ultrasound, CT scan, or MRI) every 6-12  months is recommended. Although most clinicians still  monitor a-fetoprotein (AFP) levels as part of HCC surveil-  lance programs, AFP screening in patients with chronic hep-  atitis C has been shown to be highly nonspecific and is no  longer officially recommended.   Approximately 85% of persons with acute HCV infection  develop chronic infection; the other 15% will clear the virus  spontaneously within the first 6 months of infection,  although the rate of viral clearance appears to be less com-  mon in African Americans and those coinfected with HIV.   In approximately 20% of patients with chronic hepatitis C,  cirrhosis develops over 20-25 years of infection. By the time  a patient comes to clinical attention and undergoes liver  biopsy, he or she has had chronic hepatitis C for more than  two to three decades, and the biopsy provides a window on  the level of liver injury during these previous decades. In  addition, the level of necroinflammatory activity and fibrosis  on such a biopsy provide prognostic information for future  progression; the more severe the level of necroinflammatory  activity and fibrosis found on initial biopsy, the greater the  risk of progressing to cirrhosis over the ensuing 20 years.  Progression to cirrhosis is more common in persons infected  at older ages (particularly men), those who drink more than  50 g of alcohol daily, those who are obese or have substantial  hepatic steatosis, and those with HIV coinfection. Once cir-  rhosis develops, the 10-year prognosis remains very good  (80% survival) until signs of hepatic decompensation begin  to appear (declining hepatic synthetic function, gastroin-  testinal bleeding associated with portal hypertension, ascites  and edema, coagulopathy, hepatic encephalopathy, life-  threatening bacterial infections, and hepatorenal failure);  once hepatic decompensation has begun, the 10-year prog-  nosis falls to 50% or less.   Finally, HCV cirrhosis increases the risk of HCC dramat-  ically. Among patients with cirrhosis associated with HCV  infection, HCC will develop at a rate estimated at between  1% and 4% annually, affecting 2-7% of cirrhotic patients  over 10 years. The occurrence of HCC is confined primarily  to patients who have had chronic hepatitis C for two to three  decades and who have cirrhosis or, at the very least, advanced  fibrosis; HCC rarely occurs in patients with chronic hepatitis C  in the absence of cirrhosis or advanced fibrosis.   Children who are infected with HCV are more likely to clear  the virus spontaneously, to have milder hepatitis, and to  progress less frequently to cirrhosis. In one study of German  children who acquired hepatitis C genotype 1 as a result of  cardiac surgery during infancy, 45% cleared the virus   spontaneously, and, at a mean of 2 1 years after infection, only  3 of 17 had histologic evidence of progressive liver disease.   Coinfection with HCV and HIV is common. Approximately  25% of HIV-infected persons in the Western world have con-  comitant HCV infection. About 6% of HIV-infected persons  fail to acquire detectable anti-HCV; therefore, HCV RNA  should be tested in HIV-positive patients with risk factors for  HCV infection or unexplained liver disease. Since the advent  of HAART in 1996, liver disease has become an increasingly  important cause of morbidity and mortality in patients with  HIV/ AIDS. In addition, HIV infection accelerates the course  of disease associated with HCV infection. In one series, cir-  rhosis developed within 15 years in 25% of coinfected  patients, compared with only 6.5% of those who had HCV  infection alone. Finally, the likelihood of achieving an SVR to  treatment for chronic hepatitis C is lower in HCV-HIV coin-  fection than in HCV alone: 14-29% in genotype 1 and  43-73% in genotypes 2 and 3, following 48 weeks of therapy  with PEG IFNa and ribavirin.   As previously discussed, coinfection with HCV and HBV  increases the risk and rate of development of cirrhosis and  HCC, relative to those observed in patients infected with  either virus alone.   Patients with hepatitis C and high body mass index or  hepatic steatosis, or both, are at increased risk for develop-  ment of fibrosis. Moderate-to-severe steatosis has been asso-  ciated with advanced fibrosis and a decrease in response to  interferon-based therapy.   Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis acceler-  ates the progression of liver damage of chronic hepatitis C  patients and correlated with specific HCV genotype and visceral  obesity. Hepatology. 2001;33:1358-1364. [PMID: 11391523]   Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hep-  atitis C virus infection in the United States, 1999 through 2002.  Ann Intern Med. 2006;144:705-714. [PMID: 16702586]   Dienstag IL, McHutchison IG. American Gastroenterological  Association medical position statement on the management of  hepatitis C. Gastroenterology. 2006;130:225-230. [PMID:  16401485]   Dienstag IL, McHutchison IG. American Gastroenterological  Association technical review on the management of hepatitis C.  Gastroenterology. 2006;130:231-264. [PMID: 16401486]   Fried MW, Shiftman ML, Reddy R, et al. Peginterferon alfa-2a plus  ribavirin for chronic hepatitis C virus infection. N Engl J Med.  2002;347:975-982. [PMID: 12324553]   Hadziyannis SI, Sette H Jr, Morgan TR, et al. Peginterferon-alpha-  2a and ribavirin combination therapy in chronic hepatitis C: A  randomized study of treatment duration and ribavirin dose.  Ann Intern Med. 2004;140:346-355. [PMID: 14996676]   Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and  Ribavirin for 12 weeks vs. 24 weeks in HCV genotype 2 or 3.  N Engl J Med. 2005;352:2609-2617. [PMID: 15972867]   Manns MP, McHutchinson JG, Gordon SC, et al. Peginterferon  alfa-2b plus ribavirin compared with interferon alfa-2b plus  ribavirin for initial treatment of chronic hepatitis C: a ran-  domised trial. Lancet. 2001;358:958-965. [PMID: 11583749]   O'Leary JG, Chung, RT. Management of hepatitis C virus coinfec-  tion in HIV-infected persons. AIDS Read. 2006;16:313-316.  [PMID: 16795921]   Reddy KR, Wright TL, Pockros PJ, et al. Efficacy and safety of pegy-  lated (40-kd) interferon alpha-2a compared with interferon  alpha-2a in noncirrhotic patients with chronic hepatitis C.  Hepatology. 2001;33:433-438. [PMID: 11172346]   Seeff LB, Hollinger FB, Alter HJ, et al. Long-term mortality and  morbidity of transfusion-associated non-A, non-B and type C  hepatitis: a National Heart, Lung, and Blood Institute collabo-  rative study. Hepatology. 2001;33:455-463. [PMID: 11 172349]   Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and  ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J  Med. 2007;357:124-134. [PMID: 17625124]   Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement  of fibrosis in patients with hepatitis C who have sustained response  to interferon therapy. Ann Intern Med. 2000;132: 517-524. [PMID:  10744587]   Strader DB, Wright T, Thomas DL, et al. Diagnosis, management,  and treatment of hepatitis C. Hepatology. 2004;39:1147-1171.  [PMID: 15057920]   ► Infection occurs only in the presence of HBV and is  detected by demonstrating anti-HDV (distinctions  between IgM and IgG anti-HDV are not helpful).   ► HDV RNA detected in serum by molecular hybridization  or PCR assays is helpful in confirming the diagnosis.   ► Testing for IgM and IgG anti-HBc helps distinguish  between acute, simultaneous HBV-HDV coinfection (IgM  anti-HBc-positive) and HDV superinfection in patients  with chronic HBV infection (IgG anti-HBc-positive).   Infection with hepatitis D virus (HDV) occurs worldwide,  but incidence and prevalence data vary substantially from  region to region and are influenced periodically by immi-  gration patterns of patients from high endemic areas. On a  worldwide basis, 15 million people with chronic hepatitis B  are estimated to harbor concomitant HDV infection.  Although hepatitis D was first identified and recognized  in southern Europe during the 1990s, the prevalence and  incidence of HDV infection declined dramatically, presum-  ably in parallel with measures introduced to control HBV  infection and with shifts in the migration patterns that amplified   its spread in the 1970s. A higher prevalence of HDV infection  persists in older southern European populations, representing  residual infection in the cohort of patients infected several  decades ago when HDV infection was endemic there.   In nonendemic areas, HDV is transmitted primarily by  percutaneous routes, especially in injection drug users and  their sexual contacts. In parts of the Mediterranean and  other endemic areas, transmission is perpetuated by close  personal contact (eg, within families).   HDV, the agent that causes hepatitis D or "delta," as named  originally, is a unique hepatitis virus with the smallest known  genome (1.7 kb) of any animal RNA virus. The 36-nm HDV  virion comprises an RNA genome, a single HDV-encoded  antigen, and a lipoprotein envelope provided by HBV.   Although under unusual circumstances HDV can repli-  cate autonomously, generally it is a defective virus that  requires the simultaneous presence of HBV for complete  virion assembly and secretion. Consequently, HDV infection  and replication can occur only in a host with HBV infection.  HDV infection can be acquired during simultaneous acute  HBV-HDV coinfection, which is limited in duration by the  duration of the HBV infection, and acute HDV superinfec-  tion of a person with chronic hepatitis B (including inactive  carriers), in whom HDV infection almost invariably  becomes chronic, lasting as long as the underlying chronic  HBV infection. Because HDV "takes over" the replicative  machinery of HBV, HDV infection usually results in sup-  pression of HBV replication; thus, patients with both HBV  and HDV infection tend to have markers of low-level HBV  replication (HBsAg positive, HBeAg negative, anti-HBe pos-  itive) and low-level or undetectable HBV DNA.   In acute HDV infection, microvesicular steatosis and  granular eosinophilic necrosis may be seen histologically. In  chronic hepatitis D, necroinflammatory activity is often  severe, but no specific histologic features are noted, and  HDV antigen (HDVAg) is localized by immunohistochemi-  cal staining in hepatocyte nuclei. HDV genotypes (I — III) and  specific clinical features of hepatitis D seem to cluster in dis-  tinct geographic areas. Genotype I is most common in the  Western world and Africa, where acute hepatitis D is more  likely to be fulminant, and chronic infection is more likely to  progress rapidly to cirrhosis. Genotype II is predominantly  an Eastern genotype and is thought to be less pathogenic  than genotype I. Genotype III is seen almost exclusively in  Central and South America, where HDV superinfection in  persons with underlying chronic hepatitis B tends to be asso-  ciated with severe, often fulminant, hepatitis.   Acute coinfection is characterized by hepatitis, which can be  severe, with hepatocellular necrosis and inflammation. The   majority of cases, however, are self-limited, with clearance of  HBV and therefore HDV. Fulminant hepatitis is infrequent  overall, reported in approximately 5% of outbreaks of coin-  fection among injection drug users and their sexual partners,  but is still more than 10 times more common than in  patients with acute hepatitis B alone.   Most cases emanate from acute HDV superinfection of a  patient with underlying chronic hepatitis B, including those  with chronic hepatitis and inactive carriers. In chronic HBV-  HDV infection, HDV viremia continues, although at lower  levels than is seen during the period of acute HDV superin-  fection. On biopsy, necroinfiammatory lesions are notable  and are typically more severe than those seen in patients with  chronic HBV infection alone. Episodes that resemble acute  hepatitis can also mark the course in chronic coinfection.  Labrea fever is an unusual form of delta hepatitis (HDV  superinfection in a population with endemic HBV infection)  described in the Amazon basin and in which fulminant hep-  atitis results in jaundice, fever, and black vomitus.   HDV infection is detected by demonstrating the presence of  anti-HDV. Distinctions between IgM and IgG anti-HDV are  not helpful. The nucleocapsid HDV protein is always encap-  sidated within an envelope of HBsAg; therefore, circulating  levels of HDVAg are undetectable, and commercial HDVAg  assays are not available. HDV RNA can be detected in serum  by either molecular hybridization or PCR assays, which are  helpful in confirming the diagnosis and in monitoring  viremia during a course of antiviral therapy.   In patients with HDV infection, testing for IgM and IgG  anti-HBc helps distinguish between acute, simultaneous  HBV-HDV coinfection (IgM anti-HBc-positive) and HDV  superinfection in someone already harboring chronic HBV  infection (IgG anti-HBc-positive).   Because of its requirement for chronic HBV infection, HDV  infection can be prevented by vaccinating susceptible per-  sons with hepatitis B vaccine. No effective vaccine is available  for preventing HDV superinfection in persons who are  already HBsAg-positive.   Despite the reliance of HDV on concomitant HBV infection,  the oral polymerase inhibitors that suppress HBV replication  have not been shown to be effective in the treatment of hep-  atitis D. IFNa is currently the only licensed drug for treat-  ment of HDV. Clinical trials in the early 1990s provided   evidence than IFNa is effective in the treatment of HDV  infection, but the rate of relapse is high, and efficacy is pro-  portional to the dose and duration of treatment; high-dose,  long-duration therapy lasting at least 1 year is required. More  recently, PEG IFNa monotherapy for 12 months has been  shown to result in a 43% SVR; the addition of ribavirin does  not offer further benefit. Patients with decompensated cir-  rhosis resulting from chronic hepatitis D are good candidates  for liver transplantation; even before the widespread use of  HBIG and polymerase inhibitors to prevent recurrent hepa-  titis B after liver transplantation, patients with hepatitis D  were less likely to experience HDV-HBV reinfection of the  allograft. Currently, with efficient antiviral therapy to pre-  vent recurrent HBV infection post-transplantation, recur-  rent hepatitis D after transplantation is even less of a threat.   Acute coinfection resolves in 80-95% of cases, following  clearance of HBV, without which HDV infection cannot con-  tinue. In 2-20% of cases, however, fulminant hepatitis devel-  ops; in series from endemic areas, 30% of cases of fulminant  hepatitis B represent simultaneous acute hepatitis D. In addi-  tion, 2-5% of cases of acute HBV-HDV coinfection result in  chronic infection. Finally, in acute simultaneous HBV and  HDV infection among injection drug users, case fatality rates  approaching 5% have been reported.   Unlike acute coinfection, HDV superinfection results in  chronic HDV-HBV in almost all cases, fostered by the per-  sistence of HBV infection. Similar to acute coinfection, acute  HDV superinfection results in fulminant hepatitis in 2-20%  of cases. Superinfection rarely resolves. In some outbreaks of  severe HDV superinfection in populations with a high rate of  HBV infection, mortality exceeding 20% has been reported.   Initial descriptions of chronic hepatitis D were consistent  with severe liver disease; however, some patients with chronic  HDV infection have very mild liver disease and may even be  inactive HDV carriers. Generally, chronic hepatitis D pro-  gresses more frequently and more rapidly to cirrhosis than  chronic hepatitis B. Although chronic HBV infection is a  well-recognized risk factor for the development of HCC, a  similar association, albeit less well established, has been  demonstrated for chronic HDV infection. Overall, the pat-  tern of disease progression appears to vary with geography,  genotype, and mode of transmission. Slowly progressive,  mild disease is more common in endemic areas. On the other  hand, HDV-associated disease appears to be more severe in  nonendemic areas, where injection drug use is the main form  of transmission.   Canbakan B, Senturk H, Tabak F, et al. Efficacy of interferon alpha-  2b and lamivudine combination treatment in comparison to  interferon alpha-2b alone in chronic delta hepatitis: a random-  ized trial. / Gastroenterol Hepatol. 2006;21:657-663. [PMID:  16677149]   Castelnau C, Le Gal F, Ripault MP, et al. Efficacy of peginterferon  alpha-2b in chronic hepatitis delta: relevance of quantitative  RT-PCR for follow-up. Hepatology. 2006;44:728-735. [PMID:  16941695]   Farci P. Treatment of chronic hepatitis D: new advances, old chal-  lenges. Hepatology. 2006;44:536-539. [PMID: 16941704]   Lau DT, Doo E, Park Y, et al. Lamivudine for chronic delta hepati-  tis. Hepatology. 1999;30:546-549. [PMID: 10421666]   Niro GA, Ciancio A, Gaeta GB, et al. Pegylated interferon alpha-2b  as monotherapy or in combination with ribavirin in chronic  delta hepatitis. Hepatology. 2006;44:713-720. [PMID: 16941685]   Wedemeyer H, Heidrich B, Manns MP. Hepatitis D virus infection —  not a vanishing disease in Europe! Hepatology. 2007;45: 1331-1333.  [PMID: 17464980]   ► Diagnosis is established by demonstrating the presence  of serum IgM antibody to hepatitis E virus (anti-HEV) by  immunoassay or HEV RNA by PCR.   ► IgM anti-HEV is detectable for only a few months after  acquisition of HEV, and IgG anti-HEV for -1 year.   Outbreaks occur in the Indian subcontinent, Central America,  Africa, northwest China, and the Central Asian Republics (the  former Soviet Union), where hepatitis E virus (HEV) infection  is endemic. HEV is transmitted predominantly through the  fecal-oral route, and most reported outbreaks of infection  have been related to the consumption of fecally contaminated  drinking water. Unusual for an enteric virus, HEV is not read-  ily spread via person-to-person transmission. The highest  attack rate occurs in young adults, a subpopulation that, ordi-  narily, would be immune to enterically transmitted endemic  agents. Genotypes 3 and 4, more common in the United  States, are relatively nonvirulent and associated with inappar-  ent infection, whereas genotypes 1 and 2, common in endemic  areas, are relatively virulent, accounting for the clinically  apparent, often severe disease in these regions.   In countries where HEV infection is not endemic, the dis-  ease has been observed in travelers returning from endemic  regions; in nonendemic countries, HEV accounts for less  than 1% of cases of acute viral hepatitis. HEV can infect pigs,  suggesting that some cases of human transmission may  result from contact across species.   HEV is a small, 32-34 nm, nonenveloped spherical, 7600-  base-pair RNA virus (genus Hepacivirus) that was identified  in 1983. Transmission is through the fecal-oral route and,  like other hepatitis viruses, the main target cells are hepato-  cytes. Various geographically distinct isolates have been clas-  sified into at least four human genotypes (plus a fifth in  nonhuman hosts), but all genotypes share at least one major  serologically cross-reactive epitope, despite substantial  genomic variability, permitting the development of an effec-  tive vaccine.   The incubation period for hepatitis E ranges from 2 to 10 weeks;  the clinical course of acute hepatitis E is similar to that of  acute hepatitis A, but generally acute hepatitis E is more  severe. Like acute hepatitis A, acute hepatitis E has an insidi-  ous onset, most commonly beginning with a prodromal  phase of a few days with flulike symptoms, fever, abdominal  pain, nausea and vomiting, dark urine and clay-colored  stools, diarrhea, and, in a small proportion of cases, a tran-  sient macular skin rash. The prodromal phase is followed by  the development of jaundice in icteric cases, resolution of the  prodromal symptoms, pronounced elevation of amino  transaminase levels, elevated bilirubin levels, and, in a pro-  portion of patients with cholestatic features, more often in  hepatitis E than in the other hepatitides, alkaline phosphatase  elevations. Histologically, cholestasis with rosette formation  of hepatocytes and polymorphonuclear leukocytes may be  prominent. Acute hepatitis E can be very severe in pregnant  women, in whom the mortality rate can reach 15-25%.   The diagnosis of HEV infection is established by demon-  strating the presence of serum IgM anti-HEV by immunoas-  say or HEV RNA by PCR. IgM anti-HEV is undetectable after  a few months, and even IgG anti-HEV does not persist much  beyond 1 year.   Immunoglobulin, produced in countries where HEV in  endemic, has not been shown to confer protection against  HEV. Prophylactic measures to minimize the occurrence of  HEV infection involve improved sanitation and sanitary  handling of food and water. Boiling water appears to reduce  the risk of infection. Because person-to-person transmission  is rare, isolation of affected patients is not indicated.   Recently a recombinant polypeptide vaccine underwent a  phase 2, randomized, double-blind, placebo-controlled trial  in Nepal on nearly 2000 volunteers, mostly male members of  the Nepalese army. The volunteers received three doses of the  vaccine or placebo at 0, 1, and 6 months. A total of 69 cases  of definite HEV infection occurred at least 14 days after the  third injection, 3 in the vaccine group (0.3%) and 66 in the   placebo group (7.4%). The efficacy of the vaccine was 85.7%  after two doses and 95.5% after all three. The vaccine was  well tolerated, with similar serious adverse events in the two  groups. Studies are underway to determine the length of pro-  tective efficacy of the vaccine and its safety in different sub-  population groups, including pregnant women.   noted, fulminant hepatic failure occurs more frequently dur-  ing pregnancy, resulting in an inordinately high mortality  rate of 15-25%, primarily affecting women in the third  trimester. In addition, acute hepatitis E can cause hepatic  decompensation in patients with preexisting liver disease  and in persons who are malnourished.   Treatment is largely supportive (see the discussion of hepati-  tis A treatment earlier in this chapter).   Acute hepatitis E is self-limited; acute illness usually lasts 1-4  weeks, although some patients have a prolonged cholestatic  hepatitis lasting 2-6 months. Neither persistent viremia  (chronic hepatitis E) nor cirrhosis follows acute infection.  Fulminant hepatitis can occur, however, with an overall case  fatality rate of 0.1-4%. For unclear reasons, as previously   Chau TN, Lai ST, Tse C, et al. Epidemiology and clinical features of   Gastroenterol. 2006;101:292-296. [PMID: 16454833]  Emerson SU, Purcell RH. Running like water-the omnipresence of   15575050]  Krawczynski K. Hepatitis E vaccine-ready for prime time? N Engl   J Med. 2007;356:949-951. [PMID: 17329703]  Shrestha MP, Scott RM, loshi DM, et al. Safety and efficacy of a   895-903. [PMID: 17329696]  This chapter is a substantially revised version of a chapter written   This chapter discusses a group of conditions that result in  chronic inflammation of the liver, ultimately leading to  fibrosis, cirrhosis, and liver failure. The epidemiology, patho-  genesis, and management of autoimmune hepatitis, Wilson  disease, and oCj-antitrypsin deficiency are described.   ► Characterized by the presence of autoantibodies and  elevated serum IgG levels.   ► Diagnosis is made on the basis of serologic findings  (abnormal liver biochemical tests, autoantibodies, ele-  vated IgG) and histologic findings, and by ruling out  other chronic liver diseases (drug-induced liver injury,  viral hepatitis, inherited and metabolic liver disorders).   ► Overlap syndromes include features of other chronic  liver disorders (eg, primary biliary cirrhosis, primary  sclerosing cholangitis).   Autoimmune hepatitis (AIH) comprises of a heterogeneous  group of chronic inflammatory disorders identified by the  presence of circulating autoantibodies and elevated serum  y-globulins. The pathogenesis of the disease is unclear,  although it is believed that genetic predisposition in suscep-  tible individuals ultimately leads to an immunologic process  directed against hepatocytes. Among the many suspected  inciting factors in those genetically predisposed are toxins  and infectious agents. The inflammatory disorder can result  in hepatocellular necrosis and collapse or in fibrosis and  cirrhosis. The disease is present in all racial groups and all age  groups but is more common in women than in men, with a   frequency of 3.6:1. It is responsible for approximately 5.9%  of the liver transplantations performed in the United States.   Krawitt EL. Autoimmune hepatitis. N Engl J Med. 2006;354:54-66.  [PMID: 16394302]   The mechanism of hepatic injury in AIH is not well charac-  terized. There appear to be both genetic and environmental  influences. The disease is classified into three distinct sub-  types based on the presence of autoantibodies. The clinical  relevance of this classification system is, however, unclear as  it is not certain that autoantibodies play a role in disease  pathogenesis. Type 1 disease is present in patients who test  positive for antinuclear antibody (ANA) or anti-smooth  muscle antibody (ASMA), or both. This is the most common  form and has been linked to HLA DRB 10301 (DR3) and  DRB 10401 (DR4). Type 2 disease is present in patients who  are positive for anti-liver kidney microsomal (ALKM) anti-  body. This form is common in Europe and is often present in  younger women in the second and third decades of life. The  linkage is to HLA DRB 10701. Type 3 disease has been  described in those who are positive for the antibody to the  anti-soluble liver antigen (ASLA).   The frequency with which autoantibodies occur varies in  the general population. For example, a positive ANA result is  found in 67% of patients with AIH. It is present alone in 13%  of patients but is accompanied by the ASMA in an additional  54%. It is important to realize, however, that the autoanti-  body by itself is not diagnostic (see later discussion of diag-  nostic criteria, and Table 40-1). It can be present in patients  who have primary biliary cirrhosis, primary sclerosing  cholangitis, viral hepatitis, drug-induced hepatitis, and non-  alcoholic steatohepatitis (NASH). ASMA is present in 87% of  patients with AIH. It is seen alone in 33% of patients and in  combination with ANA in 54% of patients. The target anti-  gen is thought to be actin and nonactin components of the   "Addition of points achieved for all autoantibodies (maximum, 2 points). For details, see reference cited below.  Prior to steroid therapy a definite diagnosis requires a score > 7, while a probable diagnosis requires a score of  6 or higher.   AIH, autoimmune hepatitis; ANA, antinuclear antibody; SMA, smooth muscle antibody; LKM, liver kidney micro-  somal (antibody); SLA, soluble liver antigen; IgG, immunoglobulin G.   Adapted from: Hennes EM, Zeniya M, Czaja AJ, et al. Autoimmune, Cholestatic and Biliary Disease: simplified  criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169-176.   smooth muscle. In fact, a serologic test for a component of  actin (F-Actin) is now used in place of the ASMA assay by  many laboratories in screening for AIH. The ALKM antibody  is seen in 4% of patients and is often seen in the absence of  ANA and ASMA. The target is thought to be the enzyme  CYP2D6, which shares homology to hepatitis C. As a result,  the ALKM antibody can be falsely positive in patients who  are chronically infected with the hepatitis C virus.   In addition to the presence of autoantibodies and elevated  y-globulins, the patient's gender, a detailed clinic history, a  multitude of diagnostic serologic tests, liver biopsy findings,  and the response to a trial of steroids aid in the diagnosis of  AIH. The goal of the clinical evaluation is to solidify the diag-  nosis of AIH while eliminating processes that may mimic  AIH (Table 40-1). Thus, several other causes of hepatitis  need to be excluded (see "Differential Diagnosis," later).   Historic information helps elucidate potential toxin-  induced causes of hepatitis, including alcohol. Serologic eval-  uations help eliminate viral hepatitis and inherited liver  diseases (eg, Wilson disease, hemochromatosis, rjCj-antitrypsin  deficiency). Additionally, primary sclerosing cholangitis and  primary biliary cirrhosis need to be excluded. Personal and  family history of AIH should be sought.   The most common presenting symptoms are fatigue (seen in  87% of patients), dark urine and light-colored stools (77%),  right upper quadrant pain (48%), and anorexia (30%).  Physical examination findings include hepatomegaly (seen in  78% of patients), spider angiomata (58%), palpable spleen  (40%), scleral icterus (46%), ascites (20%), and encephalopa-  thy (14%).   AIH is associated with several other autoimmune disor-  ders. Among the most common are autoimmune thyroiditis,  rheumatoid arthritis, and ulcerative colitis. Additional condi-  tions, although rare, include insulin-dependent diabetes mel-  litus, Sjogren syndrome, Graves disease, dermatitis  herpetiformis, vitiligo, myasthenia gravis, pernicious anemia,  and celiac sprue.   The presentation of AIH is variable. Severe AIH character-  ized by marked elevation in transaminases (> 10 times the  upper limit of normal) is the presentation in around 40% of  patients. Approximately 3% of these patients have liver fail-  ure on presentation. Around 40% of those with untreated  severe AIH disease die within 6 months; 40% of the survivors  are cirrhotic at presentation, and 54% have varices within  2 years. The 5-year mortality is approximately 58%. In patients   who have an alanine aminotransferase (ALT) level more than  10 times the upper limit of normal or serum y-globulins  three times the upper limit normal or who have bridging  necrosis on histology, 82% are cirrhotic within 5 years, and  mortality is 45% during this period of time.   Liver biopsy should be performed and the resulting histologic  evaluation should be consistent with findings known to be  present in AIH. Findings consistent with interface hepatitis,  and presence of a lymphoplasmacytic infiltrate in the portal  area, are reliable clues and helpful histologic findings.  Histologic changes suggestive of biliary tract disease (eg, gran-  ulomas), as seen in patients with primary biliary cirrhosis  should not be present in the canonical form of AIH.   Among patients whose diagnosis is not straightforward,  response to corticosteroids can aid in determining if AIH is  likely. As a result of discrepancies and difficulties in diagno-  sis, a scoring system for AIH has been designed. This is  shown in Table 40-1. Prior to treatment with corticosteroids,  a definite diagnosis implies a score of greater than 7; a prob-  able diagnosis implies a score of 6 or higher.   Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune  Hepatitis Group Report: review of criteria for diagnosis of  autoimmune hepatitis. / Hepatol. 1999;31:929-938. [PMID:  10580593]   Hennes EM, Zeniya M, Czaja AJ, et al. Autoimmune, Cholestatic  and Biliary Disease: simplified criteria for the diagnosis of  autoimmune hepatitis. Hepatology. 2008;48:169-176.   The differential diagnosis of AIH includes various forms of  acute and chronic hepatitis. These include toxin-induced  hepatitis, hepatotropic (hepatitis A-E viruses) and nonhepa-  totropic viral hepatitis (cytomegalovirus, Epstein-Barr virus,  herpes simples virus, and varicella virus) infections, meta-  bolic liver disorders such as NASH, and inherited liver disor-  ders such as hemochromatosis, Wilson disease, and  a -antitrypsin deficiency.   The cornerstone of treatment is the use of immunosuppres-  sive agents (Table 40-2). Induction of remission should  include corticosteroids. Noncorticosteroid immunomodula-  tory agents such as azathioprine and mycophenolate mofetil  may be used for maintenance.   In three distinct randomized clinical trials on adults with  severe AIH, those who received prednisone as part of the ini-  tial therapy had clinical and histologic improvement in addi-  tion to lower mortality when compared with those who did  not receive the drug. Table 40-3 summarizes clinical out-  comes of two published trials. Improvement in clinical  indices occurs, as well, in patients who are already cirrhotic  at the time of diagnosis. As a result, corticosteroids remain  the standard therapy for AIH, either given alone or in com-  bination with azathioprine.   Although therapy is effective, side effects of corticos-  teroid therapy include osteopenia, diabetes mellitus,  hypertension, and Cushing syndrome. Budesonide (a gluco-  corticoid with a high hepatic first-pass clearance) and   a Data from Soloway RD, Summerskill WH, Baggenstoss AH, et al. Clinical, biochemical, and histo-  logical remission of severe chronic active liver disease: a controlled study of treatments and early  prognosis. Gastroenterology. 1972;63:820-833.   b Data from Murray-Lyon IM, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in  active chronic hepatitis. Lancet. 1973;1:735-737.   deflazacort (a derivative of prednisolone with decreased risk  of osteopenia and diabetes mellitus) have been used to help  limit side effects associated with prednisone. However, there  is not enough evidence to show they are equivalent or supe-  rior to prednisone.   Azathioprine has been used as monotherapy for the treat-  ment of AIH, but only after remission has been induced and  sustained and then corticosteroids tapered off. Many practition-  ers do not use azathioprine alone unless there is some com-  pelling reason to avoid corticosteroids, given the evidence that  corticosteroids are superior to many other immunomodulators  for induction of remission. Potential side effects of azathioprine  include leukopenia, pancreatitis, and drug-induced hepatitis.   Cyclosporine has been used with some promising results,  especially in children, as a result of concerns of the side  effects of steroids. Biochemical improvement as evidenced by  decreased ALT and y-globulin levels and increased albumin  often occurs. There is improvement in average growth veloc-  ity, and side effects (hypertension and renal impairment) are  minimal when serum levels are kept low.   Mycophenolate has been tried as a rescue therapy in  patients with AIH. It normalizes ALT and improves the abil-  ity to taper prednisone to lower doses. In addition, histology  is improved and the medicine is well tolerated except for mild  leukopenia.   Cyclophosphamide, tacrolimus, and methotrexate have  been used either alone or in combination with corticosteroids  with limited success.   Czaja AJ, Freese DK; American Association for the Study of Liver  Disease. Diagnosis and treatment of autoimmune hepatitis.  Hepatology. 2002;36:479-497. [PMID: 12143059]   Response to prednisone is excellent, with 80-100% of  patients responding. Even among cirrhotic patients, reversal  of signs of decompensation (ascites, jaundice, coagulopathy)  can occur with treatment. Failure of bilirubin to decrease to  less than 15 mg after 2 weeks of corticosteroid therapy sug-  gests a very poor prognosis.   For many patients with AIH, lifelong immunosuppressive  therapy has usually been the norm. This has led investigators  to ask whether remission can be maintained in some patients  after complete withdrawal of therapy. Indeed, studies suggest  that between 10% and 40% of persons remain in remission  after therapy is withdrawn.   Relapse after therapy withdrawal does not preclude attain-  ment of sustained remission, although it usually requires the  reinstitution of high-dose steroid therapy. The laboratory  markers that correlate with remission are serum y-globulin  levels and stage of fibrotic disease. Patients with markedly ele-  vated globulin levels and cirrhosis are most at risk. Many  practitioners obtain a liver biopsy to ensure that there is no  inflammatory activity before withdrawing therapy. For  patients who fail immunosuppressive therapy, liver transplan-  tation is an option if they are deemed suitable candidates.   Czaja AJ, Menon KV, Carpenter HA. Sustained remission after  corticosteroid therapy for type 1 autoimmune hepatitis: a retro-  spective analysis. Hepatology. 2002;35:890-897. [PMID:  11915036]   The preceding section describes AIH in its classic form.  There are, however, variants of the disorder in which sero-  logic and clinical characteristics are mixed with other forms  of chronic (often immune-mediated) liver disorders. These  groups of syndromes are known as overlap syndromes. The  prevalence of overlap syndromes among patients with AIH,  primary sclerosing cholangitis (PSC), and primary biliary  cirrhosis (PBC) has been estimated at about 18%. The two  most common variants are AIH-PBC and AIH-PSC overlaps.   In the majority of these patients, serologic evaluations show  the presence of antimitochondrial antibodies (AMAs) but  histologic characteristics of AIH are present. These patients  are treated as classic AIH and have an excellent response to  steroid therapy. A second group of patients frequently classi-  fied as AIH-PBC overlap are negative for AMA, positive for  ANA or ASMA, or both, but have histologic findings consis-  tent with PBC. This entity has been termed autoimmune  cholangitis or immune cholangiopathy. Many practitioners  do not regard this as an overlap syndrome but rather con-  sider it to be an AMA-negative form of PBC. These patients  are usually treated with ursodiol. The benefit of corticos-  teroids in this setting is controversial.   Patients with this overlap syndrome have serologic findings  suggestive of AIH (presence of ANA or ASMA, or both) but  radiographic findings suggestive of PSC. This entity should  be suspected in patients with a clinical diagnosis of AIH who  present with pruritus and have radiographic or histologic  findings of PSC, known inflammatory bowel disease (specif-  ically ulcerative colitis), and elevated alkaline phosphatase.  Treatment of these patients is difficult. Corticosteroids alone  or in combination with azathioprine have not been shown to  be very effective. The addition of ursodiol to corticosteroids  and azathioprine, however, has been shown in one small  study to be helpful (see Chapter 52).   Cjaza AJ. Frequency and nature of the variant syndromes of  autoimmune liver disease. Hepatology. 1998;28:360-365.  [PMID: 9695997]   Floreani A, Rizzotto ER, Ferrara F, et al. Clinical course and out-  come of autoimmune hepatitis/primary sclerosing cholangitis  overlap syndrome. Am J Gastroenterol. 2005;100:1516-1522.  [PMID: 15984974]   Talwalkar JA, Keach JC, Angulo P, et al. Overlap of autoimmune  hepatitis and Primary biliary cirrhosis: an evaluation of a mod-  ified scoring system. Am ] Gastroenterol. 2002;97:1191-1197.  [PMID: 12014727]   ► Genetic defect is a mutation in a P-type copper-dependent  ATPase, ATP7B.   ► Copper deposition in many tissues, with liver and neu-  rologic disease the most prominent manifestations.   ► Consider in any young person with chronic hepatitis or  cirrhosis.   ► Diagnosis is challenging and requires measurement of  serum ceruloplasmin levels, measurement of urinary  copper, and an ophthalmic examination; all three tests  are necessary as only 40% of patients have abnormali-  ties in all three.   ► Liver biopsy is often necessary to confirm or stage  disease.   Wilson disease is a rare disease of impaired biliary excretion  of copper. It is an autosomal-recessive disorder with preva-  lence of approximately 1 in 30,000 persons. The defective  gene is on chromosome 13 and has been identified as a cop-  per dependent P-type ATPase.   Ala A, Walker AP, Ashkan K, et al. Wilson's disease. Lancet.  2007;369:397-408. [PMID: 17276780]   The defective gene, ATP7B, encodes a transmembrane pro-  tein with two important physiologic roles: (1) transport of  copper across the canalicular membrane into the biliary  tract, and (2) transport of copper into the trans-Golgi net-  work, where it complexes with an acute phase reactant and  copper-binding protein, ceruloplasmin. When ATP7B is  absent, copper accumulates within the lysosomes in the cell  and is absent in the biliary secretions. This leads to accumu-  lation of hepatocellular copper. Additionally, because copper  is required for stability of ceruloplasmin, its serum half-life is  markedly decreased in persons with Wilson disease. The low  level of ceruloplasmin in patients with Wilson disease  accounts for its use as a screening test (see later discussion).   Wilson disease is a disease of young people, manifesting most  commonly in the second and the third decades of life. It is  unusual for Wilson disease to manifest after the age of 40 and  when it does, neurologic complications are often the principal   presenting symptoms. Copper deposition in hepatic tissue  can lead to liver disease in the form of chronic hepatitis or  cirrhosis, or can present in a fulminant form known as ful-  minant Wilson disease.   In fulminant Wilson disease there is marked transaminase  elevation, with the aspartate aminotransferase (AST) level  often greater than the ALT (additional AST is present as a  result of accompanying Coombs-negative hemolytic anemia).  Alkaline phosphatase is low, jaundice and liver failure invari-  ably result, and survival is almost always dependent on the  availability of liver transplantation.   A more indolent form of liver disease results in cirrhosis.  Patients may present with compensated disease or have sig-  nificant evidence of hepatic dysfunction by the time of diag-  nosis. Physical signs of advanced liver disease are common,  with spider angiomata, splenomegaly, and ascites.   In addition to liver disease, patients with Wilson disease may  have neurologic manifestations that represent the presenting  features in 40-50% of patients. The resulting clinical mani-  festations occur as a result of copper deposition in many  parts of the brain, including but not limited to the putamen,  globus pallidus, caudate, and thalamus. Associated neuro-  logic disorders include (1) a Parkinson-like movement disor-  der, (2) ataxia, (3) dystonia, and (4) tremors. Psychiatric  manifestations may also occur and occasionally can domi-  nate the presentation, with decline in performance status  (eg, worsening school grades) and behavioral changes.   In addition to the liver and central nervous system, cop-  per is deposited at other sites, leading to a range of disease  manifestations. Deposition in the eye can result in Kayser-  Fleischer rings and sunflower cataracts; both are visible on  slit-lamp examinations. The former is a golden-brown pig-  ment in the outside rim of the cornea, whereas the later is  visualized as multicolored cataracts. Deposition of copper  also occurs in the kidneys, predominantly in the proximal  tubules, where a Fanconi-like syndrome may manifest.  Proximal renal tubular acidosis and nephrolithiasis are pos-  sible consequences. Chondrocalcinosis, osteomalacia, and  osteoarthritis are also common in patients with Wilson dis-  ease. Table 40-4 summarizes the clinical spectrum of Wilson  disease.   The diagnosis of Wilson disease is often challenging but is  based on a combination of astute clinical suspicion and lab-  oratory data. The disease should be suspected in any young   person who presents with unexplained, chronic active hepa-  titis or cirrhosis. Serum ceruloplasmin is an acute phase reac-  tant and may be normal in approximately 20% of patients  with Wilson disease due elevated levels in inflammatory con-  ditions. Regardless, the initial screening test is the measure-  ment of serum ceruloplasmin.   In patients with low ceruloplasmin or in whom there is a  high clinical suspicion of Wilson disease, additional tests are  needed for confirmation. These include slit-lamp examina-  tions to look for Kayser-Fleischer rings and 24-hour urinary  collection, which will show increased urinary excretion of  copper (> 100 mcg/24 h). Abnormalities in all three tests —  ceruloplasmin, slit-lamp examination, and urinary copper  measurement — are present in only about 40% of patients.   For some patients a liver biopsy is necessary and may  show histologic evidence of copper deposition within the  liver. In addition, measurement of the hepatic tissue content  of copper can show elevated copper levels (normally -55 meg  copper/g dry liver vs > 250 meg copper/g dry liver in Wilson  disease). This is measurement is often helpful when the diag-  nosis is in doubt.   Although the genetic locus is known, mutational analysis  is not widely used in clinical settings because of the multi-  tude of mutations that have been identified. The most com-  mon mutation, a substitution of histidine with glutamine on  amino acid 1069 of the coding sequence (H1069Q), is pres-  ent in approximately 30% of patients with Wilson disease.   Although widespread clinical utility of genetic testing is not  common, the identification of a mutation within a family  helps in screening relatives of the index case.   Ferenci P, Czlokowska A, Merle U, et al. Late-onset Wilson's dis-  ease. Gastroenterology. 2007;132:1294-1298. [PMID: 17433323]   Page RA, Davie CA, MacManus D, et al. Clinical correlation of  brain MRI and MRS abnormalities in patients with Wilson dis-  ease. Neurology. 2004;63:638-643. [PMID: 15326235]   The differential diagnosis of Wilson disease includes acute  and chronic hepatitides and depends on the form of presen-  tation. In patients with fulminant Wilson disease, acute  toxic injury, acute viral hepatitis, acute vascular hepatic  injury, and AIH should be considered. For those presenting  with chronic hepatitis, considerations should include toxic  injury, chronic viral hepatitis, NASH, other inherited liver  disorders, and AIH.   Treatment of Wilson disease is geared toward mobilizing  accumulated tissue copper (Table 40-5). At the same time,  attempts should be made to prevent further copper absorption  through the gastrointestinal tract. The first goal is accomplished  by the use of chelating agents such as D-penicillamine and  trientine. These agents bind tissue copper and then lead to  elimination through the urinary tract.   D-Penicillamine is felt to be the first agent of choice,  although its use is sometimes limited by side effects. These  include allergic hypersensitivity reactions, proteinuria,  immunosuppression, and a plethora of dermatologic changes.  Penicillamine also interferes with the metabolism of pyridoxine,   so it is usual to supplement for vitamin B 6 , especially in chil-  dren and pregnant women.   In patients who are unable to tolerate D-penicillamine,  trientine should be used. Zinc, which competes with copper  for intestinal absorption and therefore reduces the amount  of copper that can be absorbed, is also a widely used thera-  peutic choice. Many preparations are available, and gastroin-  testinal upset has been associated especially with the acetate  form.   Lastly, dietary instructions should stress the avoidance of  foods that are rich in copper, which include liver, chocolate,  shellfish, and nuts.   Roberts EA, Schilsky ML; Division of Gastroenterology and  Nutrition, Hospital for Sick Children, Toronto, Ontario,  Canada. A practice guideline on Wilsons disease. Hepatology.  2003;37:1475-1492. [PMID: 12774027]   Produces a spectrum of disease; liver, lung, hemato-  logic, and dermatologic complications are possible.   Liver complications most often result from deposition of  a poorly degradable mutant of oc, -antitrypsin (a., -AT) in  hepatocytes.   Liver biopsy shows characteristic PAS-positive granules  that are resistant to diastase.    Adult: 250-500 mg/day to maxi  mum of 1200-1500 mg/day  in 2-4 divided doses    Give 1 h before or 2 h after eating  Many possible acute-onset and delayed   side effects  Monitor: complete blood count, proteinuria  Give vitamin B 6 , 50 mg weekly   CXj-Antitrypsin deficiency is an autosomal co-dominant dis-  ease that affects about 1 in 2000-5000 persons. It is most  common in people of northern European descent.   Stoller JK, Aboussouan LS. Alpha 1 -Antitrypsin deficiency. Lancet.  2005;365:2225-2236. [PMID: 15978931]   To date more than 100 mutant alleles of the culprit  SERPINA1 gene have been identified and implicated in lung,  liver, or hematologic disease. The alleles are characterized  phenotypically on the basis of their migration on pH gradi-  ent gels, with faster migrating variants, A (anodal), to slower  migrating variants, Z. Normally migrating alleles are denoted  as M; thus, individuals homozygous for the gene defect are  denoted as MM. Individuals with ZZ alleles have severe defi-  ciency of oCj -antitrypsin (aj-AT).   2. Deficiency alleles characterized by serum o^-AT levels of  less 80 mg/dL or decreased activity (eg, Z alleles). The Z  allele is the most common deficiency variant, accounting  for 95% of all a^AT deficiency. A single mutation of  lysine to glutamate at position 342 is responsible.   3. Null variants in which there is a complete lack of circu-  lating o^-AT.   4. Dysfunctional variants in which the mutant protein  results in a novel function, such as the Pittsburgh allele,  which acts as a thrombin inhibitor.   Lomas DA, Mahadeva R. Alpha 1 -antitrypsin polymerization and  the serpinopathies: pathobiology and prospects for therapy.  / Clin Invest. 2002;110:1585-1590. [PMID: 12464660]   fourth and fifth decades of life as a result of unopposed activ-  ity of leukocyte elastase. This lung disease is accelerated in  patients who smoke. A second clinical entity is panniculitis,  which is characterized by the appearance of painful cuta-  neous nodules at sites of trauma. Additionally, hematologic  problems can occur in persons who have the Pittsburgh allele,  as noted above.   Chronic liver disease, unlike the associated lung disease,  occurs due to accumulation of an insoluble and nonde-  graded mutant protein within hepatocytes. The spectrum of  liver abnormalities includes chronic hepatitis, cirrhosis, and  hepatocellular carcinoma. Among the patients with chronic  hepatitis, the risk of cirrhosis has been estimated at between  12% and 50%. More than 25% of those with neonatal hepa-  titis die in the first decade of life.   Evaluation of o^-AT levels is usually the first step in the diag-  nostic workup of patients with suspected o^-AT deficiency.  For individuals with low circulating levels of a^AT, pi-  typing is then performed to look for abnormal alleles that  might lead either to lack of or for abnormal forms of aj-AT  For patients with liver disease, histologic evaluation of the  liver biopsy samples shows the presence of globules that are  periodic acid-Schiff-positive and diastase-resistant.   American Thoracic Society; European Respiratory Society.  American Thoracic Society/European Respiratory Society state-  ment: standards for the diagnosis and management of individ-  uals with alpha- 1 antitrypsin deficiency. Am } Respir Crit Care  Med. 2003;168:818-900. [PMID: 14522813]   The differential diagnosis is the same as for the other forms  of chronic hepatitis discussed earlier.   O^-AT deficiency causes several significant chronic clinical  problems, including emphysema, which occurs mostly in the   The only effective therapy for liver disease is transplantation in  advanced cirrhosis. Recombinant a t -antitrypsin, however, can  be used in patients whose main presentation is emphysema.   Hemochromatosis classically refers to HFF-mediated  genetic iron overload, but several alternatively medi-  ated genetic iron overload syndromes have been  described.   C282Y is the major mutation and H63D the minor muta-  tion of the HFE gene; individuals with two copies of  C282Y or one copy of both mutations (compound het-  erozygote) are at risk for iron overload.   Excess iron deposition in tissues leads to end-organ  damage; advanced hemochromatosis typically involves  the liver first and may also involve the pancreas, heart,  and pituitary gland.   Most patients are identified by laboratory screening or  family history and are asymptomatic at diagnosis.   Symptomatic patients usually present with nonspecific  complaints of fatigue, arthralgias, and abdominal pain.   Screening studies include serum iron/total iron-binding  capacity (abnormal if > 45% in women, > 50% in men)  and serum ferritin (abnormal if > 200 mcg/dL in  women, > 300 mcg/dL in men); if either test is positive,  genetic testing should be pursued.   Liver biopsy to assess iron concentration and hepatic  iron index is indicated if serum ferritin is > 1000  mcg/dL, liver tests are abnormal, or hepatomegaly is  noted on physical examination.   Most cases of hemochromatosis worldwide and over 90% of  cases in the United States result from the autosomal-recessive  inheritance of two copies of the major mutation (C282Y) of  the HFE gene. Individuals with this genotype are described as  C282Y homozygotes. Ten to 15% of Caucasian populations   are heterozygotes, possessing one copy of the major muta-  tion. This mutation is believed to have originated more than  6000 years ago amid Celtic or Viking ancestry. It has been  postulated that the mutation may have had a potential selec-  tive advantage, preventing iron deficiency in the setting of  scarce resources such as red meat.   Prevalence estimates of homozygosity for the C282Y  mutation in populations of Northern European descent are  as high as 5 in 1000 persons. Prevalence rates vary by gender  and ethnicity. The disease is more common in men, which is  attributed to increased dietary iron consumption as well as  iron losses in women during menstruation. The disease is  rarely seen in African Americans, Mexican Americans, and  Asians. Approximately 90-95% of HF£-related hemochro-  matosis cases are related to homozygosity for C282Y.   One copy of the H63D mutation, the minor mutation of  the HFE gene, may be found in 15-40% of Caucasian popu-  lations. About 4% of cases of hemochromatosis result from  the inheritance of one copy of the major mutation, C282Y,  and one copy of the minor mutation, H63D. These individu-  als are described as compound heterozygotes. However, the  great majority of compound heterozygotes will not develop  clinically significant iron overload. The risk has been esti-  mated to be 200 times less than in C282Y homozygotes.  H63D homozygotes typically do not develop clinically signif-  icant iron overload.   Phenotypic expression of these altered gene states is vari-  able and, as a result, the proportion of patients who go on to  develop clinically significant hemochromatosis remains  uncertain. Overall, secondary causes of iron overload are still  more common than primary iron overload syndromes.   The quantity of total body iron is closely regulated and is  estimated to be approximately 3 g in women and 5 g in men.   Most of this iron is incorporated into red blood cells. The  remainder is stored in the liver and a small amount in skele-  tal muscle. Almost all iron absorption occurs in the duode-  num. After iron is absorbed, it circulates bound to the carrier  protein transferrin for distribution to tissues. In addition to  taking up inorganic iron in this way, the duodenal entero-  cytes may also take up iron in the form of heme.   Most of the circulating iron is taken up within sites of  erythropoiesis, where it is incorporated into hemoglobin by  developing erythrons. The liver serves as a storage reservoir  for iron and then releases iron back into circulation as  needed. As red blood cells senesce, they are phagocytosed by  macrophages which then process and release iron for recy-  cling into newly developing cells at a controlled rate.   The amount of iron absorbed from food can be up-  regulated quickly when excess iron is lost or utilized, such as  through menstruation, pregnancy, or gastrointestinal bleed-  ing. Small amounts of iron, on the order of 1-2 mg daily, are  lost as cells of the gastrointestinal and urogenital tracts are  shed. An additional 1-2 mg of iron are lost daily by women  during their reproductive years. However, the human body  has no effective physiologic mechanism for excreting excess  iron. The duodenal enterocytes must correctly sense or be  signaled to absorb enough iron to replace losses but no more.   The duodenal enterocytes, hepatocytes, and macrophages  all appear to play important roles in iron homeostasis.  Because they function at sites distant from one another, it has  been hypothesized that they communicate via a hormone or  hormones. Multiple factors influence iron absorption,  including both systemic and intestinal factors. Systemic fac-  tors include the level of body iron stores, erythropoietic  activity, hemoglobin concentration, and oxygen saturation as  well as the presence or absence of inflammatory cytokines.  Intestinal factors include pancreatic insufficiency and distur-  bances in pH. Disorders of iron metabolism develop when  disease states overwhelm the homeostatic mechanisms. For  example, infections or chronic inflammation induce iron  sequestration by macrophages and signal a decrease of iron  absorption, leading to the anemia of chronic disease.  Conversely, disorders of erythropoiesis, such as the tha-  lassemias, release signals promoting iron absorption by  developing erythrons that overwhelm the inhibitory signals  generated by excessive accumulation of iron stores.   Sharma N, Butterworth J, Cooper BT, et al. The emerging role of  the liver in iron metabolism. Am } Gastroenterol. 2005;100:  201-206. [PMID: 15654801]   In hereditary hemochromatosis, one or more genetic muta-  tion leads to excess iron absorption relative to body iron  stores. The excess iron is stored in the liver initially but, if  unrecognized and untreated, the iron may deposit in multi-  ple end organs when hepatic storage is saturated, leading to  the phenotypic expression of the disease. Iron spillover has   been observed once total body stores reach 4.5 g with hepatic  levels in excess of 400 mcg/g of tissue.   In 1996, Feder and colleagues published the discovery of  a candidate gene for hemochromatosis located on the short  arm of chromosome 6, now called HFE. As noted earlier, two  mutations are now recognized. The major mutation results  from a tyrosine substitution for cysteine at the 282 amino  acid position on the gene and is abbreviated Cys282Tyr or  simply C282Y. The minor mutation results from an aspartate  substitution for histidine at the 63rd amino acid position and  is abbreviated His63Asp or simply H63D.   Feder IN, Gnirke A, Thomas W, et al. A novel MHC class Hike  gene is mutated in patients with hereditary haemochromatosis.  Nat Genet. 1996;13:399-408. (PMID: 8696333]   The initial model for iron overload in HFE-related  hemochromatosis postulated that the HFE mutation acted at  the level of the developing duodenal crypt cell. These cells  elaborate iron transporters (DMT-1), as they differentiate  and migrate towards the villus tip (Figure 41-1). Within this  so-called crypt-programming model, the crypt cells would  correctly assess or "sense" the amount of iron in circulation  through HF£-dependent uptake of transferrin-bound iron at  their basolateral membrane and thereby program produc-  tion of the appropriate number of iron transporters in the  differentiating cell. The HFE mutation would disable normal  uptake of iron by the nascent crypt cells, leading to incorrect  "sensing" of an iron-deficient state and to programming of  an excessive number of iron transporters (Figure 41-2).   The crypt-programming model has been challenged by  recent experimental data. Changes in iron absorption occur  within hours of a change in iron status, whereas enterocyte  maturation takes days. Furthermore, other forms of iron  overload, such as juvenile hemochromatosis, occur in the  absence of HFE mutation. This suggests the existence of other  factors with a more fundamental role in iron homeostasis.   Investigators have shifted their focus from the duodenum  to the liver, where the protein hepcidin is now considered the  key regulator of iron absorption. It was first described by  Park and colleagues, who named it after its site of synthesis  in the liver and its antibacterial properties. Hepcidin is a  25 amino acid peptide encoded by the HAMP gene. There is  an inverse relationship between the level of hepcidin and  iron absorption. In mouse models of hereditary hemochro-  matosis, decreasing hepcidin production by silencing the  HAMP gene encoding hepcidin results in severe iron over-  load. In iron-deficient mice, hepcidin production is also  decreased, leading to increased iron absorption. In HFE  knockout mice with iron overload, stimulating hepcidin pro-  duction successfully reverses the iron overload.   Similarly, humans with HFE-related hereditary hemochro-  matosis have low levels of hepcidin mRNA in liver biopsy   ▲ Figure 41-1. Hepcidin model. Hepcidin normally functions as a regulatory protein, inhibiting release of iron from vil-  lus enterocytes and macrophages, which in turn inhibits iron absorption. A: Normal. B: HFF-related hemochromatosis.   (Adapted, with permission, from Pietrangelo A. Hereditary hemochromatosis— a new look at an old disease. N Engl J Med.  2004;350:2389.)   specimens despite iron overload. Weinstein and colleagues  reported on two patients with large hepatic adenomas overex-  pressing hepcidin who presented with severe microcytic ane-  mia. Resection of the masses reversed the hematologic  abnormalities.   Hepcidin appears to have several targets. At the level of  the enterocyte, hepcidin binds to ferroportin at the basolat-  eral cell surface, leading to internalization and degradation.  This, in turn, limits iron export from enterocytes, leading to  accumulation of iron within these cells and decreased iron  absorption. Reticuloendothelial macrophages also have fer-  roportin receptors, and the effects of hepcidin here are  thought to be similar.   The mechanism by which HFE mutations lead to iron  overload is incompletely understood. HFE mutations lead to  low levels of hepcidin, which leads to unchecked release of  iron from duodenal enterocytes and macrophages. This  leads, in turn, to uncontrolled iron absorption and the  hemochromatosis phenotype (see Figure 41-2). However,  the pathways by which HFE mutations lower hepcidin levels  remain to be elucidated. One theory is that HFE is a partici-  pant in hepatocyte sensing of body iron status. Hepatocytes  elaborate TfR2 receptors on their surface which may bind to  diferric transferrin (Tf) in portal blood, possibly sensing the   circulating level of iron by this means. HFE mutations could  theoretically influence the sensing of diferric Tf by hepato-  cytes and lead to lower levels of hepcidin. Recent work sug-  gests that hepatocytes in culture do not directly respond to  changes in iron status with changes in hepcidin production.  Rather, the sensing function might be performed by Kupffer  cells or perhaps cells in the hepatic sinusoids, which in turn  signal hepatocytes to modify hepcidin expression by an  unknown mechanism.   Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regu-  lation in HFE-associated haemochromatosis and the liver as a  regulator of body iron homoeostasis. Lancet. 2003;361:669-673.  [PMID: 12606179]   Fleming RE, Bacon BR. Orchestration of iron homeostasis. N Engl  J Med. 2005;352:1741-1744. [PMID: 15858181]   Nemeth E, Turtle MS, Powelson J, et al. Hepcidin regulates cellular  iron efflux by binding to ferroportin and inducing its internal-  ization. Science. 2004;306:2090-2093. [PMID: 15514116]   Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimi-  crobial peptide synthesized in the liver. / Biol Chem. 2001;  276:7806-7810. [PMID: 11113131]   Roy CN, Enns CA. Iron homeostasis: new tales from the crypt.  Blood. 2000;96:4020-4027. [PMID: 11110669]   ▲ Figure 41-2. Crypt-programming model. The HFE mutation interferes with duodenal uptake of iron. A: Normal. B: HFE-   related hemochromatosis. (Adapted, with permission, from Pietrangelo A. Hereditary hemochromatosis— a new look at an  old disease. N Engl J Med. 2004 ; 350:2389.)   Weinstein DA, Roy CN, Fleming MD, et al. Inappropriate expres-  sion of hepcidin is associated with iron refractory anemia:  implications for the anemia of chronic disease. Blood. 2002;  100:3776-3781. [PMID: 12393428]   The fact that only a small percentage of C282Y homozygotes  develop signs and symptoms of iron overload suggests that  other genetic and environmental modifiers are present.  Perhaps other proteins influencing hepcidin expression may  compensate for the effects of the HFE mutation.   Alcohol consumption is a major environmental factor  modifying disease activity. Much higher rates of cirrhosis have  been observed in patients with hereditary hemochromatosis  who consume more than 60 g of alcohol per day. Investigations  into the mechanism of action of alcohol on exacerbating dis-  ease activity have demonstrated down-regulation of hepcidin   activity as well as increased C/EBPoc, DMT-1, and ferroportin  expression in animal models. In addition, it is believed that  alcohol and iron deposition may act synergistically to promote  fibrosis through increased oxidative stress and hepatic stellate  cell activation.   Although HFE mutations are responsible for the great  majority of cases of hemochromatosis worldwide, the com-  mercial availability of testing for HFE mutations soon iden-  tified individuals and subpopulations with significant iron  overload in the absence of these mutations. Three other gene  mutations have been identified that cause autosomal-  recessive iron overload with a phenotype very similar to that  of HFE- related hemochromatosis. They are the HJVgene on  chromosome 1, the HAMP gene on chromosome 19, and the  TfR2 gene on chromosome 7. All three mutations decrease   AD, autosomal dominant; AR, autosomal recessive; OMIM, Online Mendelian Inheritance in Man database.   Data from the OMIM database, available at: http://www.ncbi.nln.nih.gov/omim/online, and from Pietrangelo A. Hereditary hemochromatosis-   a new look at an old disease. N Engl J Med. 2004;350:2383.   hepcidin levels and lead to a primarily hepatocellular depo-  sition of excess iron (Table 41-1).   The term juvenile hemochromatosis was first used in 1979  to describe an overload syndrome that resembled HF£-related  hemochromatosis but with iron loading and end-organ dam-  age at an early age. This form of severe hemochromatosis  appears to be caused by mutations in either the hemojuvelin  (HJV) or HAMP genes. HJV mutations have been identified in  12 families from France, Greece, and Canada. The mechanism  by which hemojuvelin modulates hepcidin expression is  unknown. Mutations in HJV appear to be more common than  mutations of the HAMP gene, which encodes hepcidin.  HAMP mutations may lead to severe and potentially fatal iron  overload before age 30, corroborating the critical role of hep-  cidin in iron homeostasis.   TfR2 mutations lead to a milder form of iron overload  similar to HFE. Mutations have been identified in individu-  als from France and Japan. The predominant site of TfR.2  expression is in hepatocytes. The mechanism by which TfR2  mutations lead to low hepcidin levels and iron overload is  unknown.   Ferroportin is the target of hepcidin in duodenal entero-  cytes and macrophages. Two mutations have been identified  that lead to autosomal-dominant iron overload. One muta-  tion inactivates ferroportin and leads to retention of iron in  duodenal enterocytes and macrophages. The result is a pri-  marily reticuloendothelial distribution of iron. Circulating  levels of iron tend to be lower than in HRE-related  hemochromatosis. The second ferroportin mutation par-  tially disables the interaction between ferroportin and hep-  cidin. This leads to effects similar to low levels of hepcidin  with a primarily hepatocellular distribution of iron similar to  HF£-related disease.   Recognition of these different genes, and the influence of  their proteins on iron metabolism, has led to a new classifi-  cation of iron overload syndromes in the Online Mendelian  Inheritance in Man (OMIM) database (see Table 41-1).   It is likely that the constitutive expression of hepcidin or  up-regulation in response to iron depends on the hepcidin-  regulating activities of the proteins noted in the OMIM,  including HFE, TfR2, and HJV. These may function inde-  pendently or interdependently. The relative importance of  the different proteins on hepcidin expression and therefore  iron metabolism is reflected by the severity of iron overload  that develops in their absence: Mutations in the HJV (or  HAMP) gene lead to an early development of severe iron  overload, whereas either HFE or TfR2 mutations alone lead  to a milder phenotype that develops later in life, if at all.   It is now apparent not only that mutations in multiple  genes may lead to the hemochromatosis phenotype but also  that various combinations of mutations may be responsible  for the variable presentation of the disease. Merryweather-  Clarke and colleagues, for example, described two families of  C282 heterozygotes with different mutations of the HAMP  gene. Family members inheriting one copy of C282Y and one  allele with the HAMP mutation develop significant iron  overload. Pietrangelo and colleagues described patients with  "juvenile hemochromatosis" but without either the HAMP  or HJV mutations. The severe phenotype in their cases devel-  oped from inheritance of both HFE and TfR2 mutations and  their additive effects on iron metabolism.   Merryweather-Clarke AT, Cadet E, Bomfor A, et al. Digenic inher-  itance of mutations in HAMP and HFE results in different types  of haemochromatosis. Hum Mol Genet. 2003;12:2241-2247.  [PMID: 12915468]   Pietrangelo A. Hereditary hemochromatosis-a new look at an old  disease. N Engl J Med. 2004;350:2383-2397. [PMID: 15175440]   Iron overload is typically an insidious process. Patients are  commonly asymptomatic until 10-20 g of iron stores have   accumulated in parenchymal tissues. Diagnosis is typically  made earlier in men, as iron overload is often delayed by men-  strual losses and decreased dietary intake in women. As a result,  while men are typically diagnosed in the fourth to fifth decade  of life, women are diagnosed on average a decade later. As the  use of screening laboratory measures has increased, more  patients are now being diagnosed in an asymptomatic stage.   1 . Initial presentati Clinical manifestations of early iron  overload include unexplained fatigue, arthralgias, weight loss,  abdominal pain, and reduced libido. Identification of the most  common genetic abnormalities associated with hereditary  hemochromatosis has led increasingly to diagnosis in asymp-  tomatic individuals. The value of genetic testing in patients  without evidence of overt iron overload is controversial.   Hereditary hemochromatosis can lead to iron deposition  within multiple organ sites. Complications by organ system  are reviewed below.   2. Liver — Elevated liver enzymes, hepatomegaly, or cirrhosis  is present in greater than 95% of patients with clinically sig-  nificant hereditary hemochromatosis. Liver manifestations  usually do not begin until liver stores become saturated (6-7 g) .  The majority of deaths related to hereditary hemochromato-  sis (89%) are attributable to complications of cirrhosis.  Overall, the risk of hepatocellular carcinoma in patients with  hereditary hemochromatosis who develop cirrhosis is 200  times that of the general population (5% annual risk after the  development of cirrhosis). Pathologically, the presence of  "iron-free" nodules on histologic examination has correlated  with onset of hepatocellular carcinoma.   With treatment, elevations in liver function tests and  hepatomegaly are reversible. No strong evidence currently  exists with respect to the reversibility of portal hypertension  with treatment.   3. Cardiac — Iron deposition within cardiac tissue can lead to  either dilated cardiomyopathy or a mixed dilated-restrictive  picture. Conduction disturbances such as atrial fibrillation  or sick-sinus syndrome have also been linked with hereditary  hemochromatosis. The extent of cardiac involvement is  highly variable and does not necessarily correlate with the  extent of other organ involvement. Dysrhythmias and car-  diomyopathy are the leading cause of sudden death in  patients with iron overload.   With phlebotomy, both the cardiomyopathy and dys-  rhythmias associated with iron deposition can be reversed,  albeit to a variable extent.   4. Endocrine — Diabetes mellitus and hypogonadism are the  most commonly described endocrinopathies associated with  hereditary hemochromatosis. The onset of diabetes has been  described in up to 65% of patients with symptomatic iron  overload. The mechanism is believed to be twofold: both  direct damage to pancreatic islet cells by iron deposition as  well as increased insulin resistance due to higher circulating  iron levels. The incidence of diabetes is increased in patients   with a family history of diabetes, suggesting that a genetic  predisposition is at least partially responsible. Unlike the car-  diac disturbances, the diabetes associated with hereditary  hemochromatosis is often nonreversible despite therapy for  iron overload.   Reduced secretion of gonadotropin as a result of iron  interference in the hypothalamic-pituitary axis can lead to  hypogonadism. This is the second most common form of  endocrinopathy associated with hereditary hemochromato-  sis and can present as impotence, amenorrhea, and reduced  libido, as well as osteoporosis. Secondary hypothyroidism is  a less common form of endocrinopathy seen in men with  hereditary hemochromatosis. Patients who develop hypogo-  nadism or hypothyroidism often require lifelong hormone  supplementation.   5. Arthropathy — Twenty to 70% of symptomatic patients  present with complaints of arthropathy. Classically, the sec-  ond and third metacarpophalangeal and proximal interpha-  langeal joints of the hands are involved. In addition, the  wrists, shoulders, knees, and ankles can be affected.  Radiographically, joint space narrowing is accompanied by  squared-off bone ends and hook-like osteophytes. These  changes resemble those of calcium pyrophosphate crystal  deposition disease (pseudogout). It has been difficult to tease  apart the contribution of hereditary hemochromatosis to  arthropathy given the relatively high prevalence of joint dis-  ease in the general population. Significant improvement in  symptoms is not often observed with treatment of the under-  lying iron overload.   6. Pigmentation — The classically described metallic or  slate-gray hue described as "bronzing" is a result of increased  melanin in the dermis. In addition, direct iron deposition in  the dermis contributes to the gray appearance. Although best  appreciated by examining the volar (unexposed) portion of  the forearms, additional sites of involvement include the  face, neck, dorsum of the hands, lower legs, and genital  regions. Cutaneous atrophy, flattening of the nails, and loss  of body hair has also been described. Estimates of the preva-  lence of bronzing in symptomatic individuals range from  18% to 47%. Data is sparse with respect to changes in pig-  mentation with phlebotomy therapy.   1. General approach — Patients suspected of iron overload,  based on either symptoms or routine laboratory testing,  should undergo a thorough history and review of systems.  Emphasis should be placed on eliciting symptoms suggesting  involvement of the gastrointestinal, cardiac, endocrine, and  rheumatologic systems. Because the C282Y homozygous  state does not necessarily translate into clinical disease, the  diagnosis of hereditary hemochromatosis is determined by a  combination of genetic, serologic, and clinical features.  Current diagnostic markers include gene analysis, iron stud-  ies, liver biopsy, and response to therapy.   2. Serum iron Studies — Initial evaluation usually begins  with serologic testing of iron studies. All serologic testing  should be conducted in the fasting state. The transferrin sat-  uration is regarded as the single best screening test for hered-  itary hemochromatosis. Although widely accepted as an  accurate marker of the genetic defect in HF£-associated  hemochromatosis, there is controversy over the optimal cut-  off level. Previously suggested levels include transferrin satu-  ration of 45% or higher, 55% and higher, and 60% and  higher, as thresholds. With increasing thresholds, sensitivity  is sacrificed for greater specificity. The unsaturated iron-  binding capacity (UIBC) has also been examined as a single  test for screening patients for hereditary hemochromatosis  with similar results to the transferrin saturation.   Serum ferritin has also been employed as an index of the  body's iron stores. Although the ferritin level is typically  greatly elevated in hereditary hemochromatosis, ferritin may  also be elevated as an acute phase reactant in additional  inflammatory states in the absence of the genetic disease,  notably alcoholic liver disease, nonalcoholic steatohepatitis,  and chronic hepatitis C. Combined measurement of the per-  cent transferrin saturation and serum ferritin provides a  simple means to exclude patients from further analysis. If  either is elevated in the absence of a known inflammatory  condition, further genetic testing for hereditary hemochro-  matosis is indicated.   1. Liver biopsy — Liver biopsy provides information relevant  to the diagnosis and staging of hemochromatosis. Sampling  of liver tissue provides documentation of fibrosis or cirrhosis.  It also helps evaluate for additional causes of liver disease.  Biopsy also allows determination of the hepatic iron index  (ratio of hepatic iron concentration to age of the patient). An  index greater than 1.9 is highly supportive of hereditary  hemochromatosis and helps to distinguish that disease from  alcoholic liver disease.   With the widespread availability of genetic testing, liver  biopsy for diagnostic purposes is now reserved for cases in  which either genetic testing is unavailable or non—HFE-  related iron overload is suspected in patients with suggestive  iron studies but a normal HFE gene analysis. Current guide-  lines also recommend biopsy in C282Y homozygotes or  C282Y/H63D compound heterozygotes older than age 40,  with a serum ferritin level greater than 1000 and abnormal  liver enzymes or hepatomegaly, or both. If none of these indi-  cators of chronic liver disease is present, studies have sug-  gested that the presence of significant fibrosis or cirrhosis is  unlikely and liver biopsy may be deferred, provided treatment  to deplete iron stores is initiated. The presence of abnormal  liver enzymes and hepatomegaly at any age are indications to  pursue a biopsy. Younger C282Y homozygotes with normal  iron studies can defer biopsy with repeat testing of iron stud-  ies every 5 years. The guidelines of the American Association   for the Study of Liver Diseases (AASLD) recommend biopsy  for simple C282Y heterozygotes with elevated iron studies  and liver enzymes.   2. Quantitative phlebotomy— Although not providing  information with respect to the extent of disease, quantitative  phlebotomy can be used to diagnose iron overload. The cal-  culated iron storage can be assessed by determining the num-  ber of phlebotomies required to produce iron deficiency. Four  phlebotomy sessions of 500 ml each will remove approxi-  mately 1 g of iron. Calculated iron storage greater than 5 g is  considered abnormal.   3. Imaging Studies — Noninvasive imaging techniques such  as computed tomography and magnetic resonance imaging  (MRI) have not yet seen widespread use in the diagnosis or  staging of hereditary hemochromatosis. Recent studies have  found a relatively high concordance between MRI and liver  biopsy with respect to detection of hepatic iron levels.  Noninvasive imaging is useful for advanced disease but not  feasible for screening of early disease.   4. Genetic testing — Discovery of the HFE gene, and the  C282Y and H63D mutations, has revolutionized the diagno-  sis of hereditary hemochromatosis. Genetic testing for these  mutations should be undertaken in any patient with suspi-  cion of iron overload based on the results of laboratory test-  ing. The results of genetic testing, however, must be combined  with a patient's clinical presentation as penetrance of the  genetic defect is variable, in some recent estimates below 1%.   A. Family screening — Screening of first-degree relatives of  C282Y homozygotes is universally recommended. Siblings  have a 1 in 4 to 1 in 2 chance of inheriting the mutation,  depending on whether the parents are homozygous or het-  erozygous for the mutation. Children of C282Y homozygotes  have an approximately 1 in 20 chance of inheriting two  copies of the C282Y mutation.   Once an individual is identified with hemochromatosis,  his or her spouse should be genotyped if the couple has more  than one child. If the spouse has at least one copy of the  major or minor mutation, then the children should undergo  HFE gene testing. It is more cost-effective to directly geno-  type an only child. Genetic screening of family members is  preferred over phenotypic screening methods due to  improved efficiency, as biochemical iron overload is not  always present initially. Screening of first- to third-degree rel-  atives of carriers may detect up to 40% of at-risk individuals.   B. Population-based screening — Hereditary hemochro-  matosis satisfies many of the criteria set forth by the U.S.  Preventative Services Task Force and World Health  Organization to determine diseases appropriate for popula-  tion screening. Hereditary hemochromatosis has adequate  prevalence with a prolonged latent phase. In addition, treatment   for the disease has been shown to be widely successful in  forestalling associated complications that, if untreated, can  be associated with significant morbidity and mortality.  Moreover, testing for hemochromatosis is relatively inexpen-  sive, widely available, and reliable.   Issues that have hindered acceptance of widespread  screening guidelines for hereditary hemochromatosis have  included varying case definitions, variable phenotypic  expression, as well as disagreement over the cost-effectiveness  of general population screening.   Ombiga I, Adams LA, Tang K, et al. Screening for HFE and iron  overload. Semin Liver Dis. 2005;25:402-410. [PMID: 16315134]   Qaseem A, Aronson M, Fitterman N, et al. Screening for hereditary  hemochromatosis: a clinical practice guideline from the  American College of Physicians. Ann Intern Med. 2005;143:  517-521. [PMID: 16204164]   Phlebotomy has been the mainstay of treatment for iron over-  load. Initiation of therapeutic phlebotomy has been demon-  strated to have significant survival benefit in patients with  and without cirrhosis. Every four phlebotomy treatments  removes approximately 1 g of iron. Although an optimal reg-  imen has not been specified, early and rapid depletion of iron  stores is the goal of therapy. Weekly phlebotomy is generally  instituted in the early phase of treatment, with frequent mon-  itoring of the hemoglobin as well as ferritin levels. In most  cases, the therapeutic goal is a serum ferritin level less than  50 mcg/L. After initial depletion of iron stores, maintenance  phlebotomy can be performed two to four times a year with  ongoing periodic monitoring of serum ferritin levels.  Maintaining appropriate follow-up is the key to avoiding the  damaging long-term effects of iron deposition, avoiding cir-  rhosis, and improving overall survival.   With the general success and relatively low cost of phle-  botomy, chelation therapy for hereditary hemochromatosis  is only rarely employed. Subcutaneous desferrioxamine (1-2 g  daily infused over 8 hours) is typically used when phle-  botomy is contraindicated or in the case of specific cardiac  disease that can be improved with aggressive iron depletion.   HFE-related hemochromatosis is the most common autoso-  mal-recessive disorder in Caucasians with an incidence of  approximately 1:250 population. It remains underdiagnosed,  although early diagnosis before the development of cirrhosis is  essentially curative. The discovery of HFE has led to a rapid evo-  lution of our understanding and management of this disease.   It now appears that hepcidin is the key regulator of iron  homeostasis, influenced by multiple proteins, including  HFE, TfR2, and HIV. Mutations in multiple genes may lead  to the hemochromatosis phenotype. The unifying feature is  iron overload that begins with early expansion of the plasma  iron compartment, resulting from inappropriate release of  iron from villus enterocytes and macrophages. Progressive  parenchymal iron deposition ensues with the potential for  severe organ damage.   The phenotypic expression of hemochromatosis may be  influenced by multiple other host and environmental factors.  For example, C282Y homozygotes experience increased rates  of cirrhosis and a poorer prognosis when faced with added  insults to the liver such as alcohol or nonalcoholic steatohep-  atitis. In addition, patients with both hereditary hemochro-  matosis and hepatitis C have been found to be less responsive  to treatment with combination interferon and ribavirin.   Areas for future investigation include the molecular  mechanisms of action of hepcidin and the proteins that  influence its production, including HFE, TfR2, HIV, and pos-  sibly others. Testing for the multiple genes implicated in the  hemochromatosis phenotype may become commercially  available in the foreseeable future. Potential therapeutic  applications of our rapidly expanding knowledge of iron  metabolism include administration of exogenous hepcidin  for the treatment of iron overload and hepcidin antagonists  to treat anemia associated with chronic inflammatory states.   Adams PC. Review article: the modern diagnosis and management  of haemochromatosis. Aliment Pharmacol Ther. 2006;23:  1681-1691. [PMID: 1681791 1]   Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochro-  matosis: current concepts and progress. Am J Med. 2006;119:  391-399. [PMID: 16651049]   ► In the United States, excessive alcohol use is defined as  ingestion of >14 drinks/week in women and > 21  drinks/week in men (1 drink = 12 oz beer, 1.0 oz malt  liquor, 5 oz wine, or 1.5 oz 80 proof "hard liquor.")   ► Factors accelerating liver injury in alcoholic liver disease  (ALD) include female gender, Latino and African-  American ethnicity, chronic hepatitis C infection, aceta-  minophen overdose, and hereditary hemochromatosis.   ► 75% of Asians have decreased ability to metabolize  ethanol, resulting in acetaldehyde accumulation and  subsequent flushing.   ► Diagnosis of excessive alcohol use is suggested by  increased serum ALT and AST levels, AST:ALT ratio of  2-3:1, and MCV > 100.   ► Accurate history of substance intake and CAGE ques-  tionnaires aid in the diagnosis of alcohol abuse.   ► Liver biopsy and liver imaging cannot distinguish ALD  from nonalcoholic steatohepatitis (NASH).   ► Although 90-100% of heavy drinkers will develop  hepatic steatosis, only 10-35% will develop alcoholic  hepatitis, and 8-20% will develop cirrhosis.   Alcohol use in human history has played an important role in  religion, medicine, and nutrition. The first use of alcohol dates  back to the late stone-age Neolithic period (circa 100,000 bc)  with the archeological discovery of beer jugs. Egyptian pic-  tographs suggest wine consumption as early as 4000 bc. The  use of wine and beer for medical purposes began circa 2000 bc.  Sentiment toward moderation in drinking was documented in  a Chinese imperial edict in the 12th century bc. The associa-  tion of alcohol with liver disease appeared to have been  noticed by the ancient Egyptians, who linked the use of beer   with ascites, and the ancient Greeks, who described the  association with jaundice and gastrointestinal bleeding.   Alcohol-related health problems contribute to significant  health care costs worldwide. In 2003, the prevalence of alcohol-  related disorders was 1.7% worldwide, and alcohol was the  third leading cause of death in the United States. Studies have  shown that per capita alcohol consumption in both men and  women is associated with mortality from liver cirrhosis.   Not all those who consume alcohol will develop Alcoholic  Liver Disease (ALD) and liver cirrhosis. Among heavy  drinkers, 90-100% will develop hepatic steatosis in 10 years,  but only 10-35% will develop steatohepatitis and 8-20% will  develop cirrhosis in the same period (Figure 42-1).   Epidemiologic research involving alcohol use is not without  limitations. The definition of one alcohol drink varies glob-  ally and individually. In the United States, the definition used  by the Centers for Disease Control and Prevention is about  0.5 oz, or 13.7 g of pure alcohol. This is equivalent to 12 oz  of beer, 8 ozof malt liquor, 5 oz of wine, or 1.5 ozof 80-proof  "hard liquor." In the United Kingdom and lapan, one drink  equals 8 g and 19.75 g, respectively.   Mandayam S, Jamal MM, Morgan TR. Epidemiology of alcoholic liver  disease. Semin Liver Dis. 2004;24:217-232. [PMID: 15349801]   McCullough AJ, O'Connor IF. Alcoholic liver disease: proposed  recommendations for the American College of Gastroenterology.  Am J Gastroenterol 1998;93:2022-2036. [PMID: 9820369]   The amount of alcohol consumption required for progres-  sion to liver cirrhosis reported by Lelback and colleagues in   (Reproduced, with permission, from McCullough AJ,  O'Connor JF. Alcoholic liver disease: proposed recommenda-  tions for the American College of Gastroenterology. Am J  Gastroenterol. 1998:93:11.)   1975 was 80 g of ethanol daily (equivalent to 1 L of wine, a  half pint of hard liquor, or 8 beers) consumed for 10-20  years. However, as noted, not all who ingest significant  amounts of alcohol will develop cirrhosis. Several cofactors  are known to accelerate progression of liver disease, and the  risk for ALD increases with ingestion of more than 35 drinks  per week. A "safe" amount is believed to be 21 drinks per  week for men and 14 drinks per week for women, in the  absence of the cofactors listed below.   1. Age — Despite the legal alcohol drinking age of 21 years in  the United States, a 2004 study revealed that 50% of high  school students drank some amount of alcohol, and 20% of  all alcohol consumption is suspected to be in individuals  younger than age 21. Early alcohol use is associated with  alcoholism later in life. At the opposite end of spectrum, an  emergency department screening study revealed that 24.5%  of subjects older than 65 years met criteria for alcohol abuse.  However, the highest rate of alcohol abuse morbidity occurs  among individuals aged 45-64 years, with a prevalence rate  of 94.8 per 100,000.   2. Gender — The overall prevalence of alcohol abuse and  related liver disease is higher among men than women.  However, women are more prone than men to alcohol-  related liver injury and fibrosis progression for the same  amount of alcohol consumption. This may be due to differ-  ent rates of alcohol metabolism, lower body mass index,  effects of estrogens, or an increased intestinal permeability to  endotoxin.   3. Ethnicity — Susceptibility to ALD is believed to vary  among different ethnic groups. In the United States, alco-  holic cirrhosis-related deaths are highest in Hispanic males,  followed by black non-Hispanics, white non-Hispanics, and  black Hispanics. The prevalence among females is highest in  black non-Hispanics, followed by white Hispanics, white  non-Hispanics, and black Hispanics. Studies in the United  Kingdom suggest that South Asian men are more susceptible   to alcohol-related liver injury than European men. It is  unclear whether these differences are due to genetic polymor-  phisms, types of alcohol consumed, or access to health care.   individuals with ALD also have chronic hepatitis C. The  combination of HCV and ALD accelerates the progression  and severity of liver disease, increases the risk for hepatocel-  lular carcinoma, and decreases the likelihood of virologic  response to interferon-alfa therapy. The acceleration of liver  disease has been postulated to be due to an increase in viral  replication, a decrease in liver regenerative capability, and an  increase in quasispecies complexity. Patients with HCV who  consume excessive alcohol succumb at an earlier age. This  affects the mortality in women more than men.   5. Hepatitis B (HBV) infection— In a large population  study performed in Taiwan, the data suggest that chronic  HBV infection and alcohol consumption increase the risk for  the development of hepatocellular carcinoma.   6. Hepatocellular carcinoma— ALD and hepatitis C are the  two most common causes of hepatocellular carcinoma. In a  Veterans Administration study of patients between 1993 and  1998, the prevalence rate of hepatocellular carcinoma in  patients with cirrhosis secondary to alcohol use was 9.1 per  100,000, whereas the rate was 7.0 per 100,000 in patients with  HCV. The risk of hepatocellular carcinoma increases after  consuming more than 60 g of alcohol per day for more than  10 years. Recent studies have also shown that there has been  a dramatic increase in the incidence of hepatocellular carci-  noma associated with hepatitis C infection, and the inci-  dence may be comparable to that of ALD. The effect of  alcohol and HCV in the development of hepatocellular car-  cinoma appears to be synergistic.   7. Medications — Patients with ALD appear to be at an  increased risk for liver injury after ingestion of multiple or  above recommended therapeutic doses of acetaminophen.  This is believed to be due to rapid depletion of glutathione  stores and competition with cytochrome P450 (CYP) 2E1.  Although other medications may also compete with CYP450,  there are limited data on increased hepatoxicity in the setting  of ALD.   8. Iron overload — The liver is able to tolerate high levels of  intrahepatic iron without progression to fibrosis. However,  when a cofactor, such as alcohol, is involved, liver damage is  accelerated. Similar synergistic effects are also seen in nonal-  coholic fatty liver disease, chronic HCV, and porphyria  cutanea tarda. Both iron and alcohol generate reactive oxy-  gen species that promote lipid peroxidation with consequent  damage to cellular integrity. Alcohol has also been shown to  suppress hepcidin activity in animal models. Excessive alco-  hol consumption (> 60 g/day) in patients with hemochro-  matosis is associated with accelerated fibrogenesis, increased  risk for hepatocellular cancer, and lower long-term survival.  Because consumption of more than three drinks daily is   associated with increased serum markers (ferritin) of iron  overload from ALD, HFE genetic testing can differentiate  ALD from hereditary hemochromatosis. Primary iron over-  load may be distinguished from secondary iron overload  when the hepatic iron index is greater than 1.9 micromole  per gram dry weight of liver per year of life.   9. Diet and lifestyle — There are limited data on dietary and  lifestyle factors that may influence the natural history of ALD.  Coffee may be protective in ALD and related cirrhosis. Studies  on the effect of tobacco have been conflicting. Some studies have  suggested that obesity (basal metabolic index > 25 kg/m 2 ) for  more than 10 years accelerates progression of ALD. Pork  products, on the other hand, have been shown to be associ-  ated with alcoholic hepatitis and cirrhosis but not steatosis.  Other lifestyle factors that may be associated with ALD pro-  gression include single status, urban dwelling, unemployment,  lower socioeconomic background, daily alcohol ingestion,  and variable alcoholic beverage ingestion.   Anand BS, Thornby J. Alcohol has no effect on hepatitis C virus  replication: a meta-analysis. Gut. 2005;54:1468-1472. [PMID:  16162952]   Anand BS, Velez M. Assessment of correlation between serum  titers of hepatitis C virus and severity of liver disease. World J  Gastroenterol. 2004;10:2409-2411. [PMID: 15285030]   Chen CM, Yoon YH, Yi HY, et al. Alcohol and hepatitis C mortality  among males and females in the United States: a life table analy-  sis. Alcohol Clin Exp Res. 2007;31:285-292. [PMID: 17250621]   Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular  carcinoma: the effect of lifetime intake and hepatitis virus infec-  tions in men and women. Am J Epidemiol. 2002;155:323-331.  [PMID: 11836196]   Douds AC, Cox MA, Iqbal TH, et al. Ethnic differences in cirrhosis  of the liver in a British city: alcoholic cirrhosis in South Asian  men. Alcohol Alcohol. 2003;38:148-150. [PMID: 12634262]   Fletcher LM, Dixon IL, Purdie DM, et al. Excess alcohol greatly  increases the prevalence of cirrhosis in hereditary hemochro-  matosis. Gastroenterology. 2002;122:281-289. [PMID: 11832443]   Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular  carcinoma. Gastroenterology. 2004;127(Suppl 1):S87-S96. [PMID:  15508108]   The metabolic breakdown products of alcohol are essential  in the progression of ALD. Ethanol is metabolized by alcohol  dehydrogenase in the hepatic cytosol to acetaldehyde, which  is subsequently metabolized in the mitochondria by  acetaldehyde dehydrogenase. There are various acetaldehyde  dehydrogenase isoforms. Seventy- five percent of Asians have  a deficiency in acetaldehyde dehydrogenase 2, which results  in accumulation of acetaldehyde, causing flushing. A similar  mechanism is seen with the drug disulfiram (Antabuse),  which inhibits acetaldehyde dehydrogenase, causing  acetaldehyde accumulation and resultant flushing, tachycar-  dia, nausea, vomiting, hypotension, and headache within  15-30 minutes of alcohol ingestion.   Ethanol may also be metabolized in minor hepatic path-  ways involving the microsomal enzyme oxidation system, via  CYP2E1, and the enzyme catalase. The stomach can metabo-  lize ethanol via gastric alcohol dehydrogenase. Women have  less gastric alcohol dehydrogenase than men, offering a pos-  sible explanation for the observed increased female suscepti-  bility to the effect of alcohol.   Although detailed mechanisms of ethanol-induced liver  injury are incompletely understood, recent scientific advances  have furthered our understanding of cellular and immuno-  logic mechanisms through the use of in vitro and in vivo  models.   Animal models of alcohol ingestion have demonstrated  susceptibility of the hepatic pericentral area to hypoxemia  due to competitive oxygen consumption by ethanol metab-  olism. Decreased intestinal permeability during alcohol  ingestion results in an increase in serum endotoxin  (lipopolysaccharide) levels, leading, in turn, to activation of  Kupffer cells, which secrete cytokines such as tumor necrosis  factor a (TNFa). It is believed that TNFa can induce cyto-  toxicity through caspase-dependent and -independent path-  ways, leading to increased mitochondrial permeability and  ultimately cell death. Both ethanol and decreased glutathione  levels can sensitize the liver to TNFa-induced cytotoxicity.   In alcoholic hepatitis, elevated interleukin (IL)-18 levels  result in neutrophil accumulation in the liver. Subsequently,  neutrophil release of reactive oxygen species results in hepa-  tocyte injury. Acute ethanol ingestion may also result in a  suppressed T-cell response, decreased monocyte function,  and increased levels of IL-1 and IL-6.   Ethanol metabolites, acetaldehyde and hydroxylethyl, may  potentially play a major role in alcoholic liver injury. These  metabolites bind to proteins to form adducts that result in  altered intracellular protein function, and these adducts may  also act as a neoantigen that can stimulate immune-mediated  injury. Autoantibodies to various structures of the liver, such  as liver membrane antigen, liver-specific protein, and  CYP450, can be found in patients with ALD.   Frezza M, di Padova C, Pozzato G, et al. High blood alcohol levels  in women. The role of decreased gastric alcohol dehydrogenase  activity and first-pass metabolism. N Engl J Med. 1990;322:  95-99. [PMID: 2248624]   Hoek IB, Pastorino JG. Cellular signaling mechanisms in alcohol-  induced liver damage. Semin Liver Dis. 2004;24:257-272.  [PMID: 15349804]   Thiele CM, Freeman TL, Klassen LW. Immunologic mechanisms  of alcoholic liver injury. Semin Liver Dis. 2004;24:273-287.  [PMID: 15349805]   In the early stages, patients with ALD exhibits subtle and often  no abnormal physical findings. It is usually not until develop-  ment of advanced liver disease that stigmata of chronic liver dis-  ease become apparent. Early ALD is usually discovered during  routine health examinations when liver enzyme levels are found  to be elevated. These usually reflect alcoholic hepatosteatosis.  Microvesicular and macrovesicular steatosis with inflammation  are seen in liver biopsy specimens. These histologic features of  ALD are indistinguishable from those of nonalcoholic fatty liver  disease. Steatosis usually resolves after discontinuation of alco-  hol use. Continuation of alcohol use will result in a higher risk  of progression of liver disease and cirrhosis.   In patients with acute alcoholic hepatitis, clinical manifes-  tations include fever, jaundice, hepatomegaly, and possible  hepatic decompensation with hepatic encephalopathy, variceal  bleeding, and ascites accumulation. Tender hepatomegaly may  be present, but abdominal pain is unusual. Occasionally, the  patient may be asymptomatic. Table 42-1 summarizes diag-  nostic features of ALD.   In patients with alcoholic hepatitis, the serum aspartate  aminotransferase (AST) to alanine aminotransferase (ALT)  ratio is greater than 2:1. AST and ALT levels are almost always  less than 500. The elevated AST to ALT ratio is due to defi-  ciency of pyridoxal-6-phosphate, which is required in the  ALT enzyme synthetic pathway. Furthermore, alcohol  metabolite-induced injury of hepatic mitochondria results  in AST isoenzyme release. Other laboratory findings include  red blood cell macrocytosis (mean corpuscular volume > 100)  and elevations of serum y-glutamyl transferase, alkaline  phosphatase, and bilirubin levels. Folate level is reduced in  alcoholic patients due to decreased intestinal absorption,  increased bone marrow requirement for folate in the pres-  ence of alcohol, and increased urinary loss. The magnitude of  leukocytosis reflects severity of liver injury.   Histologic features include Mallory bodies, giant mito-  chondria, hepatocyte necrosis, and neutrophil infiltration at  the perivenular area. Mallory bodies, which are also present  in other liver diseases, are condensations of cytokeratin com-  ponents in the hepatocyte cytoplasm and do not contribute  to liver injury. Up to 70% of patients with moderate to severe  alcoholic hepatitis already have cirrhosis identifiable on  biopsy examination at the time of diagnosis.   Radiographic imaging may show features suggestive of cirrho-  sis, such as a nodular liver surface, reversal of portal vein flow,  splenomegaly, and gallbladder wall edema. Characteristic find-  ings on ultrasound, computed tomography, and magnetic  resonance imaging are summarized in Table 42-1.    Palmar erythema  Spider angioma  Gynecomastia  Parotid enlargement  Dupuytren contracture  Impotence  Testicular atrophy  Decreased body hair  Peripheral muscle wasting    Enlarged or shrunken liver  Increased echogenicity  Nodular surface  Nodules (regenerating  or dysplastic)    Enlarged hilar periportal space  Enlarged or shrunken liver  Prominent intrahepatic fissure  Increased size of caudate lobe and   ALT, alanine aminotransferase; AST, aspartate aminotransferase;  CT, computed tomography; MCV, mean corpuscular volume; MRI,  magnetic resonance imaging; PT, prothrombin time; PTT, partial  thromboplastin time.   Liver biopsy is not mandatory for the diagnosis of ALD or  acute alcoholic hepatitis, but it may be helpful when the diag-  nosis is uncertain. The histology may help determine prog-  nosis and perhaps encourage alcohol cessation. In the setting  of severe thrombocytopenia or a hypercoagulation state,  transjugular liver biopsy is the procedure of choice. The need  for liver biopsy in this situation should be decided on an  individual basis, considering the risk of the procedure and  potential adverse effects of corticosteroid therapy.   Screening for alcohol abuse is an important part of a routine  history and physical examination. Several standard screening  questionnaires have been developed. The most commonly  used is the CAGE questionnaire. Nearly all alcoholic patients  will have two positive responses, and 50% will have positive  responses to all four questions listed below.   It must be emphasized that accurate assessment of alco-  hol use still requires obtaining a careful history from the  patient or family members. New laboratory tests have been  developed to screen for recent or chronic alcohol use, but  these are seldom used due to lack of commercial availabil-  ity. The carbohydrate-deficient tranferrin (CDT) test is  based on a decreased carbohydrate moiety to transferrin  caused by chronic alcohol use. However, CDT levels may be  affected by serum transferrin concentrations, hypertension,  primary biliary cirrhosis, liver malignancy, chronic viral  hepatitis, decompensated liver disease, female sex, and age.  The new turbimetric CDT assay appears to have fewer lim-  itations. Other experimental serologic tests for recent alco-  hol use include 5-hydroxytryptophol, ethyl glucuronide,  phosphatidyl ethanol, sialic acid level, (3-hexosaminidase,  mitochondrial AST levels, and alcohol metabolites such as  erythrocyte acetaldehyde and acetaldehyde adducts.   greater than 500 in alcoholic hepatitis. Careful review of the  patient's history may reveal risk factors suggestive of either  disease.   Patients with ALD may have elevated transferrin saturation  and ferritin levels similar to those seen in hemochromatosis.  In murine models, alcohol causes down-regulation of hep-  cidin expression in the liver and a subsequent increase in the  iron transporters ferroportin and DMT-1 in the duodenum.  Genetic testing may reveal the HFE gene, but this does not rule  out concurrent alcohol- related liver disease. When genetic  testing is equivocal, a hepatic iron concentration (HIC) greater  than 71 meg of iron per gram of dry liver weight and a hepatic  iron index greater than 1.9 (HIC divided by patient's age) may  help determine the amount of total body iron overload and  establish the diagnosis of hereditary hemochromatosis.   Concurrent intake of alcohol can lower the toxicity threshold  of acetaminophen, resulting in AST levels significantly  greater than 500 IU/L. A careful history of the amount of  alcohol and acetaminophen ingestion, as well as measure-  ments of the serum acetaminophen level, can help determine  therapeutic options, including need for liver transplantation  referral.   Complications of ALD are similar to those for non-alcohol-  related chronic liver disease. During severe acute alcoholic  hepatitis, the major causes of death are liver failure, gas-  trointestinal bleeding, hepatorenal syndrome, and sepsis.  Until the introduction of the Maddrey discriminant func-  tion (MDF), there was no method for predicting the severity  of alcoholic hepatitis. The MDF, which is calculated as 4.6 X  [patient's prothrombin time - control prothrombin time] +  total bilirubin (mg/dL), identifies patients with a high risk  for early mortality. An MDF of 32 or higher is associated with  spontaneous survival of 50-65%, whereas MDF below 32 is  associated with survival of approximately 90%.   McCullough AJ, O'Connor IF. Alcoholic liver disease: proposed  recommendations for the American College of Gastroenterology.  Am J Gastroenterol. 1998;93:2022-2036. [PMID: 9820369]   Niemela O. Biomarkers in alcoholism. Clin Chim Acta. 2007;377:  39-49. [PMID: 17045579]   Alcoholic hepatitis is indistinguishable by liver histology from  nonalcoholic steatohepatitis (NASH). However, the ALT is  usually twice that of AST in NASH, and the AST is rarely   Table 42-2 contrasts the efficacy of various medical therapies  that have been used in the treatment of ALD.   Reversal of liver disease and improvement in survival occur  with abstinence. With cessation of alcohol use, less than 20%  of patients will demonstrate progression of liver disease.  Five-year survival improves from 34% to 60% for those with  decompensated liver disease. Six months of sobriety, along  with treatment programs and support networks, is a good   Table 42-2. Efficacy of various medical therapies  for alcoholic liver disease.   predictor of long-term success. Patients with chronic HCV  infection should abstain from any alcohol intake, due to the  risk for rapid acceleration of liver disease.   Standard fluid, mineral, and vitamin replacement and with-  drawal precautions are mandatory for patients hospitalized  with decompensated liver cirrhosis. Enteral as well as tube  feeding has been found to be associated with decreased mor-  tality. Continued enteral nutrition support after hospitaliza-  tion also improves long-term morbidity. Dietary protein  should not be restricted in alcoholic hepatitis for fear of  hepatic encephalopathy. In the setting of hepatic encephalopa-  thy, branched-chain amino acids (BCAAs) maybe considered.  Patients with liver cirrhosis usually have protein malnutri-  tion with decreased BCAAs (leucine, isoleucine, and valine).  A decrease in BCAA has been associated with serum hypoal-  buminemia and elevated arterial ammonia levels. Recent for-  mulations have resolved the poor taste by incorporation of  BCAA into granules. Despite some small clinical studies sug-  gesting benefit in improving metabolite profile and hepatic  encephalopathy, there is still a lack of convincing evidence to  justify the use of this expensive supplement to significantly  improve morbidity and mortality. In patients with alcoholic  hepatitis or fulminant hepatic failure, BCAA has not been  found to influence short-term or long-term survival.   Charlton M. Branched-chain amino acid enriched supplements as  therapy for liver disease. J Nutr. 2006;136:295S-298S. [PMID:  1635102]   Thirteen randomized controlled trials have examined corti-  costeroid therapy in severe acute alcoholic hepatitis.  Although five studies have shown benefit in survival, mostly  in rural populations, the remaining studies have been equiv-  ocal. Significant improvement in liver function is evident at  7 days after initiation of therapy. Overall, corticosteroid  therapy is beneficial in improving 30- and 60-day mortality   only in patients with severe acute alcoholic hepatitis and an  MDF greater than 32, in the absence of acute gastrointestinal  bleeding, renal failure, acute infection, or pancreatitis. Two-  month survival with corticosteroid therapy is about 80%, but  up to 40% of patients still die in 6 months. The benefit of  corticosteroid therapy may be present up to 1 year.   A recent study demonstrated the use of the Lille model  (formula available online at http://www.lillemodel.com) in  attempting to identify poor outcome at 6 months of follow-up  in patients with MDF of 32 or higher treated with either pred-  nisolone (40 g/day orally) or methylprednisolone (32 mg/day  intravenously) for 28 days. Patients with a score greater than  0.45 using the Lille model had a mortality rate of 76% at  6 months. This study suggests that alternative therapies  should be considered in patients with scores above 0.45 after  1 week of treatment with steroids.   Prednisolone may have a theoretical advantage over pred-  nisone because it does not require hepatic metabolism for  the active component. It is given at a dose of 40 mg daily for  4 weeks, followed by a rapid 4-week taper. Although use of  corticosteroids in the treatment of ALD was recommended  in a 1998 American College of Gastroenterology guideline,  clinical use has been infrequent.   Maddrey WC, Boitnott JK, Bedine MS, et al. Corticosteroid ther-  apy of alcoholic hepatitis. Gastroenterology. 1978;75:193-199.  [PMID: 352788]   Mathurin P. Corticosteroids for alcoholic hepatitis — what's next?  J Hepatol. 2005;43:526-533. [PMID: 16026887]   TNF has been implicated in the pathogenesis of ALD, and  elevated levels are found in patients with alcoholic hepatitis.  Anti-TNF treatment prevents liver injury in a murine model  of ALD, and this therapy has also been studied in humans.   Pentoxyphylline, an inhibitor of TNF, at 400 mg orally  three times per day, was shown to decrease the risk of hepa-  torenal syndrome in patients whose MDF is greater than 32.  The 28-day mortality for the pentoxyphylline group was 24%,  compared with 46% for the placebo group. Survival benefit  was related to a reduction in mortality associated with the  hepatorenal syndrome. The decrease in serum TNFa levels  was not statistically significant when compared with placebo.   Treatment with anti-TNF monoclonal antibody (inflix-  imab, a chimeric mouse and human antibody that neutral-  izes soluble TNFa) and etanercept (a p75-soluble TNF  receptor Fc fusion protein) has yet to reveal survival benefit  in clinical trials for ALD, which are often inadequately sized  and include some patients suffering fatal complications.   Naveau S, Chollet-Martin S, Dharancy S, et al. Foie-Alcool group  of the Association Francaise pour l'Etude du Foie. A double-  blind randomized controlled trial of infliximab associated with  prednisolone in acute alcoholic hepatitis. Hepatology.  2004;39:1390-1397. [PMID: 15122768]   Based on the involvement of reactive oxygen species in the  pathways of ALD, pilot studies using antioxidants have been  performed. Vitamin E (1000 IU daily for 3 months) failed to  show a benefit despite improvement in serum levels of biliru-  bin and the prothrombin time.   In a small study, SAMe, a precursor to glutathione, at  1200 mg orally per day improved survival in patients with  alcoholic liver cirrhosis with Childs-Pugh class A or B.  However, this benefit was not substantiated in a Cochrane  Review. Colchicine was also determined to be ineffective in  alcoholic liver cirrhosis.   Polyenylphosphatidylcholine (PPC), given to 789 patients  with alcoholic liver fibrosis in a Veterans Administration  Cooperative Trial, benefited those who abstained from alco-  hol use but not those who continued a moderate amount of  alcohol consumption.   Because pericentral (zone 3) hepatocytes are relatively  oxygen poor and are sensitive to hypoxic injury caused by  alcohol and thyroid hormone, suppression of thyroid hor-  mone using propylthiouracil was attempted in a clinical trial.  Survival benefit was seen at 2 years when compared with  placebo but only in abstinent patients. However, these find-  ings have not been replicated in other trials.   The use of milk thistle seed has been used for 2000 years  in Europe for treatment of liver diseases. The active ingredi-  ent is believed to be silymarin, which is made of silybin, silid-  ianin, and silicristin. Silybin is believed to be the most active  compound. Silymarin is believed to enhance liver regenera-  tion and protect hepatocytes from toxicity, although the  mechanism is still unclear. However, clinical trials have yet to  demonstrate a clear benefit.   No benefit was seen using anabolic steroids for alcoholic  hepatitis or cirrhosis. Treatment with disulfiram, which  inhibits acetaldehyde dehydrogenase, is contraindicated in  patients with liver disease.   Therapies related to hepatic regeneration (insulin, glucagons,  and malotilate) and extracorporeal support (molecular  absorbent recirculating system) have been evaluated in clinical  trials, but the use of these agents remains experimental. Future  therapies may include antifibrotic agents, IL-10, and possibly  thalidomide.   Although in rare cases liver cirrhosis is reversible, the disease  process remains mostly irreversible. Liver transplantation  remains the only definitive therapy. Today, survival after liver   transplantation is similar for patients with ALD and non-  ALD. The requirements for transplant listing are the same as  those for other types of liver disease, except for a 6-month  sobriety prerequisite along with psychiatric evaluation and  rehabilitation assistance (ie, Alcoholics Anonymous).  Specific requirements vary among the transplant centers.  Relapse to alcohol use after transplant listing results in delist-  ing. Re-listing is possible in many institutions, but only after  3-6 months of sobriety.   There are limited data on transplant survival in patients  transplanted for acute alcoholic hepatitis, but it is believed to  be similar to that in nonacute ALD, non-ALD, and alcoholic  hepatitis with MDF less than 32.   Neuberger J, Schulz KH, Day C, et al. Transplantation for alcoholic  liver disease. / Hepatol. 2002;36:130-137. [PMID: 11804676].   The prognosis for patients with ALD depends on the liver  histology as well as cofactors, such as concomitant chronic  viral hepatitis. Among patients with alcoholic hepatitis, pro-  gression to liver cirrhosis occurs at 10-20% per year, and  70% will eventually develop cirrhosis. Despite cessation of  alcohol use, only 10% will have normalization of histology  and serum liver enzyme levels.   As previously noted, the MDF has been used to predict  short-term mortality (ie, MDF > 32 associated with sponta-  neous survival of 50-65% without corticosteroid therapy,  and MDF < 32 associated with spontaneous survival of  90%). The Model for End-Stage Liver Disease (MELD) score  has also been found to have similar predictive accuracy in 30-  day (MELD > 11) and 90-day (MELD > 21) mortality.   Liver cirrhosis develops in 6-14% of those who consume  more than 60-80 g of alcohol daily for men and more than  20 g daily for women. Even in those who drink more than  120 g daily, only 13.5% will suffer serious alcohol-related  liver injury. Nevertheless, alcohol-related mortality was the  third leading cause of death in 2003 in the United States.  Worldwide mortality is estimated to be 150,000 per year.   Dunn W, Jamil LH, Brown LS, et al. MELD accurately predicts  mortality in patients with alcoholic hepatitis. Hepatology.  2005;41:353-358. [PMID: 15660383].   Sheth M, Riggs M, Patel T. Utility of the Mayo End-Stage Liver  Disease (MELD) score in assessing prognosis of patients with  alcoholic hepatitis. BMC Gastroenterol. 2002;2:2. [PMID:  11835693]   Nonalcoholic fatty liver disease (NAFLD) is an overarch-  ing concept that includes simple steatosis and nonalco-  holic steatohepatitis (NASH).   NAFLD is commonly associated with the metabolic syn-  drome, obesity, diabetes, and hyperlipidemia; 80% of  patients with the metabolic syndrome have NAFLD.   Patients generally present without clinical symptoms  but with mild transaminase elevations; NAFLD is the  most common cause of increased serum transaminase  levels.   NAFLD is a clinical diagnosis after exclusion of other  causes of liver disease.   Ultrasound, computed tomography, and magnetic reso-  nance imaging are useful for the detection.   Nonalcoholic fatty liver disease (NAFLD) is characterized by  hepatic steatosis, the hepatocellular accumulation of triglyc-  erides in the absence of significant alcohol consumption.  Simple steatosis connotes fat accumulation in the absence of  inflammation in the liver. By contrast, nonalcoholic steato-  hepatitis (NASH) indicates the presence of inflammation  and fibrosis in association with hepatic steatosis. NAFLD is  sometimes used as an overarching term that includes simple  steatosis and NASH, but is also commonly employed to con-  note simple steatosis.   Whereas the histopathology of NAFLD and NASH is sim-  ilar to that of alcohol-related liver disease, the etiology is  quite distinct. An abundance of basic and clinical research  has demonstrated that the metabolic underpinnings of   NAFLD are rooted in insulin resistance. Indeed, NAFLD is  commonly associated with other manifestations of insulin  resistance including obesity, diabetes, and hyperlipidemia.  Although early studies suggested NAFLD to be a benign con-  dition, it is now apparent that NAFLD is a major cause of  liver-related morbidity and mortality.   The absence of signs and symptoms, combined with a lack of  sensitive and specific diagnostic tests, makes estimation of the  prevalence of NAFLD difficult. Elevated liver enzymes are not  sensitive for detecting NAFLD and there is no current con-  sensus that histopathology is a gold standard for diagnosis.  Although likely an underestimate for these reasons, the preva-  lence of NAFLD is considered to be in the range of 20% in the  United States and between 10% and 24% of the general pop-  ulation. By contrast, the prevalence of NASH is much lower,  and in the range of 2% to 3%. As a result, the prevalences of  NAFLD and NASH easily exceed chronic hepatitis C (HCV)  infection, which afflicts 1.8% of the U.S. population.   Population-based studies have revealed that NAFLD is  more common in men than women. It is more common in  Hispanics compared with whites and more common in  whites than blacks. It is assumed that the prevalence of  NAFLD will increase over time in parallel to the epidemic  of obesity and diabetes. Of particular concern is that  NAFLD is increasing in the pediatric population, with  prevalences estimated at around 3% of children and 20-50%  of obese children.   Browning ID, Szczepaniak LS, Dobbins R, et al. Prevalence of  hepatic steatosis in an urban population in the United States:  impact of ethnicity. Hepatology. 2004;40:1387-1395. [PMID:  15565570]   Ruhl CE, Everhart JE. Determinants of the association of over-  weight with elevated serum alanine aminotransferase activity in  the United States. Gastroenterology. 2003;124:71-79. [PMID:  12512031]   B. Association of NAFLD with the Metabolic  Syndrome, Obesity, Diabetes, and Hyperlipidemia   Insulin resistance represents the most important risk factor  for the development of NAFLD. Because insulin resistance is  also the hallmark of the metabolic syndrome, it is not sur-  prising that there is a close connection between NAFLD and  the metabolic syndrome. Indeed, steatosis may simply  characterize the hepatic manifestation of the metabolic  syndrome. The metabolic syndrome is generally defined as  the coexistence of three or more of the following findings:  (1) increased waist circumference, (2) hypertriglyc-  eridemia, (3) hypertension, (4) elevated fasting plasma  glucose, and (5) low high-density lipoprotein (HDL) choles-  terol level. Patients with metabolic syndrome have a 4- to  11 -fold higher risk of developing NAFLD, and the preva-  lence of metabolic syndrome in patients with NAFLD ranges  from 18% to 67%, depending on body weight. In NAFLD  patients with the metabolic syndrome, the risk of NASH is  elevated threefold.   There is also a close association of NAFLD with obesity.  The prevalence of obesity in patients with NAFLD is  reported to vary from 30% to 100%. In obese patients (body  mass index [BMI] > 30) the risk of NAFLD is elevated 4.6-  fold. Importantly, the frequency of NASH also varies in pro-  portion to weight. The prevalence of NASH is 3% of the lean  population, but rises to 19% in obesity and to nearly 50% in  morbidly obese individuals. Consistent with the close rela-  tionship of NAFLD with the metabolic syndrome, NAFLD is  more common in individuals with an abdominal concentra-  tion of fat, even at lower BMI.   The prevalence of NAFLD is high in the type 2 diabetic  population (50%), and the prevalence of type 2 diabetes in  NAFLD patients ranges from 10% to 75%. The prevalence of  NAFLD appears to increase as continuous function of fasting  plasma glucose. Importantly, NASH is disproportionately rep-  resented in type 2 diabetics, with significant fibrosis and cir-  rhosis present in approximately 20%. In hyperlipidemic  patients, the overall prevalence of fatty liver is 50%, with  hypertriglyceridemia and mixed dyslipidemia conferring a  fivefold risk of NAFLD. The prevalence of hyperlipidemia  associated with NAFLD varies from 20% to 90%. In keeping  with a strong link to the metabolic syndrome, low HDL cho-  lesterol levels are also commonly observed in patients with  NAFLD. Emerging evidence suggests that hypertension is  linked to NAFLD through its relationship to insulin resistance.   102:399-408. [PMID: 17311652]  Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome   Med. 2005;143:722-728. [PMID: 16287793]  Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty   Parekh S, Anania FA. Abnormal lipid and glucose metabolism in  obesity: implications for nonalcoholic fatty liver disease.  Gastroenterology. 2007;132:2191-2207. [PMID: 17498512]   Current concepts indicate that insulin resistance is the pri-  mary metabolic defect leading to NAFLD (Figure 43-1 ). This  leads to an influx into the liver of free fatty acids that are  liberated due to a failure of insulin to suppress hormone-  sensitive lipase in adipose tissue. In addition, elevated insulin  levels associated with insulin resistance promote continued  synthesis of triglycerides in the liver. These two sources of  triglycerides result in lipid-engorged hepatocytes (ie,  macrovesicular hepatic steatosis alone). The presence of  NAFLD appears to be a relatively innocuous occurrence, and  it does not appear that progressive liver injury necessarily  ensues. Although many patients with NAFLD have coexisting  type 2 diabetes, this is not uniformly true. Indeed, steatosis  and insulin resistance may be present in the absence of other  components of the metabolic syndrome.   A prevailing hypothesis suggests that NASH evolves as a  progression from NAFLD. In this regard, the presence of  NALFD represents a first "hit." According to this theory, NASH  develops due to a second hit whereby hepatocytes laden with  triglycerides are vulnerable to additional insult. Although   A Figure 43-1. Insulin resistance is the foundation hepatic  steatosis. Type 2 diabetes is a consequence of insulin resist-  ance, but obesity can also result in insulin resistance. As  indicated by the question mark, it is not known whether  there is progression of benign steatosis to nonalcoholic  steatohepatitis (NASH). NAFLD, nonalcoholic fatty liver dis-  ease. (Reproduced, with permission, from Parekh S, Anania  FA. Abnormal lipid and glucose metabolism in obesity: impli-  cations for nonalcoholic fatty liver disease. Gastroenterology.  2007:132:2191-2207.)   definitive data to support individual second hits are lacking,  two categories have been described and have gained some  acceptance. These are oxidative stress and specific cytokines  plus lipopolysaccharides. Free fatty acids and hyperinsuline-  mia potentiate lipid peroxidation and the release of hydroxy  free radicals, which directly injure hepatocytes by recruitment  of necroinflammatory mediators. Chronic liver injury sus-  tained over time will then lead to activation of hepatic stellate  cells, creating the potential for hepatic fibrosis.   At least in certain animal models of NASH, lipopolysac-  charides are released into the portal vein and are potent ago-  nists for tumor necrosis factor a (TNFa) production, with  the subsequent release of interleukins. Interestingly, the same  mechanisms appear to be pathogenic in alcoholic hepatitis  and produce quite similar histopathologic lesions. The com-  bination of oxidative stress and necroinflammatory  cytokines is associated with compromised mitochondrial  function, which impairs electron transport and depletes  adenosine triphosphate. This renders hepatocytes incapable  of handling the enhanced oxidative stress. In this setting, the  increased oxidative stress may overwhelm the intrinsic  antioxidant capacity of the liver.   The majority of patients with NAFLD, but a lesser frac-  tion of those with NASH, never progress to fibrosis, which  results from a complex series of molecular events in response  to all types of liver injury. However, in the setting of excess  oxidative stress, stellate cells in the liver may become acti-  vated, and this results in increased deposition of extracellu-  lar matrix. Excess extracellular matrix eventually disrupts  normal signal transduction between cells and the matrix on  which they rest, as well as the normal flow of nutrients and  blood in the liver sinusoids. The result is a wound-healing  response that can compromise liver function.   Leptin is a cytokine-like hormone that circulates at  increased concentrations in patients with the metabolic syn-  drome. Emerging evidence suggests that leptin may play an  important pathogenic role in the development and progress of  NASH. Leptin is synthesized by adipocytes, but also by acti-  vated hepatic stellate cells. Among its diverse activities, leptin  promotes liver fibrosis, apparently as part of a wound healing  response.   Adiponectin, also known as adipocyte complement-related  protein (ACRP30), is a hormone produced by omental fat.  Adiponectin stimulates glucose utilization and fatty acid oxi-  dation in the liver by activating adenosine monophosphate-  activated protein kinase (AMPK). Adiponectin is correlated  positively with insulin sensitivity and negatively with intra-  abdominal fat. Adiponectin gene expression and secretion  are decreased in obesity and are lower in patients with  insulin resistance, type 2 diabetes, and other conditions asso-  ciated with the metabolic syndrome than in age- and sex-  matched controls. Adiponectin levels measured in patients  with NAFLD or NASH were found to be lower than those in  age- and sex-matched controls and correlate negatively with  hepatic fat. Low levels of adiponectin expression may predis-  pose patients to the progression to NASH.   Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a  complication of insulin resistance. Med Clin North Am.  2007;91:1125-1149. [PMID: 17964913]   Most patients with NAFLD present because abnormal serum  transaminase levels are discovered incidentally or in panels  of laboratory tests sent for screening purposes. In general,  patients with NAFLD are asymptomatic. If present, symp-  toms tend to be nonspecific and constitutional but may  include right upper quadrant discomfort. On physical exam-  ination, associated findings are limited to hepatomegaly.   Because NAFLD is a diagnosis of exclusion, historical  information is important. Several risk factors that increase the  likelihood of NAFLD may be elicited in the history.  Importantly, alcohol use must be limited to qualify as NAFLD,  so that the maximum rate of alcohol intake is two standard  drinks per day (140 g ethanol/week) for men, and one stan-  dard drink per day (70 g ethanol/week) for women. Other  important risk factors for NAFLD include age, obesity, and  type 2 diabetes. A family history of diabetes, obesity, and liver  disease without a clear etiology provides important cues.   Modest elevations of alanine aminotransferase (ALT) and  aspartate aminotransferase (AST) are typically present at lev-  els in the range of two- to threefold the upper limit of normal.  However ALT and AST can range up to 10 times the upper  limit of normal in NAFLD. The AST/ ALT ratio is typically  less than 1.0, and this helps to distinguish NAFLD from alco-  holic liver disease (ALD). Because NAFLD is very common  in the general population, it is also important to exclude  other common and uncommon causes of elevated transami-  nase levels. These include viral hepatitis, autoimmune hepa-  titis, hemochromatosis, thyroid disease, drugs and, if  appropriate, Wilson disease and aj-antitrypsin deficiency. It  is often useful to obtain a fasting lipid profile and plasma  glucose concentration.   Imaging studies play key roles in the diagnosis of NAFLD.  The mainstay is ultrasonography, which reveals a diffuse  echogenic pattern in the setting of hepatic fat accumulation.  Ultrasound is also the least invasive imaging modality and is  relatively inexpensive. The sensitivity for ultrasound detec-  tion of NAFLD is in the range of 60-90%, with a specificity  around 90%. These numbers depend on the degree of fat  infiltration and will decline in mild cases of NAFLD. In the  setting of morbid obesity, sensitivity and specificity of ultra-  sound are also lessened due to body habitus. Computed  tomography is a reasonable but more costly imaging modal-  ity for detecting hepatic fatty infiltration, which appears as a   low radiographic attenuation of the liver when compared  with the attenuation of the spleen or paraspinal region. The  sensitivity of computed tomography for detecting NAFLD  approaches 90%. Magnetic resonance imaging allows for  quantitation of hepatic fat and is the most sensitive but also  the most expensive modality for detecting steatosis. These  radiographic techniques share the important limitations that  they cannot distinguish simple steatosis from NASH, nor can  they assess the stage of disease (ie, degree of inflammation)  or the presence of fibrosis.   The value of liver biopsy in the management of NAFLD is  controversial. Histologic features that can be appreciated in  NAFLD include hepatocellular steatosis and balloon degen-  eration, mixed inflammatory-cell infiltrates, necrosis, glyco-  gen nuclei, and Mallory hyaline. Liver biopsy can also assess  degree of fibrosis. An important limitation of liver biopsy is  that sampling error can be substantial, leading to both over-  estimation and underestimation of degree of severity.  Although liver biopsy is the only procedure that can distin-  guish between simple steatosis and NASH, its value in clini-  cal practice remains uncertain. NASH accounts for a very  small fraction of patients when compared with the high  prevalence of NAFLD in the population. Therefore, most  patients will have steatosis alone by biopsy, and this carries a  favorable prognosis. Moreover, there are no approved thera-  pies for NAFLD or NASH, so distinguishing between these  two entities would not likely influence management. On the  other hand, histopathology does provide prognostic infor-  mation and, importantly, can exclude coexisting conditions.  The latter consideration may become even more important  as the prevalences of obesity and diabetes increase in the  population. With progress in the area of surrogate markers  for inflammation and fibrosis, the decision to subject  patients to liver biopsy may be simplified.   Adams LA, Angulo P. Role of liver biopsy and serum markers of  liver fibrosis in non-alcoholic fatty liver disease. Clin Liver Dis.  2007;11:25-35. [PMID: 17544970]   Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score:  a noninvasive system that identifies liver fibrosis in patients  with NAFLD. Hepatology. 2007;45:846-854. [PMID: 17393509]   Although both the prevalence and understanding of NAFLD  have increased, therapies for this common condition remain  very limited. At present, there are no reliable evidence-based  treatments. Efforts to develop effective management strate-  gies, including improving insulin resistance and reducing  oxidant stress in the liver, are based on current understand-  ing of NAFLD pathogenesis. Current approaches include  both weight loss and pharmacotherapies.   Considering the strong association among obesity, NAFLD,  and type 2 diabetes, it is logical that improving insulin resist-  ance would represent the cornerstone of therapy for NAFLD.  Because rapid weight loss can induce or exacerbate NASH,  gradual weight loss constitutes the main objective. Gradual  weight loss can be achieved through therapeutic lifestyle mod-  ifications, pharmacologic treatment, and bariatric surgery.   supported by randomized controlled clinical trials, lifestyle  modifications are generally accepted as meritorious for the  treatment for NAFLD. Because weight loss through reduced  caloric intake and increased physical activity improves insulin  resistance, it is logical to think it would also lead to improve-  ments in NAFLD. When taken together, results from small tri-  als and case series indicate that sustained weight loss of  approximately 10% achieved by therapeutic lifestyle changes  is associated with improvements in serum aminotransferase  levels. Possibly due to limited time duration of study,  histopathologic improvements have not yet been demon-  strated. Nevertheless, a 2002 American Gastroenterology  Association position paper on NAFLD advocated weight loss  in the absence of randomized studies, citing the benefits of  weight loss on cardiovascular risk profile.   2. Pharmacologic weight reduction— Appreciating that  weight loss through therapeutic lifestyle modifications is not  always successful, pharmacologic options are frequently sought.  At present, two drugs, orlistat and sibutramine, are approved by  the U.S. Food and Drug Administration for weight loss.   Orlistat reduces the absorption of dietary triglycerides by  inhibiting gastric and pancreatic lipase. In randomized trials  compared with dietary changes alone, orlistat reduced  weight modestly over a 1-year period by 4-8 lbs. This was  accompanied by significant reductions in blood pressure and  plasma cholesterol, with improved glucose control. Orlistat  has been studied for the treatment of NAFLD in small case  series and pilot studies. Significant weight reductions  achieved using orlistat have been associated with improve-  ments in liver enzymes and hepatic fat on ultrasound.  Improvements in liver histology appear to require approxi-  mately 10% reductions in body weight. Limitations to the  use of orlistat include dyspepsia, bloating, diarrhea, and  steatorrhea; decreased absorption of fat-soluble vitamins; as  well as a requirement for three-times daily dosing.   Sibutramine is both a serotonergic and a noradrenergic  reuptake inhibitor, which promotes satiety. Sibutramine  achieves modest weight reductions in the range of 6-12 lbs at  1 year. Improvements in metabolic parameters include  reduced plasma insulin concentrations in type 2 diabetic  patients. When used for NAFLD, sibutramine performed  similarly to orlistat in promoting weight loss, reducing  transaminase elevations, and decreasing hepatic steatosis as  assessed by ultrasound. The safety profile of sibutramine has  proved favorable, with side effects that include dry mouth,   headache, insomnia, and constipation. There is also a mild  increase in diastolic blood pressure (+2 mm Hg) associated  with the administration of sibutramine. It is important to  note that none of these pharmacotherapies is FDA approved  for NAFLD and would be used as off-label if prescribed for  NAFLD or NASH.   Dixon JB, Bhathal PS, Hughes NR, et al. Nonalcoholic fatty liver  disease: improvement in liver histological analysis with weight  loss. Hepatology. 2004;39:1647-1654. [PMID: 15185306]   Harrison SA, Fincke C, Helinski D, et al. A pilot study of orlistat  treatment in obese, non-alcoholic steatohepatitis patients.  Aliment Pharmacol Ther. 2004;20:623-628. [PMID: 15352910]   Sabuncu T, Nazligul Y, Karaoglanoglu M, et al. The effects of sibu-  tramine and orlistat on the ultrasonographic findings, insulin  resistance and liver enzyme levels in obese patients with non-  alcoholic steatohepatitis. Rom ] Gastroenterol. 2003;12:189-192.  [PMID: 14502318]   Because insulin resistance is central to pathogenesis, atten-  tion has been focused on antidiabetic agents that reduce  insulin resistance as therapies for NAFLD and NASH.  Although metformin showed initial promise in laboratory  animals, results in human trials have not born this out. The  thiazolidinediones (TZDs), rosiglitazone and pioglitazone,  have met with more success. These drugs activate the nuclear  hormone receptor peroxisome proliferator-activated recep-  tor y (PPARy). A fundamental mechanism whereby PPARy  agonists work is to increase insulin sensitivity by enhancing  adiponectin production in subcutaneous and visceral fat.  TZDs have proven effective in the treatment of type 2 dia-  betes, although weight gain is a well-recognized side effect.  Early results suggest that TZDs are effective at improving  both transaminase levels and histopathology. Larger random-  ized controlled trials of longer duration are ongoing.   3. Bariatric surgery — Surgery to promote weight loss is  considered for obese patients who are unable to lose weight  by therapeutic lifestyle modifications. Current evidence sug-  gests that bariatric surgery is beneficial for many morbidly  obese patients with NAFLD. Bariatric surgery includes pro-  cedures that restrict caloric intake and those that promote  malabsorption of nutrients. For obese patients to qualify for  bariatric surgery, their BMI must exceed 40. Patients may  also be candidates if their BMI exceeds 35 and if they suffer  from a significant obesity-related disease.   Depending on the type of procedure, bariatric surgery  has achieved weight loss (defined as the percentage of the  pounds above ideal body weight) in the range of 48-70%,  with a mean of 61%. Postoperative mortalities ranged from  0.5% to 1.1%. Importantly, metabolic parameters were  markedly improved: type 2 diabetes and hypertension  resolved in 77% and 62% of patients, respectively, with  improvement of cholesterol and triglycerides in 70%.  Resolution of the metabolic syndrome has been reported in  96% of patients at 1 year following surgery. Bariatric surgery  may lower mortality rates compared with medically man-  aged patients by as much as 89%.   NAFLD largely improves in patients who undergo  bariatric surgery, with reduced steatosis, inflammation, and  fibrosis all reported in several studies that utilized different  surgical approaches. Whereas bariatric surgery appears to be  generally safe, underlying hepatic reserve must be considered  in the selection of patients in order to avoid hepatic failure in  patients with cirrhosis.   Klein S, Mittendorfer B, Eagon JC, et al. Gastric bypass surgery  improves metabolic and hepatic abnormalities associated with  nonalcoholic fatty liver disease. Gastroenterology. 2006; 130:  1564-1572. [PMID: 16697719]   Mathurin P, Gonzalez F, Kerdraon O, et al. The evolution of severe  steatosis after bariatric surgery is related to insulin resistance.  Gastroenterology. 2006;130:1617-1624. [PMID: 16697725]   Several medical therapies have sought to improve out-  comes by reducing oxidant stress in the liver, which  appears to play an important role in the pathogenesis of  NASH. Ursodeoxycholic acid (UDCA) is a hydrophilic bile  acid with hepatoprotective properties. UDCA has shown  little efficacy in the treatment of NAFLD or NASH.  Vitamin E (a-tocopherol) is an antioxidant that has been  utilized alone, but limited data on effectiveness preclude  recommending its use. A combination of UDCA and vita-  min E has shown promise in the treatment of NASH.  Betaine is a precursor of S-adenosyl methionine and a  metabolite of choline. It has shown promise for the treat-  ment of NASH in a limited study, which suggested that  larger clinical trials are warranted, especially considering  its limited side effect profile.   Based on a strong association between NAFLD and dyslipi-  demia, particularly elevated triglyceride and low HDL choles-  terol concentrations in plasma, the use of lipid-lowering  agents has been tested in pilot studies. In general, the use of  statins and fibrates has led to improvements in serum  transaminases. However, mixed results and limited  histopathologic data preclude recommending these therapies  for the treatment of NAFLD. Because patients with NAFLD  are at increased risk of adverse cardiovascular events, it is  important to point out that the use of statins does not appear  to carry any additional risk of hepatotoxicity in these patients.   Cohen DE, Anania FA, Chalasani N. National Lipid Association  Statin Safety Task Force Liver Expert Panel, assessment of statin  safety by hepatologists. Am J Cardiol. 2006;97:77C-81C. [PMID:  16581333]   A challenging aspect in the care of patients with NAFLD is  predicting natural history (Figure 43-2). At present, there are  no agreed upon biomarkers that permit the clinician to  determine prognosis accurately. Rather, histopathology is  required to predict which patients with NAFLD are likely to  progress to cirrhosis. Progression of liver disease is depend-  ent on the degree of damage that is present on a liver biopsy  specimen. Hepatocellular steatosis in the absence of inflam-  mation and fibrosis suggests the NAFLD will not progress  and that the clinical course will be benign. By contrast, the  presence of steatohepatitis and more advanced fibrosis por-  tend a worse prognosis, with increased likelihood of progres-  sion to cirrhosis. Whereas the overall prevalence of NAFLD  approximates 20% of the population, only about 10% of  these individuals (ie, 2-3% of adults in the United States)  have NASH. Approximately 20% of patients with NASH will  progress to cirrhosis.   Although the overall risk of cirrhosis due to NAFLD is  modest, certain groups are at particular risk. Important risk  factors for NASH include obesity, diabetes, and advanced   Up to 23% may progress to cirrhosis; 5% risk  of hepatocellular carcinoma   ▲ Figure 43-2. The natural history of nonalcoholic fatty  liver disease depends on histopathology. Nonalcoholic  fatty liver (NAFL) progresses very slowly, if at all, when  fat alone is present on liver biopsy. By contrast, the pres-  ence of nonalcoholic steatohepatitis (NASH) is associated  with a more accelerated progression to fibrosis.  (Reproduced, with permission, from Parekh S, Anania FA.  Abnormal lipid and glucose metabolism in obesity: implica-  tions for nonalcoholic fatty liver disease. Gastroenterology.  2007:132:2191-2207.)   age. In the setting of morbid obesity, steatosis is present in up  to 90% of patients, with NASH in up to 40% and advanced  fibrosis or cirrhosis in the range of 13-14%. The prevalence  of NAFLD in diabetic patients is approximately 50%, with  disproportionately high representation of NASH. Fibrosis or  cirrhosis is present in up to 20% of diabetic patients.  Severely obese patients with diabetes have hepatic steatosis  at rates of nearly 100%, of which 50% have NASH and 19%  have cirrhosis. Age is also a negative prognostic indicator,  with markedly increased rates of fibrosis (10-fold) in NASH  patients older than 45 years (40%) compared with only 4%  of NASH patients younger than 45 years.   Assessments of prognosis in NAFLD patients may also be  guided by the demographics of cryptogenic cirrhosis. Prior  to the appreciation of NAFLD as disease entity, the patho-  physiologic basis of cirrhosis in many patients was charac-  terized as cryptogenic. It is now considered likely that most  of these individuals suffered from NASH, which led to cir-  rhosis and liver biopsies that had progressed beyond the  point at which the etiology could be discerned. Indeed,  patients with cryptogenic cirrhosis are more likely to exhibit  features of the metabolic syndrome. In patients awaiting  liver transplantation due to cryptogenic cirrhosis, there was  increased prevalence of obesity and diabetes compared with  matched controls. NASH may occur even following liver  transplantation for cryptogenic cirrhosis, as has been  described in patients with the diagnosis of NASH that come  to transplantation.   Hepatocellular carcinoma is now recognized as a poten-  tial complication of NAFLD that progresses to NASH with  cirrhosis. This risk is compounded when diabetes is present,  suggesting the possibility that chronic hyperinsulinemia may  provide a carcinogenic stimulus.   Overall, up to 40% of patients with cirrhosis attributable to  NASH will die of liver-disease related complications or will  receive a liver transplant. Of all liver transplants, approxi-  mately 10% are attributable to NASH-induced cirrhosis.  Survival for patients with NAFLD is reduced compared with  the general population, with liver disease ranking as the third  leading cause of death when NAFLD is present, as compared  with the 13th leading cause of death in the general population.   Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver  Dis. 2007;11:191-207. [PMID: 17544979]   Fassio E, Alvarez E, Dominguez N, et al. Natural history of non-  alcoholic steatohepatitis: a longitudinal study of repeat liver  biopsies. Hepatology. 2004;40:820-826. [PMID: 15382171]   Burke A, Lucey MR. Non-alcoholic fatty liver disease, non-alcoholic  steatohepatitis and orthotopic liver transplantation. Am ]  Transplant. 2004;4:686-693. [PMID: 15084161]   ► Diagnosis can often be made during physical examina-  tion by checking for fetor hepaticus and asterixis, and  evaluating mental status using serial 7's and the "A"  deletion test.   ► Precipitating factors include gastrointestinal bleeding,  sepsis, azotemia, sedative or analgesic use, and non-  compliance with medications.   ► Consider other causes (eg, infections, intracranial bleed-  ing, metabolic abnormalities), in patients with known  cirrhosis and prior evidence of portal system  encephalopathy who present with altered mental status.   ► Mental changes in patients with subclinical or minimal  hepatic encephalopathy can impair automobile han-  dling skills; patients and their families should be  advised of this risk.   Hepatic encephalopathy, also referred to as portal systemic  encephalopathy (PSE), is a complex neuropsychiatry disor-  der resulting from chronic parenchymal liver disease with  liver cell failure, often in conjunction with portal systemic  shunts, either naturally occurring or surgically created.  However, PSE can occur in individual with normal liver tests  or with large spontaneous or surgically created shunts. PSE is  characterized by changes in personality, level of conscious-  ness, motor function, and cognition. Changes in cognition  may be quite subtle, as pointed out below.   Hepatic encephalopathy can be characterized as being  episodic or chronic resistant. The episodic form may be  spontaneous, precipitated, or recurrent; in the chronic resist-  ant form, patients have persistent mild stage 1-2 or severe  stage 2-4 disease. Patients can have minimal or subclinical  encephalopathy with no obvious abnormalities in cognition,   personality, or behavior but with abnormal psychometric  tests. Patients with advanced chronic liver disease and long-  standing portal systemic shunting may also develop evidence  of non-Wilsonian hepatolenticular degeneration.   Table 44-1 summarizes putative toxins that have been impli-  cated in the pathogenesis of hepatic encephalopathy.  Although the precise pathogenesis of hepatic encephalopathy  is unknown, accumulation of nitrogenous products derived  from the gut can have adverse effects on brain function and  is believed to play a major role.   Ammonia produced by the intestine may enter the sys-  temic circulation as a result of decreased hepatic function or  portal systemic shunts. Once in brain tissue, it can block chlo-  ride channels, modulate the Y- amm °butyric acid (GABA)  receptor, up-regulate peripheral benzodiazepine receptors,  and increase brain glutamine. Several lines of evidence sup-  port the concept that ammonia plays a key role in the patho-  genesis of hepatic encephalopathy. Ammonia levels are  elevated in portal blood, peripheral blood, and cerebrospinal  fluid (CSF). Factors precipitating PSE are often those that  result in an increased nitrogen load and elevated blood  ammonia levels. Treatment strategies are aimed at decreasing  gut production of ammonia as well as decreasing blood  ammonia levels. It should be pointed out, however, that there  is often not a direct correlation between peripheral blood and  ammonia levels and stages of hepatic encephalopathy.   Another putative gut-derived naturally occurring media-  tor is a benzodiazepine-like compound. Elevated benzodi-  azepine levels have been found in blood and CSF.  Benzodiazepine antagonists can ameliorate encephalopathy,  although this effect is often transient.   Other putative mediators include short-chain fatty  acids, mercaptans, aromatic amino acids, and manganese.  Manganese may deposit in basal ganglia and induce  extrapyramidal symptoms.    Produced by intestine; of bacterial origin  Blocks chloride channels  Modulates GABA receptor  Up-regulates peripheral benzodiazepine receptors  Increases brain glutamine  Elevated in portal blood  Elevated in peripheral blood and CSF  Precipitating factors often increase NH 3 /N 2 load  Treatment strategies aim to decrease blood  NH 3 levels    Synergistic effects with NH 3 causing obtundation  factulose decreases levels  tack of correlation between plasma levels and  grade of hepatic encephalopathy    Synergistic effects with NH 3  tack of correlation between plasma levels and grade  of hepatic encephalopathy    Patients with liver failure have increased aromatic  amino acids and decreased branched-chain  amino acids   Patients with PSE can have focal neurologic abnormali-  ties such as increased deep tendon reflexes, unilateral or  bilateral Babinski sign, and other findings such as ataxia,  dysarthria, tremor, or myopathy, usually with long-standing  chronic systemic shunting. These are infrequently encoun-  tered clinically.   2. Mental status changes— The stages of hepatic  encephalopathy are summarized in Table 44-2. Careful men-  tal status testing should be performed in all patients with  chronic parenchymal liver disease and cirrhosis of the liver.  One approach is to ask the patient to calculate serial 7's.  Patients can also be asked to write their name, and to draw a  square, a star, and a spiral. Another very useful bedside test is  the "A" deletion test in which the patient is asked to delete all  letter A's in a paragraph of newsprint in a 1- to 2-minute  period. The physician then calculates the number of A's that  were not deleted.   Table 44-3 summarizes the diagnostic approach to a patient  with suspected chronic PSE. The usual criteria include docu-  mented chronic parenchymal liver disease; evidence of por-  tal systemic shunts; mental status changes, which can be  subclinical; and clinical improvement with measures  directed at decreasing ammonia production by the gut. The  electroencephalogram (EEG) in patients with stage 2, 3, or  4 encephalopathy is usually abnormal and shows a decrease  in mean cycle frequency. It is not usually necessary to per-  form an EEG.   1. Precipitating factors for portal systemic  encephalopathy — In any patient with PSE it is important  to identify precipitating factors. Table 44-4 summarizes pre-  cipitating factors and the mechanisms by which they can trig-  ger an episode of PSE. A common problem is noncompliance   1. Physical findings— The diagnosis of PSE often can be  made on the basis of physical examination alone. Patients  may have a fetor hepaticus; this is a pungent breath odor  caused by the breakdown products of sulfur-containing  amino acids such as cysteine and methionine and consisting  of dimethyl sulfides methanethiol and ethanethiol. Asterixis  or a metabolic flapping tremor is characteristic but not  pathognomonic of PSE. It can also occur in patients with  chronic renal failure, pulmonary failure, and congestive heart  failure.    Abnormal psychometric tests but no obvious abnor-  malities in consciousness, personality, or behavior    Trivial lack of awareness, short attention span,  reversed day-night sleep cycle   with prescribed medications (eg, lactulose, because of side  effects such as diarrhea).   The high prevalence of spontaneous portal systemic  shunting in patients with persistent hepatic encephalopathy  is not generally appreciated. A recent case-controlled study  compared prevalence of spontaneous portal systemic shunts  in cirrhotic patients having recurrent or persistent PSE with  that in cirrhotic patients who did not have overt signs of PSE.  Fourteen patients with persistent or recurrent PSE were  matched with 14 patients without evidence of PSE. The PSE  evaluation included psychometric tests, EEG, mental status  examination, spiral computed tomography scan, arterial and  venous ammonia levels, and cerebral magnetic resonance  imaging. Ten of 14 patients (71%) with recurrent PSE were  found to have spontaneous shunts compared with 2 of 14  cirrhotic controls (14%). The patients with spontaneous  portal systemic shunts also had a much higher incidence of  abnormal results on psychometric tests (71% vs 7%). The  key finding is that large spontaneous shunts might often  sustain the chronicity of PSE; the presence of large  shunts should therefore be sought in patients with cirrhosis  and recurrent or persistent PSE. Examples are shown in  Figures 44-1A and B.   Riggio O, Efrati C, Catalano O, et al. High prevalence of sponta-  neous portal systemic shunts in persistent hepatic encephalopa-  thy: a case control study. Hepatology. 2005;42:1158-1165.  [PMID: 16250033]   important to assess all patients with established cirrhosis for  the presence of minimal or subclinical encephalopathy  (MHE). This is underscored by a recent study that assessed  whether the ability to drive a car is impaired in cirrhotic  patients with MHE. In a standardized on-road driving test  covering 22 miles in 90 minutes designed for patients with  brain impairment, a professional driving instructor blinded  to the patients' diagnosis and test results assessed their  driving performance. Four global driving categories (car  handling, adaptation to lanes, overtaking, awareness of  pedestrians and bike riders) and total score for driving per-  formance were rated using a 6-point scale. Of 274 consecu-  tive patients with liver cirrhosis, 48 fulfilled the medical and  driving criteria, 14 of them with and 34 without MHE.  Forty-nine individuals with gastrointestinal disease and nor-  mal liver findings served as controls. MHE was assessed by  the trail-making test, digital symbol test, and complex choice    ▲ Figure 44-1. A and B: Large splenic mesenteric-renal  vein shunts.   reaction test. The striking findings were that MHE resulted in  impaired car-handling skills and adaptation to traffic situa-  tions. Indeed, the instructor had to intervene in the driving  of 5 of the 14 patients with MHE to avoid an accident. It is  important to emphasize that the fitness to drive a car can  clearly be impaired in patients with cirrhosis and MHE, and  such patients and their families should be advised of this risk.  In patients with known cirrhosis and prior evidence of  PSE who present with altered mental status, causes other  than PSE may need to be considered. Patients with cirrhosis  and advanced liver disease can develop intracranial hemor-  rhages, infections (including meningitis), sepsis, and meta-  bolic abnormalities (including hypokalemia and  hypoglycemia). In addition, patients with alcohol-related cir-  rhosis could present with dual problems of alcoholic with-  drawal and PSE, which is a very difficult combination of  disorders to treat. The only benzodiazepine that can be used  for patients with both PSE and alcohol withdrawal is  lorazepam because the latter drug is excreted to a greater  extent in the kidneys than other benzodiazepines.   Wein C, Koch H, Popp B, et al. Minimal hepatic encephalopathy:  fitness to drive. Hepatology. 2004;39:739-745. [PMID: 14999692].   The management of PSE is summarized in Table 44-5. Initial  treatment includes identifying and treating any precipitating  factors. Attention to nutrition is also important. Rigid pro-  tein restriction is not appropriate. Patients need at least  25-35 kcal/kg and more than 200 g of carbohydrate to spare  protein metabolism.   term (60-80 g/day)  Patients need > 25-35 kcal/kg and > 200 g   nitrogen products in stool  Branched-chain amino acids are costly and data   • Decreases fecal pH by inhibiting production of  NH 3 by fecal flora   (1-2 g/day) for prolonged use  No evidence of potentiation of response to lactulose    A few small trials suggest 5.0 g twice daily is  beneficial; no large RCTs   Medical treatment for PSE is based largely on efforts to  control the generation of putative neuroactive toxins, most  notably ammonia. Lactulose, a synthetic disaccharide con-  sisting of galactose and fructose, is not metabolized by intes-  tinal disaccharidases and therefore reaches the colon, where  it is broken down by the fecal flora. The breakdown of lactu-  lose to short-chain fatty acids results in a decreased fecal pH  that inhibits ammonia production by urea splitting microor-  ganisms, and traps fecal ammonia, acidifying it to ammo-  nium chloride and resulting in an increase in fecal nitrogen  excretion. Interestingly, lactose can be used in lactase-  deficient patients with good results. The lactulose dose needs  to be titrated so the patient is experiencing two to three loose  bowel motions per day. If necessary, the fecal pH can be  checked; if lactulose is, in fact, resulting in acidification of  the stool, the fecal pH should be 5.0 and not the usual 7.0.  Patients on lactulose should be cautioned as to the ingestion  of foods that have a laxative effect (eg, excess simple sugars  containing fructose, which can augment diarrhea). If diar-  rhea persists, the lactulose dose should be reduced.   Antibiotics such as neomycin and metronidazole, which  can alter the fecal flora, are not recommended for routine use   in patients with PSE. Controlled studies have shown that  neomycin in doses as high as 6 g/day is not significantly bet-  ter than placebo in reducing ammonia levels. Rifaximin, a  poorly absorbed antibiotic, has been shown to be equivalent  to neomycin or paromomycin in the treatment of PSE and  appears to be better tolerated. In one study, rifaximin was  significantly better than nonabsorbable disaccharides in low-  ering blood ammonia concentration. The usual dosage is  200 mg three times daily.   Other treatments have included zinc, sodium benzoate,  and vancomycin, but no large randomized controlled trials  have been performed that would permit further assessment  of these treatment modalities.   Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cogni-  tive functions and health-related quality of life in patients with  cirrhosis who have minimal hepatic encephalopathy.  Hepatology. 2007;45:549-559. [PMID: 17326150]   Williams R, James OF, Warnes TW, et al. Evaluation of the efficacy  and safety of rifaximin in the treatment of hepatic encephalopa-  thy: A double-blind, randomized, dose-finding and multi-cen-  tre study. Eur J Gastroenterol Hepatol. 2000;12:203-2008.  [PMID: 10741936]   ► All patients with cirrhosis and ascites on admission  should undergo diagnostic paracentesis.   ► Diagnosis of spontaneous bacterial peritonitis (SBP) is  usually established by an elevated ascitic fluid polymor-  phonuclear leukocyte (PMN) count > 250 cells/mL  Whereas some patients with ascites have peritoneal fluid  PMN counts > 250 cells/mL, all patients with SBP do.   ► The most useful parameter for classifying ascites is the  serum-albumin peritoneal fluid albumin gradient (SAAG).   ► With 98% accuracy a SAAG value > 1.1 g/dL is consis-  tent with ascites secondary to portal hypertension.   ► SAAG values < 1.1 g/dL can occur in ascites due to  infection, inflammation, or neoplasm.   The major causes of ascites are listed in Table 45-1. In North  America and Europe, 90% of the cases of ascites are due to  cirrhosis, malignancy, and congestive heart failure. In Europe  and other countries tuberculous peritonitis is not uncom-  mon. Ascites is a cardinal manifestation of decompensated  cirrhosis of the liver. Approximately 50% of patients with cir-  rhosis will develop ascites within 10 years. The development  of ascites in patients with cirrhosis provides important prog-  nostic information as up to 50% of such patients will die  within 5 years.   Five major factors are involved in the pathogenesis of cir-  rhotogenic ascites: portal hypertension, hypoalbuminemia,   Portal hypertension is universally present in patients with  ascites secondary to cirrhosis of the liver. Two major mecha-  nisms contribute to the development of portal hypertension:  (1) distortion of the hepatic vascular architecture caused by  reduction in the intrahepatic arterial bed as a result of fibro-  sis and nodule formation, and (2) increased production of  vasodilatory substances, most importantly nitric oxide  synthase.   Hypoalbuminemia results from decreased albumin syn-  thesis that, in turn, is secondary to impaired hepatocellular  synthetic function. It should be emphasized that there is no  critical level of serum albumin at which ascites formation  takes place. In one large series of cirrhotic patients with  ascites, serum albumin levels ranged from 2.3 to 3.8 g%.   Increased sodium retention appears to be related primarily  to abnormalities of proximal tubular function, and increased  proximal tubular reabsorption of sodium. The latter occurs  due to increased aldosterone secretion in response to changes  in effective circulating blood volume. Activation of the renin-  angiotensin-aldosterone system contributes to abnormal  sodium retention.   It has long been appreciated that cirrhotic patients have  an impaired ability to excrete a water load. A major factor in  the abnormal water retention is abnormal delivery of sodium  in the distal tubule with a consequent inability to generate  free water. This is augmented by increased vasopressin secre-  tion (antidiuretic hormone [ADH]) in response to a  decreased effective circulating blood volume.   Table 45-2 lists key hormone alterations in cirrhotogenic  ascites. In decompensated cirrhosis, serum levels of renin, aldos-  terone, ADH, and norepinephrine are all increased. In patients  who respond to diuretic therapy, there is normalization of these   levels. However, in patients with refractory ascites, despite  expansion of intravascular volume, serum renin, ADH, aldos-  terone, and norepinephrine remain inappropriately elevated.   Circulatory dysfunction is important in cirrhotogenic  ascites. Initially, plasma volume, cardiac output, and heart rate  increase because the splanchnic circulation behaves function-  ally as a large arteriovenous fistula. With progression of liver  disease, portal pressure increases further, as does splanchnic  vasodilation. There is increased sodium retention and ascites  formation. The renin-angiotensin-aldosterone system and  sympathetic nervous system become activated in parallel with  intense reduction in urinary sodium excretion to values of   less than 10 mEq/24 h. Increased secretion of ADH occurs at  later stages, which explains why hyponatremia is a later event in  decompensated cirrhosis.   Table 45-3 contrasts changes in mean arterial pressure,  plasma volume, cardiac index, plasma renin level, and norep-  inephrine level in cirrhotic patients with and without hepa-  torenal syndrome with values in healthy individuals. In  patients with cirrhosis, plasma volume is increased 50%  above normal; additionally, the cardiac index is increased as  are plasma renin and norepinephrine levels. In patients with  hepatorenal syndrome, similar changes persist despite  intravascular volume repletion.   The key factors leading to the development of cirrhotogenic  ascites are summarized below. Cirrhosis gives rise to portal  hypertension, which results in splanchnic arterial vasodilation.  Splanchnic arterial vasodilation then leads to a decreased effec-  tive arterial circulating blood volume and activation of the  renin-angiotensin and sympathetic nervous systems, which, in  turn, results in renal vasoconstriction and sodium retention.  The splanchnic vasodilation causes increased capillary pressure  and permeability that contribute to ascites. Splanchnic arterial  vasodilation also results in increased venous return and  increased cardiac output as it acts as an arteriovenous fistula.  This, in turn, can result in pulmonary vasodilation and infre-  quently results in the hepatopulmonary syndrome.   Although circulating blood volume is increased in cirrho-  togenic ascites, the effective blood volume (ie, the fraction  present within the intrathoracic circulation that is able to  influence baroreceptors, the sympathetic nervous system, and  the renin-angiotensin system [ADH] ) is actually reduced. This  mechanism promotes sodium and water retention. A large  volume of blood enters and leaves the portal venous system  rapidly due to decreased splanchnic resistance. The hyperdy-  namic circulation leads to vasodilation of the pulmonary cir-  culation to allow increased venous return. Increased venous  return and arterial hypertension of the systemic circulation  lead to increased blood volume, tachycardia, and increased  cardiac output, as summarized in Table 45-3.   Table 45-3. Comparative findings in cirrhotic ascites with and without  hepatorenal syndrome.   Reproduced, with permission, from Arroyo V, Navasa M. Ascites and spontaneous bacte-  rial peritonitis. In: Schiff ER (editor). Schiff's Diseases of the Liver, 10th ed. Lippincott  Williams & Wilkins, 2007:542.   Patients with decompensated cirrhosis and ascites often  exhibit peripheral stigmata of chronic parenchymal liver dis-  ease. These include spider angiomata, palmar erythema,  gynecomastia, parotid enlargement, Dupuytren contracture,  paucity of axillary and pubic hair, and testicular atrophy,  with the north-south testicular diameter being less than 3 cm.  The triad of findings of parotid enlargement, gynecomastia,  and Dupuytren contracture usually implies an alcoholic etiol-  ogy leading to the patient's cirrhosis. The triad of findings of  hepatomegaly, ascites, and increased venous collateral of the  anterior abdominal walls always indicates the presence of  portal hypertension.   A diagnosis of cirrhosis can be made on the basis of two  physical findings and two laboratory findings. The two phys-  ical findings are asterixis and ascites; the two laboratory find-  ings are hypoalbuminemia (serum albumin levels < 2.8 g/dL)  and prolongation of the prothrombin time (international  normalized ratio [INR] > 1.6). The presence of "classical"  physical findings (eg, bulging flanks, shifting dullness, and a  fluid wave), however, are only about 60-70% accurate in  predicting the presence of ascites.   Patients with ascites should always be evaluated with diag-  nostic paracentesis to determine the cause. The most useful  parameter to classify ascites is the serum-ascites peritoneal  fluid albumin gradient (SAAG), which is calculated by sub-  tracting the ascites albumin concentration from the serum  value. With approximately 98% accuracy a difference of  greater than 1.1 g/dL is consistent with ascites secondary to  portal hypertension. Conversely, gradients less than 1.1 g/dL   are associated with ascites due to inflammation, infection,  malignancy, and disorders such as pancreatogenous ascites,  tuberculous peritonitis with ascites, and malignancy. Thus,  the underlying cause can be readily differentiated.   In patients with cirrhotogenic ascites, measurement of  urine electrolytes is important. If ascites is due to cirrhosis,  urine sodium excretion will be low (eg, frequently < 10  mEq/24 h) and potassium excretion increased to a value of  greater than 30 mEq/24 h. This can also be used as a baseline  measurement to determine the effectiveness of diuretic ther-  apy as distal-acting agents such as spironolactone frequently  cause a reversal of the abnormal sodium-potassium ratio. In  addition, if patients with cirrhotogenic ascites are found to  have high urine sodium excretion it would suggest another  complicating factor such as malignancy.   In patients with ascites it is important to obtain an ultrasound  examination not only to confirm the diagnosis of ascites, but  also to assess the patency of the portal and hepatic veins. This is  because portal or hepatic vein thrombosis can occur in the set-  ting of cirrhosis of the liver. Ultrasonography can detect as little  as 100 mL of fluid in the peritoneal cavity whereas on physical  examination ascitic fluid volume usually needs to exceed 2 L to  be evident. Patients with cirrhosis can develop umbilical hernias  when long-standing ascites is present. Such hernias can actually  increase in size if ascites persists uncontrolled.   Because sodium retention is a major factor in the develop-  ment of ascites, a key goal of therapy is the attainment of a  negative sodium balance. To achieve this, sodium output   must exceed sodium input. Accordingly, appropriate sodium  restriction is very important in the treatment of ascites and  in maintenance of cirrhotic patients who are ascites free. In  older studies severe salt restriction (22 mmol/24 h) was asso-  ciated with a shorter time for resolution of ascites. More  recent studies, however, have shown that there is little differ-  ence in diuretic responsiveness with sodium intakes of 50-90  mmol/day. Most authorities now believe that restriction of  salt to 4 g/day is reasonable. This translates into a sodium  intake of 2000 mg/day (or 20 mEq/day). Patients need  detailed dietary instructions as to hidden sources of sodium  in their diet.   Bed rest often facilitates diuresis because upright posture  activates sodium-retaining systems and impairs renal profu-  sion and sodium excretion. It is usually not necessary to  restrict water intake unless the serum sodium is less than  125 mEq/dL. Water restriction should not be prescribed if  fever, sepsis, bleeding, or azotemia are present.   Diuretics are usually required in patients with ascites, espe-  cially those with moderate to severe ascites who retain sodium  avidly and for whom sodium restriction will not be sufficient  to retain negative sodium balance. In such cases, it is reasonable  to begin with a potassium-sparing diuretic such as spironolac-  tone initially, given as a dosage of 100-200 mg/day. This can be  increased cautiously to 400 mg/day, but one needs to watch for  hyperkalemia and metabolic acidosis. The spironolactone dose  need not be split and can be given once daily. An effect of  spironolactone can be noted as early as 3 days after initiation of  treatment. Effective therapy with spironolactone usually results  in a reversal of the potassium-sodium abnormalities in the  urine, with an increase of sodium excretion to more than  10 mEq/day and a decrease in potassium secretion. Other  potassium-sparing diuretics include amiloride and tri-  amterene. It is often necessary to add a loop diuretic, such as  furosemide or torsemide. Furosemide is given initially at a  dosage of 20-40 mg/day and can be increased to 160 mg.  Torsemide is administered at a dosage of 10-20 mg/day and  can be increased to 80 mg/day.   Patients with cirrhosis, ascites, and edema initially loose  excess fluid from their extremities rather than abdominal  fluid. It is reasonable to expect patients with cirrhosis and  ascites who have been placed on a diuretic regimen and  sodium restriction to lose between 0.5 and 1.0 kg/day. Losses  greater than this can occur, especially with brisk diuresis, and  may precipitate an episode of oliguric hepatic failure.   B. Managing Patients Who Do Not Respond  to Salt and Fluid Restriction and Diuretics   The patient's fluid intake and output and urine sodium excre-  tion should be monitored closely, especially if urine sodium  excretion exceeds 50 mEq/day. This would suggest that the  patient is obtaining salt-laden foods in the hospital or surrep-  titiously ingesting large amounts of fluid (eg, > 2500 mL/24 h).  In this regard, patients may also be ingesting large amounts of  ice, as one pint of ice intake yields over 800 mL of fluid.   Five percent of cirrhotic patients with ascites develop refrac-  tory ascites. The following criteria are usually employed to  establish diagnosis of refractory ascites. Failure to respond to  spironolactone, 200-400 mg/day; furosemide, 160 mg/day;  restriction of dietary sodium intake to 10 mEq/day; and  water restriction to 1.5-2.0 L/day, accompanied by urinary  sodium excretion of less than 10 mEq/24 h.   If the patient is stable, the following options are available.  Patients may respond to a large volume paracentesis.  Furosemide given intravenously as a bolus results in higher  initial concentrations of the drug being delivered to the renal  tubule, but this may not be sustained. Accordingly, a  furosemide drip infusing 20 mg/h can be effective in restor-  ing diuretic responsiveness by achieving sustained elevated  furosemide levels in the renal medulla.   In this setting, it is reasonable to consider adding either  metolazone or hydrochlorothiazide, which act on the  ascending limb, or administering furosemide at 20 mg/h  intravenously.   2. Large-volume paracentesis— It has been demonstrated  that large-volume paracentesis (ie, removal of 4-6 L/day of  fluid) with albumin replacement of 8.0 g/L of ascitic fluid  removed is an effective approach in patients with refractory  ascites. The rationale for including albumin is that studies  have indicated that side effects occurred in 30% of patients  undergoing large-volume paracentesis alone compared with  16% in patients who had paracentesis plus albumin replace-  ment. Large-volume paracentesis is more effective than  diuretics in eliminating ascites and shortening the duration  of hospitalization. However, it should be emphasized that  this procedure does not eliminate the need for continued  diuretic therapy. Contraindications to large-volume paracen-  tesis include sepsis, spontaneous bacterial peritonitis (SBP),  recent gastrointestinal bleeding, azotemia, marked wasting,  and low blood pressure.   3. Transjugular intrahepatic portosystemic shunting  (TIPS) — The North American Study for the Treatment of  Refractory Ascites was a multicenter randomized trial in  which 109 patients with refractory ascites were randomized  to medical therapy (sodium restriction, diuretics, and total  paracentesis) or medical therapy plus TIPS. Although TIPS  was found to be effective in 60% of patients with refractory  ascites, and more effective than paracentesis, there was no  difference in survival and, importantly, an increased risk of  portal systemic encephalopathy and shunt problems in TIPS  patients. The study authors concluded that although TIPS  plus medical therapy appeared to be superior to medical  therapy alone for the control of ascites, it did not improve  survival, decrease hospitalization rates, or improve overall  quality of life.   In contrast, a recent meta-analysis compared the effect of  TIPS and large-volume paracentesis in cirrhotic patients  with refractory ascites using data from four randomized   Table 45-4. Outcomes in patients undergoing  transjugular intrahepatic portosystemic shunt (TIPS)  for refractory ascites.   a Factors associated with transplant-free survival: age, serum biliru-  bin, and serum Na*.   Data from Salerno F, Camma C, Enea M, et al. Transjugular intra-  hepatic portosystemic shunt for refractory ascites: a meta-analysis  of individual patient data. Gastroenterology. 2007;133:825-834.   precipitation of portal systemic encephalopathy. The latter  may occur if diuretic-induced hypokalemia develops.   A recent report has helped to define the natural history of  cirrhotic ascites and identify prognostic factors (Table 45-5).  Two hundred sixty-three cirrhotic patients were followed for  a mean of 40.9 months after onset of their first episode of  ascites. The average Child-Pugh score was 8.3 and the aver-  age Model for End-Stage Liver Disease (MELD) score was  10.6. The incidence of dilutional hyponatremia was 28%.  Refractory ascites occurred in 11.4%, and hepatorenal syn-  drome in 7.6%. Overall probability of survival at 1 year was  85%, and at 5 years was 56.5%. The 1-year probability of sur-  vival was 26.5% after dilutional hyponatremia, 31.6% after  refractory ascites, and 38.5% after type 2 hepatorenal syn-  drome. The authors concluded that survival of cirrhotic  patients with a first episode of ascites is relatively high and is  minimally influenced by age, Child-Pugh score, and develop-  ment of dilutional hyponatremia.   controlled trials of 305 patients (149 allocated to TIPS, and  156 to paracentesis). Cumulative probabilities of transplant-  free survival and of hepatic encephalopathy were estimated  using Kaplan-Meyer methodology. The data are shown in  Table 45-4. This meta-analysis provides evidence showing  that TIPS significantly improves transplant-free survival.   Significant complications can result from inappropriate use  of diuretic therapy. One should be very careful about admin-  istering diuretics to cirrhotic patients hospitalized with  marked wasting, cachexia, and tense ascites, as oliguric  hepatic failure can be triggered in these fragile patients.  Other complications of diuretic therapy include hypona-  tremia, hypokalemia, metabolic acidosis, muscle cramps, and   Planas R, Montoliu S, Balleste B, et al. Natural history of patients  hospitalized for management of cirrhotic ascites. Clin  Gastroenterol Hepatol. 2006;4:1385-1394. [PMID: 17081806]   Sanyal AJ, Genning C, Reddy KR, et al. The North American Study  for the treatment of Refractory Ascites. Gastroenterology.  2003;124:634-641. [PMID: 12612902]   Salerno F, Camma C, Enea M, et al. Transjugular intrahepatic por-  tosystemic shunt for refractory ascites: a meta-analysis of indi-  vidual patient data. Gastroenterology. 2007;133:825-834.  [PMID: 17678653]   SBP is defined as infection of a previously sterile ascitic fluid  without an apparent intra-abdominal source of infection.  The prevalence of SBP in unselected hospitalized patients   Table 45-5. Outomes and survival in patients hospitalized for management  of cirrhotic ascites.   Probability of survival at 1 year for all patients was 85%; at 5 years, 56.5%.  b For type 1 hepatorenal syndrome, survival was 7 days.   Data from Planas R, Montoliu S, Balleste B, et al. Natural history of patients hospitalized for manage-  ment of cirrhotic ascites. Clin Gastroenterol Hepatol. 2006;4:1385-1394. [PMID: 17081806]   with cirrhosis and ascites ranges between 10% and 30%.  The diagnosis is established by an elevated ascitic fluid  polymorphonuclear leukocyte (PMN) count greater than  250 cells/mL. Ascitic fluid cultures are positive in 50-90% of  cases, depending on the volume of the ascitic fluid culture.  Inoculations of 10-20 mL of fluid into 100-mL culture bot-  tles led to a much higher culture positivity rate versus inocu-  lum of 1-3 mL (ie, 3% vs 53%).   The vast majority of patients with SBP have portal hyper-  tension, ascitic fluid albumin concentration less than 1 g/dL,  and SAAG greater than 1.1 g/dL. Neutrocytic ascites is  defined as ascitic fluid containing greater than 250  PMNs/mL. Many patients with neutrocytic ascites, especially  outpatients, have neutrocytic ascites without culture positiv-  ity or evidence of SBP. In contrast, all patients with SBP have  ascitic fluid PMN counts greater than 250 cells/mL and usu-  ally other findings as well. In one survey, the prevalence of  SBP in a population of 427 cirrhotic outpatients (defined as  PMN > 250 cells/mL) was 3.5%. Of the 15 patients with neu-  trocytic ascites, 6 were culture positive (1.4%) and 9 were  culture negative (2.1%). Eight other patients (1.9%) had bac-  terial ascites. The organisms cultured from the ascitic fluid in  asymptomatic patients with culture-positive neutrocytic  ascites and bacterial ascites were predominantly gram-positive  organisms. The conclusion drawn was that SBP in outpa-  tients with cirrhotic ascites is much less frequent, occurs in  patients with less advanced liver disease, and may have a bet-  ter outcome than its counterpart in hospitalized patients.   It is important to recognize the distinction between SBP  and primary bacterial peritonitis (PBP). PBP develops in  patients who have ascites and a perforated viscus, as in rup-  tured diverticulitis and appendicitis. Peritoneal fluid in PBP  in cirrhotic patients with ascites who have developed a per-  forated viscus has the following characteristics: protein  concentration greater than 1.0 g/dL and frequently greater  than 3.0 g/dL; glucose concentration less than 50 g/dL;  marked elevation of ascitic fluid white blood cell count  often greater than 5000 PMNs/mL; ascitic fluid lactic dehy-  drogenase (LDH) content threefold greater than serum  LDH. If PBP is suspected, computed tomography or mag-  netic resonance imaging should be performed to exclude a  perforated viscus, and antibiotic coverage broadened  against anaerobic organisms.   Bacterial translocation, which is the passage of viable  microorganisms in the intestinal lumen to the mesenteric  lymph nodes and other extraintestinal locations, is a major  factor in the development of SBP. These are most commonly  gram-negative organisms from the intestinal flora. Such  translocation is facilitated by depression of the hepatic retic-  uloendothelial system as well as altered intestinal permeabil-  ity due to edema and hypervolemia. The hepatic  reticuloendothelial system is depressed in patients with cir-  rhosis. It is recognized that 90% of reticuloendothelial cell   function resides in Kupffer cells and endothelial and sinu-  soidal cells. Intrahepatic shunting with portal hypertension  results in decreased contact of microorganisms with reticu-  loendothelial cells. In addition, there is decreased phagocytic  activity. Additional factors include decreased activity in  ascitic fluid and decreased compliment (fibronectin), and  this correlates directly with total protein level in the ascitic  fluid. As previously noted, the ascitic fluid protein in SBP is  characteristically less than 1.0 g/dL. Neutrophil dysfunction  also results in decreased chemotaxis and decreased phago-  cytic and killing capacity.   Clinical features of SBP are summarized in Table 45-6. It  should be emphasized that SBP can occur in patients who  are only minimally symptomatic and that abdominal pain  is present in only about half the patients with SBP. Certain  laboratory findings also predict the first episode of SBP  (Table 45-7).   Although SBP can occur in patients with asymptomatic cir-  rhotic ascites, the diagnosis should be suspected in all hospi-  talized cirrhotic patients with ascites, especially if abdominal  pain and tenderness are present. The diagnosis should also be  suspected if fever, leukocytosis, signs of sepsis, worsening  renal function, worsening of encephalopathy, and a recent  gastrointestinal bleed have occurred. In particular, cirrhotic  patients admitted with variceal bleeding and ascites have a   ■"Clinical presentation can vary from minimally symptomatic or  asymptomatic to severe abdominal pain and fever.  b Signs and symptoms in 489 patients with SBP.  Data from McHutchinsonJG, Runyon BA. Spontaneous bacterial peri-  tonitis. In: Surawicz CM, Owen, RL (editors). Gastrointestinal and  Hepatic Infections. WB Saunders, 1994:17.   Table 45-7. Predictors of a first episode of  spontaneous bacterial peritonitis (SBP).   40% chance of developing SBP. Accordingly, all cirrhotic  patients with recent gastrointestinal bleeding should be  administered antibiotic prophylaxis to prevent SBP.   A diagnostic paracentesis should be performed in all patients  with cirrhosis and ascites who are admitted to the hospital,  even if the admission is for other reasons. Evidence that the  diagnosis of SBP is correct and that antibiotic treatment is  appropriate can be obtained by doing a repeat paracentesis  within 48 hours after initiation of therapy. In patients who  are responding to treatment, a decrease in PMNs of at least  50% should be evident after 48 hours of treatment. If the  ascites neutrophil count is greater than 250 cells/mL antibi-  otic therapy should be initiated, especially if any of the clini-  cal features outlined earlier are present. Most cases of SBP are  due to gut bacteria such as E coli and Klebsiella, with occa-  sional streptococcal and, infrequently, staphylococcal infec-  tions. In these cases, broad-spectrum therapy is warranted.   Current guidelines call for the use of a third-generation  cephalosporin such as cefotaxime or ceftazidime, given at a  dosage of 2 g/8 h. Other third-generation cephalosporins,  such as ceftizoxime or ceftriaxone, are also suitable antibi-  otics. The cephalosporins have been shown to be as effective  as, if not more effective than, combinations of ampicillin and  an aminoglycoside.   Antibiotic therapy usually can be discontinued after 5 days.  The use of intravenous albumin in the treatment of SBP is  supported by randomized controlled trials that have shown   that antibiotics and intravenous albumin given at a dosage of  1.5 g/kg at the time of diagnosis and then 1.0 g/kg at day 3  reduces the incidence of renal impairment and improves  hospital survival compared with antibiotics given alone.   Predictors of resolution and survival in SBP include  young age, absence of acidemia and renal impairment, peak  serum bilirubin levels of 5 mg% or less, and community-  rather than hospital-acquired SBP. The 1-year survival rate is  approximately 40%.   Patients who have recovered from an episode of SBP are  at a high risk of recurrence. Long-term prophylaxis with nor-  floxacin or trimethoprim-sulfamethoxazole is effective in  preventing SBP recurrence.   Patients with cirrhosis who develop recurrent SBP in the  face of norfloxacin and prophylactic therapy can be treated  with cefotaxime plus metronidazole. As previously noted,  patients with cirrhosis and gastrointestinal bleeding are pre-  disposed to develop bacterial infections. Approximately 20%  of these patients are already infected upon admission and an  additional 50% will develop the infection during hospitaliza-  tion. For these patients, a short-term, 7-day course of antibi-  otic prophylaxis is appropriate.   It is well established that norfloxacin is highly effective in  preventing recurrent SBP in cirrhosis. A recent study by  Fernandez and colleagues demonstrated that primary pro-  phylaxis with norfloxacin not only reduces the incidence of  SBP, but also, importantly, delays the development of hepa-  torenal syndrome and improves survival. Sixty-eight patients  who met the inclusion criteria were randomized to receive  either norfloxacin (400 mg/day) or placebo. The results are  outlined in Chapter 46, which discusses hepatorenal syn-  drome (see Table 46-2). Primary prophylaxis of SBP with  norfloxacin was effective by causing selective intestinal  decontamination and reducing bacterial translocation.   Evans LT, Kim WR, Poterucha JI, et al. Spontaneous bacterial peri-  tonitis in asymptomatic patients with cirrhotic ascites.  Hepatology. 2003;37:897-901. [PMID: 12668984]   Fernandez J, Navasa M, Planas R, et al. Primary prophylaxis of  spontaneous bacterial peritonitis delays hepatorenal syndrome  and improves survival in cirrhosis. Gastroenterology. 2007;33:  818-824. [PMID: 17854593]   Runyon BA. Ascites and spontaneous bacterial peritonitis. In:  Feldman M, Friedman LS, Brandt LJ (editors). Sleisenger and  Fordtran's Gastrointestinal and Liver Disease, 8th ed, vol 2.  Saunders Elsevier, 2006;1935-1964.   Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on  renal impairment and mortality in patients with cirrhosis and  spontaneous bacterial peritonitis. N Engl J Med. 1999;341:  403-409. [PMID: 10532325]   ► Type 1 hepatorenal syndrome— rapid and progressive  impairment of renal function defined by doubling of the  initial serum creatinine level to > 2.5 mg/dL or 50%  reduction of the initial 24-hour creatinine clearance to  < 20 mL/min in less than 2 weeks.   ► Type 2 hepatorenal syndrome— impairment in renal  function leading to serum creatinine level > 1.5 mg/dL  that does not meet the criteria for type 1.   ► Frequent precipitants include gastrointestinal bleeding,  sepsis, spontaneous bacterial peritonitis, aggressive  diuresis and paracentesis, nonsteroidal anti-inflammatory  drugs (NSAIDs), and intravenous contrast agents.   ► Intravenous albumin, 1.5 g/kg, should be administered  at the time of diagnosis of hepatorenal syndrome.   Hepatorenal syndrome is characterized by functional kidney  failure in patients with end-stage liver disease. It results in  intense renal vasoconstriction without any other identifiable  kidney pathology. Clinical features of hepatorenal syndrome  include oliguria, dilutional hyponatremia, progressive azotemia,  and hypotension. Frequent precipitants include gastroin-  testinal bleeding, sepsis, aggressive diuresis, and paracentesis.  However, many patients develop hepatorenal syndrome as a  consequence of chronic end-stage liver disease without any  identifiable precipitating factors.   Hepatorenal syndrome develops in 5% of patients with  chronic liver disease who present with upper gastrointesti-  nal bleeding, 30% of patients admitted with spontaneous  bacterial peritonitis, 10% of patients with ascites treated with  total paracentesis, and 25% of patients with severe alcoholic   hepatitis. The probability of hepatorenal syndrome developing  in a patient with cirrhosis and new onset of ascites is 7-10%.  The 5-year probability of hepatorenal syndrome developing in  a patient with cirrhosis and recurrent ascites is 40%.   1 . Type 1 hepatorenal syndrome— Type 1 is characterized  by rapid and progressive impairment of renal function  defined by a doubling the initial serum creatinine to a level  higher than 2.5 mg/dL or a 50% reduction of the initial 24-  hour creatinine clearance to a level lower than 20 mL/min in  less than 2 weeks.   2. Type 2 hepatorenal syndrome— Type 2 is defined as  impairment in renal function (serum creatinine > 1.5 mg/dL)  that does not meet the criteria for type 1. Prerenal failure is a  preischemic state and may lead to ischemic tubular necrosis.   Arroyo V, Gines P, Gerbes A, et al. Definition and diagnostic crite-  ria of refractory ascites and hepatorenal syndrome in cirrhosis.  International Ascites Club. Hepatology. 1996;23:164-176.  [PMID: 8550036]   In patients with cirrhosis and ascites there is activation of the  renin-angiotensin and sympathetic nervous systems, result-  ing in elevated levels of renin, aldosterone, and norepineph-  rine. If cirrhotic patients undergo diuresis successfully, the  levels of renin, aldosterone, norepinephrine, and antidiuretic  hormone all decrease. However, in patients with end-stage  liver disease complicated by hepatorenal syndrome, levels of  renin, aldosterone, antidiuretic hormone, and norepineph-  rine are raised and remain persistently elevated despite vig-  orous attempts at volume expansion. This consequence  occurs in part because of decreased systemic vascular resist-  ance and splanchnic arteriolar vasodilation. The splanchnic  vasodilation results from increased nitric oxide synthesis.  The combination of decreased systemic vascular resistance   and arterial underfilling leads to the stimulation of systemic  vasoconstrictors which, in turn, causes renal vasoconstriction.  In the early stages of cirrhosis, increased systemic and local  vasodilators may act to preserve renal function. The vasodila-  tors include prostacyclin, prostaglandin E 2 , nitric oxide, atrial  natriuretic peptide, and the kallikrein-kinin system.  Vasoconstrictors include angiotensin II, norepinephrine, neu-  ropeptide Y, endothelin-1, adenosine, thromboxane A 2 , cys-  teinyl leukotrienes, and F 2 -isoprostanes. With the development  of hepatorenal syndrome, there is decreased production of  local vasodilators and increased production of vasoconstric-  tors. The net result is intense renal vasoconstriction affecting  primarily the renal cortex. NSAIDS, and aspirin, by virtue of  their inhibition of prostaglandin synthesis, may actually inter-  fere with the production of local vasodilators in the kidney and  can trigger or precipitate an episode of hepatorenal syndrome  in cirrhotic patients with marginal renal function.   Planas R, Montoliu S, Balleste B, et al. Natural history of patients  hospitalized for management of cirrhotic ascites. Clin  Gastroenterol Hepatol. 2006;4:1385-1394. [PMID: 17081806]   The major and minor criteria for diagnosis of hepatore-  nal syndrome are summarized in Table 46-1. Hepatorenal  syndrome is characterized by oliguria (< 500 mL/24 h), an   1. Chronic or acute hepatic disease with advanced hepatic failure and  portal hypertension   2. Low glomerular filtration rate indicated by serum creatinine  > 1.5 mg/dL or 24-h creatinine clearance < 40 mL/min   3. No shock, ongoing bacterial infection, sepsis, spontaneous bacterial  peritonitis, renal fluid losses (diuretics), ongoing breathing problems,  or treatment for toxic drugs (NSAIDs, ASA, aminoglycosides)   4. No improvement in renal function (ie, decreased serum creatinine to  values < 1.5 ml/dL) after diuretic withdrawal and expansion of  plasma volume with 1.5 L of plasma expander   5. Proteinuria < 500 mg for 24 h, and normal renal ultrasound (ie, no  evidence of obstructive uropathy or parenchymal renal disease)   Reproduced, with permission, from Arroyo V, Gines P, Gerbes AL, et al.   unremarkable urinary sediment, a low rate of sodium secre-  tion (< 10 mEq/L), a low urine output in the absence of  diuretics, and a progressive rise of plasma creatinine.   The onset of renal failure is typically insidious but can be  precipitated by acute insults such as gastrointestinal bleed-  ing, sepsis, spontaneous peritonitis, and overly rapid diure-  sis, especially in patients who have marked ascites but no  peripheral edema. Although diuretics can cause azotemia  and appear to trigger an episode of hepatorenal syndrome,  the syndrome usually progresses even after diuretics have  been discontinued and expansion has occurred with infusion  of plasma expanders.   The differential diagnosis of hepatorenal syndrome includes  acute tubular necrosis and other forms of renal disease such  as glomerulonephritis and vasculitis. Patients with cirrhosis  and ascites may develop acute tubular necrosis after a course  of aminoglycoside therapy, the administration of a radiocon-  trast agent, or an episode of sepsis or bleeding. A fractional  excretion of sodium above 2% and granular and epithelial  cell casts in the urine sediment point to a diagnosis of acute  tubular necrosis. Early in the course of hepatorenal syn-  drome, fractional excretion of sodium is usually below 1%  and the urinary sediment is benign. It has been suggested  that persistent hepatorenal syndrome with survival between  2-4 weeks or longer can result in sufficiently persistent severe  renal ischemia and acute tubular necrosis, and the resultant  changes in the fractional excretion of sodium.   It is important to recognize incipient hepatorenal syndrome  and take preventive measures. Hepatorenal syndrome devel-  ops in patients with systemic bacterial infections (ie, sponta-  neous bacterial peritonitis or severe alcoholic hepatitis, or  both), and it is important to provide prophylactic treatment  to guard against its development. This includes the adminis-  tration of intravenous albumin (1.5 g/kg) at the time of diag-  nosis of spontaneous bacterial peritonitis or sepsis, and  another dose of albumin (1.0 g/kg) after 48 hours of antibi-  otic treatment. Improvement in underlying liver disease has  been documented in patients with hepatorenal syndrome  and severe alcoholic hepatitis who have received pentoxi-  fylline (400 mg three times daily for 28 days).   It is well established that norfloxacin is highly effective in  preventing recurrent spontaneous bacterial peritonitis in  cirrhosis. A recent study by Fernandez and colleagues  demonstrated that primary prophylaxis with norfloxacin  not only reduces the incidence of spontaneous bacterial peri-  tonitis, but, importantly, also delays the development of  hepatorenal syndrome and improves survival. Sixty-eight   Table 46-2. Effectiveness of norfloxacin in preventing  spontaneous bacterial peritonitis (SBP). a   a Patients were randomized to receive norfloxacin (400 mg/day) or  placebo. Main end points of the trial were 3-month and 1-year  probability of survival. Secondary end points were 1-year probabil-  ity of developing SBP and hepatorenal syndrome.  Data from Fernandez J, Navasa M, Planas R, et al. Primary prophy-  laxis of spontaneous bacterial peritonitis delays hepatorenal syn-  drome and improves survival in cirrhosis. Gastroenterology.  2007:33:818-824.   patients who met the inclusion criteria were randomized to  receive either norfloxacin (400 mg/day) or placebo. The  results are shown in Table 46-2. Note the decreased proba-  bility of spontaneous bacterial peritonitis at 1 year, decreased  incidence of hepatorenal syndrome, and survival in nor-  floxacin recipients compared with patients receiving placebo.   Fernandez J, Navasa M, Planas R, et al. Primary prophylaxis of  spontaneous bacterial peritonitis delays hepatorenal syndrome  and improves survival in cirrhosis. Gastroenterology. 2007;33:  818-824. [PMID: 17854593]   Accumulating data suggest that combination therapy with  midodrine and octreotide may be effective and safe. The  rationale for such therapy is that midodrine is a systemic  vasoconstrictor and addresses the question of inappropriate  vasodilation, and octreotide is an inhibitor of endogenous  vasodilators. The use of terlipressin, a vasopressin, has also  been studied.   Some general considerations with regard to the use of  midodrine and octreotide follow. These drugs should be  used for at least 7-14 days because the improvement in renal  function usually occurs slowly. Therapy should be aimed at  reducing the serum creatinine level to below 1.5 mg/dl (130  u,mol/L). The effective doses of these drugs have varied in  several studies. The recommended dosage for midodrine is  usually 7.5 mg subcutaneously three times daily, and for  octreotide, 200 meg subcutaneously three times daily.   Terlipressin dosage is 1.0 mg intravenously every 6 hours  and is doubled on day 4 if serum creatinine has not decreased  30% from baseline.   The concomitant administration of albumin (1.5 g/kg on  the first day, followed by 20-40 g/day) as a plasma expander  appears to be necessary for the vasoconstrictor drugs to have  a beneficial effect. The recurrence of hepatorenal syndrome  after discontinuation of therapy in patients whose serum cre-  atinine level normalizes is uncommon.   In one study of 13 patients with hepatorenal syndrome  reported by Wong and colleagues, five patients were given  midodrine (7.5-12.5 mg three times daily) and octreotide  (100-200 meg subcutaneously three times daily). The dose of  midodrine was increased until a mean arterial pressure of at  least 15 mm Hg was achieved.   Esrailian and colleagues compared the survival of  patients with hepatorenal syndrome who received octreotide  and midodrine treatment with a concurrent control group of  hepatorenal syndrome patients who did not receive this  treatment. Of the 81 patients, 60 were treated with  octreotide plus midodrine, and 21 were controls. Mortality  was significantly lower in the treatment group (43%) than  in the controls (71%) (P < 0.05). Furthermore, 24 study  patients (40%) had a sustained reduction of serum creati-  nine compared with only 2 controls (10%). This retrospec-  tive strongly suggests that octreotide plus midodrine  treatment may improve 30-day survival. As the authors  emphasize, a randomized controlled trial is needed to eval-  uate this treatment modality.   Two recent studies have demonstrated that terlipressin is  an effective treatment to improve renal function in type 1  hepatorenal syndrome. Sanyal and colleagues studied 112  patients with type 1 hepatorenal syndrome, as defined by a  doubling of serum creatinine to greater than 2.5 mg/dL in  less than 2 weeks despite plasma volume expansion. Patients  were randomized to receive either terlipressin (1 mg intra-  venously every 6 hours) plus albumin (100 g on day 1 and 25 g  daily until end of treatment) or placebo plus albumin. The  terlipressin dose was doubled on day 4 if serum creatinine  had not decreased 30% from baseline. Treatment was contin-  ued until day 14 unless treatment success, death, dialysis, or  transplantation occurred. Treatment success was defined by a  decrease in serum creatinine to 1.5 mg/dL or less for at least  48 hours without dialysis, death, or relapse of hepatorenal  syndrome. Treatment success at day 14 was noted in 14 of 56  terlipressin recipients (25%) versus 7 of 56 placebo recipients  (12.5%). However, 6-month survival was only marginally  better in the terlipressin recipients compared with those who  received placebo (42.9% vs 37.5%, respectively).   Martin-Llahi and colleagues studied 46 patients with  type 1 hepatorenal syndrome. Improvement in renal function  occurred in 10 of 23 patients (43.5%) who received terli-  pressin plus albumin versus 2 of 23 patients (8.7%) who  received albumin alone. Survival at 3 months was only mar-  ginally better in the terlipressin recipients compared with the  placebo-treated group (27% vs 19%, respectively).   Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatore-  nal syndrome with administration of midodrine and octreotide.  Hepatology. 1999;29:1690-1697. [PMID: 10347109]   Esrailian E, Pantangco ER, Kyulo NL, et al. Octreotide/Midodrine  therapy significantly improves renal function and 30-day sur-  vival in patients with type 1 hepatorenal syndrome. Dig Dis Sci.  2007;52:742-748. [PMID: 17235705]   Martin-Llahi M, Pepin MN, Guevara M, et al. Terlipressin and  albumin vs albumin in patients with cirrhosis and hepatorenal  syndrome: a randomized study. Gastroenterology. 2008;134:  1352-1359. [PMID: 18471512]   Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with  cirrhosis and type 1 hepatorenal syndrome: A retrospective  multicenter study. Gastroenterology. 2002;122:923-930. [PMID:  11910344]   Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospec-  tive, double-blind, placebo-controlled trial of terlipressin for type 1  hepatorenal syndrome. Gastroenterology. 2008;134:1360-1368.  [PMID: 8471513]   Wong and colleagues studied efficacy of TIPS as a treatment  for type 1 hepatorenal syndrome in ascitic cirrhotic patients  following improvement in systemic hemodynamics with a  combination of midodrine, octreotide, and albumin. In this  study, 14 ascitic cirrhotic patients with type 1 hepatorenal  syndrome received medical therapy until their serum creati-  nine decreased to less than 1.5 mg/dL for at least 3 days fol-  lowed by TIPS if there were no contraindications. Patients  were assessed at 1 week and at 1, 3, 6, and 12 months post-  TIPS with serial measurements. All patients received oral  midodrine (2.5 mg/dL), intravenous octreotide (25 mcg/h),  and intravenous albumin (50 g/day). The medical therapy   with midodrine and octreotide led to improvement in 10 of  the 14 patients as evidenced by a fall in serum creatinine  from 2.6 mg/dL to 0.84 mg/dL post-medical treatment. The  authors concluded that TIPS was an effective treatment for  type 1 hepatorenal syndrome in patients with cirrhosis and  ascites, following improvement of renal function with com-  bination treatment of midodrine, octreotide, and albumin.   There is scattered additional information on the use of  TIPS in patients who fulfill the criteria of hepatorenal syn-  drome. In two reports, one describing 16 such patients and  another describing 7 patients, improvement in serum creati-  nine was noted over a 16-week period. However most of the  patients died within 6 weeks or 6 months of the procedure.   Brensing KA, Textor I, Strunk H, et al. Transjugular intrahepatic  portosystemic stent-shunt for hepatorenal syndrome. Lancet.  1997;349:697-698. [PMID: 9078203]   Guevara M, Gines P, Bandi JC, et al. Transjugular intrahepatic por-  tosystemic shunt for hepatorenal syndrome: effects on renal  function and vasoactive systems. Hepatology. 1998;28:416-422.  [PMID: 9696006]   Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin,  and TIPS in selected patients with cirrhosis and type 1 hepatore-  nal syndrome. Hepatology. 2004;40:55-64. [PMID: 15239086]   Patients with hepatorenal syndrome can be treated with dial-  ysis; this is most frequently done when a patient is waiting for  liver transplantation. Although evidence suggests that  improvement in liver function may result, most patients with  hepatorenal syndrome who undergo dialysis do not survive  in the absence of liver transplantation.   ► Nonselective (3-blockers are the first-line treatment for pri-  mary prophylaxis of variceal hemorrhage in patients with  medium to large esophageal and high-risk small varices.   ► Endoscopic variceal ligation is an alternative to pharma-  cologic therapy for appropriate candidates.   ► Management of acute variceal hemorrhage includes  resuscitation, antibiotic prophylaxis, use of vasoactive  agents, and endoscopic treatment with band ligation.   ► Balloon tamponade can be used as a bridge to trans-  jugular intrahepatic portosystemic shunt (TIPS) or surgi-  cal shunt therapy.   ► Hepatic venous pressure gradient (HVPG) measure-  ments have prognostic and therapeutic value.   ► TIPS, surgical shunt procedures, or liver transplantation are  the treatment options for patients who do not respond to  medical therapy.   ► Gastric varices contiguous with esophageal varices can  be treated as esophageal varices; those below the gas-  troesophageal junction are best treated with endo-  scopic injection of glue.   ► TIPS is the preferred rescue procedure for uncontrolled  variceal bleeding.   ► Chronic bleeding from portal hypertensive gastropathy  is treated with (3-blockers or TIPS based on the severity  of hemorrhage.   Chronic liver disease and cirrhosis are the 12th leading causes  of mortality in the United States. Portal hypertension and its  consequences are progressively debilitating complications of   cirrhosis (Table 47-1). Variceal hemorrhage, spontaneous  bacterial peritonitis, and the hepatorenal syndrome are  chiefly responsible for the high morbidity and mortality rates  in patients with cirrhosis.   Esophageal varices develop at a rate of 5-8% per year in  patients with cirrhosis and portal hypertension, and up to  80% of patients with cirrhosis will eventually develop this  complication. Variceal hemorrhage occurs in 25-35% of  patients with cirrhosis and large esophagogastric varices. The  majority of bleeding episodes occur within the first year of  diagnosis of cirrhosis. Bleeding from esophageal varices is  associated with 15-20% early mortality and accounts for one  third of all deaths. If no long-term therapy is instituted after  control of acute hemorrhage, 60-70% of patients will expe-  rience recurrent variceal hemorrhage. Most of these episodes  occur within 6 months of the index bleed.   Portal hypertension develops as a result of two main factors:  (1) an increase in intrahepatic resistance, and (2) an increase  in portal blood flow. In cirrhosis, the interplay between the  increase in portal blood flow and the increase in hepatic and  portocollateral vascular resistance leads to a cycle of worsen-  ing portal hypertension. Systemic vasodilation occurs with  the increased release of neurohormonal vasodilators (eg,  nitric oxide, glucagon, tumor necrosis factor, prostaglandins,  and other cytokines) and results in a hyperdynamic circula-  tory system. This is further complicated by angiogenesis,  which increases splanchnic blood flow. The increased resist-  ance occurs, in part, from sinusoidal encroachment, collagen  deposition, vascular tree pruning, and nodular regeneration.  These elements, together with the overexpression of endoge-  nous vasoconstrictors (eg, endothelins and leukotrienes) and  the underproduction of endogenous vasodilators (primarily  nitric oxide), are responsible for the increase in intrahepatic  and portocollateral resistance, leading to the development of  ascites or hydrothorax, or both, and the formation of varices  and portal hypertensive gastropathy (PHG). The goal of therapy   Reproduced, with permission, from Wolf AT, Grace ND. Portal hypertension. In: Bayles TM, Diehl, AM (editors).  Advanced Therapy in Gastroenterology and Liver Disease. BC Decker, 2005:675.   is to interrupt the process by decreasing portal venous blood  flow and intrahepatic and portocollateral resistance.   Patients with cirrhosis have symptoms that are nonspecific for  the presence of portal hypertension. Physical findings in cir-  rhosis that might suggest the presence of portal hypertension  include muscle wasting, spider angiomata, jaundice, ascites,  abdominal collateral vessels, and an altered mental status.   Laboratory findings include hyperbilirubinemia, hypoalbu-  minemia, thrombocytopenia, and a prolonged prothrombin  time. Other abnormalities that may coexist include anemia,  elevated creatinine level, and hyponatremia. Although the  presence of these abnormalities may indicate the presence of  portal hypertension, these values often remain normal in  patients with compensated or early cirrhosis.   Radiographic studies that strongly suggest cirrhosis include a  small, nodular liver, ascites, splenomegaly, intra-abdominal   varices, or portal and hepatic vein thrombosis; however, no  test is considered a diagnostic gold standard. The current  best test for diagnosing cirrhosis is liver biopsy.   1. Abdominal ultrasound— Abdominal ultrasound find-  ings supporting a diagnosis of cirrhosis include a nodular liver,  with increased echogenicity. In patients with more advanced  cirrhosis and portal hypertension, findings of ascites,  splenomegaly and intra-abdominal varices may be detected.  Unfortunately, ultrasonography is limited by inter-operator  variability, with a diagnostic accuracy of 85-91%. The addition  of portal and hepatic vein flow Doppler images enables the  assessment of hemodynamic changes that occur with cirrhosis.  The reversal of portal vein flow occurs with increased hepatic  resistance. This resistance results in the diversion of flow from  the portal vein through portosystemic collaterals. This mecha-  nism has been shown to be present in patients with advanced  portal hypertension. Inter-observer variability, patient posi-  tion, phase of respiration, cardiac output, and timing of meals  limit the accuracy of Doppler ultrasound.   2. Computed tomography scan and magnetic resonance  imaging — These imaging studies are limited in their abil-  ity to detect changes associated with early cirrhosis but  can accurately demonstrate later changes in liver architec-  ture, ascites, and varices. Computed tomography angiography   3. Fibroscan — Transient elastography, known as Fibroscan,  is a technique that uses pulse-echo ultrasound to measure  liver stiffness as a way of detecting fibrosis. This method of  measuring fibrosis is reported to have a low inter-observer  variability and correlates well with the severity of fibrosis and  the presence of portal hypertension.   Castera L, Vergniol J, Foucher J, et al. Prospective comparison of  transient elastography, Fibrotest, APRI, and liver biopsy for the  assessment of fibrosis in chronic hepatitis C. Gastroenterology.  2005;128:343-350. [PMID: 15685546]   Ziol M, Handra-Luca A, Kettaneh A, et al. Non-invasive assess-  ment of liver fibrosis by measurement of stiffness in patients  with chronic hepatitis C. Hepatology. 2005;41:48-54. [PMID:  15690481]   Current practice guidelines recommend endoscopic screen-  ing for the presence of esophageal varices in all patients with  cirrhosis. If varices are not present, screening endoscopy  should be repeated within 2-3 years or sooner if there is evi-  dence of hepatic decompensation. Several studies have  recently attempted to identify noninvasive predictors of  esophageal varices. A low platelet count has been associated  with the presence of varices, although the discriminating  threshold for the presence of varices ranges between 68,000  and 160,000/mm 2 . A recent study found that patients with  esophageal varices had a lower mean platelet count and a  greater rate of reduction of platelets over time compared  with those who did not have varices. However, several  patients with cirrhosis developed varices despite having a  normal (> 150,000) platelet count. Other noninvasive find-  ings, such as splenomegaly, enlarged portal vein diameter  greater than 13 mm on ultrasound imaging, and advanced  Child-Pugh class, have not been reproducible predictors of  esophageal varices. The predictive accuracy of suggested  noninvasive markers remains low, and no markers are cur-  rently recommended for clinical practice.   A promising predictor of esophageal varices is the platelet  count/spleen diameter ratio as measured by abdominal ultra-  sound. In patients with compensated cirrhosis, the higher the  ratio, the less likely it is that a patient will have varices.   Wireless capsule endoscopy has been compared with con-  ventional upper endoscopy in identifying and characterizing  esophageal varices. A high sensitivity and specificity has been  reported for the ability of wireless capsule endoscopy to  determine the presence of esophageal varices (84-96% accu-  racy), the size of esophageal varices, and the presence of red  wale signs. The potential benefits of capsule endoscopy include  decreased study time, better patient tolerance, avoidance of  intravenous conscious sedation, and possibly decreased costs.  Wireless capsule endoscopy, however, is limited by inability to   insufflate the esophagus, difficulty in measuring the length of  varices, and image quality artifacts.   D'Amico G, De Franchis R. Cooperative Study Group. Upper  digestive bleeding in cirrhosis. Post-therapeutic outcome and  prognostic indicators. Hepatology. 2003;38:599-612. [PMID:  12939586]   D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prog-  nostic indicators of survival in cirrhosis. A systematic review of  118 studies. } Hepatol. 2006;44:217-231. [PMID: 16298014]   Eisen GM, Eliakim R, Zaman A, et al. The accuracy of PillCam ESO  capsule endoscopy versus conventional upper endoscopy for the  diagnosis of esophageal varices: a prospective three-center pilot  study. Endoscopy. 2006;38:31-35. [PMID: 16429352]   Qamar AA, Grace ND, Groszmann RJ, et al. Portal Hypertension  Collaborative Group. Platelet count is not a predictor of the  presence of development of gastroesophageal varices in cirrho-  sis. Hepatology. 2008;47:153-159. [PMID: 18161700]   E. Invasive Studies to Measure Portal  Hypertension: Hepatic Venous Pressure Gradient   Hepatic venous pressure gradient (HVPG) measurements  provide information for diagnosis, prognosis, and manage-  ment of portal hypertension. The HVPG is the difference  between the wedged or occluded hepatic vein pressure and  the free hepatic vein pressure. Normal portal pressure  (HVPG) ranges from 1 to 5 mm Hg with greater than 5 mm  Hg indicating the presence of portal hypertension. In patients  with sinusoidal cirrhosis, the HVPG accurately predicts  the portal venous pressure gradient. An HVPG greater than  10 mm Hg is predictive of the development of varices.  Pharmacologically reducing the HPVG more than 10% at  1 year compared with the baseline measurement significantly  lowers the risk of developing varices. Similarly, a 10% increase  in HPVG significantly increases the risk of developing varices.   Determining a patient's HPVG also predicts variceal  bleeding, development of hepatic decompensation, determi-  nation of response to clinical treatment, and estimations of  patient survival. Variceal bleeding can occur in patients with  HVPG greater than 12 mm Hg. In patients with acute or  ongoing bleeding, an HVPG greater than 20 mm Hg is asso-  ciated with early rebleeding or uncontrolled bleeding, longer  intensive care unit stay, prolonged hospital stay, higher trans-  fusion requirements, and a lower probability of survival.   Patients achieving a reduction in HVPG to less than  12 mm Hg or a reduction in HVPG of 20% after pharmaco-  logic therapy are less likely to develop ascites, spontaneous  bacterial peritonitis, hepatorenal syndrome, and hepatic  encephalopathy. Unfortunately, only 35-45% of treated  patients respond with a 20% decrease in HVPG. Patients, who  do not achieve an HVPG of less than 12 mm Hg, or a 20%  reduction from their baseline HVPG after pharmacologic  treatment, have a greater risk of developing complications of  portal hypertension and a higher probability of death. Repeat  HPVG measurements obtained 1-3 months after initiating  treatment help guide therapeutic decisions.   Abraldes IG, Tarantino I, Turnes J, et al. Hemodynamic response to  pharmacological treatment of portal hypertension and long-  term prognosis of cirrhosis. Hepatology. 2003;37:902-908.  [PMID: 12668985]   Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pres-  sure gradient predicts clinical decompensation in patients with  compensated cirrhosis. Gastroenterology. 2007;133:481-488.  [PMID: 17681169]   Treatment of portal hypertension includes pharmacologic  management aimed at decreasing portal pressure and endo-  scopic therapy aimed at obliterating esophageal varices.  When medical treatment fails, shunt procedures can be used  to decompress high portal pressure. The goal of treatment is  to interrupt the process that leads to the development of  varices, refractory ascites, and hydrothorax.   De Franchis R. Evolving Consensus in Portal Hypertension. Report  of the Baveno IV Consensus Workshop on methodology of  diagnosis and therapy in portal hypertension. / Hepatol.  2005;43:167-176. [PMID: 15925423]   1. Pharmacologic therapy— Nonselective P-blockers  (propranolol, nadolol, and timolol) are the cornerstone of  long-term management in patients with portal hypertension  (Table 47-2). P-Blockers work by decreasing cardiac output  by blocking (3 , -receptors and by vasoconstricting splanchnic  vessels via blockade of (3,-receptors, thereby leaving oc-  adrenergic activity unopposed. Unfortunately, not all  patients respond to maximally tolerated doses of p-blockers.  In patients who fail to show a reduction in HPVG, there is  often an increase in portocolfateral resistance. The long-acting   nitrate isosorbide mononitrate, when used in conjunction  with p-blockers, has been shown to counteract this increase  in portocollateral resistance. Oral nitrates may cause sys-  temic hypotension that limits their clinical usefulness.   The use of P-blockers in patients with cirrhosis is limited by  their side-effect profile, which includes hypotension, fatigue,  lethargy, depression, and dyspnea in patients with associated  pulmonary disease. Due to concomitant diseases such as reac-  tive airway disease, congestive heart failure, bradycardia, and  heart block, 15-20% of patients are unable to take P-blockers.  In patients who are candidates for p -blocker therapy, dose titra-  tion should be adjusted to patient tolerance.   Vasopressin and its analog, terlipressin, and somatostatin  and its analogs, octreotide and vapreotide, have been the  agents used for the management of acute variceal bleeding.  These vasoconstrictive drugs act by decreasing splanchnic  blood flow, resulting in a lowering of portal pressure, and by  decreasing splanchnic hyperemia. Vasopressin has been  demonstrated to decrease HVPG by as much as 23%. Its use is  limited, however, due to significant complications, including  myocardial infarction, hypertension, hyponatremia, peripheral  vascular ischemia, bradycardia, and fluid retention. These side  effects may be ameliorated with the concurrent use of nitro-  glycerin, but caution is recommended with its use, due to the  risk of hypotension.   Terlipressin has a milder side-effect profile than vaso-  pressin and does not appear to alter renal excretion of  sodium. Its intravenous half-life is 4 hours, and its use results  in a 21% decrease in HVPG. Randomized controlled trials  comparing terlipressin with a placebo or no pharmacologic  treatment in patients with acute variceal hemorrhage have  demonstrated a significant survival benefit for terlipressin.  It is more effective and safer than either vasopressin or vaso-  pressin plus nitroglycerin.   Somatostatin has been shown to decrease portal pressure  in patients with portal hypertension, but to a lesser extent than  vasopressin. It works by inhibiting vasodilatory peptides from  the gastrointestinal tract that have been shown to contribute to  the maintenance of portal hypertension. Due to its short half-  life (2 minutes), somatostatin is used as a continuous infusion  after an initial bolus to treat acute variceal hemorrhage.   The somatostatin analogs, namely octreotide, lanreotide,  and vapreotide, have similar pharmacologic properties to  somatostatin.   Octreotide, used widely in the United States, is thought to  act through the inhibition of the vasodilator glucagon. The  intravenous half-life of octreotide, like that of somatostatin, is  short; therefore, it is given as a bolus followed by a continuous  infusion. Although intravenous octreotide may decrease portal  pressure and bleeding from esophageal varices, its use has not  been shown to improve overall survival. Similarly, vapreotide in  combination with endoscopic therapy has been shown to  decrease bleeding from esophageal varices more effectively than  endoscopic therapy alone, but without a benefit in survival.   Together with a low-sodium diet, continuous spironolac-  tone (100 mg/day) treatment results in a modest decrease in  portal pressure. Recent studies have attempted to demon-  strate the efficacy of losartan and irbesartan, angiotensin II  receptor blockers, in lowering portal pressures but the data  are inconclusive and no randomized controlled trials have  been published demonstrating clinical efficacy.   Cales P, Masliah C, Bernard B, et al. Early administration of  vapreotide for variceal bleeding in patients with cirrhosis.  N Engl J Med. 2001;244:23-28. [PMID: 11136956]   Groszmann RJ, Garcia-Tsao G, Bosch I, et al. Portal Hypertension  Collaborative Group. Beta-blockers to prevent gastroesophageal  varices in patients with cirrhosis. N Engl ] Med. 2005;353:  2254-2261. [PMID: 16306522]   EVL and sclerotherapy are local treatments for varices and  do not alter the pathophysiologic processes that lead to their  development. As such, even with successful EVL, varices  eventually recur. EVL consists of the placement of rubber  bands on variceal columns that leads to localized mucosal  and submucosal necrosis and replacement of the varix by  scar tissue. Band ligation carries the risk of causing  esophageal ulcerations that have the potential to bleed.   Sclerotherapy involves injecting a sclerosing agent  (ethanolamine oleate, sodium tetradecyl sulfate, sodium  morrhuate) into or adjacent to a varix. Sclerotherapy leads to  localized thrombosis and inflammation with subsequent scar  formation. Both local and systemic complications of scle-  rotherapy occur in 20-40% of patients. Side effects include  bacteremia, fever, chest pain, mediastinitis, acute esophageal  ulceration (with bleeding potential), and esophageal stric-  tures. Because of greater efficacy and fewer side effects,  EVL has replaced sclerotherapy as the endoscopic treatment  of choice.   Garcia-Pagan JC, Bosch J. Endoscopic band ligation in the treat-  ment of portal hypertension. Nat Clin Pract Gastroenterol  Hepatol. 2005;2:526-535. [PMID: 16355158]   3. Radiologic therapy — The transjugular intrahepatic por-  tosystemic shunt (TIPS) was first introduced in the 1980s, as  an alternative to surgically performed shunts. TIPS should be  reserved for patients who fail pharmacologic and endoscopic  management of both acute and recurrent variceal bleeding.   Placement of a TIPS bypasses the fibrosed liver and allows  for unhindered blood flow between the portal and hepatic  veins. A catheter is inserted into the right internal jugular  vein and advanced to the hepatic venous system (usually the  right hepatic vein). A needle is then used to cannulate the  liver, creating a tract to the portal vein. The transhepatic tract  is dilated, and a flexible metal stent is placed, resulting in a  shunt between the hepatic and portal veins. Placement of  TIPS is successful in greater than 90% of cases and is effec-  tive in acutely decreasing portal pressure.   Early complications of TIPS include fever, infection, renal  dysfunction, intrahepatic or intraperitoneal hemorrhage,  and liver failure. Furthermore, hyperbilirubinemia, second-  ary to hemolytic anemia, may persist until the TIPS stent is  re-epithelialized. Long-term complications from TIPS place-  ment include hepatic encephalopathy and stent occlusion.  Over 20% of patients with TIPS will either develop or have  worsening hepatic encephalopathy and should be prophylac-  tically treated with lactulose, neomycin, or rifaximin. Risk  factors for developing hepatic encephalopathy include older  age, larger stent diameter, and prior episodes of hepatic  encephalopathy. Seventy percent of patients who undergo  TIPS will develop stent occlusion within 1 year and 90% by  2 years. Angioplasty or additional stent placement is success-  ful in treating stent occlusion and decreases the reocclusion  rate to 10% at 2 years. However, these complication rates are  significantly reduced with the use of coated stents. Patients  treated with TIPS should have Doppler ultrasound surveil-  lance at regular intervals to confirm stent patency, as TIPS  dysfunction can result in variceal bleeding. However, angio-  graphic assessment and measurements of portal pressure are  more accurate in establishing TIPS dysfunction.   Absolute contraindications to TIPS placement include  right heart failure and polycystic liver disease. Relative con-  traindications include systemic infection, portal vein throm-  bosis, biliary obstruction, and severe hepatic encephalopathy.  Although TIPS can be successfully placed in most patients,  placement is associated with a 30-day mortality rate of  3-15% and a procedure-related mortality rate of 2-5%.   Boyer TD, Haskal ZJ; American Association for the Study of Liver  Diseases. The role of transjugular intrahepatic portosystemic  shunt in the management of portal hypertension. Hepatology.  2005;41:386-400. [PMID: 15660434]   Bureau C, Garcia-Pagan IC, Otal P, et al. Improved clinical out-  come using polytetrafluoroethylene coated stents for TIPS:  results of a randomized study. Gastroenterology. 2004;126:  469-475. [PMID: 14762784]   Monescillo A, Martinez-Lagares F, Ruiz-del-Arbol L, et al.  Influence of portal hypertension and its early decompression by  TIPS placement on the outcome of variceal bleeding. Hepatohgy.  2004;40:793-801. [PMID: 15382120]   4. Surgical shunt procedures — For many years, surgically  created shunts were the only treatment to prevent variceal  hemorrhage. However, with the advent of TIPS and improve-  ments in endoscopic and pharmacologic therapy, they are  rarely used today. There are two types of shunts. Total shunts  (end-to-side or side-to side shunts) decompress the liver by  diverting blood flow from the portal vein to the vena cava.  Selective shunts (distal splenorenal shunts) divert splenic  blood flow to the renal vein while preserving prograde portal  vein flow. Although both types of shunts can induce hepatic  encephalopathy, the distal splenorenal shunt that maintains  prograde portal flow is less apt to have this complication.   5. Liver transplantation — Variceal hemorrhage is not an  indication for liver transplantation. However in appropriate  candidates as determined by the Model for End- Stage Liver  Disease (MELD) scoring system, liver transplantation can  achieve up to 95% control of variceal bleeding. Liver trans-  plantation continues to be limited by organ availability.   6. Preprimary prophylaxis— Early treatment with P-blockers  prior to the development of complications of portal  hypertension might halt or delay the progression of portal  hypertension. Unfortunately, the results from a large multicen-  ter randomized controlled trial have not supported the use of   nonselective P-blockers in the preprimary prophylaxis of  portal hypertension. However, data from this trial shows that  measurements of the HVPG predict the development of  esophageal varices and hepatic decompensation.   1. Nonselective p-blockers— Because of the high morbid-  ity and mortality in patients with cirrhosis associated  with acute variceal bleeding, pharmacologic therapy aimed  at preventing initial variceal bleeding is paramount  (Figure 47-1). Nonselective P-blockers are the only estab-  lished pharmacologic therapy for primary prophylaxis of  variceal bleeding. A meta-analysis of randomized con-  trolled trials has demonstrated their efficacy in decreasing  the rates of a first variceal bleed from 24% to 15%. These  studies involved primarily patients with Child-Pugh class A  and B cirrhosis.   Current practice guidelines on the management of portal  hypertension recommend that patients with small varices  who are at increased risk of bleeding (red wale sign on  endoscopy, hepatic decompensation) be treated prophylacti-  cally with p-blockers. Patients with small varices who are not  at high risk may be started on P-blockers, but their long-term  efficacy has not been established. All patients with medium-  to large-sized varices who are judged to be compliant and are  without contraindications to or intolerance of nonselective  P-blockers should be treated with these drugs. Therapy must  be continued for a lifetime, as the risk of bleeding recurs if  treatment is discontinued.   ▲ Figure 47-1. Management algorithm for primary prophylaxis of variceal hemorrhage. EGD, esophagogastroduo-  denoscopy; EVL, endoscopic variceal ligation.   Although combining a long-acting nitrate with a nonse-  lective (3-blocker increases the number of hemodynamic  responders, it has not resulted in incremental clinical benefit  (ie, by preventing initial variceal hemorrhage or leading to  improved survival). Similarly, combining spironolactone with  P-blockers showed no benefit in decreasing rates of bleeding  episodes or survival compared with treatment using P-blockers  alone. Current data do not support the use of combination  therapy or monotherapy with nitrates for the prevention of a  first variceal bleed.   Grace ND, Garcia-Pagan JC, Angelico M, et al. Primary prophy-  laxis for variceal bleeding. In: de Franchis R (editor). Portal  Hypertension IV: Proceedings from the 4th Baveno International  Consensus Workshop. Blackwell Science, 2006:168-200.   2. Esophageal variceal ligation— Nonselective p-blockers  are considered first-line therapy for the prevention of initial  variceal hemorrhage. However, 15% of patients have con-  traindications and an additional 15-20% are intolerant of  their use. EVL is an excellent alternative for these patients.   For patients who undergo esophageal variceal ligation, it  is recommended that the procedure be performed biweekly  until the varices are obliterated. As new varices may develop  after eradication treatment, it is important to continue sur-  veillance for varices every 6 months. Endoscopic ultrasound  may be used to confirm eradication of esophageal varices,  but is likely of limited utility in clinical practice.   Recent meta-analyses have shown a benefit for EVL over  |3-blocker therapy in preventing first variceal hemorrhage,  but EVL is associated with more serious side effects and  offers no survival advantage. Randomized controlled trials of  EVL have been limited by a short duration of follow-up. The  studies with the largest number of patients and the longest  follow-up have failed to show a difference between EVL and  nonselective P-blockers, either for the prevention of initial  variceal bleeding or for survival. Combination therapy using  P-blockers plus EVL compared with EVL alone has not been  shown to decrease the risk of first variceal hemorrhage.   There is no role for endoscopic sclerotherapy, TIPS, sur-  gical shunts, or liver transplantation in the primary prophy-  laxis of variceal hemorrhage.   de la Pena J, Brullet E, Sanchez-Hernandez R, et al. Variceal ligation  plus nadolol compared with ligation for prophylaxis of variceal  rebleeding: a multicenter trial. Hepatology. 2005;41:572-578.  [PMID: 15726659]   Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Practice Guidelines  Committee of the American Association for the Study of Liver  Diseases; Practice Parameters Committee of the American  College of Gastroenterology. Prevention and management of  gastroesophageal varices and variceal hemorrhage in cirrhosis.  Hepatology. 2007;46:922-938. [PMID: 17879356]   Khuroo MS, Khuroo NS, Farahat KL, et al. Meta-analysis: endo-  scopic variceal ligation for primary prophylaxis of oesophogeal  variceal bleeding. Aliment Pharmacol Titer. 2005;21:347-361.  [PMID: 15709985]   Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligation plus  nadolol and sucralfate compared with ligation alone for the pre-  vention of variceal bleeding: a prospective, randomized trial.  Hepatology. 2000;32:461-465. [PMID: 10960435]   Patients with acute variceal bleeding may present with  hematemesis, melena, or hematochezia. The initial manage-  ment includes immediate resuscitation, administration of  prophylactic antibiotics and vasoactive agents, and diagnos-  tic endoscopy (Figure 47-2). It is important to consider elec-  tive intubation in patients with active bleeding to protect the  airway from aspiration, especially if there is concomitant  hepatic encephalopathy.   1 . Resuscitation — Resuscitative measures should be aimed  at replacing blood volume to a goal of a hematocrit of 25%,  thereby avoiding increases in portal pressure and potential  exacerbation of variceal bleeding associated with aggressive  transfusion. Correcting thrombocytopenia and coagulopa-  thy have not been shown to improve survival from an acute  variceal bleed. Nonetheless, transfusing platelets to increase  levels to greater than 50,000 and transfusing fresh frozen  plasma to reverse coagulopathy may be beneficial in the  acute setting. The excessive use of saline should be avoided in  resuscitation, as it can worsen or precipitate the formation of  ascites and volume overload.   2. Antibiotic prophylaxis— Infection in the setting of acute  variceal bleeding has been associated with early rebleeding and  a high mortality rate. Patients with bleeding from varices are at  high risk of developing infection, including spontaneous bacte-  rial peritonitis. Short-term antibiotics should be administered  to all patients with cirrhosis and acute variceal bleeding.  Norfloxacin (400 mg twice daily for 7 days) or quinolone  antibiotics with a similar spectrum of activity (eg, levofloxacin,  ciprofloxacin) are the preferred agents. In a recent study, intra-  venous ceftriaxone (1 g/day) was found to be superior to nor-  floxacin in patients with severely decompensated cirrhosis.   3. Vasoactive agents — Once variceal hemorrhage is sus-  pected, administration of vasoactive agents should be initi-  ated. These agents include vasopressin, vasopressin plus  nitroglycerin, terlipressin, and somatostatin or its analogs.  Use of vasopressin is limited by its serious side effects, which  can be counteracted by the addition of nitroglycerin. The  vasopressin analog terlipressin has fewer side effects than  vasopressin and is the only pharmacologic agent that has a  survival benefit in patients with acute variceal hemorrhage.   Octreotide has been shown to have equal efficacy to scle-  rotherapy in controlling bleeding. It is safe with very few  side effects and can be used continuously for up to 5 days.  However, its use has been associated with tachyphylaxis,  and its vasoactive effects may be transient. When combined  with endoscopic therapy, octreotide improves management  of acute bleeding compared with EVL alone, but without a  survival benefit.   A Figure 47-2. Management algorithm for acute variceal hemorrhage. EGD, esophagogastroduodenoscopy; EVL, endoscopic  variceal ligation; PHG, portal hypertensive gastropathy; TIPS, transjugular intrahepatic portosystemic shunt.   |3-Blockers should not be administered during an active  bleed, due to the physiologic blunting of heart rate in the set-  ting of hypotension.   4. Endoscopic therapy — Endoscopic evaluation should  occur as soon as possible and within the first 12 hours of a  patient presenting with an acute variceal bleed. In addition to  confirming the source of bleeding, endoscopic treatments are  successful in controlling hemorrhage in 90% of cases. EVL is  the procedure of choice. The combination of EVL and a  somatostatin analog has been shown to be more effective than  either EVL or a pharmacologic agent, given as monotherapy,  and is the treatment of choice.   5. Balloon tamponade— Balloon tamponade is 80% effec-  tive in immediate control of hemorrhage from esopha-  gogastric varices. However, serious complications occur  when the balloon is left inflated for more than 24 hours. The   complications, which occur in 20% of cases, include aspira-  tion, esophageal ulceration and necrosis, and esophageal per-  foration. Balloon tamponade is best utilized as a short-term  bridge to TIPS or liver transplantation.   TIPS is used to manage variceal bleeding when endoscopic  and pharmacologic treatments fail. In 90% of cases of uncon-  trolled bleeding, TIPS is successful in stopping bleeding.  Unfortunately, mortality remains high (27-50%), probably as a  function of the severity of illness, and rebleeding can occur  in the short and long term. Predictors of early mortality  include creatinine greater than 1.7 mg/dL, bilirubin greater than  5 mg/dL, a Child-Pugh score greater than 12, an APACHE II  score greater than 18, and a Patch prognostic index greater than  18. TIPS is the rescue therapy of choice after two failed attempts  of combined endoscopic and pharmacologic management.   The use of polytetrafluoroethylene-coated stents results  in significantly less stent dysfunction and lower clinical  relapse rates. Patients receiving coated stents, compared  with those receiving uncoated stents, had lower rates of  recurrent bleeding and hepatic encephalopathy after 2 years  of follow-up.   Bureau C, Garcia-Pagan JC, Otal P, et al. Improved clinical out-  come using polytetrafluoroethylene coated stents for TIPS:  results of a randomized study. Gastroenterology. 2004;126:  469-475. [PMID: 14762784]   Once the acute bleed has been controlled, secondary preven-  tion of rebleeding is paramount. First-line therapy for pre-  vention of recurrent variceal hemorrhage is the combination  of pharmacologic therapy and EVL. For patients who fail to  respond to medical therapy, shunts or liver transplantation  for appropriate candidates are the options (Figure 47-3A).   Pharmacologic treatment for prevention of recurring  variceal hemorrhage is initiated by administration of a  nonselective (3-blocker, titrated to tolerance. (3-Blockers  have been shown to decrease rates of rebleeding from 63%  to 42% and to decrease mortality from 27% to 20%. The  hemodynamic goal of (3-blocker therapy is to decrease the  HVPG by greater than 20% or to a level less than 12 mm Hg  (Figure 47-3B). Achieving this goal has been shown to  reduce rebleeding rates to less than 15%.   ▲ Figure 47-3A. The role of hepatic venous pressure  gradient measurements in preventing recurrent variceal  hemorrhage. EVL, endoscopic variceal ligation; TIPS,  transjugular intrahepatic portosystemic shunt.   In patients who have an incomplete response to (3-blocker  monotherapy, one can consider the addition of isosorbide  mononitrate. With combination therapy, the rebleeding  rate appears to be lower, but at a cost of significantly greater  side effects and no survival benefit.   If patients are unable to tolerate (3-blockers, EVL is the pre-  ferred endoscopic treatment to prevent recurrent variceal   A Figure 47-3B. Prevention of recurrent variceal hemorrhage. EVL, endoscopic variceal ligation; HVPG, hepatic venous  pressure gradient; TIPS, transjugular intrahepatic portosystemic shunt.   hemorrhage. Although EVL is more effective than sclerother-  apy at preventing rebleeding, the risk of rebleeding after EVL  remains high, reaching 30-50% at 2 years. The combination of  a nonselective (3-blocker and EVL has been shown to result in  a decreased rate of variceal rebleeding, a lower transfusion  requirement, a lower recurrence of esophageal varices, and a  trend toward improved survival. However, there are increased  side effects with combination therapy. Currently, combination  therapy appears to be the most rational approach for preven-  tion of variceal rebleeding, especially in high-risk patients.   EVL sessions should be performed every 7-14 days until  complete variceal obliteration is achieved. Once varices are  eradicated, continued surveillance every 6-12 months is  required to screen for recurrent varices.   In patients who do not respond to pharmacologic or  endoscopic therapy, alone or in combination, decompression  of the portal system by use of TIPS or surgical shunts is the  next option. Liver transplantation provides the only defini-  tive treatment for rebleeding as it directly addresses the  underlying liver pathology that leads to portal hypertension  and the formation of varices. However, variceal bleeding is  not by itself an indication for liver transplantation, which  should be reserved for appropriate candidates.   Numerous meta-analyses have demonstrated that TIPS is  more effective than endoscopic therapy in preventing  rebleeding from varices. The drawback of TIPS is an increase  in hepatic encephalopathy and the lack of a survival benefit.  Endoscopic and pharmacologic therapy remains the first-  line therapy for prevention of rebleeding, with TIPS reserved  as a rescue therapy.   Similarly, surgical shunting is effective at decreasing the rate  of rebleeding, but at the cost of hepatic encephalopathy and no  survival benefit. As TIPS and surgically created shunts result in  similar rates of rebleeding, encephalopathy, and mortality, the  choice of a procedure to decrease rate of recurrent bleeding  should be based on cost considerations and local expertise.   Gastric varices are present in 20% of patients with portal  hypertension and account for 10-15% of variceal bleeds.  Gastric varices can occur alone or in combination with  esophageal varices. Although the risk of bleeding from gastric  varices is lower than that from esophageal varices, gastric  variceal hemorrhages are associated with higher rates of  rebleeding (between 34% and 89%) and a higher mortality  rate. Gastric varices are more common in patients with extra-  hepatic portal vein obstruction than in patients with cirrhosis.   Management depends on the underlying etiology of the  gastric varix; therefore, it is important to identify the cause  of the varix before treatment. Varices that develop from   portal hypertension have been treated with EVL, adminis-  tration of vasoactive agents or cyanoacrylate glue, or TIPS  (see Figure 47-2). Varices that develop after splenic vein  thrombosis or stenosis, leading to isolated left-sided portal  hypertension, are best treated with splenectomy or splenic  artery embolization.   Gastric varices are classified according to their anatomic loca-  tion in the stomach and their relationship to esophageal  varices. Type 1 gastric varices, GOV1, extend from esophageal  varices to the lesser curvature of the stomach. As such they  should be treated similarly to esophageal varices (ie, using  EVL). Type 2 gastric varices, GOV2, extend from esophageal  varices to the gastric fundus. Isolated type 1 gastric varices  (IGV1) are located in the fundus, whereas isolated type 2 gas-  tric varices (IGV2) are located elsewhere in the stomach. Risk  factors for variceal bleeding include location in the fundus  (GOV2, IGV1 ), size larger than 5 mm, presence of endoscopic  red wale signs, and Child-Pugh class C cirrhosis.   Unlike esophageal varices, gastric varices can bleed with  HVPG less than 12 mm Hg. This is thought to be due to a higher  prevalence of spontaneous shunting (gastrorenal shunts),  which decreases portal pressure but does not decrease the  reversal of flow in splenic veins that result in gastric varices.   Given the high morbidity and mortality from gastric variceal  bleeds, it is reasonable to treat patients empirically with vasoac-  tive agents shown to improve bleeding outcomes in esophageal  variceal hemorrhage. Similarly, nonselective (3-blockers have  been used for prevention of recurrent variceal bleeding.   Endoscopy is essential for identifying gastric varices.  However, because these varices can lie deep in the submu-  cosa, standard endoscopy can underestimate their true  prevalence. Most gastric varices that bleed are close to the  mucosal surface and are readily identifiable.   EVL is associated with a high rate of rebleeding and is less  successful in treating gastric variceal bleeds compared with  esophageal variceal bleeds. Endoscopic variceal obturation  refers to the injection of adhesive and glue agents into a  varix. Tissue adhesives, including N-butyl-cyanoacrylate,  isobutyl-2-cyanoacrylate, and thrombin, have resulted in  better control of initial gastric variceal bleeding than EVL.  Furthermore, gastric variceal obturation with AT-butyl-  cyanoacrylate has a lower rate of rebleeding and an overall  survival benefit compared with EVL. Documented side  effects from use of glue include fever, sepsis, retroperitoneal  abscess formation, and distal embolization. Embolic compli-  cations to cerebral arteries, pulmonary arteries, coronary   arteries, renal veins, and inferior vena cava have been docu-  mented. The only agent (off label) available in the United  States is 2-octyl-cyanoacrylate (Dermabond).   If endoscopic therapy fails, placement of a Linton-  Nachlas tube or Sengstaken-Blakemore tube can be lifesaving  as a temporizing procedure. Balloon tamponade should only  be used as a bridge to more definitive therapy (TIPS or liver  transplantation), due to its associated complications.   Lo GH, Lai KH, Cheung IS, et al. A prospective, randomized trial  of butyl cyanoacrylate injection versus band ligation in the  management of bleeding gastric varices. Hepatology. 2001;33:  1060-1064. [PMID: 11343232]   Tan PC, Hou MC, Lin HC, et al. A randomized trial of endoscopic  treatment of acute gastric variceal hemorrhage: N-butyl-2-  cyanoacrylate injection versus band ligation. Hepatology.  2006;43:690-697. [PMID: 16557539]   Hemorrhage control using TIPS can be achieved in more  than 90% of cases. TIPS, however, is recommended after one  failed attempt of endoscopic management of gastric variceal  bleeding or after early rebleeding. Unfortunately, the compli-  cation of hepatic encephalopathy and lack of survival benefit  still exist. Surgical shunts are an alternative to TIPS in  patients with Child-Pugh class A cirrhosis.   Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gas-  troenterologic, and radiologic approach to the management of  gastric varices. Gastroenterology. 2004;126:1175-1189. [PMID:  15057756]   PHG describes the endoscopic appearance of gastric ery-  thema with a whitish mosaic-like pattern that is found in  51-98% of patients with cirrhotic and noncirrhotic portal  hypertension. In part, PHG develops as a result of increased  resistance to portal flow, but there is no linear correlation  between the development of PHG and the level of portal pres-  sures. The development of PHG has been correlated with the  duration and severity of liver disease, presence and size of gas-  troesophageal varices, and previous eradication of varices by  banding or sclerotherapy. The pathogenesis of PHG is not  clearly understood but may be related to the overproduction  of nitric oxide, which results in capillary dilation, or increased  levels of vascular endothelial growth factor, which results in  increased angiogenesis.   PHG is characterized by mucosal congestion, with dilated  capillaries and venules in the mucosa and submucosa of the  stomach. Endoscopically, the gastric mucosa appears erythe-  matous and edematous, with a characteristic mosaic pattern,  often described as a snakeskin appearance. In PHG, the   gastric mucosa is friable and may have associated hemor-  rhagic spots. The gastric mucosa in patients with PHG bleeds  easily on contact and is more susceptible to damage by nox-  ious stimuli such as bile acids, aspirin, and nonsteroidal anti-  inflammatory drugs. PHG is most prominent in the gastric  body and fundus, but may be noted diffusely. Several endo-  scopic classification systems for PHG have been proposed  but there is no consensus on the best system.   Patients with PHG typically present with chronic anemia  and more rarely with acute blood loss. An estimated 8% of  upper gastrointestinal hemorrhage in patients with cirrhosis is  due to PHG bleeding, and tends to occur in patients with severe  PHG. Mortality from PHG bleeding is reported to be very low.   First-line treatment for PHG includes medical therapies  aimed at decreasing gastric blood flow (eg, (3-blockers,  octreotide, vasopressin). Small studies have shown efficacy of  propranolol in decreasing rates of chronic and recurrent  bleeding from PHG. If medical therapy is not tolerated or  fails to reduce bleeding rates, TIPS may be beneficial.   Surgical shunts or liver transplantation are not recom-  mended for the treatment of PHG, and endoscopic therapy  has no proven benefit or safety profile. It remains to be seen  how advances in argon plasma coagulation, cryotherapy, and  photodynamic therapy may evolve in the future as therapeu-  tic options for PHG.   Primignani M, Carpinelli L, Preatoni P, et al. Natural history of  portal hypertensive gastropathy in patients with liver cirrhosis.  The New Italian Endoscopic Club for the Study and Treatment  of Esophageal Varices (NIEC). Gastroenterology. 2000;119:  181-187. [PMID: 10889167]   Sarin SK, Shahi HM, Iain M, et al. The natural history of portal  hypertensive gastropathy: Influence of variceal eradication. Am  J Gastroenterol. 2000;95:2888-2893. [PMID: 11051364]   Over the past 30 years, major advances in pharmacologic and  endoscopic therapy for primary and secondary prophylaxis  of variceal hemorrhage, together with a better understanding  of resuscitative measures, has led to a marked improvement  in the morbidity and mortality associated with variceal hem-  orrhage. Early mortality from variceal bleeding has been  reduced by 50% to its present 15%. The advent of TIPS as a  rescue procedure has reduced surgical shunts to a footnote.  Future research will be directed toward finding alternative  drugs for patients who cannot tolerate or do not benefit from  the use of (3-blockers. Moreover, the TIPS literature will have  to be reassessed with the development of coated stents.  Finally, a noninvasive test is needed that will give informa-  tion similar to that now obtained by measurements of the  HVPG for the diagnosis, prognosis, and management of  patients with cirrhosis and portal hypertension.   ► No specific diagnostic tests establish the presence of a  drug-induced liver injury; the diagnosis is often one of  exclusion.   ► Evidence of hepatic injury days to months after adding a  therapeutic drug suggests possible drug-induced injury.   ► In patients with few if any symptoms of liver injury, the  problem may be detected only by biochemical tests  showing elevated aminotransferase, bilirubin, or alkaline  phosphatase levels.   ► Consider a drug-induced etiology in any patient who devel-  ops acute hepatitis with jaundice (hepatocellular injury).   Awareness of drug-induced reactions affecting the liver has  increasingly become a matter of concern on several fronts.  The economic consequences of removing an approved drug  from the market or markedly restricting its use are tremen-  dous and even a suggestion of hepatic risk leads to a careful  review of the data on which the approval was made. Drug-  induced injuries that lead to clinically severe liver disease gar-  ner much attention even if only a few cases are recognized  (or even suggested). The challenge is to improve the methods  by which the risk of drug-related hepatotoxicity with a spe-  cific drug is assessed (and hopefully predicted) so that an  effective risk management plan can be developed.   Almost all drugs in current use have been suggested as a  cause of some liver alterations, most often asymptomatic ele-  vations of aminotransferases. Major issues include determin-  ing the threshold of tolerance (risk-benefit factor) for mild to  moderate injury caused by drugs that are effective in the  treatment of serious illnesses.   Hepatic injury that occurs rarely (< 1 in 10,000) is desig-  nated as an idiosyncratic reaction. Idiosyncrasy is defined as   a response or reaction that is host dependent and apparently  dose independent. Because of the rarity of significant events,  a severe adverse event may not be detected during preap-  proval development during which a limited (several thou-  sand) number of patients are exposed. The causes of these  rare reactions have remained largely unknown. The chal-  lenge for further research is to identify why an agent that is  well tolerated by many thousands of patients may cause a  devastating injury in a few.   Drug-induced liver disease is usually indistinguishable  (clinically and histologically) from liver injury of other  causes and may only be detected through awareness of the  possibility, suspicion, careful history, exclusion of other likely  causes, and inquisitive persistence by the clinician. Drugs  recently approved and introduced receive special attention.   Careful attention should be given to the time of onset,  duration of therapy, and nature of the hepatic injury, as well  as to the presence of other drugs that may enhance produc-  tion or accumulation of reactive intermediates or interfere  with drug transport. Most clinicians prescribe a relatively  limited panel of drugs. It is essential that they become famil-  iar with the hepatic risk profile and patterns of manifestation  of each. Difficulties in establishing a diagnosis are com-  pounded by the status of the underlying disease, concomi-  tant illnesses, and polypharmacy. Ingenuity and persistence  are required.   Considerable supportive evidence implicating a drug as  the cause of a liver injury is found if there is resolution of  manifestations of liver injury (deceleration) following with-  drawal. The problem in a patient who is receiving many  drugs is in deciding which agent to remove when evidence of  liver injury is found.   The profile of frequency, type of reaction, and possible  extent of injury for each drug a patient is receiving must be  considered. Minimal biochemical abnormalities, especially  minor elevations of serum aminotransferases (less than three  times the upper limit of normal), do not necessarily indicate  that clinically important liver injury is occurring. Patients   with elevated aminotransferase levels and clinical jaundice  are in a group at considerable risk of an adverse outcome.   The conceptual framework of differentiating types of  hepatic adverse reactions into those that are predominantly  hepatocellular (elevated aminotransferase levels) and those  that are predominantly cholestatic injury (elevated alkaline  phosphatase levels) has served us well. However, with many  drugs there are elements of both patterns of injury, leading to  a category of a mixed reaction.   Cholestatic disorders range from mild elevations of alka-  line phosphatase levels found only on routine biochemical  testing to symptomatic cholestatic syndromes with jaundice  and pruritus that resemble primary biliary cirrhosis and pri-  mary sclerosing cholangitis. Hepatic steatosis (fatty liver) of  both the microvesicular and macrovesicular types is fre-  quently noted in liver biopsy and is a near-constant finding  in obese and diabetic patients. The contribution of a drug to  the pathogenesis of the fat is often difficult to assess. Drugs  that cause mitochondrial injury may lead to microvesicular  fat accumulation. A few drugs (eg, amiodarone) lead to an  acquired phospholipidosis. Several drugs are established  causes of hepatic granulomatous inflammation indistin-  guishable from those found in a variety of infections and  sarcoidosis.   Tumors induced or promoted by therapeutic drugs range  from benign hepatic adenoma, associated with long-term use  of oral contraceptives, to angiosarcomas, cholangiocarcino-  mas, and hepatocellular carcinomas.   1. Clinical manifestations of drug-induced hepato toxicity  are often clinically indistinguishable from those of liver  disease caused by other etiologies.   2. The risk of developing serious liver injury from a drug-  induced hepatocellular injury is considerably greater than  that from cholestatic injury, at least in the short run.   3. The appearance of clinically apparent liver disease in  patients who have predominantly hepatocellular injury  with clinical jaundice requires immediate attention and  in many cases hospitalization.   4. Histologic evidence of injury, especially in patients who  have hepatocellular injury, is often more severe than is  suggested by clinical signs or laboratory studies.   Hepatic injury from a drug may have a somewhat specific  "signature" as regards time of onset, type of injury, and  propensity to develop severe disease. However, exceptions  occur and many drugs, even those that predominantly cause  hepatocellular injury, will on occasion present with a mixed  hepatocellular and cholestatic injury or even predominant  cholestatic injury.   It may be difficult or impossible to assess the contribution  of a drug to hepatic injury in a patient who has an underly-  ing disease or a condition that itself is known to cause liver  injury (eg, disseminated carcinoma or fungal disease,   chronic hepatitis or cirrhosis, HIV infection and AIDS, and  multiorgan involvement from an autoimmune process).  Furthermore, in settings in which many drugs are used, espe-  cially in the elderly, assigning attribution to any one agent is  difficult. Additional consideration must be given to a role for  herbal compounds, which may be the cause or at least con-  tribute. Obtaining an accurate history from the patient of the  use of herbal products may be especially difficult. The vari-  able timing of stopping, restarting, and substitution of drugs  adds to the difficulties. Knowing the relative hepatic risks of  individual agents the patient is receiving and the expected  time of onset is helpful. Dilemmas are heightened when one  or more of the drugs suspected to have caused hepatoxicity  are required in the treatment of a serious underlying illness.   Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Saf.  2007;30:277-294. [PMID: 17408305]   Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver  injury: an analysis of 461 incidences submitted to the Spanish  Registry over a 10-year period. Gastroenterology. 2005; 129:  512-521. [PMID: 16083708]   Bjornsson E, Olsson R. Outcome and prognostic markers in severe  drug-induced liver disease. Hepatology. 2005;42:48 1-489. [PMID:  16025496]   Chang CC, Petrelli M, Tomashefski IF, et al. Severe intrahepatic  cholestasis caused by amiodarone toxicity after withdrawal of  the drug-a case report and review of the literature. Areh Pathol  Lab Med. 1999;123:251-256. [PMID: 10086516]   Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug  Discov. 2005;4:489-499. [PMID: 15931258]   Maddrey WC. Drug-induced hepatotoxicity 2005. / Clin Gastro-  enterol. 2005;39:S83-S89. [PMID: 15758665]   Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. ] Hepatol.  2005;43:901-910. [PMID: 16171893]   Watkins PB. Idiosyncratic liver injury: challenges and approaches.  Toxicol Pathol. 2005;33:1-5. [PMID: 15805049]   Zimmerman HJ. Drug- induced liver disease. Clin Liver Dis. 2000;4:  73-96. [PMID: 11232192]   Selection of drugs that accomplish therapeutic goals and  have an excellent record as regards causing hepatic injury,  while a worthy goal, may be impossible. There are few drugs  that have not been implicated as the cause of some form of  liver injury. Often, however, there are no effective therapeu-  tic alternatives that are hepatically risk free.   There may be few clinical signs or symptoms suggesting liver  injury, even in a patient who has biochemical and histologic  evidence of considerable damage. Early symptoms sometimes  associated with drug-induced injuries are nonspecific and  include loss of appetite, fatigue, lassitude, and occasionally a   dull discomfort more prominent in the right upper quadrant  of the abdomen. All these symptoms may be attributed to an  underlying condition. These are the same symptoms that are  often found in patients who have chronic viral hepatitis B or C  or alcohol-induced liver disease. With a few drugs, there is  the concomitant presence of fever, rash, or eosinophilia — the  hallmarks of hypersensitivity reactions.   Rarely are imaging or serologic tests of any value in diagno-  sis or in differentiating drug-induced injury from liver dis-  eases of other etiologies.   The appearance of clinical jaundice in a patient with  hepatic injury is an indication of an adverse prognosis, with a  fatal outcome occurring in approximately 10%. Age of the  patient, level of alanine aminotransferase (ALT), and the height  of the bilirubin elevation all independently predict the like-  lihood of death or the need for liver transplantation.   For several drugs that have been implicated in the pathogen-  esis of liver injury, there is evidence that genetically con-  trolled metabolic pathways play important roles in  determining which individuals are likely to have an adverse  reaction affecting the liver. The expression of genes induced  by a drug or one or more of its metabolic products (height-  ened or dampened) influences individual susceptibility to  injury, and the patterns of genes affected may allow predic-  tion of a group of individuals at increased risk.   Extensive evaluations of genetic polymorphisms focusing  on enzymes that metabolize or transport metabolic products  and those that influence the responses to injury are being  undertaken as part of efforts to unravel the mystery of what  causes the rare reaction designated as idiosyncratic.   One approach utilizing genetic testing is to identify a  group of individuals who have experienced an adverse reac-  tion and compare the gene profile of those patients with  those who have received the drug and have not had a prob-  lem. Thus far, there is too little experience to fully assess the  value of this approach.   The development of reliable tests to detect hepatitis A-E has  made the task of excluding viral hepatitis more straightfor-  ward and certain. The finding of antimitochondrial antibod-  ies in a patient who has biochemical evidence of cholestasis  and jaundice may go far to resolve whether the patient has  primary biliary cirrhosis or a drug-induced syndrome that  resembles the disorder. However, it must be recalled that  patients with liver disorders of all types may develop super-  imposed drug-induced injury, which, especially in patients  with cirrhosis and decreased hepatic reserve, is more likely to  cause clinically significant disease.   Several drugs cause chronic hepatitis syndromes that may  be largely indistinguishable from autoimmune hepatitis.  Misdiagnosing those patients as having autoimmune hepa-  titis may lead to the institution of corticosteroid therapy  and continuation of the drug. Corticosteroids serve to  blunt the manifestations of the underlying ongoing injury  while continued drug use leads to further damage.  Generally drugs that cause chronic hepatitis are taken long  term and the extent of the injury may correlate with the dura-  tion of therapy.   Drugs that cause a pattern of chronic hepatitis include  minocycline, nitrofurantoin, and methyldopa. The majority  of patients who develop drug-induced chronic hepatitis are  women, and many have increased serum globulin levels as  well as the presence of autoantibodies. Clinical onset of illness  may be as an acute hepatitis in a patient in whom liver biopsy  changes suggesting long-standing disease are found (acute on  chronic pattern). Histologic changes maybe indistinguishable  from autoimmune hepatitis. In some patients chronic hepati-  tis may present as insidious progressive hepatic failure in a  patient who develops hepatosplenomegaly and evidence of  portal hypertension or ascites.   Maddrey WC. Drug-induced hepatotoxkity 2005. / Clin Gastroenterol.  2005;39:S83-S89. [PMID: 15758665]   The vast majority of drug-induced elevations of serum  aminotransferases occur in minimally symptomatic or  asymptomatic patients who require no treatment. Removal of  the causative agent is generally followed by resolution of the  biochemical abnormalities over several days to weeks. Some  drugs cause a hepatic reaction that mimics autoimmune  injury. Even in these situations, withdrawal of the likely cul-  prit is generally followed by gradual resolution. With some  drugs that cause symptomatic hepatitis, especially if the  increase in aminotransferases is associated with the concomi-  tant presence of clinical jaundice, careful evaluation and often  hospitalization to allow careful monitoring is required.   If drug-induced acute liver failure occurs, the patient  should be viewed as a potential candidate for liver transplan-  tation and referred to a transplant capable center. The estab-  lished treatments of supporting serum glucose, minimizing  infections, and preventing (or treating) hepatic encephalopa-  thy, should be instituted.   Corticosteroid therapy has not definitely been established  to be useful in the treatment of drug-induced liver injury,  although these agents have often been used in patients with  drug-induced liver injuries associated with manifestations of  a hypersensitivity reaction. Examples include the severe liver  injury caused by halothane or the Stevens-Johnson syn-  drome and severe hepatitis, which may be found as part of a  reaction to diphenylhydantoin.   In many patients who have drug-induced hepatocellular  injury, a gradual decrease in the aminotransferase levels  occurs within 1-2 weeks of removing the drug. The decrease  may not occur immediately, especially with drugs whose par-  ent compound or metabolic products accumulate in the  hepatocytes. For the first several days after drug withdrawal,  processes already in place may proceed, causing early con-  cern as to whether the drug was the cause. With some drugs,  continued evidence of liver injury may persist for weeks to  months and cause a pattern of chronic injury. The longer  abnormalities persist, the greater the possibility that perma-  nent hepatic injury will develop or that the diagnosis of a  drug-induced injury was not correct.   Rechallenge with a suspected drug to establish a diagno-  sis of drug- induced injury is seldom necessary and if the ini-  tial event has been severe (such as a presentation with clinical  jaundice and marked elevations of aminotransferases), may  be dangerous.   Acetaminophen hepatotoxicity is the most frequent cause of  acute liver failure in the United States and is likely the cause  of (or a major contributor to) the elevations of aminotrans-  ferases often found on routine evaluation. Ingestion of exces-  sive amounts of acetaminophen (> 10-15 g), widely used in  suicidal attempts, predictably leads to liver injury ranging  from elevated aminotransferases to acute liver failure and in  some patients death or the need for liver transplantation. In  therapeutic doses (< 4 g/day), acetaminophen is usually safe  and well tolerated. However, the safety margin of patients  who are regular users of alcohol appears to be diminished  and these individuals are at increased risk of developing  acetaminophen-induced liver injury.   Factors that predispose patients to hepatic injury from  acetaminophen in nonsuicidal situations include the dose  ingested and whether the patient has been a regular user of  alcohol. First and most important is the dose of acetamino-  phen. Patients may have underestimated or understated the  amount ingested, especially as acetaminophen is present in  many widely used combination products. Ingestion of 4 g of  acetaminophen given as a single agent or in combination  with opioids was shown to elevate aminotransferase levels to  greater than three times the upper limit of normal in  31-44% of healthy individuals. Second is the concomitant  use of alcohol. CYP2E1 is the cytochrome P450 subspecies  involved in the metabolism of ethanol and in the metabolism  of acetaminophen. CYP2E1 is induced in patients regularly  using alcohol, therefore potentially leading to more aceta-  minophen being metabolized to yield the reactive metabolite  N-acetyl-p-benzoquinone imine (NAPQI). In individuals  who are regularly using alcohol, doses of acetaminophen  near or possibly even within the suggested therapeutic range   may lead to liver injury. In addition, the intracellular con-  centration of glutathione (which has the major role in bind-  ing to NAPQI, leading to its excretion as mercapturic acid) is  lowered in patients who regularly use alcohol, further pro-  moting the potential for injury.   Larson AM, Poison J, Fontana RJ, et al. Acetaminophen-induced  acute liver failure: results of a United States multicenter, prospec-  tive study. Hepatology. 2005;42:1364-1372. [PMID: 16317692]   Watkins PB, Kaplowitz N, Slattery IT, et al. Aminotransferase ele-  vations in healthy adults receiving 4 grams of acetaminophen  daily: a randomized controlled trial. JAMA. 2006;296:87-93.  [PMID: 16820551]   Isoniazid (INH) has been an established cause of liver injury  for the past four decades. Elevations of aminotransferase lev-  els are found in 10-20% of patients who receive the drug,  with the onset of these elevations within several weeks of  beginning treatment. In most patients, the elevated amino-  transferase levels are not associated with symptoms sugges-  tive of liver injury and often the levels return to normal  during continued treatment (adaptation). In patients with  elevated ALT levels, discontinuation of INH is usually fol-  lowed by resolution over several weeks. A few patients  develop clinically evident liver disease. Many years of obser-  vation of patients receiving INH allow the following conclu-  sions to be made:   1. Patients older than 50 years are at increased risk of develop-  ing clinically important INH-induced liver injury (~1%).   2. Children younger than age 16 years seldom show evidence  of hepatic injury from INH.   3. Prodromal signs and symptoms are vague and include  loss of appetite. If clinically apparent jaundice develops,  there is an approximately 10% mortality.   4. Continued use of INH after the appearance of even non-  specific symptoms and signs of liver injury and, especially  after the presence of jaundice, is associated with an  increased likelihood of development of severe injury.   5. Patients who have hepatitis B, hepatitis C, and HIV are at  increased risk of developing liver injury from INH.   6. There appears to be an increased risk of INH-induced  hepatic injury in chronic alcoholics.   7. Combining INH with several other drugs also used to  treat tuberculosis (eg, rifampin and pyrazinamide)  increases the likelihood of injury.   There is general agreement that the principal mechanism  of INH-induced hepatic injury stems from the effects of an  intermediary metabolite. The specific toxic intermediate has  not been definitely established but is likely a hydrazine  derivative. Genetic polymorphisms of the genes for N-  acetyltransferase and CYP2E1, both of which have impor-  tant roles in the metabolism of INH, have been shown to   influence susceptibility to INH-induced liver injury. Slow  acetylators of INH by NAT2 are at higher risk of developing  hepatotoxicity than are rapid acetylators and are more likely  to develop severe injury. Individuals who are CYP2E1 cl/cl  (wild type) have more CYP2E1 activity than do those who  are CYP2E1 cl/c2 or c2/c2 and are at increased risk.   Awareness of the risk of INH-induced liver injury and  regular monitoring of aminotransferase levels in patients  receiving the drug have proven effective in identifying evi-  dence of hepatic injury early, at a time when withdrawal of  the drug leads to resolution.   Huang YS, Chern HD, Su WJ, et al. Cytochrome p450 2E1 geno-  type and the susceptibility to antituberculosis drug-induced  hepatitis. Hepatology. 2003;37:924-930. [PMID: 12668988]   Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N-  acetyltransferase 2 gene as a susceptibility risk factor for antitu-  berculosis drug-induced hepatitis. Hepatology. 2002;35: 883-889.  [PMID: 11915035]   Maddrey WC. Drug-induced hepatotoxicity 2005. / Clin Gastroenterol.  2005;39:S83-S89. [PMID: 15758665]   Minocycline, a tetracycline derivative used in the long-term  treatment of acne, has been established to cause several types  of liver damage including acute hepatitis, occasionally with  features of a hypersensitivity reaction including Stevens-  Johnson syndrome, with fever and lymphadenopathy,  chronic hepatitis closely simulating autoimmune hepatitis,  and, rarely, acute liver failure. In some patients, cholestatic  features may be prominent or even predominate.   Of particular interest is a minocycline-induced syndrome  that closely simulates autoimmune hepatitis. The majority of  the affected patients are women who often have taken the  drug for months. Hyperglobulinemia and the presence of  antinuclear antibodies and anti-DNA antibodies are found in  some. The role of minocycline in the causation or unmasking  of an autoimmune hepatitis is important in that misdiagno-  sis and treatment of presumed autoimmune hepatitis type 1  with corticosteroids may mask the minocycline-induced liver  injury, which then progresses relatively unnoticed.   way to the reduction in cholesterol. There have been remark-  ably few instances of clinically significant liver injury reliably  attributable to statins. The risk of statin-induced acute liver  failure is less than 1 in 1 million, and cases of statin-induced  significant liver injury are rarely found in large series of  patients with acute liver failure.   In asymptomatic patients who have elevations of amino-  transferases, withdrawing the statin is followed by a return of  ALT to normal. In some patients, adaptation occurs during  continued treatment or treatment with a reduced dose.  Increases of bilirubin associated with the elevations of amino-  transferases are extremely uncommon and, if observed, are  matters of concern.   There is no convincing evidence that patients with abnor-  mal baseline aminotransferase levels, underlying steatohepati-  tis, or chronic hepatitis C are at increased risk of hepatotoxicity  from statins. A few reports suggesting autoimmune hepatitis  may be triggered by statins have been reported.   Ezetimibe, an inhibitor of intestinal uptake of intestinal  and biliary cholesterol, is another agent widely used to lower  cholesterol and is often given along with a statin. There have  been isolated reports of ezetimibe in individual hepatic  injury. Overall, the agent has an excellent safety record.   Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated  liver enzymes are not at higher risk for statin hepatotoxicity.  Gastroenterology. 2004;126:1287-1292. [PMID: 15131789]   Cohen DE, Anania FA, Chalasani N. An assessment of statin safety  by hepatologists. Am ] Cardiol. 2006;97:77C-81C. [PMID:  16581333]   Larson AM, Poison J, Fontana RJ, et al. Acetaminophen-induced  acute liver failure: results of a United States multicenter,  prospective study. Hepatology. 2005;42:1364-1372. [PMID:  16317692]   Stolk MF, Becx MC, Kuypers KC, et al. Severe hepatic side effects  of ezetimibe. Clin Gastroenterol Hepatol. 2006;4:908-911.  [PMID: 16797241]   Tolman KG. The liver and lovastatin. Am J Cardiol. 2002;89:  1374-1380. [PMID: 12062731]   Vuppalanchi RA, Teal E, Chalasani N. Patients with elevated base-  line liver enzymes do not have higher frequency of hepatotoxi-  city from lovastatin than those with normal baseline liver  enzymes. Am } Med Sci. 2005;329:62-65. [PMID: 15711421]   The era of the widespread often long-term use of statin drugs  to lower low-density lipoprotein and cholesterol levels  through inhibition of HMG-CoA began in the 1980s.  Millions of patients have received these drugs. Increases of  aminotransferase level to more than three times the upper  limit of normal occur in 1-3% of patients receiving statins,  and in several series the extent of the elevation appears  directly related to the dose.   Statin-induced aminotransferase elevations are noted  within weeks to months of initiating therapy, and the  increases appear to be linked in some as yet undetermined   Hepatotoxicity from the widely used combination of amoxi-  cillin and clavulanic acid has been recognized and is  attributed to the clavulanic acid component. In large series  of drug-induced injury from around the world, amoxicillin-  clavulanate is among the most frequently identified drugs  causing liver injury.   The frequency of hepatic injury from amoxicillin-clavulanate  is low (-1-3 in 100,000), and the range of clinical and labo-  ratory manifestations is broad. Because the drug is generally  used as short duration therapy (7-10 days), and the appear-  ance of evidence of liver injury is often delayed for weeks after   initiation of therapy, many cases of hepatic injury appear well  after the course of the therapy has been completed and the  role of amoxicillin-clavulanate may be overlooked. The types  of liver injury from amoxicillin-clavulanate include hepato-  cellular necrosis, cholestatic reactions and, in some patients,  a mixed hepatocellular-cholestatic presentation. Some  patients (one to two thirds) have signs of hypersensitivity,  with rash and fever at the time hepatic injury is recognized,  whereas others present with jaundice and evidence of a  bland cholestasis. In general, the liver injury from amoxicillin-  clavulanate is mild and self-limiting, with a gradual and  complete resolution of the process over several days to weeks.   Advancing age and prolonged therapy are factors associated  with the development of the cholestatic injury.  Predominantly hepatocellular injury is more frequent in  younger patients. A few instances of severe hepatocellular  injury leading to death or the need for transplantation have  been reported.   The increased used of imaging modalities — ultrasound, com-  puted tomography (CT), and magnetic resonance imaging  (MRI) — over the past few decades has led to an increase in the  detection of hepatic masses. In the noncirrhotic patient or in  patients with no history of extrahepatic malignancies, most of  these lesions are benign. Diagnosis is often made on the basis  of radiographic appearance and only in rare equivocal cases is  histologic analysis required. In patients with cirrhosis or those  with chronic hepatitis B infections, the detection of a hepatic  mass often raises the suspicion of a hepatocellular cancer and  frequently additional diagnostic (including histologic) and  therapeutic interventions are necessary.   Liver lesions are often classified on the basis of appearance  (cystic or solid) and histologic composition (hepatocellular  or biliary). They can also be classified based on malignant  potential (benign or malignant), and when, malignant, can be  classified based on origin of the cancerous cells (primary or  metastatic). In adults, malignant tumors are more common  than benign tumors and metastatic lesions account for most  forms of liver neoplasms. The differential diagnosis of liver  lesions includes benign lesions (eg, hemangioma, focal nodu-  lar hyperplasia, adenoma, focal regenerative hyperplasia, sim-  ple hepatic cysts, polycystic liver disease, bile ductular  cystadenoma, and bile ductular hamartomas) and malignant  lesions (eg, primary hepatocellular cancer, cholangiocarci-  noma, metastatic tumors, lymphoma).   Blonski W, Reddy KR. Evaluation of nonmalignant liver masses.  Curr Gastroenterol Rep. 2006;8:38-45. [PMID: 16510033]   ► Cavernous hemangiomas, focal nodular hyperplasia,  hepatic adenomas, and nodular regenerative hyperpla-  sia are the most common benign tumors of the liver.   ► Cavernous hemangiomas are usually asymptomatic and  can be identified by their classic appearance on CT  and MRI.   ► Focal nodular hyperplasia is common in young women  and can be identified by the presence of a central stel-  late scar on CT or MRI.   ► Hepatic adenomas are common in women of childbear-  ing age, especially after prolonged oral contraceptive  use. Because necrosis, hemorrhage, or rupture can  occur, they should be surgical excised when identified.   ► Nodular regenerative hyperplasia is associated with  many systemic illnesses. Patients present with signs of  portal hypertension. Radiographic characteristics are  nonspecific, and histologic evaluation shows no fibrosis.   In clinical practice the most commonly encountered lesions  are cavernous hemangiomas, focal nodular hyperplasia (FNH),  hepatic adenoma, and nodular regenerative hyperplasia.   Mortele KJ, Ros P. Benign liver neoplasms. Clin Liver Dis.  2002;6:119-145. [PMID: 11933585]   This is the most common benign lesion of the liver, with a  prevalence that ranges from 1% to 20% of the general popu-  lation. Approximately two thirds of all cavernous heman-  giomas are found in the right lobe of the liver, and more than  90% are solitary. More than 80% occur in women. Although  lesions can be small (often < 1 cm), larger lesions, especially  those greater than 4 cm (giant hemangiomas), also occur;  some can be as large as 25 cm (Figure 49-1).   Findings on laboratory evaluation are usually normal, but  signs of portal hypertension such as thrombocytopenia may be    ▲ Figure 49-1. Magnetic resonance images of a 25-cm giant hemangioma of the left hepatic lobe. The lesion is very  bright on the T2-weighted image (A) but dark on the T1 precontrast image (B). Dynamic postgadolinium images show  gradual nodular enhancement from the periphery to the center of the lesion on early arterial (C), late arterial (D), and  delayed phase views (E). Arrows in B indicate the area of the hemangioma. (Courtesy of Dr Cheryl Sadow, Department  of Radiology, Brigham and Women's Hospital.)   noted in patients with very large hemangiomas. The diagnos-  tic modalities available include ultrasound, CT, and MRI.  Ultrasound has sensitivity of 60-70% and specificity of  60-80% for detection of hemangiomas. Because of nonspecific  findings on ultrasound, contrast-enhanced CT or MRI is often  necessary for diagnosis of cavernous hemangiomas.   On CT scan, the lesions are characterized by progressive  enhancement during the arterial phase that begins at the  periphery of the lesion and progresses inward. The intensity  of enhancement during this arterial phase resembles that of  the aorta. Small hemangiomas are difficult to diagnose on  contrast-enhanced CT because of inability to detect the step-  wise enhancement seen in larger lesions. Because of this  apparent homogenous enhancement, they may resemble  hypervascular liver masses. Overall, the sensitivity of contrast-  enhanced CT for diagnosis of cavernous hemangiomas is  estimated at around 90%, with specificity of around 90%.   On MRI, cavernous hemangiomas appear hypodense on  Tl-weighted images, hyperdense on T2, and with gadolin-  ium show the classic peripheral enhancement with progres-  sive inward enhancement (see Figure 49-1).   Most cavernous hemangiomas are asymptomatic. They are  usually discovered during abdominal imaging for unrelated  symptoms. Treatment is usually not necessary, and there is  often no need for continued surveillance. In the few  instances where lesions are very large (> 10 cm), symptoms  such as nausea, vomiting, and early satiety can occur. In  these cases, surgical resection can be performed to alleviate  symptoms.   A common benign lesion of the liver, FNH is seen in 0.9% of  the population. It is the second most common hepatic lesion  after cavernous hemangiomas. FNH is more common in  women, occurring with a frequency of 8:1. Lesions are most  often solitary, but approximately 20% of patients have multi-  ple lesions.   The mechanisms underlying development of FNH are not  well understood. It has been suggested that proliferation of  hepatocytes secondary to vascular malformation or vascular  injury may lead to FNH. Given the higher incidence in  women, a correlative link has been made to the use of oral  contraceptive pills (OCPs). However, data suggesting a  causative link or even the influence of OCPs on the growth of  FNH are controversial. Indeed, many clinicians believe there is  no link.   In more than 70% of patients with FNH, lesions are detected  incidentally. In the remaining patients, symptoms (especially  right upper quadrant discomfort) prompt evaluation. FNH  can be classified into two broad categories: the more preva-  lent classic FNH, and nonclassic FNH. Classic lesions are  nodular, vascular lesions with bile duct proliferation.  Radiographically, the lesions are often identified by the pres-  ence of a central scar; however, 95% of nonclassic lesions lack  this feature. Histologically, the lesions are well circumscribed  with proliferating hepatocytes and Kupffer cells. A central  vascular scar is invariably present in the classic form of FNH.   Ultrasound can be used for the diagnosis of FNH. The cen-  tral scar is seen on only 20% of ultrasounds. Doppler imaging  shows increased blood flow with a pattern of abnormal blood  vessels that emanate radially from a central feeding artery  ("spoke-wheeling"). Because ultrasound is not considered the  preferred diagnostic modality to rule out FNH, additional  imaging with CT or MRI is usually the norm.   On contrast-enhanced CT, the lesion is isodense with the  liver on precontrast and postcontrast images but shows  homogenous enhancement during the arterial phase, along  with the central scar (Figure 49-2). Figure 49-3 shows the typ-  ical MRI features of FNH. The lesion is isointense in T2-  weighted images with a bright central scar (see Figure 49-3 A).   It is isointense or hypointense with a central dark scar on Tl-  weighted images (see Figure 49-3B), homogenously vascular  except for the central scar in the arterial phase (see Figure  49-3C), isointense in the portal phase (see Figure 49-3D), and  shows subsequent delayed enhancement of the central scar  (see Figure 49-3E).   There is no indication to treat a patient with asymptomatic  FNH because malignant transformation is not felt to occur  with typical FNH lesions. Symptoms caused by FNH are  present in 30% of patients. These patients often present with  right upper quadrant pain. Surgical resection is indicated if  patients have pain that is felt to be secondary to the FNH  lesions, or if there is doubt about the diagnosis of FNH.   Mathieu D, Kobeiter H, Maison P, et al. Oral contraceptive use and  focal nodular hyperplasia of the liver. Gastroenterology.  2000;118:560-564. [PMID: 10702207]   Nguyen BN, Flejou JF, Terris B, et al. Focal nodular hyperplasia of  the liver: a comprehensive pathology study of 305 lesions and  recognition of new histologic forms. Am J Surg Path.  1999;23:1441-1454. [PMID: 10584697]   Nino-Murcia M, Olcott EW, leffrey RB Ir, et al. Focal liver lesions:  pattern- based classification scheme for enhancement at arterial  phase CT. Radiology. 2000;215:746-751. [PMID: 10831693]   This rare liver tumor is most commonly diagnosed in women  aged 20-40 years. The major risk factors are OCP use, glyco-  gen storage diseases, diabetes, and androgen use. Among  patients who use OCPs there is a 30-fold increase in prevalence  of hepatic adenomas. The tumors are usually solitary and  increase in size during states of enhanced estrogen levels, such  as pregnancy and OCP use (see Figure 9-28). Of note, hepatic    A Figure 49-2. Computed tomographic scans of focal nodular hyperplasia. The lesions are barely visible in the early  arterial phase image (A) and not visible in the postvenous phase (C) but can be detected as two homogenous hyper-  vascular images in the late arterial phase with contrast (B, arrows). A central scar is present. (Courtesy of Dr Cheryl  Sadow, Department of Radiology, Brigham and Women's Hospital.)    ▲ Figure 49-3. Magnetic resonance images of focal nodular hyperplasia. The lesion is isointense with the liver on the  T2-weighted image, but a bright scar is visible (A). On the T1-weighted precontrast image, the lesion remains isoin-  tense to slightly hypointense with liver, but a dark central scar is visible (B). Dynamic postgadolinium T1 image shows  a homogenous hypervascular lesion except for a dark central scar (C). The lesion becomes isointense in the portove-  nous phase (D), with delayed enhancement of the central scar (E). Arrows indicate the location of the lesion. (Courtesy  of Dr Cheryl Sadow, Department of Radiology, Brigham and Women's Hospital.)   adenomatosis is a distinct entity from hepatic adenomas.  Although the former syndrome is characterized by the pres-  ence of multiple hepatic adenomas, there is no association  with OCP use and it occurs equally in men and women. In  addition, laboratory data usually show an elevated alkaline  phosphatase level.   In approximately 20% of cases, hepatic adenomas are  detected during radiographic imaging for unrelated issues in  asymptomatic patients. However, many patients present with  abdominal pain due to encroachment on neighboring tissue  or overt hemorrhage of the tumor. Laboratory evaluation is  usually normal in patients without hemorrhage. Histologic  evaluation of hepatic adenomas often shows a circumscribed  capsular tumor containing hepatocytes that appear normal  but are architecturally distorted in that bile ducts, portal  venous tracts, and terminal hepatic veins are absent. The  lesion often has a high fat and glycogen content, and necro-  sis and frank hemorrhage may be present.   Ultrasonographic evaluation can show a hyperechoic mass  due to the intracellular fat, with areas that are hypoechoic as a  result of hemorrhage. In the absence of contrast, CT usually   shows a lesion hypodense to the liver parenchyma if there is no  intramural blood. With contrast there is brisk, early enhance-  ment as a result of the vascular nature of the tumor followed  by an equally brisk washout due to arteriovenous shunting.  On MRI, hepatic adenomas appear as hyperintense lesions on  T2-weighted images (Figure 49-4A). On postgadolinium  images, they show early arterial enhancement that rapidly  washes out (Figure 49-4B and 4C).   Unlike the other benign hepatic lesions, hepatic adenomas  produce significant associated morbidity. The lesion can lead  to life-threatening hemorrhage due to tumor necrosis and  rupture. In addition, hepatic adenomas have the potential for  malignant transformation. Although adenomas may be dis-  covered incidentally, right upper pain due to encroachment on  neighboring tissues or from necrosis is common. Shock from  hemorrhage resulting from rupture is a life-threatening emer-  gency that requires emergent resuscitation and surgical  therapy. For asymptomatic patients, surgical resection of the  adenoma is the therapy of choice. OCPs can be stopped and  lesions followed expectantly; however, such an approach is  best in patients in whom surgical excision is not a valid option.    A Figure 49-4. Magnetic resonance images of hepatic adenoma: T2-weighted images (A) show three heterogenous  masses (arrows). Dynamic postgadolinium T1 images shows early arterial enhancement (B and C) with washout in the  delayed image (D). (Courtesy of Dr Koenraad Mortele, Department of Radiology, Brigham and Women's Hospital.)   This is a disorder characterized by benign proliferation of  hepatocytes, resulting in nodules that range in size from  0.1 cm to 1 cm. It is associated with many systemic diseases,  including but not limited to rheumatoid arthritis, Felty syn-  drome, Raynaud phenomena, myeloproliferative diseases,  lupus erythematosus, polyarthritis nodosa, hereditary hem-  orrhagic telangiectasia, and amyloidosis, as well as with ana-  bolic steroid use.   Patients often present with marked signs of portal hyperten-  sion, esophageal varices, upper gastrointestinal bleeding,  thrombocytopenia, and ascites. Radiologic appearance is  nonspecific, showing multiple nodules throughout the liver   that can be confused with cirrhosis. However, histologic eval-  uation shows nodules that have no associated fibrosis.   Treatment focuses on management of the complications of  associated portal hypertension and hepatic dysfunction, as  discussed in Chapters 44 to 47.   Predisposing conditions include hepatitis B with or with-  out cirrhosis, cirrhosis from hepatitis C, alcoholic liver dis-  ease, hemochromatosis, primary biliary cirrhosis, and  possibly ^-antitrypsin deficiency and nonalcoholic  steatohepatitis.   ► Screening and surveillance programs for early detection  use ultrasound with or without a-fetoprotein every  6-12 months.   ► CT or MRI of suspicious lesions can identify typical radi-  ographic characteristics.   In the United States, hepatocellular carcinoma (HCC) has an  incidence of approximately 2.4 in 100,000 persons. Globally,  it is the fourth most common cancer, with a much greater  incidence in the Middle East and Africa. Interestingly, during  the past few decades the average age at occurrence of cancer  has decreased.   1. Hepatitis B — HCC occurs at a rate of 2.5% per year in  patients who have hepatitis B with cirrhosis. Even among  patients without cirrhosis who are only carriers of hepatitis B  virus (HBV), the incidence ranges between 0.5 and 1.0%  annually. Older age groups appear to be at the highest risk of  developing HCC. Asians, Africans, and patients with HBV  infections acquired through vertical transmission are also at  increased risk of developing HCC. In contrast, North  Americans and Europeans have a lower incidence of HCC,  with various cohorts reporting rates of 0-0.46% per year. The  difference in HCC rates may be related to the acquisition of  the HBV infection later in life among non-Asian and non-  African patients. Interestingly, among Asian patients who lose  the HBV surface antigen, the risk of HCC remains unchanged.  Based on the increased risk of HCC among HBV-infected  patients, surveillance is recommended (Table 49-1).   2. Hepatitis C — Patients with hepatitis C are at the highest  risk of developing HCC. Various studies have shown the inci-  dence of HCC to be between 2% and 8% per year. Although  individuals infected with hepatitis C virus (HCV) who have  bridging fibrosis, but not cirrhosis, may be at risk for HCC,  this risk appears to be very low. All patients with hepatitis C  and cirrhosis should undergo surveillance. Whether patients  with bridging fibrosis should undergo screening is currently  controversial.   3. Alcoholic liver disease— The annual incidence of HCC  in patients with purely alcoholic liver disease is not entirely  clear. However, based on available data, it appears the inci-  dence may be in the range of HCV-related cirrhosis, and sur-  veillance is recommended.   4. Nonalcoholic steatohepatitis— The exact incidence of  HCC in patients with nonalcoholic steatohepatitis (NASH) is  unknown. Diabetes mellitus, a condition commonly associ-  ated with NASH, was found to be a risk factor for HCC.  Whether this suggests that NASH patients are at higher risk   Table 49-1. Recommended surveillance for patients at  risk for hepatocellular carcinoma (level III 3 ).   For noncirrhotic hepatitis B carriers not listed above, risk of HCC  varies depending on severity of underlying liver disease and  current and past hepatic inflammatory activity; patients with  high HBV DNA concentrations and those with ongoing hepatic  inflammatory activity remain at risk for HCC  Non-hepatitis B cirrhosis   Although the following groups have an increased risk of HCC  no recommendations for or against surveillance can be made  because lack of data precludes assessment of whether  surveillance would be beneficial:   HBV, hepatitis B virus; HCC, hepatocellular carcinoma.  'American Association for the Study of Liver Diseases level III:  opinion of respected authorities, descriptive epidemiology.  Reproduced, with permission, from Bruix J, Sherman M; Practice  Guidelines Committee; American Association for the Study of Liver  Diseases. Management of hepatocellular carcinoma. Hepatology.  2005;42:1210.   of developing HCC is not clear, but surveillance of NASH  patients with cirrhosis is recommended.   5. Genetic or inherited liver diseases— Patients with  hemochromatosis who develop cirrhosis have an increased  incidence of HCC that is reported to be 3-4% per year. In  contrast, in Wilson disease and oCj-antitrypsin deficiency, the  incidence rates of HCC are not at present very clear. HCC  has been reported in patients who have aj-antitrypsin defi-  ciency with or without cirrhosis. In Wilson disease, the inci-  dence of HCC is exceedingly low. Surveillance of patients  with hemochromatosis and cirrhosis is recommended. For  patients with cXj -antitrypsin deficiency, the American  Association for the Study of Liver Diseases (AASLD) does  not recommend surveillance due to insufficient data. Lastly,  patients with hereditary tyrosinemia can develop HCC and  in one study, primary liver cancers occurred in up to 40% of  patients.   HCC surveillance of patients with primary biliary cirrhosis  who are cirrhotic is recommended based on a study that shows   an incidence similar to that of patients with HCV cirrhosis.  The association between autoimmune hepatitis and HCC is  not clear, but case reports have illustrated the occurrence of  HCC in such patients with cirrhosis. Although surveillance of  patients with autoimmune hepatitis and cirrhosis is not rec-  ommended, most practitioners do so because of a concern  that cirrhosis in all forms elevates the risk of HCC.   7. Other conditions — Anatoxin, produced by Aspergillus  flavus, is clearly associated with HCC, particularly among  patients infected with HBV.   8. Fibrolamellar hepatocellular carcinoma— This tumor,  which is a distinct primary HCC, tends to occur in patients  without cirrhosis who are in their 20s to 40s. The long-  term prognosis is generally good with either resection or  transplantation.   Degos F, Christidis C, Ganne-Carrie F, et al. Hepatitis C virus  related cirrhosis: time to occurrence of hepatocellular carci-  noma and death. Gut. 2000;47:131-136. [PMID: 10861275]   Elmberg M, Hultzcrantz R, Ekbom A, et al. Cancer risk in patients  with hereditary hemochromatosis and in their first-degree rela-  tives. Gastroenterology. 2003;125:1733-1741. [PMID: 14724826]   El-Serag HB, Mason AC. Rising incidence of hepatocellular carci-  noma in the United States. N Engl J Med. 1999;340:745-750.  [PMID: 10072408]   El-Serag HB, Mason AC. Risk factors for the rising rates of primary  liver cancer in the United States. Arch Intern Med. 2000;  160:3227-3230. [PMID: 11088082]   Hassan MM, Hwang LY, Hatlen CJ, et al. Risk factors for hepatocel-  lular carcinoma: synergism of alcohol with viral hepatitis and  diabetes mellitus. Hepatology. 2002;36:1206-1213. [PMID:  12395331]   Sherman M. Hepatocellular carcinoma: epidemiology, risk factors,  and screening. Semin Liver Dis. 2005;25:143-154. [PMID:  15918143]   Shibuya A, Tanaka K, Miyakawa H, et al. Hepatocellular carcinoma  and survival in patients with primary biliary cirrhosis.  Hepatology. 2002;35:1172-1178. [PMID: 11981767]   Owing to the increased risk of HCC in certain populations  (ie, HCC risk > 1 .5% per year for non-HBV cirrhosis, > 0.2% for  HBV carriers), surveillance measures have been implemented,  often using a combination of serologic and radiologic tests.   In the one large-scale study performed to date, from China,  18,816 patients were randomized to either surveillance with  ultrasound and a-fetoprotein every 6 months or no monitor-  ing. A 37% decrease in HCC-related mortality was noted in  those who were screened compared with the unscreened  cohort. The 1-, 3-, and 5 -year mortality rates in the screened  group were 66%, 53%, and 46% compared with rates of 31%,  7%, and 0%, respectively, in the control group. These data need  further confirmatory studies. However, based on the premise  that early diagnosis of HCC will lead to early treatment and  reduction in mortality, surveillance measures are widely imple-  mented in the patients groups identified in Table 49-1.   1. Serologic screening — A persistently elevated a-fetoprotein  level is a risk factor for subsequent HCC. Absolute a-fetoprotein  levels have inadequate sensitivity and specificity to detect HCC.  However, very high (> 500 ng/mL) levels are generally associ-  ated with the presence of HCC, and if a mass is identified on  subsequent imaging, biopsy is not necessarily needed to confirm  the diagnosis. Other serologic studies such as des-y-carboxy  prothrombin (an abnormal prothrombin induced in patients  deficient in vitamin K), glycosylated a-fetoprotein ratio, a-  fucosidase, and glypican 3 need further investigation before  being considered for HCC screening.   2. Radiographic imaging— Ultrasound is widely used for  HCC surveillance. On ultrasonography either a hyperechoic  or a hypoechoic lesion can be seen. Ultrasound has low sen-  sitivity (-65%) but excellent specificity for the detection of  liver lesions (> 90%). However, there is concern that its accu-  racy may be limited in obese individuals and in those with  multiple cirrhotic nodules.   HCC surveillance is recommended in at-risk populations,  with ultrasonography performed every 6-12 months. Most  hepatologists, however, use a combination of ultrasonogra-  phy and a-fetoprotein every 6 months for surveillance. If a  lesion greater than 1 cm is identified or a previously known  nodule enlarges, further diagnostic evaluation with either  contrast-enhanced CT or MRI should be performed.   Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of  screening for hepatocellular carcinoma. / Cancer Res Clin Oncol.  2004;130:417-422. [PMID: 15042359]   Because a significant fraction of patients with HCC are being  diagnosed at early stages due to surveillance, many are  asymptomatic at presentation. However, any patient with  compensated cirrhosis who suddenly develops signs and  symptoms of worsening hepatic function should undergo  appropriate studies to exclude the development of HCC.   Among the patients who present with symptoms, weight  loss, fatigue, anorexia, right upper quadrant pain, jaundice, and  pruritus may be noted. Patients may also present with variceal  hemorrhage, ascites, or hepatic encephalopathy. Physical exam-  ination findings often show stigmata of portal hypertension  and cirrhosis. Occasionally, hepatomegaly may be present. In  patients suspected of having HCC who present with peritoneal  signs, hemoperitoneum should be suspected as a consequence  of hemorrhage related to the tumor. Additional clinical find-  ings may be secondary to associated paraneoplastic syndromes,  including hypercholesterolemia, cryoglobulinemia, carcinoid  syndrome, hypercalcemia, dysfibrinogenemia, erythrocytosis,  and hypoglycemia.   With the exception of an a-fetoprotein, laboratory testing is  generally not very useful and radiographic studies are   required to make a diagnosis. Nevertheless, the diagnosis of  HCC can be made using a combination of radiographic, lab-  oratory, or pathologic studies. The size of the tumor influ-  ences the diagnostic evaluation.   1. Lesions larger than 2 cm— A nodule greater than 2 cm in  size that has radiographic characteristics typical of HCC  (ie, early arterial enhancement) usually is HCC; in such cases,  a biopsy to confirm the diagnosis is not generally required.  Many medical societies advocate confirmation by a second  imaging modality and, if confirmed, initiation of treatment  for HCC. Similarly, if a mass with characteristics typical of  HCC is found on one imaging study and the oc-fetoprotein  level is greater than 200 ng/mL, a biopsy is not recommended  and treatment of HCC is advised. In all other scenarios, a liver  mass biopsy is recommended to obtain a diagnosis.   2. Lesions 1-2 cm in size — These lesions are most often  identified on routine HCC surveillance with ultrasound.  Contrast-enhanced CT, MRI, or both are recommended for  better characterization. If both studies confirm HCC, by  showing typical imaging characteristics, then treatment for  HCC may be initiated. Patients who are candidates for liver  transplantation typically do not undergo the procedure until  lesions are larger than 2 cm. Many centers monitor the size of  lesions and list patients once the size criterion is met. It is not  unusual for the imaging results to be equivocal. In these  instances, a liver mass biopsy is recommended. If a negative  result is obtained in an individual with risk factors for HCC  (eg, chronic HBV infection or cirrhosis), then enhanced follow-  up with MRI or CT is recommended at a very short interval  to ensure stability of the lesion.   3. Lesions smaller than 1 cm — These lesions have a very  low probability of being HCC. The AASLD recommends an  ultrasound every 3-4 months for up to 2 years and if no  growth is documented, reverting back to typical HCC surveil-  lance guidelines thereafter. Alternatively, if the lesion enlarges,  additional diagnostic testing with CT, MRI, or biopsy is  recommended.   4. Metastases — Many patients with HCC have metastases  to the portal and hepatic veins and inferior vena cava.  Metastases to the portal, pancreatic, and para-aortic lymph  nodes have also been reported. Other sites of metastasis  include the lung, bone, myocardium, and adrenal gland.  Imaging by Doppler ultrasound, contrast-enhanced CT, or  MRI can be used to identify a thrombus in the major vessels.  A contrast-enhanced CT or MRI scan is often required for  nodal involvement.   The differential diagnosis of HCC is very broad and includes  benign and malignant lesions. Among these are cholangiocar-  cinoma, hepatic adenoma, hemangioma, FNH, cystic neo-  plasms, metastatic tumors, peliosis hepatis, and lymphoma.   Therapeutic management of HCC is influenced by the tumor  size and extent, underlying liver function, and the patient's  performance status. The best system of staging patients,  appears to be the Barcelona Clinic Liver Cancer Proposal  (Figure 49-5). Treatment options include resection, trans-  plantation, percutaneous ablation, transarterial emboliza-  tion, chemotherapy, and radiation.   Bruix J, Sherman M. Practice Guidelines Committee, American  Association for the Study of Liver Diseases. Management of  hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.  [PMID: 1625051]   Surgical resection is an option in patients with HCC who do  not have underlying cirrhosis. However, this constitutes only a  small proportion of patients with HCC. Studies have shown  that surgical resection may be a viable option for carefully cho-  sen patients with cirrhosis. Based on available data, it appears  that patients who have compensated cirrhosis with a normal  bilirubin and hepatovenous portal gradient (discussed in  Chapter 47) less than 10 mm Hg may be appropriate candi-  dates provided there is only a solitary tumor. Even with such  strict selection of patients with cirrhosis, the risk of hepatic  decompensation after surgery is approximately 30%.   After resection, the recurrence rate is approximately 70%.  Clinical studies have not shown any presurgical or postsurgi-  cal adjuvant therapies to be effective; thus, adjuvant therapy  is not usually recommended.   Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contribut-  ing to early and late phase intrahepatic recurrence of hepatocel-  lular carcinoma after hepatectomy. J Hepatol. 2003;38:200-207.  [PMID: 12547409]   Both cadaveric and live donor liver transplantation have  been used in patients with HCC. Based on the Milano crite-  ria, carefully chosen patients with HCC who undergo liver  transplantation have a 5-year survival rate of 70%. The  patients who fulfill these criteria usually have a solitary nod-  ule no more than 5 cm in size or three nodules each no more  than 3 cm and no evidence of metastasis. The United  Network for Organ Sharing (UNOS) has created a priority  system for such patients. However, as previously noted,  lesions need to be larger than 2 cm for the Model for End-  Stage Liver Disease (MELD) points (the system used for pri-  oritizing transplant necessity, discussed in Chapter 50) to be  awarded. For patients who meet the criteria, a MELD score of  22 is given at the time of listing with an increase in the MELD  score every 3 months while on the waiting list.   In many transplant systems, the wait time can be long even  with the priority MELD system, extending up to 12 months or  more. Most centers with wait times greater than 6 months   ▲ Figure 49-5. Algorithm for staging and management of hepatocellular carcinoma (HCC). CLT, cadaver liver transplantation; LDLT, living donor liver  transplantation; M, metastasis; N, node; PEI, percutaneous ethanol injection; PS, performance status; PST, performance status test; RF, radiofrequency  (ablation). (Reproduced, with permission, from BruixJ, Sherman M; Practice Guidelines Committee; American Association for the Study of Liver Diseases.  Management of hepatocellular carcinoma. Hepatology. 2005 ; 42:1210.)   practice some form of preoperative therapy. For patients with  small tumors, percutaneous ablative techniques using either  radiofrequency ablation or ethanol can be considered. The  major concerns with these techniques are hemorrhage, liver  failure, and tumor seeding. For patients with larger tumors,  transarterial chemoembolization can be considered. This tech-  nique is associated with a significant risk of hepatic decom-  pensation and liver failure.   Llovet JM, Bra C, Bruix J. Prognosis of hepatocellular carcinoma:  the BCLC staging classification. Semin Liver Dis. 1999;19:  329-338. [PMID: 10518312]   Percutaneous ablative techniques for HCC using either  ethanol or radiofrequency remain a viable option as either a  bridge to transplant or for poor surgical candidates. The 5-  year survival rate is satisfactory, particularly for tumors  smaller than 2 cm, and can be as high as 50%. The major  risks with this procedure are hemorrhage, hemoperitoneum,  and seeding of the needle track.   Sala M, Llovet JM, Vilan R, et al. Barcelona Clinic Liver Cancer  Group. Initial response to percutaneous ablation predicts sur-  vival in patients with hepatocellular carcinoma. Hepatology.  2004;40:1352-1360. [PMID: 15565564]   Transarterial embolization appears to be the only effective  noncurative option for a certain subset of patients with HCC.  Candidates without evidence of vascular or metastatic disease  or portosystemic shunting can be considered for the proce-  dure. Liver failure after embolization is a major risk. Patients  with advanced liver disease are at greater risk of morbidity and  mortality with the procedure. Chemotherapeutic agents such  as doxorubicin and cisplatin can be administered directly into  the arterial branches supplying the tumor; in such cases, the  procedure is called transarterial chemoembolization. Survival  rates up to 60% have been reported with this intervention.  Side effects related to the procedure include liver failure,  chemotherapeutic side effects, and postembolization syn-  drome related to hepatic artery occlusion.   Bruix J, Sala M, Llovet IM. Chemoembolization for hepatocellular  carcinoma. Gastroenterology. 2004;127(Suppl 1):S179— 188.  [PMID: 15508083]   Generally, chemotherapy and radiation therapy have not had  much of a role in the treatment of HCC. However, recent  studies suggest that sorafenib may be an effective palliative  option. In a recent phase III multicenter, randomized,  placebo-controlled trial of 602 patients, overall survival was  improved with sorafenib. Serious side effects were rare, and  common side effects included diarrhea, fatigue, and hand-  foot skin reaction.   Llovet IM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study  Group. Sorafenib in advanced hepatocellular carcinoma. N Engl  J Med. 2008;359:378-390 [PMID: 18650514]   ► Risk factors include biliary and liver diseases (eg, pri-  mary sclerosing cholangitis [PSC], choledocholithiasis,  hepatolithiasis, hepatitis C), chronic parasitic infection,  and typhoid carrier state.   ► Diagnosis usually requires abdominal imaging and tis-  sue sampling either by percutaneous biopsy or ERCP.   Although the incidence of cholangiocarcinoma is increasing  globally, it remains a rare cancer with an incidence of  approximately 8 per million persons.   The risk factors for cholangiocarcinoma include PSC,  choledocholithiasis, hepatolithiasis, choledochal cyst, Caroli  disease, bile duct adenoma, thorotrast, HCV infection,  chronic parasitic infection, and typhoid carrier state. Age and  smoking are also risk factors.   Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma.  Semin Liver Dis. 2004;24:115-125. [PMID: 15192785]   Patients may be asymptomatic, with abnormal findings that  are discovered incidentally on liver biochemical or imaging  tests. Alternatively, symptoms maybe present especially those  suggestive of biliary obstruction or hepatic decompensation.  Extrahepatic cholangiocarcinoma typically presents with  obstructive symptoms.   Abdominal imaging with either CT or MRI is required.  Endoscopic retrograde cholangiopancreatography (ERCP)  with cytologic brushing of the biliary tree may be required.  The role of serologic testing is not entirely clear, but of the  many markers, CA 19-9 may be of some clinical use. Its sen-  sitivity seems to be better in PSC than in non-PSC patients  with cholangiocarcinoma when a level of 100 IU/mL is used  as a cutoff.   Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in  understanding a deadly old disease. J Hepatol. 2006;45:856-867.  [PMID: 17030071]   The differential diagnosis is similar to that of HCC (see ear-  lier discussion).   The best treatment option in cholangiocarcinoma is surgical  resection, but even when patients are carefully selected, the  5-year survival rate is only 20-45%. The absence of positive  lymph nodes, a clear resection margin (> 1 cm), lack of vas-  cular invasion, and single lesions are the predictors of good  response to surgery. Patients with compromised liver func-  tion, PSC, and bilobar involvement are not candidates for  surgical resection and transplantation may be considered.  However, due to the high rate of disease recurrence, trans-  plantation is generally not associated with good outcomes. A  recent protocol using neoadjuvant chemotherapy and radia-  tion followed by exploratory laparotomy to confirm down-  staging of the tumor and subsequent liver transplantation is  reported to be associated with a good prognosis. Further  studies evaluating this approach are necessary prior to its  widespread use. Otherwise, there appears to be minimal  response to chemotherapy and radiation in this disease.   Most patients who present with cholangiocarcinoma are  not candidates for curative therapy but require palliation.  Biliary obstruction is a common complication of this disease,  and decompression using endoscopic, percutaneous, or surgi-  cal approaches is often necessary. There is interest in photody-  namic therapy, but further confirmatory studies are needed.   Overall, the prognosis is poor. Most patients develop liver  failure or biliary complications, resulting in a 5-year survival  rate of approximately 5%.   Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability,  and outcome in 225 patients with hilar cholangiocarcinoma.  Ann Surg. 2001;234:507-517. [PMID: 11573044]   Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with  neoadjuvant chemoradiation is more effective than resection  for hilar cholangiocarcinoma. Ann Surg. 2005;242:451-458.  [PMID: 16135931]   Silva MA, Tekin K, Aytekin F, et al. Surgery for hilar cholangiocar-  cinoma: a 10 year experience of a tertiary referral centre in the  UK. Eur J Surg Oncol. 2005;31:533-539. [PMID: 15922889]   Sudan D, DeRoover A, Chinnakotla S, et al. Radiochemotherapy  and transplantation allow long-term survival for nonresectable  hilar cholangiocarcinoma. Am J Transplant. 2002;2:774-779.  [PMID: 12243499]   Yeh CN, Yan YY, Yeh TS, et al. Hepatic resection of the intraductal  papillary type of peripheral cholangiocarcinoma. Ann Surg  Oncol. 2004;11:606-611. [PMID: 15172934]   Hepatitis C and hepatocellular carcinoma are among the  leading indications for liver transplantation in the  United States.   Thorough medical, psychiatric, and social evaluation is  required prior to listing patients for transplantation.   The Model for End-Stage Liver Disease (MELD) score is  widely used for prioritizing patients on the transplant  waiting list.   Liver biopsy is needed to confirm the diagnosis of acute  rejection, which is common and occurs in up to 60% of  patients.   Medical and surgical complications after transplantation  can occur immediately or years later.   Biliary strictures and leaks occur in 15% of patients after  transplantation.   Long-term immunosuppression, particularly with cal-  cineurin inhibitors, is associated with an increased risk  of renal failure.   Liver transplantation has radically changed the management  of patients with chronic liver disease and acute liver failure.  Following the first liver transplant procedure in 1963,  numerous medical, surgical, and technical breakthroughs  were required before transplantation became a viable ther-  apy in liver disease. The 1-year survival rate remained low at  25% until the introduction of cyclosporine as a long-term  immunosuppressant in the 1980s. Further medical develop-  ments in immunosuppression, including mycophenolate   mofetil, sirolimus, tacrolimus, and azathioprine, as well as  effective anti-infective treatment and prophylaxis, have  resulted in 5-year survival rates of up to 85-90%.   The United Network for Organ Sharing (UNOS) is a non-  profit scientific organization based in Virginia that is  responsible for matching donors to recipients and coordi-  nating the organ transplantation process. UNOS has  divided the United States into 1 1 regions to facilitate organ  allocation (Figure 50-1).   There are numerous indications for liver transplantation;  common and uncommon indications are listed in Table 50-1.   The hepatitis C virus (HCV) infects 150 million people  worldwide and up to 3 million people (1-1.5%) in the  United States. Based on histopathologic studies, it is believed  that 5-20% of patients with hepatitis C develop cirrhosis  after 20 years of infection. After the occurrence of cirrhosis,  decompensation (ie, variceal hemorrhage, ascites, and  hepatic encephalopathy) occurs in 25-28% of patients in a  median of 3-9 years. HCV significantly contributes to the  occurrence of hepatocellular carcinoma (HCC). Current  studies suggest that HCC occurs in 2-6% of patients with  HCV-induced cirrhosis per year.   Hepatitis C is one of the leading indications for liver  transplantation in most countries, including the United  States, accounting for up to 40% of transplant procedures  performed each year. It is expected that the proportion of  liver transplants due to HCV will increase over the next  10-15 years in response to increases in the incidence of cir-  rhosis and eventual decompensation or occurrence of HCC.    A Figure 50-1. UNOS regions. (Courtesy of the United  Network for Organ Sharing.)   Fattovich G, Pantalena M, Zagni I, et al. European Concerted  Action on Viral Hepatitis (EUROHEP). Effect of hepatitis B and  C virus infections on the natural history of compensated cir-  rhosis: a cohort study of 297 patients. Am J Gastroenterol.  2002;97:2886-2895. [PMID: 12425564]   Lawson A, Hagan S, Rye K, et al. Trent HCV Study Group. The nat-  ural history of hepatitis C with severe hepatic fibrosis. J Hepatol.  2007;47:37-45. [PMID: 17400322]   Until approximately 10 years ago, transplantation of patients  infected with the hepatitis B virus (HBV) was controversial.  The near universal recurrence of hepatitis B generally resulted  in early graft loss. A major advance in the field of transplan-  tation was the introduction of hepatitis B immunoglobulin  and antiviral therapy with nucleoside and nucleotide analogs.  This has resulted in a dramatic improvement in transplant   outcomes, and HBV infection is now a well accepted  indication with a good prognosis.   Although less prevalent than HCV in the United States,  HBV remains a common cause of decompensated liver dis-  ease and HCC globally. Approximately, 350 million people  globally and 1.25 million in the United States are infected  with HBV. The occurrence of cirrhosis is a significant prog-  nostic indicator, with a 50% 5-year survival among patients  with hepatitis B e antigen-positive disease and cirrhosis.  Both the incidence of decompensation and HCC rate are  slightly lower for HBV than for HCV. Although in the United  States the number of transplant procedures performed  because of HBV is small, it remains an indication in a large  proportion of transplants performed in many Asian and  European countries.   Alcoholic liver disease is the most common cause of cirrho-  sis in the United States and results in an estimated 12,000  deaths annually. Although there is concern that patients with  alcoholic liver disease are high-risk candidates for poor out-  comes after liver transplantation, graft loss as a result of alco-  hol abuse is uncommon. In fact, the 7-year graft survival rate  is very good, and better than rates reported for many other  indications for liver transplantation. Presently, approxi-  mately 85% transplant centers recommend a 6-month  period of abstinence from alcohol before considering a  patient for liver transplantation. This stipulated period of  abstinence remains unproven as there are no conclusive data  to suggest that any period of abstinence is associated with a  decreased risk of relapse after transplantation. The American  Association for the Study of Liver Diseases (AASLD) recom-  mends careful assessment of such patients by a health care  professional experienced in the management of patients with  addictive behavior.   Liver transplantation has been used effectively to treat several  genetic and metabolic diseases associated with liver involvement  (see Table 50-1).   Hemochromatosis is primarily a disease of Caucasians, with  a prevalence of 1 in 200-300 persons. Among patients with  untreated hemochromatosis, a significant proportion can  develop decompensated cirrhosis or HCC. For these patients,  liver transplantation is a treatment option. The survival of  patients who undergo liver transplantation for hemochro-  matosis is not comparable to that of patients with other  genetic or metabolic liver disease treated with transplanta-  tion. This may be attributable to the presence of cardiomy-  opathy in patients with hemochromatosis. Among genetic  and metabolic conditions, hemochromatosis is the most  common reason for transplantation.   This autosomal-recessive condition is a common indication  for liver transplantation in children. Patients who do not  develop liver disease as children can develop cirrhosis, which  tends to occur in the sixth and seventh decades. The outcomes  for liver transplantation in this setting are very good.   Wilson disease is an autosomal-recessive disease that can  cause either acute or chronic liver disease. In patients with  fulminant failure or decompensated cirrhosis, liver trans-  plantation is an effective therapy with a good prognosis.  Transplantation cures the defect in copper secretion, and  long-term antichelating therapy is generally not required.   A significant proportion of patients with autoimmune hepa-  titis develop decompensated cirrhosis despite immunosup-  pressant therapy. In patients with decompensated disease,  liver transplantation remains a viable option; excellent sur-  vival outcomes and 5-year survival of 90% are reported.   Similarly, primary biliary cirrhosis and primary scleros-  ing cholangitis are excellent indications for liver transplanta-  tion, and are associated with good graft survival.   Because of the increased risk of HCC in cirrhosis, most  patients undergo some form of screening, which includes  radiologic imaging or a-fetoprotein assessment, or both (see  Chapter 49). The use of screening has resulted in the earlier  detection of tumors. This has improved survival in HCC,  especially in patients with small tumors. The AASLD and  UNOS endorse liver transplantation as effective treatment for  patients with "early HCC," defined as a solitary tumor less than  5 cm or three tumors less than 3 cm. The 5-year survival rate  in this group of patients has been reported to be 70%. In 2005,  UNOS also allowed patients who meet either of these criteria  to receive a higher Model for End-Stage Liver Disease (MELD)  score at the time of being placed on the transplant list to  increase the chance of receiving a liver transplant sooner.   Sangiovanni A, Del Ninno E, Fasani P, et al. Increased survival of  cirrhotic patients with a hepatocellular carcinoma detected dur-  ing surveillance. Gastroenterology. 2004;126:1005-1014. [PMID:  15057740]   Acute liver failure is a rare but life-threatening event that in  many cases may result in death without a liver transplant. A  detailed review of liver transplantation in acute liver failure  is provided in Chapter 38.    MELD score  NOTE: MELD score = 9.57 x log e creatinine mg per dL + 3.78 x log e  bilirubin mg per dL + 1 1 .20 x log e INR + 6.43 (constant for liver  disease etiology: = cholestatic or alcoholic; 1 = all other).   A Figure 50-2. Estimated 3-month survival as a func-  tion of the MELD score. INR, international normalized  ratio; MELD, Model for End-Stage Liver Disease. (Adapted,  with permission, from Wiesner R, Edwards E, Freeman R,  et al ; for the United Network for Organ Sharing Liver  Disease Severity Score Committee. Model for end-stage liver  disease (MELD) and allocation of donor livers.  Gastroenterology. 2003 ; 124:94.)   Since 2002, UNOS has used the MELD score to determine  the need for liver transplantation in patients with cirrhosis.  As shown in Figure 50-2, the 3-month survival of patients  decreases with higher MELD scores. Many transplant centers  use a MELD score of 15 as a minimal listing threshold.  However, there continues to be a role for the Child-Pugh  score (Table 50-2). Patients with Child class B or C cirrhosis  have poor survival compared with patients who have more  compensated Child class A disease. In addition, patients with  a history of variceal hemorrhage and spontaneous bacterial  peritonitis have decreased 1-year survival and would benefit  from liver transplantation.   Score: 5-6 = Child class A; 7-9 = Child class B; > 10 = Child class C.   Kamath PS, Kim WR. Advanced Liver Disease Study Group. The  model for end-stage liver disease (MELD). Hepatology.  2007;45:797-805. [PMID: 17326206]   One of the major goals of liver transplantation is to improve  patients' quality of life. Studies have shown that prior to  transplantation, many patients experience significant  impairments due to physical and emotional stress. A meta-  analysis of quality of life showed that patients improved after  liver transplantation.   The evaluation of patients who are candidates for liver trans-  plantation occurs in a multidisciplinary setting and involves  hepatologists, transplant surgeons, anesthesiologists, psychi-  atrists, social workers, and subspecialists as needed.   Several diagnostic tests and procedures are used to evaluate  patients; these are listed in Table 50-3 and described below.   Laboratory evaluation provides information about the  underlying liver disease and assessment of liver and renal  function (see Table 50-3).   Importantly, evaluation of the risk of developing compli-  cations related to immunosuppression is needed. Routine  studies include serologic testing for cytomegalovirus (CMV),  herpes simplex virus (HSV), and Epstein-Barr virus (EBV).  Testing for histoplasmosis, schistosomiasis, and strongyloidi-  asis should be considered in patients from endemic areas. All  patients should undergo skin testing for tuberculosis with  purified protein derivative (PPD) and, if positive, computed   Dobutamine stress echocardiography  Magnetic resonance imaging and angiography of the liver  Esophagogastroduodenoscopy and colonoscopy  Cervical cancer screening  Mammogram   Prostate-specific antigen assay  Dental evaluation  Vaccination against hepatitis A and B, Pneumococcus, Haemophilus   tomography (CT) scan of the chest. Further testing and  referral to a pulmonologist may be needed if the suspicion of  tuberculosis remains.   Cardiac and pulmonary complications of liver transplanta-  tion are the leading cause of mortality. Meticulous car-  diopulmonary evaluation is required in every patient being  considered for liver transplantation. Recent data have shown  that dobutamine stress echocardiography adequately identi-  fies patients who would be at increased risk for cardiac mor-  tality. An added benefit of this test is that it can identify  patients with congenital abnormalities of the heart such as a  patent foramen ovale. If abnormalities are identified, they  can be corrected and patients reconsidered for transplant.   Muiioz SJ, ElGenaidi H. Cardiovascular risk factors after liver  transplantation. Liver Transpl. 2005;(Suppl l):S52-56. [PMID:  16237716]   Tsutsui IM, Mukherjee S, Elhendy A, et al. Value of dobutamine  stress myocardial contrast perfusion echocardiography in  patients with advanced liver disease. Liver Transpl 2006; 12:  592-599. [PMID: 16555336]   A comprehensive psychosocial evaluation of the candidate is  needed before listing. Alcohol abuse is common among liver  transplant candidates. Studies have produced controversial  evidence that duration of less than 6 months is associated  with an increased risk of relapse after surgery. Alcohol  relapse is not an ideal situation as it increases the risks of  noncompliance with immunosuppressant medications and  post-transplant alcoholic hepatitis.   Strong social support is needed after liver transplantation  to ensure compliance with medication regimens and  appointments. A comprehensive evaluation by social support  services must be considered in every patient undergoing liver  transplant evaluation.   Rocca P, Cocuzza E, Rasetti R, et al. Predictors of psychiatric dis-  orders in liver transplantation candidates: logistic regression  models. Liver Transpl. 2003;9:721-726. [PMID: 12827559]   Given the risk of infectious complications in patients taking  immunosuppressant medications, a comprehensive evalua-  tion for infectious risk is needed. This evaluation should  include serologic testing for CMV, HSV, varicella-zoster, and  EBV. Patients should undergo evaluation for Mycobacterium  tuberculosis infection using a PPD skin test and chest radi-  ograph. Patients from regions in which strongyloidiasis,  schistosomiasis, and histoplasmosis are endemic should  undergo serologic evaluation and prophylactic treatment as  appropriate.   Contraindications to liver transplantation differ among the  various liver transplant centers. Although certain absolute  contraindications are observed (Table 50-4), some condi-  tions that would be considered contraindications at one  institution are not deemed so at others. These relative con-  traindications are also listed in Table 50-4. Many of these rel-  ative contraindications may be treated with multiorgan  transplants in specialized centers.   Brain dead donor with satisfactory blood pressure and oxygenation  fiver size compatible with hepatic cavity of recipient  Factors affecting donor selection  Pre-existing liver disease  Diabetes mellitus  Uncontrolled hypertension  Active malignancy, excluding brain tumors  Active bacterial, viral, or fungal infection  Ischemia from asystole or hypotension  Active alcohol or substance abuse  Morbid obesity   Surgical options for transplantation have undergone tremen-  dous changes since the first operation. Presently, the options  include cadaveric and live donor transplantation. Cadaveric  transplantation is further differentiated into complete or  split liver transplantation.   Careful evaluation of the donor is required before consider-  ing procurement. Certain factors such as hemodynamic insta-  bility, advanced age, and hepatic steatosis have been  associated with graft nonfunction or preservation injury.  Macrovesicular steatosis in excess of 30% is associated with   initial poor graft function, graft loss, and higher 3-month  mortality rates. Microvesicular steatosis does not appear to  affect graft function. Testing for HCV, HBV, and HIV is  standard. If abnormal liver enzymes are found, a biopsy of  the donor liver should be considered to ensure that  advanced histopathologic changes are not present. In gen-  eral, however, the presence of abnormal liver enzymes in the  donor does not preclude liver transplantation. Table 50-5  summarizes the important components of the evaluation of  the donor liver.   Verran D, Kusyk T, Painter D, et al. Clinical experience gained  from the use of 120 steatotic donor livers for orthotopic liver  transplantation. Liver Transpl. 2003;9:500-505. [PMID:  12740794]   Cadaveric or orthotropic liver transplantation is the most  commonly used technique. After a suitable graft is identified,  the potential candidate for transplantation is prepared for  surgery. The technique involves removing the cirrhotic liver  with careful dissection. Prior to surgery, a venovenous bypass  is considered by some surgeons. The graft is then placed with  anastomosis of the portal vein, hepatic artery, and common  bile duct. Flow of bile during surgery is an indicator of a  functioning graft.   Split liver transplantation involves the use of the graft  by two separate recipients. Typically, the right lobe is  used for an adult recipient and the left lobe is used for  children. Although the principles of surgery remain the  same, the technique is different and beyond the scope of  this chapter.   In general, the technique for live donor transplantation is the  same as that for cadaveric transplantation; however, unlike   cadaveric transplantation, there are considerable risks to  the donor. These risks are considerable and include death.  The evaluation includes a comprehensive workup of both the  donor and recipient. In addition to the standard recipient  evaluation and the preoperative evaluation of the donor, live  donor transplantation requires a thorough psychosocial  evaluation of the donor.   Live donor transplantation can reduce the waiting time  for patients with cirrhosis. However, it is best used for candi-  dates with relatively preserved hepatic function.   Complications from liver transplantation can occur early or  late and can be related to technical problems involving the  surgical procedure, medical sequelae, or transplantation  itself. Most complications occurring immediately after trans-  plantation are technical and are related to surgery.   This complication is apparent during surgery. One of the first  signs of graft function is the production of bile. The surgeon  will note this during the surgery. Lack of bile production is  consistent with primary graft nonfunction. This is a true  emergency and most patients need to be listed for retrans-  plantation. Supportive care and aggressive medical therapy  for infectious and hemodynamic complications are needed.   Biliary complications after liver transplantation occur in up  to 15% of patients. Biliary strictures and bile leaks are the  most common biliary complications.   In the first few days to weeks after transplantation, anasto-  motic stricturing is common; its occurrence is suggested by  abnormal liver enzymes. Abdominal imaging using ultra-  sound or CT scan is required to detect biliary dilation.  Caution is required in interpreting abdominal imaging as bil-  iary dilation may not be apparent after transplantation.  Generally, these patients require endoscopic retrograde  cholangiopancreatography or percutaneous transhepatic  cholangiography. If a stricture or leak is found, then stent  insertion can be considered. Surgical reanastomosis or con-  version to Roux-en-Y is needed for cases not amenable to  endoscopic or radiologic methods.   A second form of post-transplant biliary stricture is  believed to be due to ischemic and immunologic injury.  Multiple strictures are found in the intrahepatic and  extrahepatic biliary tree. Unless a dominant stricture is  found, endoscopic, percutaneous, or surgical options are  limited. Risk factors identified in a recent study included  primary sclerosing cholangitis in the native liver, Roux-  en-Y hepaticojejunostomy, use of a high-viscosity preser-  vation solution, and postoperative CMV infection.  Occurrence of sclerosing cholangitis and cirrhosis has been  reported, sometimes resulting in retransplantation. Graft  loss rates of up to 46% at 2 years post-transplantation have  been reported.   This complication usually occurs within the first few days  after transplantation and complicates between 1.6% and  8.9% of procedures. Risk factors include technical compli-  cations during the surgical procedure, low donor size to  recipient size ratio, immunologic factors, clotting abnor-  malities, smoking, and infection. Typically patients show  lack of improvement in liver enzymes postoperatively.  Additionally, the need for clotting factors does not decrease,  and mental status changes may occur. Diagnosis usually  requires imaging of the hepatic artery using Doppler ultra-  sound, MRI, or arteriogram. Thrombosis can be treated  using interventional techniques, including thrombolysis,  angioplasty, or stent placement. However, most patients  require reoperation and reanastomosis. If these measures are  not successful, the patient may need to be relisted for a second  transplantation.   Pastacaldi S, Teixeira R, Montalto P, et al. Hepatic artery thrombo-  sis after orthotopic liver transplantation: a review of nonsurgi-  cal causes. Liver Transpl. 2001;7:75-81. [PMID: 11172388]   Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on  secondary causes. Hepatology. 2006;44:1063-1074. [PMID:  17058222]   Park JS, Kim MH, Lee SK, et al. Efficacy of endoscopic and percu-  taneous treatments for biliary complications after cadaveric and  living donor liver transplantation. Gastrointest Endosc. 2003;57:  78-85. |PMID: 12518136]   One of the most common complications after transplanta-  tion is allograft rejection. There are three forms of rejection:  hyperacute, acute, and chronic.   1. Hyperacute rejection— Hyperacute rejection is due to  recipient presensitization to donor antigens. With improved  donor and recipient antigen matching, its incidence has  become very rare. This condition requires removal of the  donor graft and a second transplantation. Patients are gener-  ally listed with highest priority for a graft.   2. Acute and chronic rejection— Acute rejection is  encountered after transplantation in up to 60% of recipients.  Episodes of acute rejection that occur within 3 months of  transplant are generally not associated with an increased  risk of graft failure or mortality. After transplantation, anti-  gen-presenting cells (APCs) present donor HLA-antigens to  the recipient CD4 T cells. APCs also release interleukin  (IL)-l, which enhances activation of T cells in response to  antigen. Activated T cells produce IL-2, which further  recruits activated T cells (CD4, CD8) into the graft. CD8 T  cells are the so-called cytotoxic cells and cause graft damage.  IL-2 is also responsible for clonal T-cell proliferation. The  severity of injury is related to the clonal expansion of cytotoxic  lymphocytes.   The pathogenesis of chronic rejection is not entirely  understood. Aberrant expression of HLA class II antigens on  bile ducts is believed to have a role. Differences in donor and  recipient class I antigens are also believed to be contributory.   For the graft to survive and function in the recipient, the  recipient's immune system needs to be suppressed, particu-  larly in the early post-transplant period. This is achieved by  treatment of the various steps of rejection described above. A  typical immunosuppression protocol is shown in Table 50-6.  The protocol may vary among institutions but the principles  remain the same. Corticosteroids are used for their potent  anti-inflammatory effects in suppressing IL-1, IL-2, IL-6,  tumor necrosis factor, and interferon-"/. Cyclosporine  and tacrolimus are calcineurin inhibitors that suppress   IL-2-dependent T-cell proliferation. Mycophenolate mofetil  and azathioprine inhibit B-cell and T-cell proliferation by  interfering with purine synthesis. Sirolimus is generally not  used as a first-line immunosuppressant due to initial concerns  of hepatic artery thrombosis and impaired wound healing. It  appears to interrupt IL-2 receptor signaling pathways.   Table 50-7 lists the common side effects of the various  immunosuppressant medications.   Perry I, Neuberger J. Immunosuppression: towards a logical  approach in liver transplantation. Clin Exp Immunol. 2005;139:  2-10. [PMID: 15606606]   1. Acute rejection — Most patients with acute rejection  present with abnormal liver enzymes. A pathway toward  evaluating abnormal liver enzymes in the post-transplant  setting is shown in Figure 50-3. To confirm rejection, a liver  biopsy is needed. Histopathologic changes of rejection  include mixed portal and lobular infiltrate, arteriolar and  ductular injury in the form, and endothelialitis and duc-  topenia. The typical treatment includes pulse steroids and,  if unsuccessful, the use of more potent immunosuppressant  agents. These include OKT3, which blocks the CD3 recep-  tor; Thymoglobulin, which causes nonselective depletion of  lymphocytes; or daclizumab and basiliximab, which are  chimeric IL-2 receptor-inhibiting monoclonal antibodies.   2. Chronic rejection — As in acute rejection, the diagnosis of  chronic rejection requires a liver biopsy. Unfortunately, there  are no effective therapies for chronic rejection and most  patients will require retransplantation.    M: 1 g orally twice daily  A: 75-100 mg orally daily   b Typical starting dose is cyclosporine, 6 mg/kg/day divided in twice-daily dosing; tacrolimus, 0.06 mg/kg/day   divided in twice-daily dosing. Dose adjustment is based on therapeutic range.    Nephrotoxicity, hypertension, alopecia,  hypercholesterolemia, neurotoxicity  (including tremor, seizure, headaches),  diabetes, nausea, vomiting   Infectious risk among transplant patients is related to expo-  sure to pathogens and the net state of immunosuppression.  In addition to immunosuppression, disrupted integrity of  the mucocutaneous and epithelial barriers, instrumentation,  uremia, diabetes, and infections with immunomodulating   ▲ Figure 50-3. Evaluation of abnormal liver enzymes or  liver function tests after liver transplantation. ERCP, endo-  scopic retrograde cholangiopancreatography.   viruses are among the factors that affect the infectious risk.  The typical pattern of infection is shown in Figure 50-4.   Commonly used approaches against Pneumocystis carinii  infection, CMV, and EBV are discussed below.   Infection with Pneumocystis carinii pneumonia (PCP) is rare  in the transplant setting. This is because prophylaxis against  PCP is practiced by all transplant centers. In the absence of  prophylaxis, the incidence of PCP is 10-12%. The standard reg-  imen is to use single-strength trimethoprim-sulfamethoxazole  (TMP-SMZ) daily for 4-12 months. Atovaquone can be  considered in patients with insensitivity to TMP-SMZ.  An additional benefit of TMP-SMZ is the decreased risk  of toxoplasmosis, Listeria monocytogenes, and Nocardia  asteroides.   CMV is the most important pathogen affecting patients after  liver transplantation. The virus can be either acquired after  transplantation from the donor or reactivated in the recip-  ient by immunosuppression (Table 50-8). The severity of  infection is affected by several factors, including the use of  cytotoxic and antilymphocyte drugs, systemic infection,  and inflammation. Cases of de novo infection and super-  infection are generally associated with clinical disease. Up  to 50% of recipients who are seronegative and receive a  seropositive donor graft will develop infection. The risk  for recipients who are CMV antibody positive is much  less, and many transplant centers do not practice routine  prophylaxis.   Diagnosis is obtained by demonstrating viremia (ie, CMV  antigenemia, polymerase chain reaction amplification, or tis-  sue biopsy). Clinical CMV infection can manifest itself in a  number of different ways. The presentation can be in the  form of leukopenia, thrombocytopenia, pneumonitis,  gastroenteritis, pancreatitis, colitis, dermatitis, neuritis, or  ophthalmitis.   In addition to its direct effect, CMV is also associated  with an increased risk of acute and chronic rejection, post-  transplantation lymphoproliferative disorder (PTLD), and  recurrent HCV   The treatment consists of intravenous ganciclovir until  clearance of virus is documented. Some transplant centers  also consider the use of anti-CMV hyperimmune globulin  for severe or recurrent disease. Patients intolerant to ganci-  clovir can be treated with foscarnet.   The ideal regimen for prevention of CMV is not known,  but the role of prophylaxis is generally well accepted. The  intensity of immunosuppression may dictate the duration  of prophylaxis. Prophylaxis should be started before reac-  tivation and continued long after documenting negative  CMV surveillance studies. The exact duration is not well  known.   ▲ Figure 50-4. Usual sequence of infections after organ transplantation. Exceptions to the usual sequence of infections  after transplantation suggest the presence of unusual epidemiologic exposure or excessive immunosuppression. CMV,  cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; PTLD, post-transplantation lymphoproliferative disease;  RSV, respiratory syncytial virus; VZV, varicella-zoster virus. Zero indicates the time of transplantation. Solid lines indicate the  most common period for the onset of infection; dotted lines and arrows indicate periods of continued risk at reduced levels.  (Reproduced, with permission, from Rubin RH, Fishman JA. Infection in organ-transplant recipients. N Engl J Med. 1998 ; 338:1743.)   PTLD is a heterogeneous group of hematologic disorders of  polyclonal or monoclonal lymphoid and nonlymphoid  organs affecting nodal and particularly extranodal sites. It is  a serious complication after transplantation and occurs in  1-3% of liver transplant recipients. Risk factors include  severity of immunosuppression and use of antilymphocyte  antibodies. The clinical presentation of PTLD is broad,  ranging from symptoms suggestive of mononucleosis to  those consistent with lymphoma or related to an affected  organ. Extranodal involvement of the liver, brain, gastroin-  testinal tract, and bone marrow is common. In a recent  study, 77% of patients with PTLD presented with extran-  odal disease.   PTLD has a close association with EBV, but not all  patients with this condition are positive for EBV. The diag-  nosis requires histopathologic examination. The treatment  generally consists of reducing immunosuppression and use  of antiviral therapy in EBV positive PTLD. If this is unsuc-  cessful chemotherapy can be considered, although the ideal  regimen remains uncertain.   Lim W, Russ GR, Coates PT. Review of Epstein-Barr virus and  post-transplant lymphoproliferative disorder post-solid organ  transplantation. Nephrology (Carlton). 2006;11:355-366. [PMID:  16889577]   Patients who undergo liver transplantation remain at risk of  developing common medical problems seen in the general  population.   The incidence of post-transplant diabetes mellitus is between  4% and 20%. This risk may be related to the use of tacrolimus  and cyclosporine. Prospective studies have shown a significant  increased incidence of hyperglycemia after administration of  these agents. The treatment includes diet, weight loss, oral  hypoglycemic agents, and insulin.   Reuben A. Long-term management of the liver transplant patient:  diabetes, hyperlipidemia, and obesity. Liver Transpl. 200 1;7  (Suppl 1):S13-21. [PMID: 11689772]   Hypertension is a common occurrence after transplantation  likely due to age and the use of calcineurin inhibitors.  Standard antihypertensive regimens are efficacious in patients  post-transplantation. Nifedipine is the agent of choice, and  |3-blockers are second-line agents.   Galioto A, Angeli P, Guarda S, et al. Comparison between nifedip-  ine and carvedilol in the treatment of de novo arterial hyper-  tension after liver transplantation: preliminary results of a  controlled clinical trial. Transpl Proc. 2005;37:1245-1247.  [PMID: 15848684]   Hyperlipidemia is a common occurrence after liver trans-  plantation, with an incidence of up to 50%. Weight loss and  dietary changes are recommended; if these strategies are  unsuccessful, treatment with a HMG CoA inhibitor is  recommended.   Reuben A. Long-term management of the liver transplant patient:  diabetes, hyperlipidemia, and obesity. Liver Transpl. 2001;7  (Suppl 1):S13-21. [PMID: 11689772]   In a landmark article by Ojo and colleagues, it was shown  that the incidence of chronic renal failure after solid organ  transplantation was 7-21% among non-renal transplant  recipients. An increased risk of renal failure was associated  with female sex, older age, hepatitis C, hypertension, diabetes  mellitus, and post-transplant acute renal failure. The study  also showed that patients who experienced chronic renal fail-  ure were at four times greater mortality risk.   Strategies to prevent renal failure are limited by the need  to use a calcineurin inhibitor to prevent rejection. Sirolimus,  a less nephrotoxic drug, has fallen out of favor as a first-line  immunosuppressant because of concerns about hepatic  artery thrombosis and impaired wound healing. However, in  patients with mild renal insufficiency, transition from a cal-  cineurin inhibitor to sirolimus can be considered when the  risk of hepatic artery thrombosis is reduced, usually many  months to years after transplantation.   Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after a trans-  plantation of a nonrenal organ. N Engl J Med. 2003;349:  931-940. [PMID: 12954741]   Pretransplant bone disease resulting from impaired vitamin D  absorption in cholestatic liver disease, low calcium intake and  activity, or use of diuretics and prednisone in autoimmune hep-  atitis is common. Inactivity after the transplant procedure and  the use of high doses of steroids further accelerate bone loss.  Consequently, post-transplant osteoporosis is a major cause of  morbidity in patients undergoing transplantation. All patients  should receive calcium and vitamin D supplementation after  transplantation. A bone densitometry scan should be consid-  ered and bisphosphonates prescribed if osteoporosis is noted.   Guichelaar MM, Kendall R, Malinchoc M, et al. Bone mineral den-  sity before and after OLT: long-term follow-up and predictive  factors. Liver Transpl. 2006;12:1390-1402. [PMID: 16933236]   Pregnancy has occurred as soon as a few weeks after liver  transplantation. Because transplantation is associated with an  increased incidence of premature and low birth weight infants,  pregnant patients should be managed by an obstetrician who  specializes in high-risk pregnancy. To minimize the risk of  rejection and graft failure, immunosuppression is continued.  Table 50-9 lists the known teratogenicity and effects on fetal  growth in pregnancy of various immunosuppressants.   Chronic headaches are noted with calcineurin inhibitors and  may require modification in dosing. A tremor is often seen in  calcineurin toxicity. Seizure disorder after transplantation  has been reported.   Table 50-9. Pregnancy risk by FDA category for  commonly used immunosuppressant medications  after liver transplantation.   Reproduced, with permission, from Mastrobattista JM, Katz AR.  Pregnancy after organ transplantation. Obstet Gynecol Clin North  Am. 2004;31:14. Original data from Armenti VT, RadomskiJS, Moritz  MJ, et al. Report from the National Transplantation Pregnancy  Resister (NTPR): Outcomes of pregnancy after transplantation. In:  Cecka JM, Terasaki PI (editors). Clinical Transplants 2002. UCLA  Immunogenetics Center, 2003:121-130; and Armenti VT, Moritz MJ,  Davison JM. Renal transplantation and pregnancy. In: Gleicher N  (editor). Principles and Practice of Medical Therapy in Pregnancy,  3rd ed. Appleton & Lange, 1998:1081-1091.   Depression and anxiety are common after transplantation.  Early identification and treatment may prevent substance  abuse relapse post-transplantation. Various antidepressants  have been shown to be effective in post-transplant patients.   Erim Y, Beckmann M, Valentin-Gamazo C, et al. Quality of life and  psychiatric complications after adult living donor liver transplan-  tation. Liver TranspL 2006;12:1782-1790. [PMID: 17133566]   Malignancy is the second most common cause of late death in  patients after transplantation and is closely associated with the  long-term use of immunosuppressants. The incidence of cancer  in patients who undergo transplant is between 4% and 16%. The  incidences of PTLD, sarcomas, uterine cervical dysplasia, and  skin cancers are clearly higher than in the general population.  However, conclusive data for other forms of cancer are lacking.  Risk factors for the development of post-transplant cancers  include smoking, alcohol, and inflammatory bowel disease.   Overall, colon cancer is no more common in post-transplant  patients than in the general population. However, patients with  primary sclerosing cholangitis and ulcerative colitis who  undergo transplantation have an incidence of colon cancer  ranging between 5.3% and 13% after liver transplantation.   Table 50-10 outlines the recommended guidelines for  screening in patients after liver transplantation.    Annual Papanicolaou smear for all  females > 18 y and any female  < 18 y who is sexually active   Reproduced, with permission, from Kasiske BT, Varquez MA,  Harmon WE, et al. Recommendations for the outpatient surveillance  of renal transplant recipients. American Society of Transplantation.  J Am Soc Nephrol. 2000;1 1 :S1-S86.   Adapted, with permission, from Kotlyar DS, Campbell MS, Reddy KR. Recurrences of diseases following  orthotopic liver transplantation. Am J Gastroenterol. 2006;101:1370-1378.   Oo YG, Gunson BK, Lancashire RJ, et al. Incidence of cancers fol-  lowing orthotopic liver transplantation in a single center: com-  parison with national cancer incidence rates for England and  Wales. Transplantation. 2005;80:759-764. [PMID: 16210962]   Trotter JF. Cancer surveillance following orthotopic liver trans-  plantation. Gastrointest Endosc Clin N Am. 2001;11:199-214.  [PMID: 11175982]   Vallejo GH, Romero CJ, de Vicente JC. Incidence and risk factors  for cancer after liver transplantation. Crit Rev Oncol Hematol.  2005;56:87-99. [PMID: 15979889]   Over the past decade the prognosis for patients who undergo  liver transplantation has improved considerably. For certain  conditions, such as amyloidosis, liver transplantation is a  cure; for others, disease recurrence is a possibility. Recurrence  of hepatitis C or hepatocellular cancer is associated with a  guarded prognosis; other conditions, such as autoimmune  hepatitis, primary biliary cirrhosis, and primary sclerosing  cholangitis, have good 5-year survival rates (Table 50-11).   Most patients who undergo liver transplantation do not  have liver- related morbidity but suffer from complications of  long-standing immunosuppression.   Kotylar DS, Campbell MS, Reddy KR. Recurrence of diseases fol-  lowing orthotopic liver transplantation. Am J Gastroenterol.  2006;101:1370-1378. [PMID: 16771963]   Recurrent hepatitis C is almost universal after transplanta-  tion. Older age of the donor, use of steroids, and rejection are   predictors of worse prognosis. Due to the impact of steroids,  many transplant centers limit the dose and duration of  steroids in immunosuppression protocols. Steroid-free  immunosuppressive protocols have been considered but  remain controversial.   The treatment of recurrent hepatitis C is more difficult  after transplantation. The use of immunosuppressant medica-  tions and comorbidities leave patients more susceptible to the  side effects of interferon and ribavirin. Hematopoietic growth  factor support is generally needed to continue treatment.   Dienstag JL, McHutchinson JG. American Gastroenterological  Association technical review on the management of hepatitis C.  Gastroenterology. 2006;130:231-264. [PMID: 16401486]   Recurrent hepatitis B is uncommon after transplantation.  The risk of recurrence is greatest among patients who are  hepatitis B e antigen positive or have high viral loads at the  time of transplantation.   Prophylactic therapy has become routine for most trans-  plant centers after transplantation. Typically, patients receive  hepatitis B immunoglobulin (HBIG) for up to 6 months or  indefinitely after transplantation. Generally, hepatitis B sur-  face antibody levels are followed and HBIG is transfused  when levels fall below 500 IU/mL. The use of nucleotide and  nucleoside analogs varies among centers. However, many  programs now use a combination of HBIG and nucleotide or  nucleoside analogs such as entecavir, lamivudine, and ade-  fovir. Adefovir is used less commonly due to the small risk of  nephrotoxicity. Lamivudine should generally be avoided due  to a high rate of viral resistance.   ► Most patients with primary biliary cirrhosis (PBC) are  asymptomatic at diagnosis but eventually develop  symptoms, including fatigue and pruritus.   ► Consider PBC in any patient in whom liver enzymes are  elevated in a cholestatic pattern; an isolated elevated  alkaline phosphatase level always requires further  evaluation.   ► Antimitochondrial antibodies have 95% sensitivity for  PBC and are central to the diagnosis.   Primary biliary cirrhosis (PBC) is a classical autoimmune  disease. Although it is predominantly a disease of middle-  aged woman, with a median age of diagnosis of approxi-  mately 50 years, 5-10% of patients are men and the reported  age range is 22-93 years. It is reported throughout the world,  but with varying geographic incidence and prevalence; the  highest reported incidence and prevalence is in northern  Europe. Antimitochondrial autoantibodies (AMAs) are  found in 95% of patients with PBC. The targets of the  autoantibodies are members of the family of the 2-oxo-acid  dehydrogenase complexes, most particularly the E2 subunits  of the pyruvate dehydrogenase complex (PDC-E2). The  immunologic injury is marked by a T- cell-mediated destruc-  tion of the intrahepatic bile ducts. The only proven therapy  for PBC is ursodeoxycholic acid (UDCA). Despite early diag-  nosis and treatment, most patients have an inexorable dis-  ease progression leading ultimately to cirrhosis and  end-stage liver disease.   Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N. Engl J  Med. 2005;353:1261-1273. [PMID: 16177252]   There have been several studies indicating the role of genet-  ics in determining the susceptibility to PBC. Particularly  important observations include the following:   1. First-degree relatives of patients with PBC have a 4-6%  prevalence of disease.   2. PBC has the highest reported concordance rate (62.5%)  in monozygotic twins of any autoimmune disease.   3. The prevalence of AMAs in first-degree relatives of  patients with PBC was 13.1% compared with 1% of  controls.   As with other autoimmune conditions, molecular mimicry is  felt to be the mechanism for the initiation of autoimmunity.  Several candidate environmental triggers have been identi-  fied, including infectious agents (viruses and bacteria) and  chemicals. These potential triggers have significant homol-  ogy to human mitochondrial proteins, particularly PDC-E2.   The T cells infiltrating the portal triads are specific for the  PDC-E2 autoepitope. However, it is not clear why the  immune attack has such specificity for biliary epithelium  when the target mitochondrial proteins are present in all  nucleated cells. Studies have suggested that the mechanism  of the metabolic processing of PDC-E2 in biliary epithe-  lium results in the autoantigen remaining immunologically  intact and available for presentation to antigen-presenting  cells. In all other cell types the autoepitope is destroyed dur-  ing apoptosis.   A Figure 51-1. Pathogenesis and natural history of primary biliary cirrhosis (PBC). It is believed that genetically sus-  ceptible patients if exposed to specific environmental triggers will develop autoimmunity through molecular mimicry,  with the primary target of the resultant antimitochondrial antibodies being pyruvate dehydrogenase E2 complex  (PDC-E2). Through an as yet undetermined process this leads to a T-cell-mediated destruction of the intrahepatic bile  ducts. Untreated, this destructive process eventually destroys a critical percentage of bile ducts and secondary injury  from retained bile salts ensues. Injury progresses to biliary cirrhosis and eventually to decompensated liver disease.  ALP, alkaline phosphatase; AMA, antimitochondrial antibody; GGT, ^glutamyl transferase; LFTs, liver function tests.   Lazaridis KN, Juran BD, Boe GM, et al. Increased prevalence of  antimitochondrial antibodies in first-degree relatives of patients  with primary biliary cirrhosis. Hepatology. 2007;46:785-782.  [PMID: 17680647]   Pares A, Rodes J. Natural history of primary biliary cirrhosis. Clin  Liver Dis. 2003;7:779-794. [PMID: 14594131]   Selmi C, Mayo MJ, Bach N, et al. Primary biliary cirrhosis in  monozygotic and dizygotic twins: genetics, epigenetics, and  environment. Gastroenterology. 2004;127:485-492. [PMID:  15300581]   The common practice of checking serum liver enzyme tests as  part of annual physical examinations has increased the per-  centage of patients with PBC who are asymptomatic at the  time of diagnosis to more than 50%. Most patients will go on  to develop symptoms over time. For those who are sympto-  matic, fatigue and pruritus are the most common complaints,  each found in approximately 20% of patients. Both of these  symptoms may be found even in early-stage disease. The  fatigue can be severe enough to have a negative impact on  quality of life. The pruritus can be either local or diffuse,   worse at night, exacerbated by heat, and profoundly distress-  ing. Other symptoms seen less commonly are dry eyes and  dry mouth (sicca symptoms), and unexplained right upper  quadrant discomfort. Jaundice is a late finding and a poor  prognostic sign as are other symptoms of hepatic decompen-  sation, including fluid retention (ascites and peripheral  edema), gastrointestinal bleeding, and encephalopathy.   The asymptomatic patient almost always lacks physical  findings. Early-stage findings include skin hyperpigmentation,  excoriations from itching, xanthelasmas, xanthomas, and  hepatomegaly. Later stages are marked by findings of portal  hypertension and hepatic decompensation: splenomegaly,  caput medusa, ascites, spider nevi, palmar erythema, jaundice,  proximal and temporal muscle wasting, and asterixis.   The liver enzymes in patients with PBC are typically in a  cholestatic pattern; that is, the alkaline phosphatase (ALP) is  elevated out of proportion to the aminotransferases. An iso-  lated elevated ALP level should first be evaluated to verify its  biliary origin by obtaining values for y-glutamyl transferase  (GGT) , 5' nucleotidase, or fractionation of the ALP. The degree  of ALP elevation does not correlate with disease severity;  rare cases have been reported of patients with normal ALP   diagnosed with early-stage PBC on the basis of positive  AMAs and consistent histology.   The presence of autoantibodies, particularly antimito-  chondrial antibodies, is the hallmark of PBC. The AMA titer  does not correlate with disease activity in patients with PBC.  Also, the absence of AMAs does not rule out the diagnosis of  PBC. There are well-described patients with "AMA-negative  PBC" who have the typical clinical, biochemical, and histo-  logic features of PBC. Other autoantibodies, most commonly  antinuclear antibodies (ANAs), are reported in PBC. Nuclear  rim and nuclear-dot patterns of ANAs are highly specific for  PBC. Serum immunoglobulin M levels are often elevated.   There are four histologic stages of PBC. Stage 1 is marked by  the presence of the florid bile duct lesion (a bile duct at the  center of a dense lymphocytic infiltrate). PBC is initially a  ductocentric process; the inflammation does not extend  beyond the portal tracts. Stage 2 is marked by loss of normal  bile ducts, development of bile duct reduplication, and  extension of the inflammation into the hepatic parenchyma.  Stage 3 is marked by bridging fibrosis of the portal triads and  progressive loss of bile ducts. Stage 4 is frank cirrhosis and  end-stage liver disease. The presence of copper deposition is  supportive of a cholestatic process.   The liver is not involved uniformly in PBC, a fact that  increases the likelihood of sampling variability. All four stages  of PBC may be seen in a single large biopsy. Convention is to  report either the highest stage of disease or the range of stages.  Although some have questioned the need for histologic stag-  ing in the diagnosis of PBC, it both aids in determining prog-  nosis and guides treatment by providing baseline histologic  findings against which treatment response can be assessed.   UDCA is the only therapy approved by the U.S. Food and  Drug Administration for the treatment of PBC. The mecha-  nism of action of UDCA remains unknown. It is a choleretic  agent. It has been shown to slow progression of disease in  patients with early-stage disease and is highly effective as  monotherapy in 25-30% of patients. As is seemingly true  with all therapies used for PBC, UDCA is not as effective in  advanced disease. There is clearly a point in the natural his-  tory of PBC where sufficient numbers of bile ducts are  destroyed and the condition has passed the point of reversibil-  ity. The appropriate dosage of UDCA is 13-15 mg/kg/day  split into two doses. It is well tolerated with the most common  side effect being diarrhea.   Although many hepatologists do not recommend consid-  eration of any therapy beyond UDCA (Figure 51-2), a more  aggressive approach in selected patients, particularly young  patients with early-stage disease, can potentially improve   A Figure 51-2. Treatment of primary biliary cirrhosis  (PBC). The most widely accepted algorithm is illustrated.  Ursodeoxycholic acid (UDCA) is initiated and patients are  then monitored for progression of disease and complica-  tions. The only other active intervention in this algorithm  is referral of patients for transplantation when their liver  disease has decompensated. LFTs, liver function tests.   outcomes (Figure 51-3). If patients have an incomplete bio-  chemical or histologic response to UDCA, the use of  colchicine and methotrexate should be considered.   In contrast to some studies that failed to show a benefit of  colchicine, several prospective double-blind trials found that  colchicine improved biochemistry profiles, symptoms  (pruritus), and histologic findings. A meta-analysis reported  that colchicine delayed the need for transplantation and  reduced the incidence of major complications.   Methotrexate has been shown in some studies to improve  biochemical and histologic findings in patients with an  incomplete response to UDCA monotherapy. Other studies  failed to show any benefit of methotrexate, either alone or in  combination with UDCA. One 10-year study suggested that  patients with early-stage disease were most likely to benefit  from methotrexate.   Short duration, randomized, placebo-controlled trials of  budesonide have shown it improves biochemical and histo-  logic findings in PBC. Longer trials will be needed to assess  the impact on survival and ensure osteopenia is not an issue.   Figure 51-3 highlights the stepwise approach for patients  with stage 1-3 disease. This approach is based on the obser-  vation that clinical response to medical therapy varies greatly  from patient to patient and that the majority of patients will  progress on UDCA monotherapy. In this approach, histology  is a critical component in decision making, both in deter-  mining whether to add additional agents to UDCA and  whether to continue those agents. The severity of the portal  inflammation is typically the major deciding factor in deter-  mining whether to add additional therapies.   Liver transplantation is the only effective therapy for patients  with end-stage PBC. These patients have post-transplant   ▲ Figure 51-3. Treatment of primary biliary cirrhosis (PBC): a stepwise approach. This algorithm highlights the use of  the baseline histologic staging to direct treatment as well as monitor the response to therapy. It also reflects the real-  ity that ursodeoxycholic acid (UDCA) monotherapy is effective in only a minority of patients and that there are subsets  of patients who respond to either colchicine or methotrexate (MTX), but there is no way to predict response. LFTs, liver  function tests.   outcomes that exceed most other indications. Disease recur-  rence has been reported — 30% at year 10 in one series — but it  is exceedingly rare to lose a graft to recurrent disease.   Corpechot C, Carrat F, Bahr A, et al. The effect of ursodeoxycholic  acid therapy on the natural course of primary biliary cirrhosis.  Gastroenterology. 2005;128:297-303. [PMID: 15685541]   Lindor K. Ursodeoxycholic acid for the treatment of primary bil-  iary cirrhosis. N Engl J Med. 2007;357:1524-1529. [PMID:  17928600]   1. Pruritus — As with primary therapy, management of pru-  ritus is most effective when one proceeds in a logical and  stepwise fashion. Cholestyramine is effective in more than  90% of patients and should be the first-line agent. The start-  ing dosage is typically 4 g, two to three times a day, and some  improvement of symptoms is usually seen within 2-4 days.  Tolerance can be an issue, with gastrointestinal side effects  (unpleasant taste and constipation) being prominent. It is  critical to educate patients regarding the need to separate the  dosing of cholestyramine from other medications. The second-  line agent for pruritus is rifampin; a dosage of 150 mg twice  daily is well tolerated and has little risk of toxicity. Oral opi-  oid receptor antagonists are a reasonable third-line agent.  Antihistamines have little role aside from use as a sleep aid.  Plasmapheresis has been effective in truly refractory cases.   2. Fatigue — This symptom can be incapacitating, even in  patients with early-stage disease. Modafinil has been shown to  be effective in two small, uncontrolled pilot trials and in per-  sonal experience. Controlled trials are awaited. The dosage is  100-200 mg/day.   3. Osteoporosis — Approximately one third of patients with  PBC develop osteoporosis, which can manifest before the  onset of jaundice. Bone density should be checked every 2 years  in patients with PBC and osteopenia managed aggressively.  While benefit has not been proven, these patients should be on  calcium and vitamin D supplementation. Alendronate has  been shown to be beneficial in two trials and estrogen replace-  ment in two studies of postmenopausal women; however, this  benefit needs to be weighed against the increased risk of  vascular disease and cancer.   4. Hyperlipidemia — Although serum lipids are often ele-  vated in PBC, patients seemingly do not have an increased risk  of atherosclerosis. This finding is explained partly by the pres-  ence of high levels of high-density lipoprotein and partly by  the presence of a subtraction of low-density lipoproteins,  called lipoprotein X, that has anti-atherogenic properties.  Thus, it is rare that PBC patients require lipid-lowering agents.  However, statin drugs can be used safely if indicated so long as  standard monitoring for hepatotoxicity is performed.   Progressive inflammatory, sclerosing, and obliterative  disease of the extrahepatic or intrahepatic bile ducts, or  both.   Disproportionate elevation of serum alkaline phos-  phatase (4-10 times normal) is seen in almost all  patients.   MRCP or ERCP shows multifocal stricturing of the intra-  hepatic and extrahepatic bile ducts.   Liver biopsy findings that are highly specific include  fibrous obliteration of small bile ducts with concentric  replacement by connective tissue in an "onion skin"  pattern.   Patients have an 8-15% lifetime risk of developing  cholangiocarcinoma, and it is often difficult to distin-  guish a dominant stricture from a cholangiocarcinoma.   Primary sclerosing cholangitis (PSC) is a disorder of  unknown etiology characterized by a progressive, inflamma-  tory, sclerosing, and obliterative process affecting medium-  sized and large extrahepatic or intrahepatic bile ducts, or  both. A vast majority of patients (prevalence rates range  from 70% to 90%) have underling inflammatory bowel dis-  ease, especially ulcerative colitis. PSC has also been associated  (although rarely) with multifocal fibrosclerosis syndromes  such as retroperitoneal, mediastinal, and periureteral fibro-  sis. In retrospect, it appears that some of these latter cases  actually represented patients with autoimmune pancreatitis  and bile duct strictures masquerading as PSC.   The median survival of patients with PSC from time of diag-  nosis to death in several series has ranged from 9 to 12 years.   Late in the course of the disease, complete biliary obstruction,  secondary biliary cirrhosis, portal hypertension with bleeding  varices, liver failure, and development of cholangiocarcinoma  may occur.   Maggs JR, Chapman RW. Sclerosing cholangitis. Curr Opin  Gastroenterol. 2007;23:310-316. [PMID: 17414848]   Patients with PSC are often asymptomatic at the time of  diagnosis. The disorder is often suspected in patients with  inflammatory bowel disease who have a persistent and oth-  erwise unexplained abnormal elevation in serum alkaline  phosphatase (ie, values at least two times the upper limit of  normal), and with abnormal values persisting for longer than  6 months. Asymptomatic patients with persistent elevations  of serum alkaline phosphatase are often screened for PSC,  and many actually turn out to have the disease.   Symptomatic patients who have PSC often present with  signs and symptoms of chronic biliary obstruction, right  upper quadrant abdominal pain, pruritus, jaundice, and  acute cholangitis. Fatigue and pruritus are common features  at presentation.   Liver tests usually demonstrate a cholestatic pattern, with serum  alkaline phosphatase disproportionately elevated to levels 4-10  times normal and serum aminotransferase usually 300 IU/L or  less. Serum albumin and globulin levels are usually normal  except in patients with advanced disease. As noted later, in the  discussion of differential diagnosis, the presence of positive tests  for antinuclear antibodies or smooth muscle antibodies, or  both, should raise the suspicion of PSC-autoimmune hepatitis  (AIH) overlap syndrome.   The diagnosis of PSC is usually established by demonstration  of the characteristic multifocal stricturing with normal and  or dilated areas of intrahepatic or extrahepatic bile ducts, or  both, on cholangiography. The typical appearance is that of  narrowing and beading of the bile ducts (Figure 52-1). These  abnormalities can be demonstrated by either magnetic reso-  nance cholangiopancreatography (MRCP) or endoscopic  retrograde cholangiopancreatography (ERCP). MRCP is cur-  rently preferred as it is a noninvasive procedure and does not  carry the risk of either pancreatitis or cholangitis. The vast  majority of patients (-85%) have both intrahepatic and  extrahepatic bile duct strictures, approximately 10% have  intrahepatic bile duct strictures alone, and 2-4% have extra-  hepatic biliary strictures alone.   It should be emphasized that patients with small duct  PSC do not demonstrate cholangiographic abnormalities. In  these patients, diagnosis is suspected on the basis of an ele-  vated serum alkaline phosphatase level and established by a  liver biopsy in conjunction with other clinical features.   Liver biopsy findings often support the diagnosis of PSC.  The most characteristic histologic finding is fibrous oblitera-  tion of small bile ducts with concentric replacement by con-  nective tissue in an "onion skin" pattern. More often,  histologic abnormalities in PSC are nonspecific and may be  similar to those seen in primary biliary cirrhosis.    A Figure 52-1. Endoscopic retrograde cholangiopancre-  atogram demonstrating diffusely narrowed intrahepatic  bile ducts and one beaded area.   PSC is frequently staged according to the histopathologic  findings. In stage 1 disease, there is enlargement, mononu-  clear cell infiltration, and scarring in the portal triads. Stage 2  disease is characterized by fibrosis extending into the sur-  rounding parenchyma, stage 3 by bridging fibrosis, and stage 4  by cirrhosis.   Four disorders need to be considered the differential diagno-  sis of patients presenting with a cholestatic picture: small  duct PSC, autoimmune pancreatitis, PSC-AIH overlap syn-  drome, and acquired immunodeficiency syndrome (AIDS).   Small duct PSC is defined by the presents of chronic cholesta-  sis and hepatic histologic findings consistent with PSC but  with normal findings on cholangiography. Small duct PSC is  found in about 5% of patients with PSC, and represents an  earlier stage of PSC associated with a significantly better long-  term prognosis. However, such patients may progress to clas-  sic PSC or end-stage liver disease, or both, with consequent  necessity of liver transplantation.   Angulo P, Maor-Kendler Y, Lindor KD. Small duct primary scle-  rosing cholangitis: a long-term follow-up. Hepatology.  2002;35:1494-1500. [PMID: 12029635]   Patients with autoimmune pancreatitis can present with bile  duct strictures, obstructive jaundice, and pancreatic duct  abnormalities. This diagnosis should be suspected in patients  with a focal mass in the head of the pancreas or narrowing of  a main pancreatic duct along with an elevated serum  immunoglobulin G 4 value. (See Chapter 27 for discussion of  autoimmune pancreatitis.)   Patients with PSC-AIH overlap syndrome have cholangio-  graphic abnormalities characteristic of PSC but serologic  features of AIH. The overlap syndrome should be suspected  in patients diagnosed with PSC who have elevated circulating  levels of antinuclear antibodies or smooth muscle antibodies  (titer > 1:40), elevated levels of immunoglobulin G, and evi-  dence of severe interface hepatitis on liver biopsy. In addi-  tion, a liver biopsy sample may reveal bile duct abnormalities  such as fibrosis and cholestasis. Abnormal cholangiography  findings are present in the vast majority of cases, the excep-  tion being patients with small duct PSC. Further, cholestatic  liver test abnormalities, such as a disproportionately elevated  serum alkaline phosphatase level, are often present.   Reports have described patients with clinical features of  AIH on presentation but with a subsequent diagnosis of PSC   when immune suppression failed to achieve clinical remis-  sion. This is noted especially in patients with AIH and ulcer-  ative colitis. If a disproportionately elevated serum alkaline  phosphatase level is demonstrated in such patients, the clini-  cian should have a heightened suspicion of PSC. This  sequence has been described, in particular, in children, ado-  lescents, and young adults. Finally, failure of a patient with  AIH to respond to immunosuppressive therapy should raise  the suspicion of an overlap syndrome, and especially the  PSC-AIH overlap syndrome.   colchicine, cholestyramine, and mycophenolate. None of  these therapies has consistently been shown to halt disease  progression. ERCP with balloon dilation of dominant stric-  tures and removal of debris may be beneficial.   Immunoglobulin G 4 -associated cholangitis (IAC) can  mimic PSC. Approximately 60% of IAC patients treated with  corticosteroids have resolution of strictures and normaliza-  tion of liver enzymes. Thus, this seeming variant of PSC  appears to be responsive to corticosteroids (see Chapter 27  for details).   Floreani A, Rizzoto ER, Ferrera F, et al. Clinical course and out-  come of autoimmune hepatitis/primary sclerosing cholangitis  overlap syndrome. Am J Gastroenterol. 2005;100:1515-1522.  [PMID: 15984974]   In patients with AIDS, cholangiopancreatography may demon-  strate a broad rage of biliary tract changes as well as pancre-  atic duct obstruction and occasionally pancreatitis. Biliary tract  lesions in AIDS include cholangiopancreatographic changes  similar to PSC. Such changes include (1) diffuse involvement  of the intrahepatic bile ducts alone, (2) involvement of both  intrahepatic and extrahepatic bile ducts, (3) ampullary steno-  sis, and (4) stricture of the intrapancreatic portion of the  common bile duct.   Associated infectious organisms that have been demon-  strated in this setting include Cryptosporidium, Mycobacterium  avium-intracellulare complex, Cytomegalovirus, Microsporidia,  and Isospora.   PSC is a progressive, debilitating disease for which few treat-  ment options are currently available. Although many classes  of drugs have been studied, none has shown efficacy in slow-  ing disease progression. A major focus of medical treatment,  therefore, is on managing symptoms.   Pruritus is common in PSC patients and is often difficult  to control; this is especially vexing when it causes nocturnal  symptoms and interferes with sleep. Medications that have  proved useful in some patients include bile salt-sequestering  agents such as cholestyramine, as well as naltrexone and  rifampin. One agent that may be helpful in promoting better  sleep is doxepin.   Ursodeoxycholic acid (UDCA) is the most extensively  evaluated treatment in patients with PSC. Doses of 10-15  mg/kg/day have not shown benefit, while doses of 20-30  mg/kg/day have shown modest improvement in liver bio-  chemical tests. However, such treatment has not resulted in  survival benefit or delay in the need for liver transplantation.   Other agents that have been studied include corticos-  teroids, cyclosporine, methotrexate, azathioprine and 6-  mercaptopurine, penicillamine, tacrolimus, pentoxifylline,   Ghazale A, Chari ST, Zang L, et al. Immunoglobulin G 4 -associated  cholangitis: clinical profile and response to therapy.  Gastroenterology. 2008;134:706-715. [PMID: 18222442]   Smith T, Befeler AS. High-dose ursodeoxycholic acid for the treat-  ment of primary sclerosing cholangitis. Curr Gastroenterol Rep.  2007;9:54-59. [PMID: 17335678]   Liver transplantation is best choice for patients with  advanced PSC; 5-year survival rates of approximately 85%  and a 10-year survival rate of approximated 70% have been  reported.   PSC is usually a progressive disease that leads ultimately to bil-  iary obstruction, secondary biliary cirrhosis, hepatic failure,  portal hypertension with bleeding varices, and the develop-  ment of cholangiocarcinoma. Several studies have identified  variables that appear to predict progression of PSC; these  include age at diagnosis, hepatomegaly, splenomegaly, serum  alkaline phosphatase, histologic stage of the disease, and  serum bilirubin levels. In particular, a serum bilirubin level of  3.0 mg/dL or higher usually portends ultimately irreversible  disease. The Mayo risk score is a well-validated statistical  model that identifies variables associated with prognosis and  PSC. This score is valuable in assessing prognosis and deter-  mining the timing for liver transplantation.   Patients with PSC are at increased risk of developing  cholelithiasis and choledocholithiasis. However, bacterial  cholangitis can develop in patients with PSC without evi-  dence of cholelithiasis or choledocholithiasis. The risk is  increased after endoscopic manipulation of the extrahepatic  biliary tree. However, cholangitis can also develop sponta-  neously with high-grade obstructing strictures. Patients with  PSC who experience a decreased secretion of conjugated bile  salts in the small intestine may develop steatorrhea as well as  impaired absorption of fat-soluble vitamins A, D, E, and K.  Metabolic bone disease is also a complication of advanced  PSC, with radiologic evidence of osteopenia, especially in the  lumbar spine, iliac crest, and femur.   Patients with PSC have an 8-15% lifetime risk of devel-  oping cholangiocarcinoma. Patients with coexisting inflam-  matory bowel disease and cirrhosis are at the highest risk.  The annual risk of developing cholangiocarcinoma has been   estimated to be 1.5%. On imaging studies, it is often difficult  to distinguish a dominant stricture from a cholangiocarci-  noma. Biliary brush cytology may facilitate the diagnosis;  however, cytologic evaluation, along with computed tomo-  graphic or magnetic resonance imaging screening tests and  serum tumor markers (carcinoembryonic antigen [CEA] or  CA 19-9), is not uniformly helpful in ruling out a diagnosis  of associated cholangiocarcinoma.   Two long-term studies have described the natural history  of PSC. The first was a study of 305 patients of Swedish  decent with PSC. One hundred thirty-four (44%) of the  patients were asymptomatic at the time of diagnosis and 22  of the 134 (22%) became symptomatic during the median  follow-up period of 63 months. The median survival rate  from the time of diagnosis to death or liver transplantation  was 12 years. The independent predictors influencing prog-  nosis were age, serum bilirubin concentration, and liver his-  tologic changes. Cholangiocarcinoma was found in 24 patients  (8%). Inflammatory bowel disease was closely associated  with PSC and had a prevalence of 8 1% in this study population.   A more recent study, which described the natural history of  PSC patients and evaluated the prognostic significance of clin-  ical, biochemical, and cholangiographic findings, afforded an   opportunity to construct a prognostic model. Two hundred  seventy-three German patients with PSC underwent a median  follow-up of 76 months (range, 1-280). Median survival from  the time of diagnosis to death or liver transplantation was  9.6 years. One hundred eight patients (39.6%) underwent liver  transplantation, and 39 (14.3%) developed hepatic biliary  malignancies. Age at diagnosis, low serum albumin, persistent  bilirubin elevation longer than 3 months, hepatomegaly,  splenomegaly, abdominal bile duct stenosis, and ductal  changes at the time of diagnosis were found to be independent  risk factors. In particular, persistent serum bilirubin elevations  lasting longer than 3 months identified a novel risk factor cor-  relating with a poor outcome.   Broome U, Olsson R, Loof L, et al. Natural history and prognostic  factors in 305 patients with primary sclerosing cholangitis. Gut.  1996;38:610-615. [PMID: 870797]   Kim WR, Therneau TM, Wiesner RH, et al. A revised natural his-  tory model for primary sclerosing cholangitis. Mayo Clin Proc.  2000;75:689-694. [PMID: 10907383]   Tischendorf JJ, Hecker H, Kriiger M, et al. Characterization, out-  come and prognosis in 273 patients with primary sclerosing  cholangitis. Am J Gastroenterol. 2007;102:107-114. [PMID:  17037993]   ► Major risk factors for cholesterol gallstones include age  > 50 years, female sex, Mexican or Native American  ethnicity, genetic predisposition, family history, preg-  nancy and parity, estrogens, obesity, and the metabolic  syndrome.   ► Gallstones are often found incidentally during abdomi-  nal ultrasonography, which has > 95% sensitivity for  cholesterol stones > 1.5 mm.   ► In -80% of cases gallstones remain asymptomatic; in  symptomatic patients, biliary colic is almost always  present, often radiating to the right scapula or shoulder.   ► Major complications of gallstone disease requiring  treatment are acute cholecystitis, choledocholithiasis,  obstructive jaundice, cholangitis and pancreatitis.   ► Acute cholangitis caused by an obstructing gallstone  should be treated by endoscopic removal of the stone  under antibiotic coverage as soon as possible.   Gallstone disease represents a considerable health problem in  Western industrialized countries. With a prevalence of  10-15% in adults in the United States and in Europe, it is one  of the most common digestive diseases. In the United States,  it is the gastrointestinal disorder that, after gastroesophageal  reflux disease, accounts for the second highest costs. The  clinical manifestations of gallstones include episodic abdom-  inal pain, acute cholecystitis, obstructive jaundice, cholangi-  tis, and pancreatitis.   In Western industrialized countries, about 80% of gall-  stones consist mainly of cholesterol. Thus, in the majority of  patients, cholelithiasis may be regarded as a disturbance of   cholesterol disposal. A complex solubilizing system in bile is  required to keep cholesterol in solution. If this system fails, or  if its capacity is exceeded by hypersecretion of cholesterol  into bile, cholesterol precipitates and gallstones may develop.   In the third National Health and Nutrition Examination  Survey (NHANES III), a large epidemiologic survey that  compiled data including gallbladder ultrasonography find-  ings, the overall prevalence of gallstones in the United States  was 7.9% in men and 16.6% in women, with a progressive  increase after age 20 years. The prevalence was high in  Mexican Americans (8.9% in men, 26.7% in women), inter-  mediate for non-Hispanic whites (8.6% in men, 16.6% in  women), and low for African Americans (5.3% in men, 13.9%  in women). Overall prevalence rates in Europe, from large  ultrasonic surveys in adults aged 30-69 years, are similar to  those in the NHANES III study. The prevalence of gallstone  disease is lower in Asians (ranging from 3% to 15%) and very  low (< 5%) in Africans. Certain ethnic groups are particularly  susceptible; among Native Americans in the western United  States, the prevalence of gallstones is over 75%.   Epidemiologic surveys and family clustering point to the  critical role of genetics in determining susceptibility to gall-  stones. The genetic component in the pathogenesis of symp-  tomatic gallstone disease in the Swedish population has been  estimated to be about 25%. Recently, a single nucleotide  polymorphism conferring an increased risk of gallstone for-  mation has been identified in the hepatic cholesterol trans-  porter ABCG5/G8 of patients with gallstones. Two additional  susceptibility loci for gallstone disease on chromosome 1, yet  to be cloned, have been localized in a genome-wide scan in  Mexican Americans and named GBD2 and GBD3 (gallbladder  disease 2 and 3) in the Online Mendelian Inheritance in Man  (OMIM) database (http://www.ncbi.nlm.nih.gov/sites/  entrez?db=OMIM).   Although in the vast majority of patients, the predisposi-  tion to gallstones appears to be polygenetic, rare forms of   monogenetic gallstone disease exist. Thus, a single gene  defect, namely, a mutation in the gene encoding the canalic-  ular phospholipid transporter (ABCB4) of the hepatocyte,  has been identified by Rosmorduc and coworkers in a rare  form of cholesterol cholelithiasis. This gene defect is associ-  ated with low phosphatidylcholine in bile and has been  named GBD1 (gallbladder disease 1) in the OMIM database.  The extremely low phospholipid levels in the bile of these  patients cause cholesterol precipitation.   The prevalence of gallstones increases with age. It is about  twice as high in women as in men. The gender difference is  at least partly due to endogenous estrogens, which increase  biliary cholesterol secretion and cholesterol saturation of  bile. Pregnancy increases the risk of gallstones because  impaired gallbladder emptying, caused by progesterone,  combines with the influence of estrogen, which increases  cholesterol hypersecretion. In obese persons an overproduc-  tion of cholesterol causes cholesterol hypersecretion into bile  and thus predisposes to gallstone formation. In many obese  patients, cholesterol gallstones may be regarded as a compo-  nent of the metabolic syndrome.   Attili AF, De Santis A, Capri R, et al. The natural history of gall-  stones: the GREPCO experience. The GREPCO Group.  Hepatology. 1995;21:655-660. [PMID: 7875663]   Everhart JE, Khare M, Hill M, et al. Prevalence and ethnic differences  in gallbladder disease in the United States. Gastroenterology.  1999;117:632-639. [PMID: 10464139]   Griinhage F, Acalovschi M, Tirziu S, et al. Increased gallstone risk  in humans conferred by common variant of the hepatic ABC  transporter for cholesterol. Hepatology. 2007;46:793-801.  [PMID: 17626266]   Katsika D, Grjibovski A, Einarsson C, et al. Genetic and environ-  mental influences on symptomatic gallstone disease: a Swedish  study of 43,141 twin pairs. Hepatology. 2005;41:1138-1143.  [PMID: 15747383]   Puppala S, Dodd GD, Fowler S, et al. A genomewide search finds  major susceptibility loci for gallbladder disease on chromosome  1 in Mexican Americans. Am J Hum Genet. 2006;78:377-392.  [PMID: 16400619]   Rosmorduc O, Hermelin B, Boelle PY, et al. ABCB4 gene mutation-  associated cholelithiasis in adults. Gastroenterology. 2003; 125:  452-459. [PMID: 12891548]   Sandler RS, Everhart IE, Donowitz M, et al. The burden of selected  digestive diseases in the United States. Gastroenterology.  2002;122:1500-1511. |PMID: 11984534]   Gallstones classified as cholesterol stones contain more than  50% cholesterol with variable admixtures of calcium salts,  bile pigments, proteins, and fatty acids. Cholesterol stones  account for about 80% of all gallstones. Pigment stones are  composed primarily of calcium bilirubinate; they contain  less than 20% cholesterol.   Because cholesterol is practically insoluble in water, solubi-  lizing lipids (bile acids and phospholipids) are required for  its incorporation into bile. Biliary lipid secretion is regulated  by ATP-binding cassette (ABC) transporters in the hepato-  cyte canalicular membrane. The bile salt export pump  (BSEP; ABCB1 1) transports bile acids into the bile, the mul-  tidrug resistance p-glycoprotein 3 (MDR3; ABCB4) translo-  cates phosphatidylcholine from the inner to the outer leaflet  of the canalicular membrane, and the transporter  ABCG5/G8 secretes cholesterol into the bile.   Cholesterol and phosphatidylcholine reach the bile as  unilamellar vesicles and are subsequently converted into  water-soluble mixed micelles by the bile acids (Figure 53-1).  Supersaturation of bile with cholesterol is the thermody-  namic requirement for the formation of cholesterol gall-  stones. It can result from secretion of cholesterol into bile  that exceeds the solubilizing capacity of bile acids and phos-  pholipids. If all cholesterol phosphatidyl vesicles cannot  be converted into water-soluble mixed micelles, unstable  cholesterol-rich vesicles remain. The unstable vesicles aggre-  gate into large multilamellar vesicles from which cholesterol  crystals precipitate. These crystals — if not expelled from the  gallbladder — become entrapped in gallbladder mucin gel,  where they grow and agglomerate to form stones.   The pathogenesis of cholesterol hypersecretion is multi-  factorial, with genetic and environmental components.   1. Causes of cholesterol supersaturation of bile— An excess  of biliary cholesterol in relation to its carriers (phospholipids    ▲ Figure 53-1. Biliary secretion and solubilization of cholesterol. Cholesterol is secreted by the ABC-binding cassette  (ABC) transporter ABCG5/G8, phosphatidylcholine by the multidrug resistance p-glycoprotein 3 (MDR3; ABCB4), and bile  acids by the bile salt export pump (BSEP; ABCB11). Cholesterol and phosphatidylcholine reach the bile as metastable  unilamellar vesicles, which are converted into water-soluble stable mixed micelles by the bile acids. If the secretion of  cholesterol into bile exceeds the solubilizing capacity of bile acids and phospholipids, cholesterol-rich vesicles remain,  which aggregate into large unstable multilamellar vesicles from which cholesterol crystals precipitate. These crystals may  aggregate and form cholesterol stones. Recent evidence indicates that a variant in the hepatocanalicular cholesterol  transporter gene ABCG8 contributes to the risk of cholesterol gallstone formation (for details see text).   and bile acids) is a sine qua non condition for the formation of  cholesterol gallstones. It may result from hypersecretion of cho-  lesterol, hyposecretion of bile acids or phospholipids, or a com-  bination of the two. Relative cholesterol hypersecretion is by far  the most common cause of supersaturation of bile. It may result  from increased synthesis of cholesterol, increased uptake by the  liver of endogenous (via low-density lipoproteins) or exogenous  (via chylomicrons) cholesterol, and increased hepatocanalicular  transport of cholesterol. An inappropriately low rate of choles-  terol 7a-hydroxylation, the rate-limiting step in the conversion  of cholesterol to bile acids, can also increase cholesterol secre-  tion into bile. This may occur in a rare genetic defect, but also  with age. A defect in the ileum characterized by impaired  absorption and increased fecal loss of bile acids, thus lowering  the amount of bile acids in the enterohepatic circulation, may  also play a role. Obese individuals secrete more cholesterol into  bile because they ingest and synthesize more cholesterol. During  weight loss, there is an increased excretion of cholesterol into  bile, often combined with decreased gallbladder emptying.   2. Destabilization of bile of bile— Supersaturatiom of bile  is a prerequisite for stone formation, but alone it is not suffi-  cient for lithogenesis. About 50% of adults have supersatu-  rated bile at least at some times during the day, but only  about 10-15% form stones. The majority of people with   supersaturated bile do not have stones because the time  required for cholesterol crystals to nucleate and to grow is  longer than the time the bile spends in the gallbladder. The sta-  bility of phospholipid cholesterol vesicles depends on their  cholesterol content and on the balance between inhibitors and  promoters of cholesterol crystal formation. Normally,  inhibitors of cholesterol crystal formation and growth appear  to outweigh the promoters. The influence of promoting and  inhibiting factors on the appearance of crystals in bile has been  assessed by the "nucleation time" or crystal "observation time."  It is much shorter in gallbladder bile from patients with cho-  lesterol gallstones than in equally supersaturated gallbladder  bile from normal subjects. A protein that promotes crystal  nucleation or growth, or both, is gallbladder mucin.  Gallbladder mucin, a mixture of high molecular weight mucus  glycoproteins, is layered at the mucosal surface of the gallblad-  der wall, where it forms a viscous bed facilitating nucleation  and aggregation of cholesterol crystals (Figure 53-2). Release  of mucin and perhaps other glycoproteins from the gallblad-  der is stimulated by deoxycholic acid.   3. Stasis of bile in the gallbladder— If the gallbladder  emptied all supersaturated bile completely before crystals had  formed, stones would not be able to grow. Thus, prolonged  retention of all or parts of the gallbladder contents seems to   ▲ Figure 53-2. Formation, growth, and aggregation of cholesterol crystals in the mucin gel layered at the mucosal surface  of the gallbladder wall (for details see text).   be another important prerequisite for lithogenesis. A high  percentage of patients with gallstones exhibit abnormalities of  gallbladder emptying. Studies of gallbladder motility using  ultrasonography have shown that patients with gallstones  have increased fasting and residual gallbladder volume and  that fractional emptying of the gallbladder is decreased  (Figure 53-3). The incidence of gallstones is increased in con-  ditions associated with infrequent or impaired gallbladder  emptying, such as fasting, parenteral nutrition, or pregnancy,  and in patients using drugs that inhibit gallbladder motility.  Gallbladder hypomotility during fasting results from lack of  gallbladder stimulation. Consequently, the risk of stone for-  mation during parenteral nutrition can be decreased by  administration of cholecystokinin. During pregnancy, both  the fasting volume and the residual volume of the gallbladder  rise with serum progesterone, which inhibits smooth muscle  contractility and impairs emptying.   Pigment stones can be divided into black pigment stones,  which are composed of either pure calcium bilirubinate or  polymer-like complexes containing mainly calcium and  mucin glycoproteins. They are more common in patients  who have chronic hemolytic states (with increased conju-  gated bilirubin in bile), liver cirrhosis, Gilbert syndrome, or  cystic fibrosis (Table 53-2). Gallbladder stones in patients  with ileal disease, ileal resection, or ileal bypass generally are  also black pigment stones. Enterohepatic cycling of bilirubin  contributes to their pathogenesis.   Brown pigment stones consist of calcium salts and uncon-  jugated bilirubin with varying amounts of cholesterol and   protein. They are caused by the presence of increased  amounts of unconjugated, insoluble bilirubin in bile.  Deconjugation of soluble conjugated bilirubin glucuronide  may be caused by bacterial enzymes when bile is infected, but  may also occur by spontaneous alkaline hydrolysis. Brown   ▲ Figure 53-3. Impaired gallbladder emptying after a  test meal in patients with gallstones measured by ultra-  sonography. (Data from Paumgartner G, Pauletzki J,  Sackmann M. Ursodeoxycholic acid treatment of choles-  terol gallstone disease. ScandJ Gastroenterol Suppl.  1994;204:27-31.)   pigment stones are frequent in Asia, where there is a high  prevalence of infection of the biliary tree. They often form in  the bile ducts, whereas cholesterol gallstones usually origi-  nate in the gallbladder.   Grundy SM. Cholesterol gallstones: a fellow traveler with metabolic  syndrome? Am J ClinNutr. 2004;80:1-2. [PMID: 15213019]   Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone dis-  ease. Lancet. 2006;368:230-239. [PMID: 16844493]   Only 20-25% of persons with gallstones have symptoms that  can be attributed to their stones. Not all symptoms in  patients with gallstones are caused by the stones. Gallstones  are often discovered incidentally during abdominal ultra-  sonography and remain asymptomatic in nearly 80% of  cases. Unspecific gastrointestinal symptoms, such as belch-  ing, heartburn, and bloating in the absence of biliary pain  should not be attributed to gallstones without considering  other diagnoses (eg, reflux disease). The discovery of gall-  stones on imaging studies does not, therefore, mean that  symptomatic gallstone disease is present.   The first symptom of gallstone disease almost always is  biliary colic. Only in about 10% of patients is the first mani-  festation of gallstone disease cholecystitis, obstructive jaun-  dice, or pancreatitis. Biliary colic results from obstruction of  the cystic duct or common bile duct by a stone that, by dis-  tention of the viscus, causes visceral pain that usually is a  severe, steady ache or fullness in the epigastrium or right  upper quadrant of the abdomen, frequently radiating to the  interscapular area, right scapula, or shoulder. Usually it begins  quite suddenly and may persist for 15 minutes to 5 hours,  subsiding gradually or rapidly. It is steady rather than inter-  mittent as would be suggested by the word colic, which must  be regarded as a misnomer, although in widespread use. The  term biliary pain appears more appropriate. There may be   concomitant nausea with or without vomiting. Nocturnal  presentation awakening the patient is common. Many  patients develop pain after eating, fatty foods often being the  culprit. Some patients have pain unrelated to eating.   After the first manifestation of biliary pain, about 30% of  patients do not have another episode, but more than 50% of  patients suffer from further attacks of pain, and the rate of  complications is 1-3% per year. By contrast, the rate of com-  plications for a carrier of a gallstone who has never had a bil-  iary colic is only 0.1-0.3% per year. If there are no further  episodes of biliary colic within 5 years after the first attack,  the natural history of the patient may be regarded as that of  asymptomatic gallstone disease.   Symptomatic gallstone disease is called uncomplicated if it  is characterized by episodes of biliary pain of less than 5 hours  only. Complicated gallstone disease should be suspected if an  episode of biliary pain persists beyond 5 hours and if clinical  or laboratory findings of acute cholecystitis, acute biliary  pancreatitis, biliary obstruction, or symptoms and signs of  other complications develop.   1. Ultrasonography — Ultrasonography of the right upper  quadrant is the method of choice for the diagnosis of gall-  bladder stones (see Figure 9-35). Its sensitivity is greater than  95% for the detection of gallstones 1.5 mm or more in diam-  eter. Complete imaging of the gallbladder in various planes  and in at least two positions of the patient is mandatory. The  characteristic finding is a mobile echogenic focus with an  acoustic shadow within the gallbladder lumen that moves in  a gravity-dependent fashion with the patient's position. The  gravity-dependent mobility of the echogenic foci allows dif-  ferentiation from gallbladder polyps or carcinoma.   Ultrasonography also offers information about the size of  the gallbladder, the presence of a thickened gallbladder wall,  and pericholecystic fluid (signs of acute cholecystitis).  Ultrasonography has high sensitivity (94%) and specificity  (78%) for the diagnosis of acute cholecystitis.   Complications such as perforation into the abdominal  cavity can be detected or excluded. Bile duct dilation may  point toward bile duct obstruction. For the detection of bile  duct stones, however, ultrasonography offers only low to  moderate sensitivity (see below).   Functional ultrasonography provides additional infor-  mation about gallbladder emptying and cystic duct patency.   2. Computed tomography (CT)— CT is occasionally useful  for the detection or exclusion of gallstones, especially calci-  fied stones, but it is less sensitive and more expensive than  ultrasound and requires exposure to radiation. It is valuable  for visualization of the biliary system in suspected biliary  obstruction. It should be used if biliary pancreatitis or com-  mon bile duct stone obstruction is suspected.   3. Magnetic resonance imaging (MRI) and cholan-  giopancreatography (MRCP)— MRI is not recommended   for screening for gallstones, but is useful for visualizing pan-  creatic ducts and bile ducts and has excellent sensitivity for  bile duct or pancreatic duct dilations. Its sensitivity for detec-  tion of bile duct stones is approximately 85%. MRCP can be  used as an alternative to ERCP to exclude bile duct stones in  the preoperative screening of patients undergoing laparo-  scopic cholecystectomy if there is a low to intermediate level  of suspicion for bile duct stones.   4. Endoscopic retrograde cholangiopancreatography  (ERCP) — ERCP is not useful for detection of gallstones in the  gallbladder but is the method of choice for the detection of  bile duct stones. In contrast to MRI, it has both diagnostic  and therapeutic value for visualization and extraction of bile  duct stones.   5. Endoscopic ultrasound— This is the most sensitive  method for the detection of ampullary stones.   6. Hepatobiliary scintigraphy— This test has no role in the  detection of gallstones and a limited one in the diagnosis of  cholecystitis. If acute cholecystitis with blockage of the cystic  duct by a gallstone is suspected, cholecystoscintigraphy  (HIDA scanning) has 95% sensitivity for detecting the cystic  duct obstruction.   7. Oral cholecystography— This modality has been  replaced by ultrasonography and is regarded as obsolete.   Kalimi R, Gecelter GR, Caplin D, et al. Diagnosis of acute cholecysti-  tis: sensitivity of sonography, cholescintigraphy, and combined  sonography-cholescintigraphy. } Am Coll Surg. 2001;193:609-613.  [PMID: 11768676]   Lammert F, Neubrand MW, Bittner R, et al. [S3-guidelines for diag-  nosis and treatment of gallstones. German Society for Digestive  and Metabolic Diseases and German Society for Surgery of the  Alimentary Tract.] Z Gastroenterol. 2007;45:971-1001. [PMID:  17874360]   Lowenfels AB, Lindstrom CG, Conway MJ, et al. Gallstones and  risk of gallbladder cancer. / Natl Cancer Inst. 1985;75:77-80.  [PMID: 3859698]   Rickes S, Treiber G, Monkemuller K, et al. Impact of the operator's  experience on value of high-resolution transabdominal ultra-  sound in the diagnosis of choledocholithiasis: a prospective  comparison using endoscopic retrograde cholangiography as  the gold standard. Scand J Gastroenterol. 2006;41:838-843.  [PMID: 16785198]   Verma D, Kapadia A, Eisen GM, et al. EUS vs MRCP for detection  of choledocholithiasis. Gastrointest Endosc. 2006;64:248-254.  [PMID: 16860077]   The differential diagnosis of acute right upper quadrant  abdominal pain should include duodenal ulcer disease, acute  pancreatitis, appendicitis, duodenal obstruction, lower rib mar-  gin syndrome, right lower lobe pneumonia, mesenteric vas-  cular ischemia, and gastroparesis. An ultrasound examination   and, if necessary, a HIDA scan will help establish the diagno-  sis of acute cholecystitis.   Acute cholecystitis is the most frequent complication of gall-  stone disease. In 90% of patients it is caused by a transient or  permanent obstruction of the cystic duct by a stone. It repre-  sents an inflammatory response to mechanical, chemical, or  bacterial causes. The increased intraluminal pressure and  distention of the gallbladder result in ischemia of the mucosa  and the wall of the gallbladder. Inflammatory agents, such as  lysolecithin, and local tissue factors may be released.  Bacterial inflammation playing a role in 50-85% of patients  with acute cholecystitis and, in general, is a secondary event  occurring late in the course. The organisms most frequently  isolated by culture of gallbladder bile in these patients  include Escherichia coli, Klebsiella species, Streptococcus  species, and Clostridium species.   Acute cholecystitis usually begins as an attack of biliary  pain that progressively worsens. Most patients have previ-  ously experienced episodes of biliary pain. When cholecysti-  tis develops, the pain, which initially is more diffuse,  becomes localized in the right upper quadrant. Peritoneal  signs of inflammation, such as increased pain with jarring or  on deep inspiration, may become apparent. Nausea and  vomiting are frequent.   Physical examination of patients with acute cholecystitis  reveals right upper quadrant tenderness. Usually there is  marked tenderness and inhibition of inspiration on deep  palpation under the right subcostal margin (Murphy sign).  An enlarged, tense gallbladder is palpable in about one third  of patients, often associated with a stone in the neck of the  gallbladder (see Figure 9-37).   Low-grade fever is usually present, but shaking chills or  rigors may occur. Mild to moderate leucocytosis is common.  Serum bilirubin and serum liver enzymes may be mildly ele-  vated in some patients, but substantial elevations suggest bile  duct obstruction concomitant with acute cholecystitis. They  may also occur when edematous, inflammatory changes  involve the bile ducts. Serum amylase levels usually are nor-  mal; if substantially elevated, they suggest pancreatitis.   Chronic cholecystitis is a chronic inflammation of the  gallbladder wall that results from repeated attacks of acute  and subacute cholecystitis or mechanical irritation of the gall-  bladder mucosa by gallstones. It may progress from asympto-  matic to symptomatic.   In 10-30% of the patients with acute cholecystitis severe  complications, such as gallbladder gangrene, empyema, or  perforation, occur. Fistulization between gallbladder and  bowel occur in less than 1% of all patients with gallstones. A  biliodigestive fistula can manifest itself by ascending cholangi-  tis or a bile acid malabsorption syndrome. In about 60% of  cases, the fistulas are located between the gallbladder and the   duodenum and remain asymptomatic. Passage of large stones  through a fistula can cause gallstone ileus, especially in the ter-  minal ileum. Aerobilia is an important sign of a biliodigestive  fistula. Magnetic resonance cholangiography (MRC) may be  valuable for diagnosis in this situation.   Mirizzi syndrome is a rare complication in which a gall-  stone becomes impacted in the neck of the gallbladder or  cystic duct, causing compression of the common bile duct  and obstructive jaundice.   Passage of gallstones into the common bile duct occurs in  approximately 10-15% of patients with gallbladder stones. In  up to 25% of elderly patients who undergo cholecystectomy,  stones in the common duct are found. The large majority of  them are cholesterol stones that originate in the gallbladder.  Stones that primarily form in the bile ducts are usually pig-  ment stones (see "Pathogenesis," earlier). An exception is the  formation of cholesterol gallstones in the bile ducts of  patients with an ABCB4 gene defect causing impaired biliary  phospholipid secretion. Most patients with common bile duct  stones present with biliary pain accompanied by abnormal  liver tests with or without jaundice. Major complications of  choledocholithiasis are obstructive jaundice, cholangitis, pan-  creatitis, and secondary biliary cirrhosis.   The presentation of acute obstruction of the common  bile duct by a stone usually includes biliary pain, similar to  the pain of cystic duct obstruction, and — if of sufficient  duration — is followed by jaundice. Most patients with  obstruction have elevated liver enzymes (alanine amino-  transferase [ALT], aspartate aminotransferase [AST]) in the  acute phase of obstruction. In the later course ALT and AST  decrease toward normal even if the obstruction persists,  whereas alkaline phosphatase rises, followed by bilirubin ele-  vation and eventually jaundice.   Transcutaneous abdominal ultrasonography has only  moderate diagnostic accuracy for the detection or exclusion  of bile duct stones. Sensitivities between 38% and 82% have  been reported. If the diameter of the common bile duct is  larger than 6 mm, a bile duct stone must be suspected (see  Table 53-3). Determination of y-glutamyl transferase (GGT),   Table 53-3. Criteria for simultaneous choledocholithiasis  in patients with gallbladder stones.   elevated GGT, alkaline phosphatase and/or ALT  Common bile duct > 10 mm in presence of gallbladder stones  Direct evidence of stone in bile ducts by ultrasound  Low probability for simultaneous bile duct stones  Common bile duct not dilated  GGT, alkaline phosphatase, and ALT within normal limits   alkaline phosphatase, ALT, and serum bilirubin levels is  mandatory for differential diagnosis in this situation.   If direct proof or exclusion of bile duct stones by ultra-  sonography is not possible, clinical symptoms and signs of  biliary obstruction guide the planning of further diagnostic  measures. If there is high suspicion of the presence of a bile  duct stone, endoscopic retrograde cholangiography (ERC) is  indicated because it permits simultaneous therapeutic inter-  vention (endoscopic papillotomy and stone extraction). Its  sensitivity and specificity for the detection of bile duct stones  are greater than 90%. However, a general recommendation  for exclusion of bile duct stones with ERC prior to laparo-  scopic cholecystectomy would expose too many patients to  unnecessary risks of this diagnostic procedure, because the  prevalence of bile duct stones in patients with gallbladder  stones, depending on age, ranges between 5% and 15% only.  If findings are questionable and bile duct stones are sus-  pected, endosonography or MRC (see Figure 9-36) may be  performed prior to ERC. Endosonography has the highest  sensitivity for the detection of stones in the common duct. It  is associated with lesser risks than the diagnostic ERC, espe-  cially for small (< 5 mm) and ampullary stones. A recent  meta-analysis of five randomized controlled studies includ-  ing a total of 301 patients did not find a significant difference  between endoscopic ultrasound and MRCP with regard to  sensitivity (93% vs 85%) and specificity (96% vs 93%) for  the diagnosis of bile duct stones.   The characteristic presentation of cholangitis involves biliary  pain, jaundice, and spiking fevers with chills (the Charcot  triad). Leukocytosis is typical, and blood cultures are positive  in about 75% of patients.   Biochemical evidence of pancreatic inflammation compli-  cates acute cholecystitis in about 15% and choledocholithia-  sis in about 30% of patients. The common cause appears to  be passage of stones through the common duct.   1. Asymptomatic gallstones— Treatment of persons with  asymptomatic gallstones, with certain exceptions (see later  discussion), is not recommended because the risks of biliary  colic, complications, and gallbladder cancer are low. Sixty to  80% of persons with asymptomatic gallstones remain  asymptomatic over follow-up periods of up to 25 years. The  probability of developing symptoms within 5 years after  diagnosis is 2-4% per year and decreases in the years there-  after to 1-2%. The yearly incidence of complications is about  0.1-0.3%. Treatment of patients with asymptomatic gall-  stones does not prolong life expectancy, because the risk of   complications caused by the stones is counterbalanced by the  operative risks. Finally, the costs of expectant management  without prophylactic cholecystectomy until symptoms or  complications occur are lower than those of an active  approach. In countries with a low prevalence of gallbladder  carcinoma, the slightly elevated risk of gallbladder carcinoma  does not justify surgical intervention in patients with asymp-  tomatic gallstones. Additionally, in diabetic patients, asymp-  tomatic gallstones should be left alone.   Prophylactic cholecystectomy is, however, indicated for  asymptomatic patients with an increased risk of gallbladder  cancer (eg, patients with a so-called porcelain gallbladder;  see Figure 9-38), patients with large stones (> 3 cm in diam-  eter), or Native Americans, whose risk of cancer is 3-5%. It is  important to distinguish between homogenous and patchy  calcifications of the gallbladder wall. Especially with patchy  calcification there seems to be a high (7%) risk of carcinoma.   Prophylactic cholecystectomy has been proposed for  patients with small gallstones (< 5 mm in size) and preserved  gallbladder motility, because they may have a high risk for  acute pancreatitis. However, further studies are needed to  support this recommendation. Some practitioners also con-  sider prophylactic cholecystectomy in patients with a high  risk of becoming symptomatic, such as children who will be  exposed to the risks of the stones for a long time.   Patients with gallstones and gallbladder polyps larger than  1 cm should be cholecystectomized irrespective of symptoms.  For polyps larger than 1 cm, the probability of neoplastic  alteration is markedly increased and a carcinoma may be  found in up to 50%. For polyps with a diameter of less than  1 cm, the risk is considerably lower, but in patients aged 50 years  or older, cholecystectomy should be considered.   In patients with asymptomatic gallstones who undergo  surgery for morbid obesity, prophylactic cholecystectomy  should be considered, because they have a 10-15% risk of  becoming symptomatic or developing complications after  surgery for obesity. During large abdominal surgery (eg, sur-  gery for obesity, extended bowel resections for Crohn dis-  ease, and radical gastrectomy with removal of lymph nodes),  simultaneous cholecystectomy for asymptomatic stones may  be performed.   Although asymptomatic patients in general should be  managed expectantly, litholytic therapy may be considered if  the stones appear to be ideal for dissolution by oral bile acid  therapy with ursodeoxycholic acid (UDCA), psychosocial  factors favor an active approach, or medical factors are pres-  ent creating a high risk for surgery.   Miller K, Hell E, Lang B, et al. Gallstone formation prophylaxis after  gastric restrictive procedures for weight loss: a randomized  double-blind placebo-controlled trial. Ann Surg. 2003;238:  697-702. [PMID: 14578732]   2. Symptomatic gallstones— Patients with symptomatic  gallstones should receive treatment. In addition to analgesic  therapy, surgical or medical options must be offered. Elective   laparoscopic cholecystectomy is the standard method of  cholecystectomy in patients with symptomatic gallstones. It  provides a permanent cure for nearly all patients. It is cost-  effective if compared with open cholecystectomy. Today, more  than 93% of all cholecystectomies are started by laparoscopy  and only 4-7% have to be converted to open cholecystectomy.  A meta-analysis of randomized studies comparing laparo-  scopic and open cholecystectomy shows identical complica-  tion rates for both methods, but on the average 3-day shorter  hospital stays and 3-week shorter convalescences. This is  reflected by the costs, which are 18% lower for laparoscopic  than for open cholecystectomy. A historic comparison shows  that complications (bile leakage, 0.4-1.5%; wound infection,  1.3-1.8%; pancreatitis, 0.3%; bleeding, 0.2-1.4%) are lower  after laparoscopic than after open cholecystectomy. The rate  of bile duct injuries is low and comparable for the two proce-  dures, ranging from 0.2-0.6%.   In patients with liver cirrhosis (Child class A or B) and  portal hypertension, laparoscopic cholecystectomy seems to  be superior to open cholecystectomy. Laparoscopic cholecys-  tectomy should not be performed if advanced gallbladder  carcinoma is suspected.   3. Preoperative diagnostic studies— Preoperative ultra-  sonography must be performed not only for diagnosis of gall-  bladder stones but also for detection of potential  complications. Preoperative determination of liver enzymes  (GGT, alkaline phosphatase, transaminases) and serum  bilirubin is mandatory to assess the likelihood of simultane-  ous bile duct stones or preexisting liver disease. The likeli-  hood of simultaneous bile duct stones is high if the diameter  of the common bile duct is greater than 6-8 mm and GGT,  alkaline phosphatase, or serum bilirubin value is elevated. It is  low if the diameter of the common bile duct is normal and  serum enzymes indicative of cholestasis are not elevated  (Table 53-3). (See also "Complications," earlier.)   Lammert F, Neubrand MW, Bittner R, et al. [S3-guidelines for diag-  nosis and treatment of gallstones. German Society for Digestive  and Metabolic Diseases and German Society for Surgery of the  Alimentary Tract.] Z Gastroenterol. 2007;45:971-1001. [PMID:  17874360]   1. Oral bile acid dissolution— In selected patients who have  symptomatic gallbladder stones without complications and  have mild and infrequent episodes of biliary pain, stone disso-  lution with UDCA may be employed. The patient must, how-  ever, be informed about the high risk of recurrent stones.  UDCA reduces cholesterol saturation of bile and also pro-  duces a lamellar liquid crystalline phase in bile that allows dis-  persion of cholesterol from stones by physical-chemical  means. In carefully selected patients with radiolucent stones  smaller than 5-10 mm in diameter in a functioning gallblad-  der, complete dissolution can be achieved with UDCA in  about 50% of patients. In general, 6-18 months of therapy are   required to achieve complete dissolution of stones 5-10 mm in  diameter, as gallstone dissolution occurs at a mean rate of  0.7-mm decrease in diameter per month. For good results  within a reasonable time period, this therapy should be limited  to radiolucent stones smaller than 5 mm in diameter. The dose  of UDCA should be 10-15 mg/kg/day. Stones larger than 15 mm  in size rarely dissolve. Pigment stones are not responsive to  UDCA therapy. Recurrence of stones in 30-50% of patients  within 3-5 years after stone dissolution have reduced the role  of gallstone dissolution to patients who want to avoid or are  unfit for cholecystectomy. A report from Japan that UDCA  may reduce the risk of biliary pain independently from disso-  lution of the stones has not been confirmed in a recent study,  which could not demonstrate a decrease of the incidence  of biliary symptoms in gallstone patients awaiting elective  cholecystectomy.   introduction of laparoscopic cholecystectomy, this nonsurgi-  cal therapeutic modality has been abandoned mainly  because of high rates of stone recurrence (11-29% at 2 years,  60-80% at 10 years). Extracorporeal shock wave lithotripsy  has maintained a limited role in the treatment of bile duct  stones resistant to endoscopic extraction.   UDCA may prevent gallstone formation in obese patients dur-  ing rapid weight loss. In patients who completed a 3-month,  520-kcal/day diet, UDCA at a dose of 600 mg/day proved  highly effective in preventing gallstone formation; gallstones  developed in only 3% of patients receiving UDCA compared  with 28% receiving placebo. In a more recent study of stone  prophylaxis by UDCA in obese patients treated by gastric  banding, 500 mg/kg/day of UDCA reduced the risk of gallstone  formation from 30% to 8% within a follow-up of 6 months.  For prophylaxis of gallstone formation during rapid weight loss  (> 1.5 kg/week) a minimal dose of UDCA of 500 mg/kg/day is  recommended until constant body weight is attained.   4. Symptomatic treatment of biliary colic— In general,  combinations of analgesics with spasmolytic drugs are used for  relief of pain. Paracetamol may be sufficient, but nonsteroidal  antirheumatic drugs, such as diclofenac or indomethacin,  may also be used in combination with N-butyl scopolamine.  Often opiates such as pethidine or buprenorphine are required.  Nitroglycerin may also be effective because it relaxes the  sphincter of Oddi. The patient should be kept NPO (nothing  by mouth). In case of vomiting, parenteral fluid and electrolyte  replacement may be indicated.   Lammert F, Neubrand MW, Bittner R, et al. [S3-guidelines for diag-  nosis and treatment of gallstones. German Society for Digestive  and Metabolic Diseases and German Society for Surgery of the  Alimentary Tract.] Z Gastroenterol. 2007;45:971-1001. [PMID:  17874360]   May GR, Sutherland LR, Shaffer EA. Efficacy of bile acid therapy  for gallstone dissolution: a meta-analysis of randomized trials.  Aliment Pharmacol Ther. 1993;7:139-148. [PMID: 8485266]   Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid  treatment of cholesterol gallstone disease. Scand } Gastroenterol  Suppl. 1994;204:27-31. [PMID: 7824875]   Paumgartner G, Sauter GH. Extracorporeal shock wave lithotripsy  of gallstones: 20th anniversary of the first treatment. Eur J  Gastroenterol Hepatol. 2005;17:525-527. [PMID: 15827443]   Shiftman ML, Kaplan GD, Brinkman-Kaplan V, et al. Prophylaxis  against gallstone formation with ursodeoxycholic acid in  patients participating in a very-low-calorie diet program. Ann  Intern Med. 1995;122:899-905. [PMID: 7755224]   1. Cholecystitis — Patients with acute cholecystitis should  undergo early elective laparoscopic cholecystectomy, ide-  ally within 72 hours after diagnosis. Four randomized  studies have compared early and late (> 6 weeks after  diagnosis) cholecystectomy in a total of 388 patients. A  meta-analysis of these studies confirms the advantages of  early elective laparoscopic cholecystectomy. Hospital stay  for the late operation was 3 days longer, and 17.5% of the  patients had to undergo emergency operation during the  preoperative waiting period. Early operation did not  increase the complication rate (13.1%) as compared with  late cholecystectomy (17.8%). When laparoscopic chole-  cystectomy was performed for acute cholecystitis, the con-  version rate ranged between 16.4% and 20.3%, being  markedly higher than for elective operation of uncompli-  cated gallstone disease.   From admission until operation the patient should be  kept NPO and intravenously hydrated with careful control of  serum electrolytes. Administration of broad-spectrum  antibiotics early in the course is recommended, because sec-  ondary infection often supervenes in what is initially a non-  infectious process.   After conservative therapy, about 75% of patients with  acute cholecystitis will recover, but about one third of them  will be readmitted because of biliary pain or complications  and about 20% will have a recurrence of cholecystitis within  1 year.   If a complication of cholecystitis, such as diffuse peri-  tonitis with suspected perforation, gangrene, or empyema,  develops an emergency operation should be performed  within 24 hours. When the patient is prepared for surgery, it  must be considered that the circulating blood volume is  often reduced in patients with cholecystitis or cholangitis.  Volume substitution with colloids or albumin solution may  therefore be indicated to prevent renal complications. In  patients older than 65 years or with markedly increased  operative risk (American Society of Anesthesiologists [ASA]  risk class > IV), percutaneous drainage of the gallbladder is  feasible and associated with low mortality.   If, because of late diagnosis or other medical reasons  (high operative risk), cholecystectomy cannot be performed  within 1-5 days, it should be performed within 6 weeks after  acute cholecystitis has subsided.   Johansson M, Thune A, Nelvin L, et al. Randomized clinical trial of  open versus laparoscopic cholecystectomy in the treatment of  acute cholecystitis. Br J Surg. 2005;92:44-49. [PMID: 15584058]   Macri A, Scuderi G, Saladino E, et al. Acute gallstone cholecystitis  in the elderly: treatment with emergency ultrasonographic per-  cutaneous cholecystostomy and interval laparoscopic cholecys-  tectomy. SurgEndosc. 2006;20:88-91. [PMID: 16333552]   Papi C, Catarci M, DAmbrosio L, et al. Timing of cholecystectomy  for acute calculous cholecystitis: a meta-analysis. Am J  Gastroenterol. 2004;99:147-155. [PMID: 14687156]   2. Choledocholithiasis — Symptomatic bile duct stones  should be removed. Data on the natural history of bile duct  stones show that symptomatic bile duct stones will cause  recurrent colic in more than 50% of the patients and com-  plications in about 25%. Asymptomatic bile duct stones  seem to be more benign than symptomatic bile duct stones.  Although long-term prospective data are not available,  short-term prospective and long-term retrospective studies  indicate that less than half of the patients become sympto-  matic and more than 20% of the stones pass spontaneously.  From these data it may be concluded that patients with  asymptomatic bile duct stones may be treated, but that treat-  ment is not usually necessary. Spontaneous passage of stones  into the bowel appears to be common, especially when the  stones are small. Examination of the feces after extracorpo-  real shock wave lithotripsy of gallbladder stones has shown  that stone fragments up to 8 mm in diameter can pass the  papilla spontaneously without severe symptoms.   Patients with symptomatic bile duct stones who have had  cholecystectomy previously should undergo endoscopic  papillotomy (EPT) and stone extraction. Patients with simul-  taneous gallbladder and bile duct stones should undergo so-  called therapeutic splitting. In this technique, ERC is  performed before or after cholecystectomy. If the probability  of simultaneous choledocholithiasis is high, preoperative EPT  and stone extraction is preferred in most hospitals. EPT and  cholecystectomy should not be performed on the same day to  exclude complications of EPT before surgery. If the probabil-  ity of choledocholithiasis is low, preoperative ERC should not  be the standard; rather — depending on availability — less-  invasive procedures should be used. Both endosonography  and MRC have high sensitivity and specificity for the detec-  tion of bile duct stones. If bile duct stones are found, preop-  erative EPT with stone removal should be performed. In  centers with high expertise, laparoscopic cholecystectomy  may be combined with laparoscopic revision of the common  duct and removal of the stones.   If endoscopic transpapillary therapy is not possible  or fails, percutaneous, transhepatic, or surgical therapy of   choledocholithiasis may be employed. In high-risk patients  the placement of an endoprosthesis may be considered for  primary therapy.   After successful endoscopic or percutaneous removal of  bile duct stones in patients with gallbladder stones, cholecys-  tectomy should be performed within about 6 weeks. This  recommendation is based on a study randomizing patients  (> 60 years of age) after endoscopic sphincterotomy and  clearance of their bile duct stones to receive either expectant  management or early laparoscopic cholecystectomy. Within a  median follow-up of approximately 5 years, 24% of patients  with the gallbladder left in situ returned with further biliary  events (cholangitis, acute cholecystitis, biliary pain, and  jaundice) as compared with only 7% (cholangitis, biliary  pain) in the cholecystectomy group. Late death was not sig-  nificantly different between the two groups.   Lau JY, Leow CK, Fung TM, et al. Cholecystectomy or gallbladder  in situ after endoscopic sphincterotomy and bile duct stone  removal in Chinese patients. Gastroenterology. 2006;130:96-103.  [PMID: 16401473]   3. Cholangitis — Acute cholangitis caused by an obstructive  gallstone should be treated as soon as possible (in septic  patients, as an emergency procedure) by endoscopic removal  of the stone. A randomized study has shown a significant  advantage of the endoscopic versus the surgical approach  with regard to complications and mortality. An accompany-  ing systemic antibiotic therapy is indicated to prevent septic  complications. If stone extraction fails, nasobiliary drainage  or a biliary stent should be placed. Nasobiliary drainage and  a biliary stent are equally effective, but nasobiliary drainage  offers the advantage of bile sampling for microbiological  tests and flushing the bile duct.   Lai EC, Mok FP, Tan ES, et al. Endoscopic biliary drainage for  severe acute cholangitis. N Engl } Med. 1992;326:1582-1586.  [PMID: 1584258]   4. Biliary pancreatitis— Management of biliary pancreatitis  depends on its severity. Most cases of biliary pancreatitis are  mild, resolve spontaneously, and may be managed expec-  tantly. After resolution, patients with gallbladder or bile duct  stones, or both, should undergo cholecystectomy and  removal of bile duct stones prior to discharge from the hos-  pital. If biliary pancreatitis is severe and is associated with  choledocholithiasis and signs of cholestasis, ERC with papil-  lotomy and stone extraction should be performed as soon as  possible, in the presence of cholangitis within 24 hours.   Note: Page numbers referencing figures are italicized and followed by an "/'. Page numbers referencing tables are italicized and fol-  lowed by a " f".   5' nucleotidase (5' NT), 98  5-aminosalicylate (5-ASA)  Crohn disease, 29  inflammatory bowel disease, 86  ulcerative colitis, 31-32  6-mercaptopurine (6-MP), 87   519  AAA (abdominal aortic aneurysm), 5/  AASLD (American Association for the Study of Liver Diseases),   435,511  ABC (ATP-binding cassette) transporters, 538  abdominal aortic aneurysm (AAA), 5/  abdominal migraine, 3t  abdominal pain. See acute abdominal pain  abetalipoproteinemia, 239  abscesses   toxicity threshold and alcoholic liver disease, 464  ACG (American College of Gastroenterology), 36  achalasia, 104, 157-159, 165-167  acinar cells, 310   acinar-cell cyst-adenocarcinomas, 317t  acquired CI immunodeficiency syndromes, 133  acquired immunodeficiency syndrome (AIDS).   See HIV/AIDS  ACRP30 (adiponectin), 469  Actinomyces israelii, 26t  acute abdominal pain   treatment for, 249-251  acute fatty liver of pregnancy (AFLP), 78f, 80, 99-101  acute GI bleeding   clinical findings, 324-326  general considerations, 324  specific causes of, 332-342  treatment for, 327-331  acute hepatic vein thrombosis, 419  acute hepatitis B, 427  acute hepatitis C, 435, 437^438  acute hepatobiliary disease, 406t  acute liver failure. See ALF  Acute Liver Failure Study Group (ALFSG), 410  acute mesenteric ischemia. See AMI  acute pancreatitis   acute rejection, 523  acute viral hepatitis, 420-423  adalimumab (ADL), 31t  Adams, F. Dennette, 4  adaptive immunity, 11, 132  Addison disease, 2t  adefovir dipivoxil, 43 1  adenocarcinomas   serous cyst, 128f, 316-318  adenomatous polyposis. See familial adenomatous polyposis  adenomatous polyposis colt (APC) gene, 261, 275  adiponectin (adipocyte complement-related protein   [ACRP30]),469  adjustable silicone gastric banding (ASGB), 213, 215  ADL (adalimumab), 31 1  adolescent bariatric surgery, 213  AdvanCE device, 364  Aeromonas spp, 26t, 55-56  AFAP (attenuated FAP), 262, 270t-271t  a-fetoprotein (AFP) levels, 439  anatoxin, 512   AFLP (acute fatty liver of pregnancy), 78f, 80, 99-101  AFP (a-fetoprotein) levels, 439  AGA (American Gastroenterological Association), 36  AIDS (acquired immunodeficiency syndrome). See HIV/ AIDS  AIH (autoimmune hepatitis)   specific causes of, 415-419  ALFSG (Acute Liver Failure Study Group), 410  alkaline phosphatase (ALP), 405, 530  ALKM (anti-liver kidney microsomal) antibody, 444  allograft rejection, 522-524  alosetron, 84t   AMAs (antimitochondrial antibodies), 448, 529  American Association for the Study of Liver Diseases   (AASLD),435, 511  American College of Gastroenterology (ACG), 36  American Gastroenterological Association (AGA), 36  American Society for Clinical Oncology, 274  American Society for Gastrointestinal Endoscopy (ASGE), 95  American wire-guided polyvinyl dilators, 146  AMI (acute mesenteric ischemia)   prognosis, 70-71  aminotransferases, 98, 405, 409  Amitiza (lubiprostone), 219, 289  amitriptyline, 84t  ammonia (NH 3 ), 473, 474t  amoxicillin, 504-505  ampicillin, 82, 93f   383, 384f  anorectal disease, 136-137  anorectum, 114-116  anoscopy, 345  antacids, 144, 198  anterior abdominal wall pain, 2t  antibiotics   inflammatory bowel disease, 86-87  anticholinergics, 2t, 83  anticoagulation, 331-332  antidepressants, 198  antidiarrheal agents, 49, 135, 287  antidiuretic hormone, 479f  antiemetics, 207   antigen-presenting cells (APCs), 14, 523  anti-liver kidney microsomal (ALKM) antibody, 444  antimitochondrial antibodies (AMAs), 448, 529  antineutrophil cytoplasmic antibodies, 24  antinuclear antibodies (ANAs), 444, 531  antisecretory agents, 196-197  anti-smooth muscle antibody (ASMA), 444  anti-soluble liver antigen (ASLA), 444  antispasmodic agents, 83, 287-288  anti-tumor necrosis factor (TNF) agents,   30-31,465  antiviral therapy, 429t, 525t  anxiolytic agents, 198  aortic dissection, 2t  aortoenteric fistula, 338  APACHE II score, 295   APBU (anomalous pancreatobiliary union), 383, 384f  APC (adenomatous polyposis coli) gene, 261, 275  APCs (antigen-presenting cells), 14, 523  appendicitis. See acute appendicitis  appendix, 110-111  argon plasma coagulation, 337, 349  aromatic amino acids, 474t  arteriovenous malformations (AVMs), 349   treatment for, 480-482  ASGB (adjustable silicone gastric banding), 213, 215  ASGE (American Society for Gastrointestinal   Endoscopy), 95  ASLA (anti-soluble liver antigen), 444  ASMA (anti-smooth muscle antibody), 444  aspirin, 175-177, 180  AST (aspartate aminotransferase)   ATP-binding cassette (ABC) transporters, 538  attenuated FAP (AFAP), 262, 270t-271t  atypical appendicitis, 9  atypical viral hepatitides, 416^417  autoimmune hepatitis. See AIH  autoimmune liver disease, 519  autoimmune pancreatitis. See AIP  AVMs (arteriovenous malformations), 349  AZA (azathioprine), 87, 446t, 447, 524f  azithromycin, 82   Bacillus cereus, 58  backwash ileitis, 25  bacterial cholangitis, 124  Bacteroides sp, 13f  balloon tamponade, 496  balsalazide, 32t  barbiturate agents, 413  bariatric surgery   recommendations, 221  barium enema, 25, 245f, 257, 265, 346  barium esophagogram, 166, 168, 171, 178  Barrett, Norman, 148   BCAAs (branched-chain amino acids), 465  bDNA (branched-chain DNA), 435  benign bile duct strictures, 381-382  benign liver lesions, 116-118  benign liver tumors, 506-510  benzodiazepines (BZDs), 474t  Bergman classification system, 356  betaine, 471   bile salt export pumps (BSEPs), 99, 538  biliary colic, 90, 194, 545  biliary disease, 88, 89-90  biliary imaging   stone disease, 121-122  biliary pain, 541  biliary pancreatitis, 543, 546  biliopancreatic diversion (BPD), 214-215, 215f  bilirubin, 403, 405  biopsy   bismuth subsalicylate, 49, 63, 84t, 198  black pigment stones, 540  blood studies, 48, 228  bloody diarrhea, 56  blunt foreign bodies, 373  body mass index (BMI), 139, 210  Boerhaave syndrome, 332t, 336   procedures, 364-365  carbohydrate intolerance, 239-240  carbohydrate-deficient tranferrin (CDT) test, 464  carbonated beverages, 284  carcinoembryonic antigen (CEA), 316, 398  carcinoids, 396  carcinomas. See also hepatocellular carcinoma   gallbladder, 124  Carnett sign, 4  Caroli disease, 125-126  castor oil, 84t   cavernous hemangiomas, 506-507  CAWP (chronic abdominal wall pain), 3t, 4  CBC (complete blood count), 78f  CBD (common bile duct) stones, 122   chest pain of unknown origin (CPUO), 163, 164f, 165  Child-Pugh scoring system, 482, 519t  Chlamydia trachomatis, 26t  cholangiocarcinoma   imaging studies, 2t, 123  choledochal cysts, 125-126, 383, 384f  choledocholithiasis, 122, 380-381, 543, 546  cholelithiasis, 122, 219, 380-381, 537  cholestatic disorders, 423, 501, 519  cholesterol hypersecretion, 539  cholesterol stones, 538-540  cholestyramine, 82, 84t  chronic abdominal wall pain (CAWP), 3t, 4  chronic anal fissures, 39  chronic appendicitis, 9  chronic cholecystitis, 123  chronic hepatitis   hepatitis C, 435  chronic hepatobiliary disease, 406t  chronic intestinal ischemia, 195  chronic intestinal pseudo-obstruction.   treatment for, 302-304  chronic pyogenic cholangitis, 124  chronic rejection, 523-524  chronic viral hepatitis, 422-423  cigarette smoking, 176  CIPO (chronic intestinal pseudo-obstruction)   versus inflammatory bowel disease, 26t, 27  Clostridium lepium, 13f  Clostridium perfringens, 58  CMI (chronic mesenteric ischemia), 71-72  CMV (cytomegalovirus), 26t, 520, 524-525  coagulopathy   coefficient of fat absorption (CFA), 302  "cold" biopsy forceps, 322  "cold" snares, 322  colic, 541  Coliforms, 13f  colitis. See also ulcerative colitis   subacute, 36  collagenous colitis, 286  colon cancer, 112f, 345  colonic ischemia, 12-1 A:  colonic motility, 243-244  colonic polyps, 112f  colonoscopy   attenuated adenomatous polyposis, 275-276  familial adenomatous polyposis, 274-275  Lynch syndrome, 269-274   modalities, 264-268  overview, 256-257  risk stratification, 257-263  colorectal polyps, 112  colorectal tumorigenesis, 257f  commensal gut bacteria, 23  common bile duct (CBD) stones, 122  common variable immunodeficiency (CVID), 132  complete blood count (CBC), 78f  complicated gallstone disease, 541  computed tomographic colonography (CTC), 266-267  computed tomographic enterography (CTE), 229  computed tomography. See CT  computed tomography colonography (CTC), 257  congenital anomalies, 130  constipation   ulcerative colitis, 32  corticotrophin-releasing hormone (CRH), 280  co-stimulatory molecules, 20  Courvoisier sign, 311  Cowden syndrome, 270t-271t, 276-277  COX (cyclooxygenase)-2 inhibitors, 151-152, 175, 180  CPB (celiac plexus block), 399-400  CPN (celiac plexus neurolysis), 399-400  CPP (cerebral perfusion pressure), 411-412  CPUO (chest pain of unknown origin), 163, 164f, 165  CRC. See colorectal cancer  c-reactive protein (CRP), 24  CRH (corticotrophin-releasing hormone), 280  cricopharyngeal achalasia, 157-159  cricopharyngeal bar, 157-159  cricopharyngeal myotomy, 159  Crohn disease (CD)   treatment for, 29-31  cromolyn sodium, 173  CRP (c-reactive protein), 24  Cryptosporidiosis, 60-6 1  Cryptosporidium, 26t  crypt-programming model, 453, 455f  crystalloid fluids, 327  CT (computed tomography)   pancreatic duct injuries, 357  CTC (computed tomographic colonography), 266-267  CTC (computed tomography colonography), 257  CTE (computed tomographic enterography), 229  CTZP (certolizumab pegol), 30, 3 It  Cullen sign, 293  curvilinear mucosal flap, 42  CVID (common variable immunodeficiency), 132  CyberKnife radiation therapy, 400  cyclooxygenase (COX)-2 inhibitors, 151-152, 175, 180  cyclophosphamide, 446t, 447  Cychspora, 26t, 61  cyclosporine   overview, 127-128  cytomegalovirus (CMV), 26t, 520, 524-525  cytotoxic chemotherapy, 432  cytotoxin-associated gene A (CagA), 176-177   storage diseases, 120-121  digital image analysis (DIA), 401  dimorphic anemia, 224  diphenoxylate hydrochloride-atropine sulfate (Lomotil),   retrieving capsules, 367  double-channel therapeutic endoscope, 329f  double-contrast barium enema (DCBE), 257, 265  D-Penicillamine, 450  drug-induced chronic hepatitis, 502  drug-induced liver disease   treatment for, 502-503  ductal adenocarcinomas, 126-127, 317t  ductal cells, 310  dumping syndrome, 208, 219  duodenal adenocarcinomas, 109f  duodenal enterocytes, 453  duodenal eosinophilia, 191-192  duodenal ulcers, 177, 332t  D-xylose absorption test, 228  dyspepsia, 189, 190t, 193f  dysphagia   ELISA (enzyme-linked immunosorbent assay), 45, 48, 228, 301  EMA (IgA antiendomysial antibody test), 233  embolization, 348-349   EMR (endoscopic mucosal resection), 153, 321, 323  emtricitabine, 432  encephalopathy, 413t  end ileostomy, 37-38  endoanal ultrasound (EAUS), 85   radiation proctitis, 351  endoscopic ultrasound. See EUS  endoscopic variceal ligation (EVL), 493  endosonography, 543  endovaginal advancement flap, 42  enemas   sodium phosphate, 84t, 96  Entamoeba histolytica, 26t, 61-62  entecavir, 431  enteral nutrition, 297  enteroaggregative E coli (EAEC), 56-57  Enterocytozoon bieneusi, 62  enterohemorrhagic E coli (EHEC), 45, 57  enteroinvasive E coli (EIEC), 57  enteropathogenic E coli (EPEC), 56  enteropathy-associated T-cell lymphoma (EATL), 235  enterotoxigenic E coli (ETEC), 56   enzyme-linked immunosorbent assay (ELISA), 45, 48, 228, 301  eosinophilic esophagitis, 172-174  eosinophilic gastroenteritis, 223, 236-237  epigastric pain, 300, 357  epinephrine, 93t, 348   primary sclerosing cholangitis, 534  erosive duodenitis, 332t  erythrocyte sedimentation rate (ESR), 24  erythromycin, 82, 197t, 206, 329  erythropoiesis disorders, 453  Escherichia coli (E colt), 26t, 45, 56-57, 246  ESD (endoscopic submucosal dissection), 321, 323  esophageal cancer, 391-392  esophageal capsule endoscopy, 365, 367  esophageal carcinomas, 104, 143  esophageal chest pain, 162-165  esophageal dilation, 146, 173  esophageal foreign bodies, 371-372  esophageal hypersensitivity, 163-165  esophageal imaging, 103-104   esophageal motility disorders, 104-105, 159-162, 164-165  esophageal motor dysphagia, 160-161  esophageal pH testing, 143  esophageal ulcers, 143  esophageal variceal hemorrhage   treatment for, 492^98  esophageal variceal ligation, 495  esophagectomy, 153  esophagitis, 332t  esophagogastric varices, 332t  esophagogastroduodenoscopy. See EGD  ESR (erythrocyte sedimentation rate), 24  ETEC (enterotoxigenic E coli), 56  ethanol, 462  EUS (endoscopic ultrasound)   therapeutic uses of, 399-401  EUS-FNA (EUS-guided fine needle aspiration), 313, 316,   400-401  EUS-guided transluminal drainage, 400  EVL (endoscopic variceal ligation), 493  EVR (early virologic response), 436  excitatory nerves, disorders of, 169-171  exocrine insufficiency, 304  extensive small bowel disease, 27  external hemorrhoids, 83  extracorporeal shock wave lithotripsy, 545  extrahepatic cholangiocarcinoma, 124-125  ezetimibe, 504   FAEEs (fatty acid ethanol esters), 292  familial achalasia, 166  familial adenomatous polyposis. See FAP  familial atypical multiple mole melanoma   (FAMMM), 277  familial intrahepatic cholestasis type 1 (FIC1), 99  familial Mediterranean fever, 2t  familial pancreatic cancer, 270t-271t, 277-278  FAMMM (familial atypical multiple mole   pancreatic cancer, 311  FAPS (functional abdominal pain syndrome), 2, 3t  "fat creeping," 38  fat malabsorption, 300  fatty acid ethanol esters (FAEEs), 292  FDA (Food and Drug Administration), 212, 288  FDG (fluoro-D-glucose), 103  FDG-PET (fluorodeoxyglucose-positron emission   fecal occult blood testing (FOBT), 263-265  fecal pancreatic elastase-1 (FPE-1), 301  fentanyl, 93t, 94  ferritin, 458  ferroportin, 456   FIC1 (familial intrahepatic cholestasis type 1), 99  FISH (fluorescence in situ hybridization), 401  fistulas 
CurrentDiagnosisAndTreatmentInGastroenterologyHepatologyAndEndoscopy Current Diagnosis and Treatment in Gastroenterology, Hepatology, and Endoscopy_djvu.txt