Liver transplantation is indicated for decompensated cirrhosis, but recurrence may occur. P ost-transplant 10-yr survival rate is 75%. y g o o r e t n e o r t s a G l Wilson \200\231s disease/hepatolenticular degeneration A rare inherited disorder with toxic accumulation of copper (Cu) in liver and CNS (especially basal ganglia; e.g., globus palli dus hypodensity puta- men cavitation). It is treatable, so screen all young patients wit h evidence of liver disease. Genetics: Autosomal recessive (gene on chromosome 13; codes fo r a copper transporting ATPase, ATP7B). Twenty-seven mutations are known; HIS1069GLU is the most common. Signs Children usually present with liver disease (hepatitis, cirrhosis, ful- minant hepatic failure); young adults often start with CNS signs: Tremor, dysarthria, dysp hagia, dyskinesias, dystonias, purposeless stereotyped movements (e.g., hand clapping), dem entia, parkinsonism, micrographia, ataxia/clumsiness. Affective features : Depression/mania , labile emotions, \206\221 libido, personality changes. Cognitive/behavioral: Memory defi cits, quick to anger, slow to solve problems, decline in IQ. Psychosis: Delusions, mutism. Kayser \200\223Fleischer rings: Cu deposits in the cornea around the iris (Descemet membran e), pathognomonic but not always present; may need slit lamp to detect. Also: Hemolysis, bl ue lunulae (nails), polyarthritis, hypermobile joints, gray skin, hypoparathyroidism. Tests Serum copper and ceruloplasmin usually low. 24 h urinary cop- per excretion is elevated (> 100 mcg/24 h, normal <40 mcg). Liver biopsy: Elevated hepatic copper content. Molecular gen etic testing can confirm the diagnosis. MRI: Basal ganglia degeneration ( frontotemporal, cerebellar, and brainstem atrophy). Management Diet : Low-copper diet (avoid shellfish, nu ts, chocolate, mush- rooms, organ meat). Chelation: Lifelong penicillamine (1,000 \200\2231 ,500 mg/24 h in 2 \200\2234 divided doses for the first 4 \200\2236 months; then maintenanc e dosing at 750 \200\2231,000 mg/24 h in 2 divided doses). se: Nausea, rash, leukopenia, an emia, thrombocytopenia, hematuria, nephrotic range proteinuria, lupus. Watch closely for th ose patients with a known penicillin (PCN) allergy \200\224they will likely have a reaction to penicillamine as well. Monitor CBC and urinary Cu (and protein) excretion. Stop if WBC is <2.5 \227 10 9 /L or platelets falling to <100 k. Alternative : Trientine dihydrochlori de 750 \200\2231,500 mg/24 h in 2 \200\2233 divided doses ( se: Rash; sideroblastic anemia) . Adjunct : Zinc. Liver transplant if severe liver disease. Screen siblings as asymptomatic homozygotes need treatment. ALF If presentation with acute liver failure, refer to transpl ant center immediately. Development of refractory coagulopathy, hemolytic anemia, and renal insufficiency due to copper build up may only respond to plasma exchange transfusion or tr ansplant. Transplant is curative. Prognosis Precirrhotic liver disease is reversible. Neuro logical damage less so. Death occurs from liver failure, variceal hemorrhage, or infection (the typical complications associated with end-stage liver disease). 233 1 -Antitrypsin deficiency 1 -Antitrypsin is one of a family of serine protease inhibi tors controlling inflammatory cascades. It is synthesized in the liver, making up 90% of se rum -globulin on electrophoresis. 1 -antitrypsin deficiency is the chief genetic caus e of liver disease in children. In adults, its deficiency causes emphysema, chronic liver d isease, and HCC. Other associations: Asthma, pancreatitis, gallstones. Decreased risk of st roke. Prevalence: 1:2,000 \200\2231:7,000. Genetics Carrier frequency: 1:10. Genetic variants are typed by their elec- trophoretic mob ility as medium (M), slow (S), or very slow (Z). S and Z types are due to single amino acid substitutions at positions 264 and 342, respectively. These result in diminished productio n of 1 -antitrypsin (S = 60%, Z = 15%). The normal genotype is PIMM, the homozygote is P IZZ; heterozygotes are PIMZ and PISZ. Symptomatic patients (e.g., cholestatic jaundice /cir rhosis; dyspnea from emphy- sema) usually have PIZZ genotype. nb: Cholestasis often remits in adoles- cence. In adults, cirrhosis HCC affects 25% of all 1 -antitrypsin-deficien t individuals >50 yrs. Tests Serum 1 -antitrypsin levels are low. Liver biopsy: Periodic acid Schiff (PAS) positive; diastase-resistant globules. Phenotyping by isoelectric focus- ing requires expertise to distinguish SZ and ZZ phenotypes. Prenatal diag- nosis is possib le by DNA analysis of chorionic villus samples obtained at 11 \200\22313 wks gestation. DNA tests are likely to find greater use in the future. Management Supportive for emphysema an d hepatic complications. Smoking cessation; consider augmentation therapy with human 1 - antitrypsin if FEV1 <80% of predicted (expensive!) liver transplant in decompensated cir rhosis. Primary biliary cirrhosis In PBC, the interlobular, intrahepatic bile ducts are damaged by chronic granulomatous inflammation causing progressive cholestasis, cirrhosis, and portal h ypertension. Cause: Possibly autoimmune. F:M ratio approaches 9:1. Prevalence: 19 \200\2235 1 cases per million population. Peak presentation: 50 yrs. Clinical features 50 \200\22360 % of patients are asymptomatic and diagnosed only after finding \206\221 alk phos on routi ne LFTs. Lethargy and pruritus are the most common symptoms in symptomatic patients, and th ey may precede jaundice by months to years. Signs : Jaundice, skin pigmentation (due to mel - anosis), xanthelasma, xanthomata, hepatomegaly, and splenomegaly. Complications: Osteopor osis is common. Malabsorption of fat-soluble vita- mins (A, D, K, E) is uncommon but in cir rhotic patients may result in osteomalacia and coagulopathy. Other complications: Portal hy pertension, ascites, variceal hemorrhage, hepatic encephalopathy, HCC (p. 305). Tests Blood tests: \206\221 Alk phos, \206\221 GGT and 5 \200\231-nucleotidase levels, and mildly \206\221 AST and ALT; late disease: \206\221 Bilirubin, low albumin, \206\221 PT/INR. 98% are AMA M 2 subtype positive (highly specific). Other autoantibodies, such as ANA, may occ ur in low titers. Immunoglobulins are elevated (especially IgM). TSH and cholesterol may be elevated. Radiology: Ultrasound, and ERCP or MRCP to exclude extrahepatic cholestasis. Liv er biopsy: Granulomas around the intrahepatic bile ducts, progressing to cirrhosis. Classic ally, nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. Tr eatment Symptomatic: Pruritus: Try cholestyramine 4 g PO bid \200\223tid. Diarrhea (usually from steatorrhea): PRN Imodium or loperamide; can also use pancreatic enzymes as there is often an associated pancreatic insuf- ficiency as well. Osteoporosis prevention (p. 305). 5 Specific: Fat-soluble vitamin prophylaxis: Vitamins A, D, and K. Consider ursodeoxycholic acid (UDCA), 13 \200\22315 mg/kg/d to all patients, which may obvi- ate the need for liver transplantation , which is the last recourse for patients with end-stage disease and/or int ractable pruritus. Recurrence in the graft 234 5 . Lindor et al. AASLD Practice Guidelines: Primary biliary cirrhosis. Hepatology . 2009;5 0(1 ):291 \200\223308. may occur but appears not to influence graft success. Other therapies that have been tried besides UCDA include colchicine and methotrexate. Prognosis Once jaundice develops, surviva l is <2yrs. In one study, at 2 yrs post-transplant, predicted survival without retransplant was 55% and actual survival was 79%. At 7 yrs, these figures were 22% and 68%, respectivel y. y g o o r e t n e o r t s a G l Primary sclerosing cholangitis PSC is a disorder of unknown cause characterized by inflamma tion, fibrosis, and strictures of both the intra- and extrahepatic bile ducts. Immunologica l mechanisms are implicated. Associations : 80% of PSC patients also have UC, but only 5% o f UC patients have PSC; also associated with human leukocyte antigen (HLA)-A1, B8, and DR3. Clinical features Chronic biliary obstruction and secondary biliary cir- rhosis lead to li ver failure and death (or transplantation) over 10 \200\22312 yrs. Symptoms: Patients may be asymptomatic and diagnosed incidentally after finding an elevated alk phos on routine LF Ts, or patients may experience fluctuating symptoms such as jaundice, pruritus, right upper quadrant (RUQ) abdominal pain, and fatigue. Signs: Jaundice, hepatomegaly, portal hyperten sion. Complications: Bacterial cholangitis, cholangiocarcinoma (10 \200\22315% lifetime ris k), \206\221 risk of colorectal cancer in those patients with concomitant UC, 30% of patie nts in some series have an overlap syndrome with type 1 AIH (p. 232). See Table 7.15. Tests Blood: \206\221 Alk phos initially followed by \206\221 bilirubin; hypergammaglobu- line mia (often first manifested as an elevated serum total protein level); AMA negative, but AN A, ASMA, and p-ANCA may be +ve. ercp or mrcp show multiple strictures of the biliary tree ( characteristic \200\234beaded \200\235 appear- ance). Liver biopsy shows a fibrous obliter ation of the bile ducts with con- centric replacement by connective tissue in an \200\234o nion skin \200\235 fashion. AASLD recommends against routine liver biopsy in PSC with typic al radiographic/ cholangiographic findings, only biopsy if elevated LFTs out of proportion to typical. Management Drugs: Corticosteroids and other immunosuppressives have shown littl e benefit in stopping the progression of disease and delaying the need for liver transplant ation; UCDA is no longer recommended at any dose for treatment of PSC. Cholestyramine 4 g P O bid/tid for pruri- tus; Antibiotics (ciprofloxacin) for bacterial cholangitis and for pro phylaxis before invasive GI procedures (like ERCP). 235 Table 7.15 Disease associations Primary biliary cirrhosis (PBC) \212 \212 \212 \212 Primary sclerosing cholangitis (PSC) Ulcerative colitis (5% of those \212 with UC have PSC ; 80% of those with PSC have UC) Crohn \200\231s disease (much rarer); HIV infection Thyroid disease Rheumatoid arthritis Sj gren \200\231s syndrome (70%) Keratoconjunctivit is, sicca syndrome Progressive systemic sclerosis Renal tubular acidosis Membranous glomeru lonephritis \212 \212 \212 \212 Endoscopic or radiologic stenting helps symptomatic dominant strictures. Liver transplantat ion is indicated in end-stage disease. Recurrence occurs in 20%; 5-yr graft survival is >60 %. Liver tumors The most common liver tumors are secondary (metastatic) tumors. They frequentl y arise from primary malignancies in the breast, lung, or gastroin- testinal tract. Primary hepatic tumors are much less common and may be benign or malignant (see Tables 7.16 and 7. 17). Symptoms Fever, malaise, anorexia, weight loss, RUQ pain (due to liver capsule stretch ). Jaundice is late (except with cholangiocarcinoma). Benign tumors are often asymptomatic; if they are large enough, they may cause symptoms due to sheer mass effect. Tumors may rup ture, causing life-threatening intraperitoneal hemorrhage. Signs Hepatomegaly (smooth or ha rd and irregular; e.g., metastases, cir- rhosis, HCC). Look for signs of chronic liver dise ase and evidence of dec- ompensation (jaundice, ascites). Feel for an abdominal mass or pri mary lesion. Listen for an arterial bruit over the liver (HCC). Tests Blood: CBC, PT/INR, L FTs, hepatitis serologies, AFP level ( \206\221 in 80% of HCC), carcino-embryonic antigen (CEA) level. Imaging: Ultrasound or CT to identify lesions and guide diagnostic biopsies. M RI is better for distinguishing benign from malignant lesions. ERCP and biopsy/brushings sh ould be performed for suspected cholangiocarcinoma. Biopsy under ultrasound or CT guidance may achieve a histological diagno- sis; exercise extreme care and caution, as seeding along biopsy tract may occur. Other investigations for metastases (e.g., CXR, mammography, endos copy, colonoscopy, CT, marrow biopsy) are tailored according to the suspected primary. Live r metastases signify advanced disease for any primary malignancy. Treatment and prognosis v ary with the type and extent of primary tumor. Chemotherapy may be effective (e.g., for lym phomas, germ cell tumors). Small, solitary metastases may be amenable to resection. In most , treatment is palliative. Prognosis: <6 \200\2239 months. Hepatocellular carcinoma HCC is a malignant tumor of hepatocytes accounting for 90% of primary liver cancers. Rare in the W est (2 \200\2233% of all cancers), but more common in China and sub-Saharan Africa (40% of cancers). Causes: Cirrhosis, due to any underlying cause (e.g., alcohol, chronic viral hepa titis, PBC, hereditary hemochromatosis, etc.); in the United States, HCV-associated liver d isease is a more common cause than HBV; yet in Asia and Africa, chronic HBV-associated live r disease is the more common underlying etiology; other causes include aflatoxin, parasites ( Clonorchis sin- ensis ), drugs (anabolic and contraceptive steroids). Management of HCC: Liver transplantation as treatment for HCC with newer selection criteria (e.g., \211 3 t umor nodules that are no more than 3 cm in diameter, or a single nodule less <5 cm and with out vascular inva- sion) show better outcomes are being achieved than previously reported. Local radiofrequency ablative therapy and intra-arterial chemoembolization are reasonable o ptions with decent 5-yr survival rates for those patients who are not surgical candidates. Sorafenib is a multikinase inhibitor that is effective in multifocal HCC. It increases time to progression and survival, but is expensive. It is first-line treatment for those who ca nnot get resec- 236 tion, ablation, or transplant; those with local invasion into vessels; or more than the all otted number of lesions for transplant. Prognosis: Often <6 months without any intervention \200\22495% 5-yr mortality. A subtype of HCC known as fibrolamellar HCC, which occurs in c hildren/ young adults, has a better prognosis (60% 5-yr survival). Prevention is key. Ensur e HBV vaccination (see Table 7.18). Do not reuse needles. Reduce exposure to aflatoxins (an tihumidity measures such as sun-drying to reduce spread of this common fungal contaminant i n stored maize); this is especially important for those who harbor chronic HBV (risk is hig hly synergistic). Cholangiocarcinoma Biliary tree malignancy; 10% of liver primaries. One- third are intrahepatic cholangiocellular cancers, and two-thirds are extrahepatic ductal ch olangiocarcinomas. Causes: PSC: Occurs in 8 \200\22313% of these patients; congenital bilia ry cysts; biliary \200\223enteric drainage surgery. The patient: Fever, abdominal pain ( a scites), malaise, bilirubin \206\221 ; alk phos \206\221 \206\221 , jaundice. Pathology: Usually slow-growing. Most are distal extrahepatic or perihilar. A Klatskin tumor is a nodu lar cholangiocarcinoma arising at the bifurcation of the common hepatic duct; it is frequen tly associated with a collapsed gallbladder. Management: 70% are not surgically resectable. Of those that are resect- able, 76% recur. Surgery: E.g., major hepatectomy + extrahepatic bile duct excision + caudate lobe resection. Postop problems: Liver failure (15%), bile le ak (17%), GI bleeding (6%), wound infection (6.5%). Palliative stenting and decompression o f an obstructed extrahepatic biliary tree \200\224percutaneously or via ERCP \200\224improv es quality of life. Prognosis: 5 months. Benign tumors Hemangiomas are the most common ben ign liver tumors. They are often an incidental finding on ultrasound or CT scan and do not require treatment. Biopsy should be avoided! Hepatocellular adenomas are common. y g o o r e t n e o r t s a G l 237 Table 7.16 Primary liver tumors Malignant HCC Cholangiocarcinoma Angiosarcoma Hepatoblastoma (children) Fibrosarcoma Leiomy osarcoma Benign Cysts Hemangioma Adenoma Focal nodular hyperplasia Fibroma Leiomyoma Table 7.17 Origin of secondary liver tumors Common in males Stomach Lung Colon Common in females Breast Colon Stomach Uterus Table 7.18 Preventing hepatitis B, hepatitis B-associated cirrhosis, chronic hepatitis, and hepatic neoplasia Use hepatitis B vaccine, 1 mL into the deltoid muscle; repeat at 1 and 6 months Indications : Everyone. Has been part of standard vaccination schedule since the 1980s, now given at in fancy. This strategy is expensive, but not as expensive as trying to identify and vaccinate at-risk groups (e.g., health care workers, IV drug users, unsafe sexual practices, hemo- d ialysis patients, and the sexual partners of known hepatitis B e antigen +ve carriers). The immunocompromised and others may need further doses. Serologies help in the timing booster shots, and find poor or nonresponders (correlates with older age, smoking, and male sex). NB: Protective immunity begins about 6 wks after the first immunizing dose. If an exposure occurs in an unvaccinated person, give hepatitis B immune globulin (HBIG) within the first 96 h and start the HBV vaccine series. If an exposure occurs in a previously vaccinated per son, check the hepatitis B surface AB titer; if >10 IU/mL, then no therapy; if <10 IU/mL, t hen give HBIG and a booster shot. Causes: Anabolic steroids, oral contraceptives, pregnancy. Only treat if symptomatic. Other common benign tumors of the liver include focal nodular hyperplasia; like hepatocellular a denomas, they commonly occur in women, but oral contraceptives do not seem to be implicated as an underlying cause. Ulcerative colitis UC is a relapsing and remitting inflammatory disorder of the colonic muc osa. It may affect just the rectum (proctitis) or extend proximally to involve part or the entire colon (pancolitis) without small bowel involve- ment. However, in 10 \200\22315% of patients it may involve the terminal ileum/ ileocecal valve due to \200\234backwash ileiti s. \200\235 Pathology: Hyperemic/hemor- rhagic granular colonic mucosa \200\234pseudopo lyps \200\235 formed by inflamma- tion. Punctate ulcers may extend deep into the lamina pro pria. Histology: See biopsy , below. Cause: Likely multifactorial etiology involving interp lay of environmental factors, genetic susceptibility, and immune system dysregula- tion. In cidence: 19.2/100,000 person years in North America. Bimodal age of onset, most patients di agnosed between 15 \200\22330, and 10 \200\22315% after age 50. More UC patients tend to be former smokers than Crohn \200\231s. Symptoms Gradual onset of diarrhea blood and mucus . Crampy abdominal discomfort is common; bowel frequency is related to severity of disease (see below). Systemic symptoms are common during attacks, e.g., fever, malaise, anorexia, w eight loss. Urgency and tenesmus occur with rectal disease. Proctitis may occasionally pres ent as obstipation or constipa- tion associated with urgency/tenesmus. Signs May be none: I n acute, severe UC: Fever, tachycardia, and a tender, distended abdomen. Extraintestinal si gns Clubbing, aphthous oral ulcers, erythema nodosum (PLATE 18), pyoderma gangrenosum, conj unctivitis, episcleritis, iritis, large joint arthritis, sacroiliitis, ankylosing spondylit is, fatty liver, PSC, cholangiocarcinoma and, very rarely, renal stones, osteomalacia, nutr itional deficiencies, and systemic amyloidosis. Tests Blood: CBC, erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), BMP, LFT, and blood cultures. Consider iron studies. Stool: Fecal leu- kocytes, fecal lactoferrin and calprotectin (correlate with disease acti vity), ova and parasites, routine culture, C. difficile toxin. To exclude infectious 238 diarrhea ( C. difficile, Salmonella, Shigella, Campylobacter, E. coli , amebae). Abdominal x-ray: No fecal shadows, mucosal thickening (islands), colonic dilatation (toxic dilatation >6 cm), perforation. Sigmoidoscopy: Inflamed, fri- able mucosa. Rectal biopsy: Inflammator y infiltrate, goblet cell depletion, glandular distortion, mucosal ulcers, crypt abscesses. Barium enema: Loss of haustra, granular mucosa, shortened colon. Never do a barium enema d uring an acute severe attack. Colonoscopy shows disease extent and allows biopsies to be ta ken. Complications Perforation and bleeding are two serious complications. Increased risk o f arterial and venous thromboembolism. Others include: \212 y g o o r e t n e o r t s a G l \200\234Toxic megacolon, \200\235 which is dilatation of colon (mucosal islands, colonic d iameter >6 cm). Colonic cancer: Risk approaches 15% with pancolitis for 20 yrs; increased r isk after 8+ years of having UC. Yearly colonoscopy surveillance with biopsy for dysplasia and early cancer is recommended after 8 yrs of coli- tis. Annual surveillance if patient ha s both UC and PSC from time of diagnosis. Some centers perform chromoendoscopy (spraying of colon mucosa with dye to increase yield and better target biopsies to areas with lesions). \212 Management: Goals of treatment are induction and maintenance of remission, reduced use of s teroids, mitigated cancer risk, improved overall quality of life, and, when possible, mucos al healing. To decide on treatment, classify severity (mild, moderate, severe, fulminant) a nd location (distal or total): Mild UC : <4 stools/day, with or without blood, no signs tox icity, normal ESR Moderate UC : >4 stools per day, may have bloody stools, minimal signs to xicity Severe UC : >6 bloody stools/d, signs of toxicity Fulminant UC : >10 bloody stools p er day, toxicity, abdominal tenderness and distension, requires transfusion, colon dilated on x-ray films. (Toxicity is fever, tachycardia, anemia, or \206\221 ESR.) 239 Treatment is based on many factors and should be coordinated in consult with gastroenterolo gy. Treat mild distal UC: Induce remission : Topical mesalamine, topical steroids, oral ami nosalicy- lates \200\224likely use combination of oral and topical (mesalamine topical > to pical steroids or oral aminosalicylates (5-ASA) (i.e., Asacol MR in 400- or 800-mg tabs, many others Lialda, Apriso, etc.). If all these measures fail, consider oral prednisone (40 \200\22360 mg/day) or infliximab. Maintain remission : Mesalamine suppositories for procti tis, enemas for distal colitis. Alternatives : Sulfasalazine, mesalamine, balsalazide, Note combo of oral and topical is better than either alone. Topical steroids do not main- tain remission. Can also consider thiopurine (6-MP) or azathioprine (AZA) (2 \200\2232.5 mg/kg/d PO) or infliximab. Treat mild-moderate extensive (total colon) uc : Induce remission : ora l sulfasalazine 4 \200\2236 g/d or 5-ASA to 4.8 g/d. Oral ste- roids if refractory to 5-ASA (prednisone 40 \200\22360 mg/d; if response, then taper). Biologic agents, infliximab (Rem icade monoclonal antibody given IV), use if steroid refractory, steroid-dependent despite AZA or reaction to 6 MP/AZA or adalimumab (Humira). Before using biologics, exclude latent TB, histoplasmosis, HBV, demyelinating disease, active infection, congestive heart failure (CHF), recent malignancy . Reference: Sandborn et. al. One-year Maintenance Outcomes Among Patients with Moderately-to Severely Active Ulcerative Colitis who Responded to Induction Therapy with adalimumab:subgroup analyzes from ULTRA 2. Alimentary P harmacology and Therapeutics Volume 37, Issue 2, pages 204 \200\223213, January 2013. Maint ain remission : Acute attack controlled, sulfasalazine, olsalazine, mesala- mine, balsalazi de maintenance therapy. Slowly taper steroids if they were used. AZA/6MP may help taper ste roids. Infliximab maintenance every 8 wks. Moderate UC: If no improvement after 2 wks, trea t as a severe UC. Severe UC : If relatively well, but severe symptoms and refractory to ora l steroids, 5-ASA or topicals, then consider infliximab. If systemically unwell and passing >6 motions daily, hospitalize. Act rapidly: \212 Initiate nutritional assessment, enteral feeding is better than parenteral if tolerated. In itiate IV hydration (e.g., 1 L of 0.9% saline + 2 L dextrose-saline/24 h, + 20 mmol K + /L; less if elderly). Consider steroids like hydrocortisone or Solu-Medrol. Avoid narcotics or anticholinergics where possible Start rectal steroids (e.g., hydrocortisone 100 mg in 100 mL 0.9% saline/12 h PR). Monitor T , pulse, and BP; record stool frequency/character. Twic e-daily exam: Document distension, bowel sounds, and tenderness. Obtain daily CBC, ESR, CRP , BMP, LFTs, abdominal x-ray. Assess stool culture and been on immunosuppression prior t o admission. Consider the need for blood transfusion (if Hb <10 g/dL) and parenteral nutrit ion (if severely malnourished). Give IV vitamins. Consult with gastroenterology and surgery is important during admission. If improving in 5 d, transfer to oral prednisolone (40 mg/2 4 h) with an adjunct, such as thiopurine or biologic. If not improving within 3 \200\2235 d ays of hospitalization and initiation of steroid IV therapy consider additional options: Co lectomy, cyclosporine, infliximab. Also, must have patient evaluated by a surgeon with high volume of colon surgeries. \212 \212 \212 \212 \212 \212 \212 \212 C. diff toxin assay, consider CMV testing if has \212 \212 \212 \212 240 \212Indications for surgery : Suspected dysplasia or carcinoma, severe colitis unresponsiv e to medical therapy or medically intolerable side effects, per- foration, massive hemorrha ge, toxic megacolon \212Procedures: With acute disease and a toxic patient, subtotal colectomy is recommended by most guidelines. Other surgeries for nontoxic refrac- tory UC include: Total proctocolec tomy with end-ileostomy, total proc- tocolectomy with ileal pouch, and anal anastomosis sur gery. Drug side effects to know: \212Sulfasalazine: Sulfapyridine intolerance \200\224headache, nausea, anorexia, and malaise. Other allergic/toxic SE : Fever, rash, hemolysis, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible oligospermia. Follow CBC. \2125-ASA: Dyspepsia, nausea headache can occur. Rare hypersensitivity reactions: Worsening colitis, pancreatitis, pericarditis, nephritis \212Steroids: Cushingoid, emotional-psychiatric, infections, glaucoma, cata- racts, GI muc osal injury, impaired wound healing, osteopenia, osteone- crosis, hyperglycemia, atherogene sis, infections \212Cyclosporine: Nephrotoxicity; K + \206\221 ; BP \206\221 (do BMP, LFT, cholesterol, and BP often; stop if raised and get expert help). Low cholesterol levels (<120 mg/dL) is a relative contraindication to cyclosporine use. \212Biologics: Infections: histoplasmosis, coccidiomycosis and Listeria , reactiva- tion o f TB, drug-induced lupus or psoriasis, hepatotoxicity, worsening of CHF, infusion site reac tions \212AZA/6MP : Must follow LFT CBC in these patients. Bone marrow toxicity, allergic reacti ons, pancreatitis, and serious infections. Onset of drug takes 3 \200\2236 months for full effect. Enzyme responsible for inactivation of the 6-MP is thiopurine S-methyltransferase (TPMT). Levels of TPMT can be com- mercially obtained and can vary among ethnic groups (10% of the popula- tion is heterozygous for the gene), and T PMT levels correlates inversely with 6-TGN levels (the active form of azathioprine). Measur ement of thiopurine metabolites, 6-TGN, and 6 MMP can help determine adequate dosing and av oid hepatotoxicity. Also must follow annual skin exams; higher rate of skin cancers in pati ents taking AZA/6MP. y g o o r e t n e o r t s a G l Crohn \200\231s disease Crohn \200\231s disease is a chronic inflammatory GI disease charac terized by transmural granulomatous inflammation. It may affect any part of the gut, but fa vors the terminal ileum and proximal colon. Unlike UC, there may be unaffected bowel betwee n areas of active disease (skip lesions). Cause: Likely multifactorial etiology involving i nterplay of environmental fac- tors, genetic susceptibility, and immune system dysregulatio n. Mutations of the NOD2/CARD15 gene increases risk autosomal recessive. Prevalence: 319/10 0,000. Active smoking is associated with worse outcomes Smoking increases risk 3 \200\2234- fold. Symptoms and signs Diarrhea, abdominal pain, and weight loss are common. Fever, malai se, anorexia occur with active dis- ease. Look for aphthous ulceration, abdominal tendernes s, right iliac fossa mass, perianal abscesses/fistulae/skin tags, anal/rectal strictures. E xtraintestinal signs: Clubbing, erythema nodosum (PLATE 18), pyoderma gangrenosum, conjunct ivitis, episcleritis, iritis, large joint arthritis, sacroilii- tis, ankylosing spondylitis , fatty liver, primary sclerosing cholangitis, cholan- giocarcinoma (rare), renal stones, o steomalacia, malnutrition, amyloidosis. Complications Small intestinal obstruction; toxic d ilatation (colonic diameter >6 cm); abscess formation (abdominal, pelvic, or ischiorectal); fistulae, e.g., colovesical (bladder), colovaginal, perianal, enterocutaneous; perforation ; rectal hemorrhage; colonic carcinoma. Tests Blood: CBC, ESR, CRP, BMP, LFT, blood culture . Serum iron, B 12 , and red cell folate if anemia. Markers of activity: Hb \206\223 ; \206\221 ESR; \206\221 CRP; \206\221 WBC; \206\223 albumin, fecal calprotectin, fecal la ctoferrin. Stool microscopy/culture and Clostridium difficile toxin (cdt) to exclude infec- tious diarrhea ( C. difficile, Salmonella, Shigella, Campylobacter, E. coli ). Colonoscopy and biopsy should be performed even when the mucosa is mac- roscopically normal (20% have microscopic granulomas). Small bowel imaging: To detect proximal and distal small bowel dis ease (strictures, small bowel dilatation, inflammatory mass, abscess or fistula). Studies i nclude small bowel follow-through, CT enterography, MR enterog- raphy. Barium enema: may sh ow \200\234cobblestoning \200\231, \200\234rose thorn \200\235 ulcers, and colonic strict ures with rectal sparing. Management Table 7.19 presents a reasonable treatment algorithm, how- ever, medications and doses need to be individualized for each patient. Severity is ha rder to assess than in UC. Severe symptoms (fever; pulse \206\221 ; \206\221 ESR; \206 \221 CRP; \206\221 WCC; \206\223 albumin) merit admission. Endoscopic findings do not ref lect overall severity of a Crohn \200\231s flare. Recommend consult with gas- troenterology to guide therapy. Mild attacks: Patients are symptomatic but systemically well. Consider i nduction with ileal release budesonide (9 mg/day), conventional steroids, AZA/6MP. Reassess in clinic for response. (See TPMT data from UC chap- ter.) If symptoms resolve on oral ste roids, taper. Budesonide and steroid can induce induction, but not maintenance. Long term s teroid-sparing regimens favored. Moderate to severe attacks: Prednisone 40 mg/d until resol ution of symptoms and return of weight gain. AZA/6MP can main- tain steroid-induced remissi on; can consider parenteral methotrexate for steroid dependent or steroid-refractory diseas e. Anti-tumor necrosis factor 241 (TNF) monoclonal antibodies (infliximab, adalimumab, certolizumab) are effective in those w ho have not responded to initial therapy. (AZA/6MP, anti-TNF can be used for maintenance of remission). Severe/fulminant attacks or disease: Admit for IV steroids, NPO, and IV hydrat ion (e.g., 1 L 0.9% saline + 2 L dextrose-saline/24 h, + 20 mmol K + /L, less if elderly). Consult gastroenterology. Then consider: \212 IV steroids: Hydrocortisone or Solu-Medrol Table 7.19 Therapies in Crohn \200\231s disease Azathioprine (2 \200\2232.5 mg/kg/d PO) or 6MP (1 \200\2231.5 mg/kg/d PO) are steroid-spari ng agents. Need monitoring of LFT, CBC. Should check TPMT enzyme level prior to initiating therapy. Aminosalicylates: Little use in Crohn \200\231s Elemental diets: Are as good as st eroids in active disease in children, but are unpalatable and relapse is more common. Metho trexate: 25 mg IM weekly for induction of remission and com- plete withdrawal from steroids in patients with refractory Crohn \200\231s dis- ease. NNT 5. There is no evidence on l ower doses. Monitor LFTS for methotrexate-induced hepatotoxicity. Biologics: Infliximab, ad alimumab, and certolizumab; used for moderate to severe Crohn \200\231s. Can be for inducti on and maintenance. Surgery: 50 \200\22380% of patients need 1 operation in their life. Ind ications for surgery: \212 \212 \212 \212 Surgery is never curative: The aim is limited resection of the worst areas. Bypass and pouch surgery is not done in Crohn \200\231s (inc reases risk of recurrence). Failure to respond to medical therapy Intestinal obstruction from strictures Intestinal per foration Local complications (fistulae, abscesses) 242 \212 \212 \212 \212 \212 \212 \212 \212 Treat rectal disease, if present, with rectal steroids twice daily. Antibiotics can be usef ul if abscess, fistulae, or perforation are identified. Monitor T , pulse, BP, and record stool frequency/character. Perform physical examination twice daily. Obtain daily CBC, ESR, CRP, BMP, and plain abdominal x-ray. Consider need for transfusion (if Hb <10 g/dL) and pa renteral nutrition. If improving after 5 d, transition to oral steroid for taper. If no res ponse (or deterioration) during IV therapy, seek surgical advice. Irritable bowel syndrome IBS is used to describe a heterogeneous group of abdominal symptom s for which no organic cause can be found. IBS patients show an exaggerated response to sti muli like meals, distension, stress, etc. Clinical features Patients are usually 20 \200 \22340 yrs old, and females are more frequently affected than males. Symptoms: Classic pati ent symptoms: A (abdominal pain), B (bloating or abdominal discomfort), C (change in bowel habit) present and stable for at least 6 months. Diagnostic criteria (modified from R ome criteria) IBS is likely if: \212 y g o o r e t n e o r t s a G Pain or discomfort is either \212 Relieved by defecation or \212 Associated with alternat ing stool form (loose and hard) and (need to have at least two of the following): \212 \212 \212 \212 Nausea, dyspareunia; pain in the back, thigh, or chest; urinary frequency; depression can also support the diagnosis. Symptoms are chronic (>3 months over 12-month p eriod), and may be exacerbated by stress, menstruation, or gastroenteritis. l \212 Altered stool passage (straining, urgency, incomplete evacuation), Abdominal bloating, dist ension, tension or hardness, Symptoms worse with eating, Passage of mucus \212 \212 Table 7.20 Management of IBS 6 , 7 Confirm diagnosis : 1) Take a good history and physical with a thorough examination. Exclude symptoms of other illnesses. 2) Elicit history to exclude any red-flag symptoms. 3) May perform testing For all: Celiac panel (anti-TTG Ab, antiendomysial Ab) For IBS with no red flags: No other testing For IBS with red flags: CBC, ESR, CRP, Thyroid studies, ova and parasites. Refer to gastroenterology. Colonoscopy and imaging. (British guidelines also recommend CBC, ESR, an d CRP if symptoms of diarrhea are predominant without red flags; American guidelines recomm end against further testing without red flags and also recom- mend against celiac testing f or those with IBS \200\223constipation.) 243 Management: For typical IBS (no red flags) dietary and lifestyle changes (adjust diet to av oid trigger foods, reduce or increase fiber as appropriate, increase exercise as tolerated, provide reassurance and follow-up care) and initi- ate medications (antispasmodics, antimo tility, laxatives, TCA or SSRI.) For those with IBS and red flags, may also consider furthe r investigation: If diarrhea is prominent, check: LFT; stool culture and testing, fecal fat ; \212 B 12 /folate; antiendomysial ab; TSH; colonoscopy should include ran- dom biopsies. If constipation is prominent, consider rectal exam, anorectal motility testing, gut transi t testing. Further investigation should be guided by severity of symptoms and can also incl ude: Upper GI endoscopy (dyspepsia, reflux) Duodenal biopsy (celiac disease); e.g., if anti -endomysial antibodies +ve. Giardia tests (p. 544) (it often triggers IBS) Small bowel radi ology (Crohn \200\231s disease) MRCP or EUS (chronic pancreatitis) Transit studies and anor ectal physiological studies are rarely used. \212 \212 \212 \212 \212 \212 \212 \212 6 Drossman, D, Camilleri M, Mayer EA, Whitehead WE. AGA Technical Review on Irritable Bowel Syndrome. Gastroenterology. 2002;123 (6): 2108 \200\2232131. 7 Khan S, Chang, L. Diagnosis and management of IBS. Nat Rev Gastroenterol Hepatol. 2010;7: 565 \200\223581. Table 7.20 (Continued) When to Refer: Just because one meets criteria for IBS, it doesn \200\231t mean the patient will never have another disease or disorder. If symptoms change or intensify, if depressio n becomes severe, if red-flag symptoms are evoked, if pain is found to be cyclical and coin cide with menstrual cycle, continue investi- gation as appropriate. Treatment Be honest wit h patients. They have a disorder, it will not cause malignancy, but it may cause symptoms. Careful explanation and reassurance are vital. Create a good relationship with your patient . Food intolerance: Can experiment with limited exclusion diets (difficult to maintain). E ncourage patient to keep a food diary. Constipation (p. 200): Increase fiber intake gradual ly; can lead to bloating Diarrhea: Bulking agent loperamide 2 mg after each loose stool; max 16 mg/d; se: Colic, nausea, dizziness, constipation, bloating, ileus Dyspeptic symptom s: May respond to metoclopramide or antacids Psychological : Emphasize positive aspects and prognosis: In 50%, symp- toms go away or improve after 1 yr; <5% worsen. Symptoms are stil l troublesome in the rest at 5 yrs. Tricyclic antidepressants (low dose) are often helpful; as are psychotherapy , cognitive-behavioral therapy . Explain that all forms of stress (se xual, physical, or verbal abuse) perpetuate IBS. Signs: Examination is often unremarkable although generalized abdominal tenderness is commo n. Insufflation of air during endoscopy may reproduce the pain. Markers of organic disease : Referral and further workup for anyone >50 with new onset symptoms; anyone with red-flag symptoms (rectal bleeding, nocturnal diarrhea, weight loss, family history of cancer, anemi a, masses, fistulae, markers, or history suggestive of IBD) (i.e., it may well not be IBS). Age >40 yrs; history <6 months; anorexia; weight \206\223 ; waking at night with pain/dia rrhea; mouth ulcers; rectal bleeding; abnormal investigations. Management : See Table 7.20. 244 Carcinoma of the pancreas Epidemiology: Fourth most common cause of cancer-related death in the United States; highly lethal; 36,800 deaths in United States in 2010. Typical patient: >60 yrs old. Risk factors: Smoking, alcohol, DM, family history. Pathology: Most are ducta l adenocarcinoma (metastasize early; late presen- tation). 60% arise in the pancreas head, 15% the tail, and 25% in the body. A minority arise from the ampulla of Vater (ampullary tu mor) or pancre- atic islet cells (insulinoma, gastrinoma, glucagonomas, somatostatinomas, V IPomas); these have a better prognosis. Symptoms and signs Tumors in the head of the pancre as classically pres- ent with painless obstructive jaundice. Tumors in the body and tail pr es- ent with epigastric pain, which typically radiates to the back and may be relieved by s itting forward. Either may cause anorexia, weight loss, DM, or acute pancreatitis. Rare fea tures include thrombophlebitis migrans, maran- tic endocarditis, hypercalcemia, Cushing \200\231s syndrome, ascites (peritoneal