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Harrison’s Manual of Medicine



Viral Hepatitis
Toxic and Drug-Induced Hepatitis
Acute Hepatic Failure

Clinically characterized by malaise, nausea, vomiting, diarrhea, and low-grade fever followed by dark urine, jaundice, and tender hepatomegaly; may be subclinical and detected on basis of elevated aspartate and alanine aminotransferase (AST and ALT) levels. Hepatitis B may be associated with immune-complex phenomena, including arthritis, serum-sickness–like illness, glomerulonephritis, and polyarteritis nodosa. Hepatitis-like illnesses may be caused not only by hepatotropic viruses (A, B, C, D, E) but also by other viruses (Epstein-Barr, CMV, coxsackievirus, etc.), alcohol, drugs, hypotension and ischemia, and biliary tract disease (Table 153-1).

Table 153-1 The Hepatitis Viruses

HEPATITIS A (HAV)   27-nm picornavirus (hepatovirus) with single- stranded RNA genome. Clinical course: See Fig. 153-1

FIGURE 153-1. Scheme of typical clinical and laboratory features of HAV. (Reproduced from Dienstag JL, Isselbacher KJ, HPIM-15, p. 1721).

Outcome   Recovery within 6–12 months, occasionally after one or two apparent clinical and serologic relapses; in some cases, pronounced cholestasis suggesting biliary obstruction may occur; rare fatalities (fulminant hepatitis), no chronic carrier state.
Diagnosis   IgM anti-HAV in acute or early convalescent serum sample.
Epidemiology   Fecal-oral transmission; endemic in underdeveloped countries; food-borne and waterborne epidemics; outbreaks in day-care centers, residential institutions.
Prevention   After exposure: immune globulin 0.02 mL/kg IM within 2 weeks to household and institutional contacts (not casual contacts at work). Before exposure: inactivated HAV vaccine 0.5–1 mL IM (dose depends on formulation); half dose to children; repeat at 6–12 months; target travelers, military recruits, animal handlers, day-care personnel.
HEPATITIS B (HBV)   42-nm hepadnavirus with outer surface coat (HBsAg), inner nucleocapsid core (HBcAg), DNA polymerase, and partially double-stranded DNA genome of 3200 nucleotides. Circulating form of HBcAg is HBeAg, a marker of viral replication and infectivity. Multiple serotypes and genetic heterogeneity. Course: See Fig. 153-2.

FIGURE 153-2. Scheme of typical clinical and laboratory features of HBV. (Reproduced from Dienstag JL, Isselbacher KJ, HPIM-15, p. 1721)

Outcome   Recovery >90%, fulminant hepatitis (<1%), chronic hepatitis or carrier state (only 1–2% of immunocompetent adults; higher in neonates, elderly, immunocompromised), cirrhosis, and hepatocellular carcinoma (especially following chronic infection beginning in infancy or early childhood) (Chap. 155).
Diagnosis   HBsAg in serum (acute or chronic infection); IgM anti-HBc (early anti-HBc indicative of acute or recent infection). Most sensitive test is detection of HBV DNA in serum; not generally required for routine diagnosis.
Epidemiology   Percutaneous (needlestick), sexual, or perinatal transmission. Endemic in sub-Saharan Africa and Southeast Asia, where up to 20% of population acquire infection, usually early in life.
Prevention   After exposure: hepatitis B immune globulin (HBIG) 0.06 mL/ kg IM immediately after needlestick, within 14 days of sexual exposure, or at birth (HbsAg+ mother) in combination with vaccine series. Before exposure: recombinant hepatitis B vaccine 10–20µg IM (dose depends on formulation); half dose to children, 40-µg dose to immunocompromised adults; at 0, 1, and 6 months; deltoid, not gluteal injection. Has been targeted to high-risk groups (e.g., health workers, gay men, IV drug users, hemodialysis pts, hemophiliacs, household and sexual contacts of HBsAg carriers, all neonates in endemic areas, or high-risk neonates in lower-risk areas). Universal vaccination of all children is now recommended in the U.S.
HEPATITIS C (HCV)   Caused by flavi-like virus with RNA genome of >9000 nucleotides (similar to yellow fever virus, dengue virus); some genetic heterogeneity. Incubation period 7–8 weeks. Course often clinically mild and marked by fluctuating elevations of serum aminotransferase levels; >50% likelihood of chronicity, leading to cirrhosis in >20%.
Diagnosis   Anti-HCV in serum. Current second- and third-generation enzyme immunoassay detects antibody to epitopes designated C200, C33c, C22- 3; may appear after acute illness but generally present by 3–5 months after exposure. A positive enzyme immunoassay can be confirmed by recombinant immunoblot assay (RIBA) or by detection of HCV RNA in serum (Fig. 153- 3).

FIGURE 153-3. Serologic course of acute hepatitis type C progressing to chronicity. HCV RNA is detectable before the ALT elevation. Antibody to C22 and anti-C33 appears during acute hepatitis C, whereas antibody to C100 appears 1 to 3 months later. (Reproduced from Dienstag JL, Isselbacher KJ, HPIM-15, p. 1721)

Epidemiology   Percutaneous transmission accounts for >90% of transfusion-associated hepatitis cases. IV drug use accounts >50% of reported cases. Little evidence for frequent sexual or perinatal transmission.
Prevention   Exclusion of paid blood donors, testing of donated blood for anti-HCV. Anti-HCV detected by enzyme immunoassay in blood donors with normal ALT is often falsely positive (30%); result should be confirmed with RIBA, which correlates with presence of HCV RNA in serum.
HEPATITIS D (HDV, DELTA AGENT)   Defective 37-nm RNA virus that requires HBV for its replication; either coinfects with HBV or superinfects a chronic HBV carrier. Enhances severity of HBV infection (acceleration of chronic hepatitis to cirrhosis, occasionally fulminant acute hepatitis).
Diagnosis   Anti-HDV in serum (acute hepatitis D—often in low titer, is transient; chronic hepatitis D—in higher titer, is sustained).
Epidemiology   Endemic among HBV carriers in Mediterranean basin, areas of South America, etc. Otherwise spread percutaneously among HbsAg+ IV drug users or by transfusion in hemophiliacs and to a lesser extent among HbsAg+ gay men.
Prevention   Hepatitis B vaccine (noncarriers only).
HEPATITIS E (HEV)   Caused by 29- to 32-nm agent thought to be related to caliciviruses. Enterically transmitted and responsible for waterborne epidemics of hepatitis in India, parts of Asia and Africa, and Central America. Self-limited illness with high (10–20%) mortality rate in pregnant women.
HEPATITIS G (HGV)   Recently identified flavivirus with RNA genome of >9000 nucleotides (distantly related to HCV). Though common (detected in 1.7% of U.S. blood donors) and associated with viremia lasting for years, HGV does not appear to cause significant liver disease.

Activity as tolerated, high-calorie diet (often tolerated best in morning), IV hydration for severe vomiting, cholestyramine up to 4 g PO qid for severe pruritus, avoid hepatically metabolized drugs; no role for glucocorticoids. Liver transplantation for fulminant hepatic failure and grades III–IV encephalopathy.

DOSE-DEPENDENT (DIRECT HEPATOTOXINS)   Onset is within 48 h, predictable, necrosis around terminal hepatic venule—e.g., carbon tetrachloride, benzene derivatives, mushroom poisoning, acetaminophen, or microvesicular steatosis (e.g., tetracyclines, valproic acid).
IDIOSYNCRATIC   Variable dose and time of onset; small number of exposed persons affected; may be associated with fever, rash, arthralgias, eosinophilia. In many cases, mechanism may actually involve toxic metabolite, possibly determined on genetic basis—e.g., isoniazid, halothane, phenytoin, methyldopa, carbamazepine, diclofenac, oxacillin, sulfonamides.

Supportive as for viral hepatitis; withdraw suspected agent. Liver transplantation if necessary.

Massive hepatic necrosis with impaired consciousness occurring within 8 weeks of the onset of illness.
CAUSES   Infections (viral, including HAV, HBV, HCV (rarely), HDV, HEV, bacterial, rickettsial, parasitic), drugs and toxins, ischemia (shock), Budd- Chiari syndrome, idiopathic chronic active hepatitis, acute Wilson’s disease, microvesicular fat syndromes (Reye’s syndrome, acute fatty liver of pregnancy).
CLINICAL MANIFESTATIONS   Neuropsychiatric changes—delirium, personality change, stupor, coma; cerebral edema—suggested by profuse sweating, hemodynamic instability, tachyarrhythmias, tachypnea, fever, papilledema, decerebrate rigidity (though all may be absent); deep jaundice, coagulopathy, bleeding, renal failure, acid-base disturbance, hypoglycemia, acute pancreatitis, cardiorespiratory failure, infections (bacterial, fungal).
ADVERSE PROGNOSTIC INDICATORS   Age <10 or >40, certain causes (e.g., halothane, hepatitis C), duration of jaundice >7 d before onset of encephalopathy, serum bilirubin >300 µmol/L (>18 mg/dL), coma (survival <20%), rapid reduction in liver size, respiratory failure, marked prolongation of PT, factor V level <20%. In acetaminophen overdose, adverse prognosis is suggested by blood pH <7.30, serum creatinine >266 µmol/L (>3 mg/dL), markedly prolonged PT.

Endotracheal intubation often required. Monitor serum glucose—IV D10 or D20 as necessary. Prevent gastrointestinal bleeding with H2-receptor antagonists and antacids (maintain gastric pH ³3.5). In many centers intracranial pressure is monitored—more sensitive than CT in detecting cerebral edema. Value of dexamethasone for cerebral edema unclear; IV mannitol may be beneficial. Liver transplantation should be considered in pts with grades III–IV encephalopathy and other adverse prognostic indicators.


For a more detailed discussion, see Dienstag JL, Isselbacher KJ: Acute Viral Hepatitis, Chap. 295, p. 1721, in HPIM-15.


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