CASE 22 143 specificity of 85 \200\223100%. It takes up to 3 days, and ELISA is faster and cheaper. ELI SA is less sensitive if an assay is used that tests only for toxin A. Tests for both toxins (TOX A/B TEST) have a sensitivity of 92 \200\22394% and a specificity of 100%. The chance of a false-negative result reduces if the test is repeated three times. Culture alone may i solate C. difficile, but does not distinguish between toxigenic and non-toxigenic strains. Flexible sigmoidoscopy with visualization of the mucosa may demon- strate non-specific coli tis, but the presence of pseudomembranes is pathognomonic (Fig. 22.3 in the central color s ection) and indicates severe disease. Plain abdominal radiography is useful to exclude toxi c dilatation (maximum colonic diameter >5.5cm). A CT scan is appropri- ate for patients wit h toxic dilatation in preference to endoscopy, to look for early signs of perforation (intr amural gas). 22c) How is severe C. difficile-associated diarrhea best treated? Treatment starts with general fluid resuscitation and withdrawal (if possible) of any offen ding antibiotic. Supportive care depends on the severity of disease at presentation, with p seudomembranous colitis being associated with hypotension, acute renal failure, abdominal p ain, disten- sion with ileus, marked peripheral leucocytosis, pseudomembranous colitis, or toxic megacolon. Before 2006, two antibiotics were commonly used. Metronidazole used to be as effective as vancomycin (response rate Fig. 22.3 (see color plate 7) Endoscopic image of the sigmoid colon, in a patient with pseu domembranous colitis. The mucosa exhibits circumferential hyperaemia and oedema. There are discrete pseudomembranes (arrow). Pseudomembranes are characteristic of pseudomembranous co litis, and indicate severe colonic involvement. OXFORD CASE HISTORIES 144 90 \200\22398%). Since then, the severity of hospital-acquired C difficile has increased an d responsiveness to metronidazole has declined. In our insti- tution, vancomycin is now fir st-line therapy in all cases. Resistance to vancomycin has not yet been described. Vancomyc in is significantly more effective than metronidazole in severe disease (98% vs 76%, p=0.02 ). On the other hand, oral vancomycin cannot be expected to have an equivalent effect in th e presence of ileus or toxic megacolon, while intravenous vancomycin is ineffective because it does not reach the intes- tinal lumen. Consequently (and without much evidence), oral v ancomy- cin and intravenous metronidazole 500mg are often used in severe cases. Teicoplanin is an alternative. To this may be added corticosteroids, on the basis that the colonic inf lammation is toxin driven, rather than infec- tive. Once again, this is empirical therapy, with only anecdotal evidence. The opinion of an experienced colorectal surgeon should be so ught in severe cases, because subtotal colectomy may be lifesaving, although the timing is always difficult to judge. Most patients have resolution of symptoms after 3 \200\2235 days . Vancomycin is generally continued for 2 weeks. Shorter courses, especially in the case of recurrent CDAD, may be associated with relapse. Following resolution of the first episode, recurrent CDAD develops in about 20%, irrespecti ve of antibiotic therapy. Recurrence probably results from impaired re-colonization with no rmal bowel flora, possibly as a consequence of the antibiotic therapy, and not from antibio tic resistance. It typically occurs 4 weeks later. Recurrence of CDAD is generally more sev ere than the initial infection, possibly because of the weakened state of a patient who oft en has multiple comorbidities. Passive immunotherapy with intravenous immunoglobulin (which contains antibodies to toxins A and B) reduces recurrence, or is effective in severe cases . Probiotics (treatment with Saccharomyces boulardii, or Lactobacillus plantarum GG) may re duce recurrence, but are ineffective as therapy. Therapies aimed at restoring bowel flora h ave been reported. Administration of donor feces (from a family member, after filtering), e ither through a nasogastric tube or at colonoscopy, have been reported to prevent recurrenc e in case series, but (perhaps not surprisingly!) such therapy remains unpopular. Other non -absorbable antibiotics such as nitazoxinide or rifaximin con- tinue to treat antibiotic-as sociated diarrhea with more antibiotics. Tolevamer, an inert polymer that binds toxins A an d B, but has no anti- microbial activity, is promising. Although inferior to current antibi otic regimens, those subjects who responded to tolevamer had fewer recur- rences (3% vs 23% after vancomycin and 27% after metronidazole). CASE 22 145 22d) Discuss the complication that has occurred and its management. Our patient with recurrent CDAD had a systemic inflammatory response syndrome (SIRS) and co lonic dilatation >5.5cm. This represents toxic megacolon and is a medical emergency whateve r the cause. Paradoxically, diarrhea may subside because of colonic dilatation and ileus, b ut tachycardia, abdominal pain, tenderness or hypotension and leucocytosis should alert the clinician to the need for (or to repeat) plain abdominal radiography. Toxic megacolon is d efined as a colonic diameter >5.5cm in a patient with SIRS, or any three of the following s igns: fever (>38 C), tachycardia (>120bpm), peripheral leucocytosis (>10.5 x 109/L), anemi a plus dehydration, altered mental status, or electrolyte disturbance. Risk factors for sev ere CDAD in our patient include recurrent CDAD and comorbidity (chronic renal disease need- ing dialysis). The lack of clinical response to treatment prompted surgi- cal consultation . Observation for a further 2 days saw no improvement, so a subtotal colectomy was carried out. It is important to recognize the limited physiological reserve of sick, elderly patien ts, so a decision to (or not to) operate should be made at an early stage by an experienced colorectal surgeon. Even timely surgery in these severely ill patients is associated with a mortality of 30%. The procedure of choice is a subtotal colectomy. Less extensive colecto my has been associated with a high mortality. Our patient made a full recovery following he r surgery. Pathology of the resected colon confirmed pseudomembranous colitis. 22e) What strategies may prevent outbreaks in hospitals? Rationalization of antibiotic use, with restrictions on cephalosporins and fluoroquinolones , reduces the incidence of CDAD. Antibiotics (even prophylactic doses, prior to certain pro cedures) should be used only when indicated. Clostridium difficile is a spore-forming bacil lus. Spores may persist for long periods in the environment and are not killed by standard alcohol-containing hand rubs available in NHS hospitals. Thorough hand washing is the only effective way of removing C. difficile spores from hands, following contact with a patient. Isolation of patients with proven CDAD may restrict spread in a ward. Of particular impor- tance is access to dedicated toilet facilities for patients with CDAD. Establishment of sp ecific wards to manage patients with CDAD, while in principle attractive, may be logistical ly impossible. Resources are often unavailable and patients still need to be managed for th eir primary illnesses. OXFORD CASE HISTORIES 146 Further reading Kelly CP, LaMont JT (2008). Clostridium difficile \200\223 more difficult than ever. N Eng l J Med; 359: 1932 \200\22340. Kuipers EJ, Surawicsz CM (2008). Clostridium difficile infection. Lancet; 371: 1486 \200 \2238. Jaber MR, Olafsson S, Fung WL, Reeves ME (2008). Clinical review of the management o f fulminant Clostridium difficile infection. Am J Gastroenterol; 103: 1 \200\2239. Gan SI, Beck PL (2003). A new look at toxic megacolon: An update and review of incidence, etiology, pathogenesis and management. Am J Gastroenterol; 98: 2363 \200\22371. CASE 23 147 Case 23 A 32-year-old woman with a history of Crohn \200\231s disease asked for advice about a plan ned pregnancy. The history of Crohn \200\231s is complex and includes: an ileal resection for small bowel Crohn \200\231s disease at 23 years of age three flares in the past 2 years that had resolved with budesonide and azathioprine two perianal fistulae that had required seton insertion a year ago. She was currently in clinical remission taking azathioprine 125mg/day (weight 65kg). A colo noscopy a year ago had at that time shown aphthoid and serpigi- nous ulcers in the transver se and descending colon. On examination of her perineum there was scarring, but no active d isease or drainage. The seton in a perianal fistula had been removed 6 months previously. Questions 23a) Will Crohn \200\231s disease affect the patient \200\231s fertility? 23b) Should the patient \200\231s azathioprine be stopped prior to her trying to conceive? 23c) If the patient presents with active disease during pregnancy, what is the best management? 23d) What advice would you give about the mode of delivery? 23e) What advice would you give about breast-feeding and the patient \200\231s medication? OXFORD CASE HISTORIES 148 Answers 23a) Will Crohn \200\231s disease affect the patient \200\231s fertility? Given that the patient \200\231s Crohn \200\231s disease is currently quiescent, her fertil ity should be normal. Patients with IBD have fewer children than the general population, bu t this is partly due to voluntary childlessness (see Case 18). On the other hand, active Cr ohn \200\231s disease or previous pelvic sepsis can reduce fertility by several mechanisms, including inflamma- tion involving the fallopian tubes or ovaries, and perianal disease ca using dyspareunia. Pelvic surgery (but not simple ileal resection) carries a risk of impair ed tubal function. Remission is the best time to try for concep- tion, and this also applie s to IVF. When conception occurs during a period of remission, about two-thirds remain in r emission during preg- nancy, which is similar to that in non-pregnant patients with Crohn \200\231s disease over a period of 9 months. In contrast, if conception occurs at a time of active disease, two-thirds have persistent activity and of these, two thirds will deterior ate. This underscores the importance of advising patients to conceive at a time when diseas e is in remission. 23b) Should the patient \200\231s azathioprine be stopped prior to her trying to conceive? Medical therapy for Crohn \200\231s disease (except methotrexate) should gen- erally contin ue during pregnancy, because the benefits of controlled disease outweigh the risks of medic ation. Given the patient \200\231s history of small and large bowel Crohn \200\231s disease and perianal disease, she should be strongly encouraged to continue her azathioprine. Most of the experience on azathioprine and mercaptopurine in pregnancy comes from the trans plant and rheumatology literature. Azathioprine is safe in these populations, with no consi stent reports of abnormalities with regard to fertility, prematurity, or congenital defects . The US Food and Drug Administration (FDA), however, currently rates azathioprine/mercapto purine as \200\230class D \200\231 ( \200\230Positive evidence of risk in humans, risk/ben efit ratio should be considered \200\231). This unfortunate advice, which is in the process of being revised, appears to stem from animal studies using a 10-fold higher dose than is tolerated by humans. There is no consistent evidence of harm to pregnant patients with IBD or the fetus, but a substantial risk that stopping the drug will be associ- ated with a rel apse with potentially adverse outcomes to the patient or pregnancy. Active Crohn \200\231s disease during pregnancy is associated with a risk of spontaneous ab ortion, prematurity, or low birth weight. Studies on CASE 23 149 animals given azathioprine (equivalent to 2.5mg/kg/d) or mercaptopurine (equivalent to 1.5m g/kg/d), report only low birth weights. High doses (10 \200\22320mg/kg/day) have been assoc iated with an increased incidence of congenital malformations, prematurity, low birth weigh t, and chromo- somal abnormalities. In humans, a follow-up study on 341 pregnancies during or after treatment with azathioprine or mercaptopurine reported no excess rates of prematur ity, spontaneous abortion, congenital abnor- malities, or neonatal/childhood infections. Th e only prospective cohort study confirms that the outcome in pregnant patients with IBD tre ated with thiopurines is no different to the general population. Consequently, despite the FDA rating, most European IBD specialists consider that these drugs are safe and best conti nued during pregnancy, because the benefit/risk ratio is strongly in favor of continued the rapy. It may be worth noting (and explaining to the patient) the risks of miscarriage (12%) and fetal abnormality (5 \200\2237%) in normal pregnancy. With the exception of methotrexa te, the greatest risk to a mother with IBD and fetus during pregnancy is active disease, no t the medication used to treat it. 23c) If the patient presents with active disease during pregnancy, what is the best management? Prednisolone or budesonide: corticosteroids cross the placental bar- rier but are rapidly c onverted to less active metabolites by placental 11-hydroxygenase, resulting in low fetal b lood concentrations. Prednisone or prednisolone are more rapidly metabolized than alterna- tive compounds. Although risks of prematurity, spontaneous abortion, or cleft palate are of ten cited, these have only been seen in animals. No increase in congenital malformations ha s been found in humans. Enemas and suppositories are considered acceptable until the third trimester. No studies on budesonide during pregnancy are available in humans with IBD, alth ough studies with inhaled budesonide suggest that the drug is safe. Toxic doses of budesoni de have demonstrated both teratogenic and embryocidal effects in animals. It is important to ask the patient whether she has stopped azathio- prine and to encourage her to restart this if she has. Depending on the severity of the flare and response to corticosteroids, anti-TNF agents can be considered. Anti-TNF antibodies are species- specific. Murine models have failed to s how any teratogenicity or embry- otoxicity. Post-marketing data of more than 500 pregnancie s, of which a third had infliximab during the first trimester, have shown no difference OXFORD CASE HISTORIES 150 to the general population (75% live births, 14% miscarriage, 11% thera- peutic termination) . There are fewer, but similar data on adalimumab from a teratology registry that is indepe ndent of industry. There is, how- ever placental transfer of infliximab (high serum concent rations have been detected in the baby of a mother who received infliximab 10mg/kg every 8 weeks during pregnancy) and of adalimumab, although it is not yet known whether this induce s antibody formation in the baby. The implications of exposure to infliximab or adalimumab on the newborn are unknown, but patients and physicians should be aware that in utero expos ure occurs, and that treatment may best be avoided in the last weeks of pregnancy if drug c irculation in the neonate is to be avoided. Specialist advice is appropriate. 23d) What advice would you give about the mode of delivery? The mode of delivery is primarily dictated by obstetric necessity, but it should be a joint decision with the patient and informed by the views of the gastroenterologist or colorecta l surgeon. The critical considerations are risks to the anal sphincter and the pelvic floor in patients whose con- tinence may subsequently be impaired after surgery, perianal diseas e, or active inflammatory bowel disease. The risk of a third-degree obstetric tear is very low with good obstetric practice, but the obstetrician needs to know the likelihood of cole ctomy, ileorectal, or pouch anal anastomosis before a decision to proceed with normal vagin al delivery is made. Decision making clearly differs between individual patients, and spe- cialist advice is ess ential. Vaginal delivery is usually acceptable if disease has been readily controlled with medical therapy, the risk of surgery is low, and there has been no perianal disease. Episio tomy should be avoided if possible, because a high rate of perianal involvement has been re ported, but is better than an uncontrolled laceration. On the other hand, Caesarian section is advisable if there is active (some would include previous) perianal disease, if hospita l admission for intensive treatment of inflammatory bowel disease has been necessary (since this is associated with the need for colectomy), or if the patient has had med- ically ref ractory disease. Treatment with azathioprine is a marker of the latter, but decisions shoul d be tailored to the individual. 23e) What advice would you give about breast-feeding and the patient \200\231s medication? Tiny amounts of azathioprine/mercaptopurine metabolites (nanomo- lar concentrations of meth yl mercaptopurine and thiouric acid) appear in breast milk, but these are undetectable in t he baby. Three studies have CASE 23 151 examined this in a small number of patients, but all are consistent. Consequently, the bene fits of breast-feeding outweigh the theoretical risks of exposure through breast milk to th e baby. This should of course be discussed with the mother, paying particular attention to the fact that the drug information sheet may advise against breast-feeding while on azathio prine of mercaptopurine. These information sheets were written before the studies were avai lable. Further reading Caprilli R, Gassull MA, Escher JC et al. (2006). European evidence-based Consensus on the d iagnosis and management of Crohn \200\231s disease: special situations. Gut; 55(Suppl. 1): i36 \200\22358. Christensen LA, Dahlerup JF, Nielsen MJ, Fallingborg JF, Schmiegelow K (2008). Azathioprine treatment during lactation. Aliment Pharmacol Ther; 28: 1209 \200\22313. Golds tein LH, Dolinsky G, Greenberg R et al. (2007). Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol; 79: 696 \200\223701. OXFORD CASE HISTORIES 152 Case 24 An 85-year-old retired schoolteacher was referred with a 1-month history of abdominal swell ing and worsening back pain, which disrupted her sleep. Over that period she had become wea k and spent most of her day in a chair. At pres- entation, she was in a wheelchair. She had no constitutional symptoms, such as weight loss, fever, or night sweats, and no nau sea, vomiting, or dyspepsia. Her bowel habit was unchanged. She had a history of ischaemic heart disease and took diclofenac for her back pain. On examination, she had ankle oedema, with abdominal distension and shifting dullness, thou ght to be due to ascites. In the left flank there was a mobile, firm, non-pulsatile mass. I t was possible to palpate above the mass, but it could not be further characterized. Vital signs were normal and there was no jaundice, signs of chronic liver disease, or lymphadenop athy. She was admitted for investigation. Questions 24a) Describe the clinical approach to a mass in the left flank. 24b) What investigations would you request? 24c) What is the differential diagnosis, based on the clinical findings and CT scan? 24d) How would you confirm the diagnosis? 24e) Discuss factors influencing the management of this case. This page intentionally left blank OXFORD CASE HISTORIES 154 Answers 24a) Describe the clinical approach to a mass in the left flank. Location: a left flank mass may be a spleen, a kidney, or arise from any other anatomical s tructure in that location (colon, mesentery, lymph nodes). Palpation above the mass effecti vely excludes an enlarged spleen. Clinical signs are important when interpreting subsequent CT scan reports. A (very) enlarged spleen is characteristically dull to percussion, has a palpable notch, and descends obliquely throughout inspiration. A palpable kidney typically is not dull to percussion due to overlying bowel, may be balotable and descends only at the end of inspiration. Mobility of a mass suggests that it does not adhere to surrounding struc- tures, unlike a t umor that has infiltrated surrounding structures. An invading small bowel tumor may still b e mobile if attached to a mobile mesentery. Associated pain or tenderness: pain in the back that wakes a patient up at night commonly i ndicates pathology. It suggests inflammation or malignancy involving a retroperitoneal stru cture or organ. Structures in the retroperitoneum include the pancreas, lymph nodes, duoden um, kidneys, and blood vessels. Tenderness is consistent with an inflamma- tory process or abscess. Consistency: fluctuation suggests contained fluid (cyst or abscess, the latter bei ng tender). A firm mass suggests organ enlargement or tumor. Pulsatility: a pulsating mass implies an arterial aneurysm. Note that arte- rial pulsation should be expansile, since pulsation may be transmitted. Our patient had a firm, non-pulsatile, non-tender, mobile mass in the left flank associated with back pain. Clinical signs excluded a spleen (able to palpate above the mass) or a kid ney (palpable, rather than balotable). This implies a retroperitoneal lesion or tumor, so b oth the choice and interpretation of investigations should reflect this. 24b) How would you investigate? Urine dipstix: microscopic haematuria associated with an abdominal mass suggests a renal tu mor. A urine dipstix was normal. Imaging: a CT scan of the abdomen and pelvis is the procedure of choice. CT scanning images the retroperitoneum and provides anatomical cross- sectional images that can be reviewed b y radiologists, physicians, or sur- geons, for management decisions. Ultrasound scan avoids exposure to CASE 24 155 radiation, but provides poor views of the retroperitoneum, is a dynamic investigation that is difficult to review on static images, and may still need to be followed by a CT scan bef ore management decisions are made. CT of the abdomen and pelvis: see Fig. 24.1. 24c) What is the differential diagnosis based on the CT results and clinical findings? The differential diagnosis includes small intestinal adenocarcinoma, lym- phoma, gastrointe stinal stromal tumor (GIST), or non-steroidal-induced inflammation. Adenocarcinoma of the small bowel is rare, with an incidence of 6 cases per million, and re presents 2% of all gastrointestinal tumors, but it is the most common primary small bowel m alignancy, making up 40% of the total. More than half occur in the duodenum, with 15 \200 \22320% in the jejunum and 10 \200\22315% in the ileum. It is more common in patients of Af rican origin, and in men. Adenocarcinoma develops in pre-existing adenomas or from dysplast ic epithelium. Risk factors for adenocarcinoma of the small bowel include familial adenomat ous polyposis, hereditary non-polyposis colon cancer (see Case 17), Peutz \200\223Jeghers s yndrome, Crohn \200\231s disease, enteric duplication cysts, Meckel \200\231s diverticula, and coeliac disease. Fig. 24.1 There is extensive retroperitoneal lymphadenopathy (small arrow) with marked thic kening of the mid small bowel loops (large arrow). A scan of the chest showed extensive med iastinal lymphadenopathy and there was a small amount of free free fluid in the pelvis. OXFORD CASE HISTORIES 156 Patients are typically elderly, presenting in their 7th decade. More than 80% occur >50 yea rs of age. Small tumors are typically asymp- tomatic and may lead to iron deficiency result ing from chronic blood loss. Non-specific symptoms with loss of appetite and weight loss ar e common. Pain and obstructive symptoms occur at a late stage. Lesions of the terminal ileu m may cause intermittent intussusception, with episodic obstructive symptoms. Surgical resection is the treatment of choice. The benefit of postopera- tive chemotherapy remains unproven. The prognosis is poor. Following resection of disease localized to the sm all bowel, 5-year survival is 50%. This drops to 30% once regional nodes are involved and to <5% with distant metastases. Primary small bowel lymphoma is the second most common, pri- mary malignant tumor of the sm all intestine, accounting for up to 25% of all small bowel tumors. The small intestine is t he most common primary extranodal site for lymphoma, making up 10% of extranodal lymphomas . Primary small bowel lymphoma is typically focal in the bowel and localized to bowel and r egional lymph nodes. Palpable periph- eral lymphadenopathy is usually absent. Mediastinal l ymph nodes are not seen on chest radiography, and the liver and spleen are not enlarged. Pr imary small bowel lymphoma is slightly more common in men and in people of European decent. Patients typically present in their 7th decade. Immunoproliferative small intestinal disea se (IPSID) occurs in young people, especially in Iran, and is distinct from primary small b owel lymphoma in that it displays a diffuse growth pattern. Risk factors for primary small bowel lymphoma include coeliac disease, primary immu- nodeficiency, AIDS, chronic immunosup pressive therapy and (possibly) Crohn \200\231s disease. Abdominal pain is the presenting symptom in more than two thirds and weight loss is reporte d in half. Less commonly, patients report fatigue and night sweats. Obstruction of the smal l bowel is evident in 10% at presentation. Acute gastrointestinal hemorrhage or perforation with an acute abdomen may also occur. Up to 50% of patients have a palpable abdominal mass . Primary small bowel lymphoma most commonly occurs in the ileum, followed by the jejunum and then the duodenum. Regional lymph nodes are affected half the time. Most primary small bow el lymphomas are B cell lymphomas, of which diffuse large cell lymphoma is the most com- mo n, followed by MALT-lymphoma. Enteropathy-associated T cell lymphoma is typical of coeliac disease. Small non-cleaved cell lymphoma CASE 24 157 (Burkitt) occurs in a minority of cases (5%) of small intestinal lympho- mas. The treatment of choice is surgical resection. If disease cannot be adequately resected, chemotherapy ma y be offered. Chemotherapy alone carries a risk of bowel perforation (up to 15%). Primary s mall bowel lymphoma localized to the bowel has a 5-year survival of <60%. Once regional lym ph nodes are involved, 5-year survival drops to 20%. Malignant gastrointestinal stromal tumors (GIST) (20 \200\22325% of all GISTs) make up abou t 12% of all malignant small bowel tumors. Conversely, about 30% of all GISTs (benign or ma lignant) occur in the small bowel. Most patients are in the 6th decade at the time of diagn osis. Malignant GISTs are most commonly >5cm in diameter. Histopathologically they consist of spindle-shaped cells, thought to originate from the interstitial cells of Cajal. This as sumption is based on the fact that they express CD117 and CD34, which are also expressed on Cajal cells. More than 90% of GISTs express CD117, which is a product of the c-kit gene an d a receptor for stem cell growth factor. Most malignant GISTs show a muta- tion in this ge ne on chromosome 4, which leads to unregulated activa- tion of the tyrosine kinase associat ed with CD117. This presents an opportunity for therapy. Tumors >5cm in diameter are either palpable or present clinically, with bleeding in more th an half of patients. Patients with ileal tumors often present with intussusception. Patient s may also present with par- tial obstruction, with abdominal pain, nausea and vomiting, an d with weight loss in a third of all cases. The treatment of choice for a malignant GIST is resection. Unfortunately tumors often recur after resection. Conventional chemotherapy does not work, but imatinib mesylate, a tyrosin e kinase inhibitor, initially shown to induce remission in patients with chronic myeloid le ukemia, is often effective in patients with unresectable or metastatic GIST. Up to 40% of p atients with a GIST of the small bowel will present with liver metastases. Lymph node metas tases are not typical. Metastatic and unresectable dis- ease carries a poor prognosis. Imat inib prolongs survival, is orally admin- istered, and is the standard of care for patients not eligible for surgery. Even so, tumor resistance eventually leads to tumor progression. Malignancies of enterochromafin cells are called carcinoid tumors. Three quarters of these tumors are in the gastrointestinal tract and are most common in the appendix, followed by t he small bowel. Small bowel tumors occur in the ileum in almost 90% and are usually <2cm in size and not palpable. Chronic, non-specific abdominal pain over a long period (>2 years) is characteristic. It is best distinguished from other OXFORD CASE HISTORIES 158 causes of long-standing abdominal pain by its episodic nature. Patients are frequently asym ptomatic until tumors are locally advanced or have metastasized. Liver metastases may be as sociated with a carcinoid syndrome (flushing, diarrhea, and wheeze), and may include valvul ar lesions of the right heart. Other tumors found in the small intestine include Kaposi sarcoma, schwannomas, ganglioneuro mas, and metastatic tumors. Melanoma is the most common metastatic tumor to the small bowel (about a third), but primaries from other sites that spread to the small bowel include car cinomas of ovary, cervix, testes, stomach, colon, kidney, liver, and lung. Based on the symptoms, the palpable mass and lymph node involve- ment on CT, the most likel y tumor in our patient was thought to be a primary small bowel lymphoma. 24d) How would you confirm the diagnosis? CT enteroclysis is the investigation of choice to image the small bowel and identify extram ural extension or lymph node involvement. If this is unavailable, separate small bowel radi ology after an abdominal and pelvic CT scan is appropriate (after the scan, because barium contrast interferes with the scan image). An abdominal CT scan is also the first investigat ion for patients presenting with an acute abdomen or sus- pected perforation. Barium studie s are absolutely contraindicated where perforation is suspected. Tumors of the duodenum and the terminal ileum may be accessible to conventional endoscopy. Double-balloon enteroscopy , where available, may access tumors beyond the reach of conventional endoscopes for biopsy . Surgical resection, prior to histo- pathological diagnosis, may be necessary if there is hemorrhage or per- foration, where enteroscopy is unavailable, or where tumors are inaccess ible to enteroscopy. 24e) Discuss factors influencing the management of this case. The first difficulty in this case was that the lesion was not within reach of conventional endoscopy, preventing a histopathological diagnosis. It was further complicated by the pati ent \200\231s advanced age, poor performance status (Performance Status 3 \200\223 more th an 50% of her day in a chair), and local lymph node involvement, which made for a very poor prog- nosis. Surgical resection risked a high mortality and low likelihood of cure. Chemot herapy would similarly be poorly tolerated with a low performance status. CASE 24 159 Fig. 24.2 A second CT scan, done 7 days later showing free intraperitoneal air (arrow) in k eeping with spontaneous perforation of the tumor. Consequently our patient was initially managed with inpatient enteral nutritional support a nd analgesia. The poor outlook was discussed with her family. Unfortunately she developed a n acute abdomen within a week of admission and a repeat CT scan showed free intraperitoneal air, indi- cating spontaneous tumor perforation (Fig. 24.2). She underwent emer- gency res ection of the tumor, but deteriorated following surgery and died. Histopathology of the res ection specimen showed an aggressive, diffuse large B cell lymphoma (Fig. 24.3 in the centr al color section). Fig. 24.3 (see color plate 8) Photomicrograph showing sheets of uniform cells (lymphocytes) infiltrating and expanding small intestinal villi (arrow). Immuno- histochemistry showed m onoclonal cells of B cell origin. OXFORD CASE HISTORIES 160 Further reading Banks PM (2007). Gastrointestinal lymphoproliferative disorders. Histopathology; 50: 42 \200\22354. Koniaris LG, Drugas G, Katzman PJ, Salloum R (2003). Management of gastrointestinal lymphoma. J Am Coll Surg; 197(1): 127 \200\22341. Siddiqui MA, Scott LJ (2007). Imatinib: a review of its use in the management of gastrointestinal stromal tumors. Drugs; 67(5): 805 \200\22320. CASE 25 161 Case 25 A 62-year-old divorced defense lawyer presented with confusion and ascites. His daughters r eported that ascites had been present for about a year. Apparently he had stopped drinking alcohol 6 months previously, but he had drunk about 20 units of alcohol per day for 30 year s. Mild confusion had been present for 3 months, but it had become worse in the 2 weeks bef ore admis- sion. Medication at the time of presentation included lactulose, frusemide 80mg/ day, and spironolactone 100mg/day. Intravenous 5% dextrose was administered on presentation to the emergency department. On examination he was disorientated in time and place. Asterixis was present, but he was af ebrile with a pulse rate of 66bpm, and blood pressure 115/60mmHg. There were multiple spide r naevi and moderate muscle wasting. The liver was palpable 4cm below the costal margin and there was a moderate amount of ascites. Rectal examination revealed melaena. Investigations showed: 9/L, platelets 100 x 109/L Hb 12.8g/dL, WCC 5.8 x 10 mol/L, urea 6mmol/L Na 129mmol/L, K 3.6mmol/L, creatinine 86 mol/L, ALP 137 IU/L, ALT 33 IU/L, albumin 24g/L Bilirubin 59 Prothrombin time 19.8 sec CRP <8mg/L \200\230Liver disease screen \200\231 normal or negative (see Case 1) Cranial CT scan showed cerebral and cerebellar atrophy with a small chronic subdural hemorr hage. The CT appearance was similar to a CT carried out 6 months previously. Abdominal ultrasound showed a small shrunken liver, gross ascites, pat- ent portal and hepa tic veins; no focal liver lesions; normal sized spleen. Questions 25a) What is the cause and pathophysiology of the disorientation? 25b) What is the immediate management? Initially the patient improved, but he deteriorated with similar symptoms 3 weeks later. Th e patient was unable to return home, because he remained too confused. 25c) What further treatment would you suggest? OXFORD CASE HISTORIES 162 Answers 25a) What is the cause and pathophysiology of the disorientation? This patient almost certainly has cirrhosis (excessive alcohol in the past, spider naevi, h ypoalbuminaemia, increased prothrombin time, thrombocytopenia, ascites, shrunken liver) and the most likely cause of the disorientation and confusion is hepatic encephalopathy. Non-h epatic causes should always be considered, including intracranial hemorrhage and Wernicke \200\231s encephalopathy. Although there was sig- nificant brain atrophy seen on the CT, th is correlates poorly with mental state. Theories to explain hepatic encephalopathy in patients with cirrhosis include: Disorder of astrocyte function with Alzheimer type II astrocytosis Changes in gene expression in the brain that up-regulate or down- regulate transportation p roteins Ammonia hypothesis GABA hypothesis Neurosteroids. Astrocytes play a key role in the regulation of the blood \200\223brain barrier, and the de toxification of chemicals (including ammonia), and it is pos- sible that neurotoxic substan ces, including ammonia and manganese, gain entry to the brain in liver failure. These neuro toxic substances may then contribute to morphological changes in astrocytes. Astrocytes may undergo Alzheimer type II astrocytosis in cirrhosis, although this is not observed in fulm inant hepatic failure. Genes coding for transportation proteins, for example the peripheral-type benzodiazepine re ceptor, may be up-regulated and others down- regulated in cirrhosis and fulminant hepatic f ailure. This may impair neurotransmission. Hyperammonaemia may affect cognitive function. Ammonia is pro- duced in the gastrointestina l tract by bacterial degradation of amines, amino acids, purines, and urea. Ammonia is also produced by entero- cytes, which contain glutaminase to convert glutamine to glutamate and ammonia that is normally detoxified in the liver by conversion to urea. In cirrhosis, the decreased functioning hepatocyte mass reduces detoxi- fication of ammonia by these processe s. Portosystemic shunting also diverts ammonia-containing blood away from the liver, and bo th factors contribute to hyperammonaemia. CASE 25 163 Ammonia is also consumed by the conversion of glutamate to glu- tamine by glutamine synthet ase by normal skeletal muscle, even though cells do not possess the enzymatic machinery of the urea cycle. Muscular glutamine synthetase activity increases in cirrhosis and portosyst emic shunting, but when muscle wasting occurs in advanced cirrhosis, this potentiates hyper ammonaemia. Glutamine synthetase is also expressed in the kidneys and cerebral astrocytes. The kidney plays a key role in ammonia excretion, but astrocytes are unable to up-regulate glutamine synthetase activity, so the brain is vulnerable to hyperammonaemia. Ammonia has m ultiple neurotoxic effects. It alters the transit of amino acids, water, and electrolytes b y astrocytes and neurons, impairs amino acid metabolism, energy utilization, and inhibits b oth excitatory and inhibitory postsynaptic potentials. Treatments that decrease blood ammon ia are associated with improvement in hepatic encephalopathy, but serum ammonia is normal i n 10% of patients with encephalopathy. Furthermore, many patients with cirrhosis have eleva ted ammonia levels without evidence for encephalopathy, and infusion of ammonia does not in duce the electroencephalographic changes associated with hepatic encephalopathy when it is administered to patients with cirrhosis. There is little role, therefore, for measuring amm onia concentrations in hepatic encephalopathy. GABA (gamma-aminobutyric acid) is a neuroinhibitory substance produced in the gastrointesti nal tract. Of all brain nerve endings, 24 \200\22345% may be GABAergic, which generate inhi bitory postsynaptic potentials. It was previously thought that encephalopathy was related t o excess GABA and stimulation of endogenous benzodiazepine receptors, since fluma- zenil im proved cerebral function in some patients. However, further work has demonstrated no change in brain GABA and it now appears that flumazenil improves mental function in only a small percentage of patients with cirrhosis. The neuronal GABA receptor complex also contains a binding site for neurosteroids, which ha ve been implicated in encephalopathy since elevated levels of allopregnanolone, the neuroac tive metabolite of preg- nanolone, has been found in the brains of cirrhotic patients dying of hepatic encephalopathy. 25b) What is the immediate management? : tracheal intubation for patients with severe encepha- Airway support lopathy may be necessary. Discontinue 5% dextrose infusion, since this is likely to exacerbate hyponatraemia (Na 129m mol/L). If the patient needs intravenous OXFORD CASE HISTORIES 164 volume expansion, 20% albumin should be considered, especially if there is renal impairment (see Case 11). , since there is both hyponatraemia and gastrointestinal Stop diuretics bleeding. The gastr ointestinal bleeding may provoke pre-renal failure, so renal function needs to be optimized by appropriate volume expansion.