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Harrison’s Manual of Medicine



Alcoholic Liver Disease
Primary Biliary Cirrhosis
Liver Transplantation

Chronic disease of the liver characterized by fibrosis, disorganization of the lobular and vascular architecture, and regenerating nodules of hepatocytes.
CAUSES   Alcohol, viral hepatitis (B, C, D), primary or secondary biliary cirrhosis, hemochromatosis, Wilson’s disease, a1 antitrypsin deficiency, autoimmune hepatitis, Budd-Chiari syndrome, chronic CHF (cardiac cirrhosis), drugs and toxins, schistosomiasis, cryptogenic.
Symptoms   Anorexia, nausea, vomiting, diarrhea, fatigue, weakness, fever, jaundice, amenorrhea, impotence, infertility.
Signs   Spider telangiectases, palmar erythema, parotid and lacrimal gland enlargement, nail changes (Muehrcke lines, Terry’s nails), clubbing, Dupuytren’s contracture, gynecomastia, testicular atrophy, hepatosplenomegaly, ascites, gastrointestinal bleeding (e.g., varices), hepatic encephalopathy.
Laboratory Findings   Anemia (microcytic due to blood loss, macrocytic due to folate deficiency), pancytopenia (hypersplenism), prolonged PT, rarely overt DIC; hyponatremia, hypokalemic alkalosis, glucose disturbances, hypoalbuminemia, hypoxemia (hepatopulmonary syndrome).
Other Associations   Gastritis, duodenal ulcer, gallstones. Altered drug metabolism because of decreased drug clearance, metabolism (e.g., by cytochrome P450), and elimination; hypoalbuminemia; and portosystemic shunting.
DIAGNOSTIC STUDIES   Depend on clinical setting. Serum: HBsAg, anti-HBc, anti-HBs, anti-HCV, anti-HDV, Fe, total iron-binding capacity, ferritin, antimitochondrial antibody (AMA), smooth-muscle antibody (SMA), anti- KLM antibody, ANA, ceruloplasmin, a1 antitrypsin (and pi typing); abdominal ultrasound with doppler study, CT or MRI (may show cirrhotic liver, splenomegaly, collaterals, venous thrombosis), portal venography, and wedged hepatic vein pressure measurement. Definitive diagnosis often depends on liver biopsy (percutaneous, transjugular, or open).
Three forms: fatty liver, alcoholic hepatitis, cirrhosis; may coexist. History of excessive alcohol use often denied. Severe forms (hepatitis, cirrhosis) associated with ingestion of 80–160 g/d for >5–10 years; women more susceptible than men because of lower levels of gastric alcohol dehydrogenase; polymorphisms of alcohol dehydrogenase and acetaldehyde dehydrogenase genes may also affect susceptibility. Hepatitis B and C may be cofactors in the development of liver disease. Malnutrition may contribute to development of cirrhosis.
FATTY LIVER   May follow even brief periods of ethanol use. Often presents as asymptomatic hepatomegaly and mild elevations in biochemical liver tests. Reverses on withdrawal of ethanol; does not lead to cirrhosis.
ALCOHOLIC HEPATITIS   Clinical presentation ranges from asymptomatic to severe liver failure with jaundice, ascites, GI bleeding, and encephalopathy. Typically anorexia, nausea, vomiting, fever, jaundice, tender hepatomegaly. Occasional cholestatic picture mimicking biliary obstruction. Aspartate aminotransferase (AST) usually <300 U and more than twofold higher than alanine aminotransferase (ALT). Bilirubin may be >170 µmol/L (>10 mg/dL). WBC may be as high as 20,000/µL. Diagnosis defined by liver biopsy findings: hepatocyte swelling, alcoholic hyaline (Mallory bodies), infiltration of PMNs, necrosis of hepatocytes, pericentral venular fibrosis.
Other Metabolic Consequences of Alcoholism   Increased NADH/NAD ratio leads to lacticacidemia, ketoacidosis, hyperuricemia, hypoglycemia. Hypomagnesemia, hypophosphatemia. Also mitochondrial dysfunction, induction of microsomal enzymes resulting in altered drug metabolism, lipid peroxidation leading to membrane damage, hypermetabolic state; many features of alcoholic hepatitis are attributable to toxic effects of acetaldehyde and cytokines (IL-1, IL-6, and TNF, released because of impaired detoxification of endotoxin).
Adverse Prognostic Factors   Short-term: PT > 5 s above control despite vitamin K, bilirubin > 170 µmmol/L (>10 mg/dL), encephalopathy, hypoalbuminemia, azotemia. Mortality is >35% if (pt’s PT in seconds) – (control PT in seconds) × 4.6 + serum bilirubin (mg/dL) = > 32.
Long-term: severe hepatic necrosis and fibrosis, portal hypertension, continued alcohol consumption.

Abstinence is essential; 8500–12,500 kJ (2000–3000 kcal) diet with 1 g/kg protein (less if encephalopathy). Daily multivitamin, thiamine 100 mg, folic acid 1 mg. Correct potassium, magnesium, and phosphate deficiencies. Transfusions of packed red cells, plasma as necessary. Monitor glucose (hypoglycemia in severe liver disease). Prednisone 40 mg or prednisolone 32 mg PO qd × 1 month may be beneficial in severe alcoholic hepatitis with encephalopathy (in absence of GI bleeding, renal failure, infection). Colchicine 0.6 mg PO bid may slow progression of alcoholic liver disease. Experimental: amino acid infusions, propylthiouracil, insulin and glucagon, anabolic steroids. Liver transplantation in carefully selected pts who have been abstinent >6 months.

Progressive nonsuppurative destructive intrahepatic cholangitis. Affects middle- aged women. Presents as asymptomatic elevation in alkaline phosphatase (better prognosis) or with pruritus, progressive jaundice, consequences of impaired bile excretion, and ultimately cirrhosis and liver failure.
CLINICAL MANIFESTATIONS   Pruritus, jaundice, xanthelasma, xanthomata, osteoporosis, steatorrhea, skin pigmentation, hepatosplenomegaly, portal hypertension; elevations in serum alkaline phosphatase, bilirubin, cholesterol, and IgM levels.
ASSOCIATED DISEASES   Sjögren’s syndrome, collagen vascular diseases, thyroiditis, glomerulonephritis, pernicious anemia, renal tubular acidosis.
DIAGNOSIS   AMA in >90–95% (directed against the E2 component of pyruvate dehydrogenase and other 2-oxo-acid dehydrogenase mitochondrial enzymes). Liver biopsy: stage 1—destruction of interlobular bile ducts, granulomas; stage 2—ductular proliferation; stage 3—fibrosis; stage 4—cirrhosis.
PROGNOSIS   Correlates with age, serum bilirubin, serum albumin, prothrombin time, edema.

Cholestyramine 4 g PO with meals for pruritus; in refractory cases consider rifampin, phototherapy with UVB light, naloxone infusion, plasmapheresis. Vitamin K 10 mg IM qd × 3 (then once a month) for elevated PT due to intestinal bile-salt deficiency. Vitamin D 100,000 U IM q 4 weeks plus oral calcium 1 g qd for osteoporosis (often unresponsive). Vitamin A 25,000— 50,000 U PO qd or 100,000 U IM q 4 weeks and zinc 220 mg PO qd may help night blindness. Vitamin E 10 mg IM or PO qd. Substituting dietary fat with medium-chain triglycerides (MCTs) may reduce steatorrhea. Glucocorticoids, D-penicillamine, azathioprine, chlorambucil, cyclosporine of no value. Most widely used agent is ursodeoxycholic acid 10–15(mg/kg)/d PO in 2 divided doses—improves symptoms and LFTs and slows progression, delaying need for liver transplantation. Colchicine less effective, and methotrexate requires more study. Liver transplantation for end-stage disease.

Consider for chronic, irreversible, progressive liver disease or fulminant hepatic failure when no alternative therapy is available. (Also indicated to correct certain congenital enzyme deficiencies and inborn errors of metabolism.)
CONTRAINDICATIONS   Absolute   Extrahepatobiliary sepsis or malignancy, severe cardiopulmonary disease, preexisting advanced cardiovascular or pulmonary disease, active alcoholism or drug abuse, AIDS.
Relative   Age >70, HIV infection, extensive previous abdominal surgery, portal and superior mesenteric vein thrombosis, lack of pt understanding.
INDICATIONS   Guidelines: expected death in 2 years; preferably in anticipation of major complication (variceal bleeding, irreversible encephalopathy, severe malnutrition and incapacitating weakness, hepatorenal syndrome); refractory ascites, progressive bone disease, severe pruritus, recurrent bacterial cholangitis, intractable coagulopathy; hepatopulmonary syndrome (intrapulmonary vascular dilatations with increased alveolar-arterial gradient), once considered a contraindication, may reverse with transplantation; bilirubin >170– 340 µmol/L (>10–20 mg/dL), albumin <20 g/L (<2 g/dL), worsening coagulopathy; poor quality of life. In fulminant hepatic failure consider for grade III-IV coma (before cerebral edema develops).
SELECTION OF DONOR   Matched for ABO blood group compatibility and liver size (reduced-size grafts may be used, esp. in children). Should be negative for HIV, HBV, and HCV.
IMMUNOSUPPRESSION   Various combinations of tacrolimus or cyclosporine and glucocorticoids, mycophenolate mofetil, azathioprine, or OKT3 (monoclonal antithymocyte globulin).
MEDICAL COMPLICATIONS AFTER TRANSPLANTATION   Liver graft dysfunction (primary nonfunction, acute or chronic rejection, ischemia, hepatic artery thrombosis, biliary obstruction or leak, recurrent hepatitis B or C); infections (bacterial, viral, fungal, opportunistic); renal dysfunction; neuropsychiatric disorders.
SUCCESS RATE   70–80% long-term survival; less for certain conditions (e.g., chronic hepatitis B, hepatocellular carcinoma).

For a more detailed discussion, see Chung RT, Podolsky DK: Cirrhosis and Its Complications, Chap. 299, p. 1754; Dienstag JL: Liver Transplantation, Chap. 301, p. 1770, in HPIM-15.

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