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Acute viral hepatitis
Chapter 3
Acute viral hepatitis
Raymond S. Koff,
MD
Key Points 1 Acute viral hepatitis is the most common cause of liver disease in the world; it and its sequelae are responsible for 1–2 million deaths annually. 2 The nonenveloped, enterically transmitted hepatitis viruses (HAV and HEV), in general, are self-limited infections, but severe hepatitis may develop in some cases; the blood-borne hepatitis viruses (HBV, HDV, and HCV) are enveloped agents associated with persistent infection, prolonged viremia, and the development of chronic liver disease and its sequelae. 3 A wide spectrum of clinical illness is well documented, ranging from asymptomatic, anicteric infection to acute liver failure (fulminant hepatitis); with the exception of acute hepatitis C, no specific treatment of acute viral hepatitis is available; liver transplantation is indicated in acute liver failure when recovery seems unlikely. 4 Highly effective and safe vaccines are available for pre-exposure immunoprophylaxis of HAV and HBV infection; for post-exposure immunoprophylaxis of HAV, immune globulin is used, while for post-exposure immunoprophylaxis of HBV both HBIG and HBV vaccine are used. 5 Neither immune globulin preparations nor vaccines are available for the prevention of HEV or HCV. HBV vaccination prevents HDV infection, but for persons with established HBV infection vaccines to prevent HDV superinfection are not available.
Acute Viral Hepatitis: Importance • • • •
worldwide, hepatitis virus infections are the most common cause of liver disease many hepatitis episodes are anicteric, inapparent, or subclinical globally, viral hepatitis is the major cause of persistent viremia with its sequelae, viral hepatitis is responsible for 1–2 million deaths annually
The Agents of Viral Hepatitis The agents of acute viral hepatitis can be broadly classified into two groups: the enterically transmitted and the blood-borne agents.
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The agents of viral hepatitis
Enterically transmitted agents These agents, namely hepatitis A virus (HAV), hepatitis E virus (HEV): – are nonenveloped viruses – survive intact when exposed to bile – are shed in feces – are not linked to chronic liver disease – do not result in a prolonged viremic or intestinal carrier state A third enterically transmitted hepatitis virus may exist 1 HAV • classified as a picornavirus, subclassified as a ‘hepatovirus’ • 27–28 nm in diameter with cubic symmetry • single-stranded, linear RNA molecule, 7.5 kb • one serotype in human beings; three or more genotypes • contains a single immunodominant neutralization site • contains three or four virion polypeptides in capsomere • replication in cytoplasm of infected hepatocyte; no definitive evidence of replication in intestine • propagated in nonhuman primate and human cell lines 2 HEV • tentatively classified in a separate family called hepatitis E-like viruses • 27–34 nm in diameter • linear RNA molecule, 7.2 kb • RNA genome with three overlapping open reading frames encoding structural proteins and nonstructural proteins involved in HEV replication: – RNA-dependent RNA polymerase (RNA replicase) – helicase – cysteine protease – methyltransferase • only one serotype identified in human beings; four to nine main genotypes • immunodominant neutralization site on structural protein encoded by second open reading frame • can be propagated in human embryo lung diploid cells • replication in vivo limited to hepatocytes 3 Other enterically transmitted agents • occasional outbreaks of other enterically transmitted hepatitis, without serologic markers of HAV or HEV
Blood-borne agents These agents, namely hepatitis B virus (HBV), hepatitis D virus (HDV), and hepatitis C virus (HCV), are: – enveloped viruses – disrupted by exposure to bile/detergents – not shed in feces – linked to chronic liver disease – associated with persistent viremia 1 HBV • human-infecting member of hepatotropic DNA-containing viruses, the ‘Hepadnaviridae’
Acute viral hepatitis
• eight genotypes (A through H): ?relationship to severity, response to therapy • 42-nm spherical particle with: – a 27-nm diameter, electron-dense, nucleocapsid core – a 7-nm thick outer lipoprotein envelope • HBV core contains circular, partially double-stranded DNA (3.2 kb in length) and: – DNA polymerase protein with reverse transcriptase activity – hepatitis B core antigen (HBcAg), a structural protein – hepatitis B e antigen (HBeAg), a nonstructural protein that correlates imperfectly with active HBV replication • HBV outer lipoprotein envelope contains: – hepatitis B surface antigen (HBsAg), with three envelope proteins: major, large, and middle proteins – minor lipid and carbohydrate components – HBsAg present in 22-nm spherical or tubular noninfectious particles, in excess of intact HBV particles • one major serotype; many subtypes based on HBsAg protein diversity • HBV mutant viruses are a consequence of poor proof-reading ability of reverse transcriptase or emergence of resistance; these include: – HBeAg-negative precore/core mutant (uncommon in USA) – HBV vaccine-induced escape mutant (rare) – lamivudine-induced YMDD mutant • liver is major but not only site of HBV replication 2 HDV • a defective RNA virus, requiring helper function of HBV for its expression and pathogenicity but not for its replication • only one serotype recognized, three genotypes • 35–37-nm spherical particle, enveloped by HBV lipoprotein coat (HBsAg) – 19-nm core-like structure • contains an antigenic nuclear phosphoprotein (HDV antigen) – binds RNA – exists in two isoforms: smaller 195 amino acid and larger 214 amino acid proteins – smaller HDV antigen transports RNA into the nucleus: essential for HDV replication – larger HDV antigen is prenylated: inhibits HDV RNA replication and participates in HDV assembly • HDV RNA is single stranded, covalently closed, and circular • HDV antigenome is a genome complementary, circular RNA found in infected hepatocyte and, to a lesser extent, in purified HDV particles • with slightly less than 1680 nucleotides, HDV RNA is the smallest RNA genome among the animal viruses; HDV resembles plant satellite viruses • RNA genome can form an unbranched rod-like structure by folding on itself through intramolecular base pairing • replication limited to hepatocyte • cell lines transfected with HDV cDNA constructs express HDV RNA and HDV antigens 3 HCV • a glycoprotein enveloped, single-stranded RNA virus • 55-nm spherical particle; 33-nm nucleocapsid core • classified among the Flaviviridae, in genus termed ‘hepacivirus’ • HCV genome comprises about 9400 nucleotides encoding a large polyprotein of about 3000 amino acid residues
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Epidemiology and risk factors
– one-third of the polyprotein comprises a series of structural proteins (an internal nucleocapsid or core (C) protein and two glycosylated envelope proteins, termed E1 and E2, present in the lipid-containing envelope of the virus) – envelope proteins may generate neutralizing antibodies – a hypervariable region is localized in E2 – remaining two-thirds of the polyprotein consists of nonstructural proteins (termed NS2, NS3, NS4A, NS4B, NS5A, and NS5B) involved in HCV replication; these are a zinc-dependent metalloproteinase in NS2/3, a nucleotide triphosphatase/helicase in NS3, a chymotrypsin-like serine protease in NS3, and RNA-dependent RNA polymerase in NS5B • only one HCV serotype identified; multiple HCV genotypes exist; genotypes are variably distributed throughout the world • genotypes correlated with likelihood of response of chronic infection to antiviral therapy
Epidemiology and Risk Factors HAV 1 Incubation period: 15–50 days (average 30 days) 2 Worldwide distribution; highly endemic in developing countries 3 HAV is excreted in the stools of infected persons for 1–2 weeks before and for at least 1 week after onset of illness 4 Viremia is short lived (usually no longer than 3 weeks); occasionally up to 90 days in protracted or relapsing infection 5 Prolonged fecal excretion (months) reported in infected neonates; frequency, level of virus in stool, and epidemiological importance are uncertain 6 Enteric (fecal-oral) transmission predominantly via person-to-person household spread; occasional outbreaks linked to common-source vehicles: • contaminated food, bivalve mollusks, water 7 Other risk factors include exposure: • in day care centers for infants, diapered children • in institutions for developmentally disadvantaged • via international travel to developing countries • via oral-anal homosexual behavior • via shared equipment by injection drug users 8 No evidence for maternal-neonatal transmission 9 Prevalence correlates with sanitary standards and large household size 10 Transmission via blood transfusion: very rare 11 Overall seroprevalence in USA: 30% and declining
HEV 1 2 3 4 5 6 7 8
Incubation period averages about 40 days Widely distributed; epidemic and endemic forms but rare in USA HEV RNA in serum and stool during acute phase The most common form of sporadic hepatitis in young adults in the developing world Largely water-borne epidemic disease Intrafamilial, secondary cases: uncommon Maternal-neonatal transmission has been documented In the USA imported cases in returning travelers, in recent immigrants from endemic regions; sporadic cases extremely rare
Acute viral hepatitis
9 Prolonged viremia or fecal shedding unusual 10 Zoonosis: swine, other animals
HBV 1 Incubation period ranges from 15 to 180 days (average 60–90 days) 2 HBV viremia lasts for weeks to months after acute infection 3 1–5% of adults, 90% of infected neonates, and 50% of infants develop chronic infection and persistent viremia 4 Persistent infection linked with chronic hepatitis, cirrhosis, hepatocellular carcinoma 5 Worldwide distribution: HBV carrier prevalence <1% in USA, 5–15% in Asia 6 HBV is present in blood, semen, cervicovaginal secretions, saliva, other body fluids 7 Modes of transmission: a Blood-borne • recipients of multiple blood products • injecting drug users • hemodialysis patients • health care and other workers exposed to blood b Sexual transmission c Tissue penetrations (percutaneous) or permucosal transfer • needlestick accidents • re-use of contaminated medical equipment • shared razor-blades • tattoos • acupuncture, body-piercing • shared toothbrushes d Maternal-neonatal, maternal-infant transmission e No evidence for fecal-oral spread
HDV 1 Incubation period is estimated to be 4–7 weeks 2 Endemic in Mediterranean basin, Balkan peninsula, European parts of former Soviet Union, parts of Africa, Middle East, and Amazon basin 3 Declining incidence with increasing use of HBV vaccine 4 Viremia short lived (acute infection) or prolonged (chronic infection) 5 HDV infections occur solely in individuals at risk for HBV infection (coinfections or superinfections) • injecting drug abusers • homosexual or bisexual adolescents and men • recipients of high-risk blood products • sexual partners 6 Modes of transmission a Blood-borne b Sexual transmission c Maternal-neonatal spread
HCV 1 Incubation period ranges from 15 to 160 days (major peak at about 50 days) 2 Prolonged viremia and persistent infection common (55–85%); wide geographic distribution 3 Persistent infection etiologically linked with chronic hepatitis, cirrhosis, hepatocellular carcinoma
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Clinical features
4 Seroprevalence of past/present infection 1.8% in USA; approaches 20% in some communities in Italy, Japan 5 Modes of transmission a Blood-borne (the predominant mode) • injecting drug use and tissue penetrations • recipients of blood/blood products (exceedingly rare in USA with estimated risk now 1:2 000 000 transfused units) b Sexual transmission: low efficiency, low frequency c Maternal-neonatal: low efficiency, low frequency d No evidence of fecal–oral transmission
Pathophysiology 1 Cell-mediated immune mechanisms largely responsible for hepatocyte injury • involves CD8+ and CD4+ T-cell responses • production of cytokines in liver and systemically 2 Direct viral cytopathic effect • postulated in immunosuppressed patients with exceedingly high levels of viral replication, but no direct evidence
Clinical Features Self-limited disease 1 Spectrum of severity ranges from asymptomatic, inapparent infection to fatal acute liver failure 2 Similar clinical syndromes for all agents beginning with nonspecific prodromal constitutional and gastrointestinal symptoms: • malaise, anorexia, nausea, and vomiting • flu-like symptoms of pharyngitis, cough, coryza, photophobia, headache, and myalgias 3 Onset of symptoms tends to be abrupt for HAV and HEV; in the others onset is usually insidious 4 Fever is uncommon except in HAV infection 5 Immune-complex-mediated, serum-sickness-like syndrome in less than 10% of patients with HBV infection; rarely in others 6 Prodromal symptoms abate or disappear with onset of jaundice, although anorexia, malaise, and weakness may persist 7 Jaundice heralded by the appearance of dark urine; pruritus (usually mild and transient) may occur as jaundice increases 8 Physical examination reveals mild enlargement and slight tenderness of the liver 9 Mild splenomegaly and posterior cervical lymphadenopathy in 15–20% of patients
Acute liver failure (see Ch. 2) 1 Characterized by changes in mental status (encephalopathy) • lethargy, drowsiness, coma • reversal of sleep patterns • personality changes 2 Cerebral edema (usually without papilledema) 3 Coagulopathy (prolongation of the prothrombin time) 4 Multiple organ failure • acute respiratory distress syndrome
Acute viral hepatitis
5 6 7 8
• cardiac arrhythmias • hepatorenal syndrome • metabolic acidosis • sepsis • gastrointestinal bleeding • hypotension Development of ascites, anasarca Case fatality rate: about 60% Serial physical examination shows: shrinking liver Extraordinarily high frequency, approaching 10–20%, in pregnant women with hepatitis E, particularly during the third trimester
Cholestatic hepatitis 1 2 3 4 5
Jaundice may be striking and persist for several months prior to complete resolution Pruritus may be prominent Persistent anorexia and diarrhea in a few patients Excellent prognosis for complete resolution Most commonly seen in HAV infection
Relapsing hepatitis 1 Symptoms and liver test abnormalities recur weeks to months after improvement or apparent recovery 2 Most commonly seen in HAV infection – IgM anti-HAV may remain positive, and HAV may once again be shed in stool 3 Arthritis, vasculitis, and cryoglobulinemia may be seen 4 Prognosis is excellent for complete recovery even after multiple relapses (particularly common in children)
Laboratory Features Self-limited disease 1 Most prominent biochemical feature is: marked elevation of serum alanine and aspartate aminotransferase levels (ALT and AST, respectively) 2 Peak aminotransferases (ALT and AST): vary from 500 to 5000 U/L 3 Serum bilirubin level uncommonly above 10 mg/dL, except in cholestatic hepatitis (see later) 4 Serum alkaline phosphatase normal or mildly elevated 5 Prothrombin time normal or increased by 1–3 s 6 Serum albumin normal or minimally depressed 7 Peripheral blood counts: normal or mild leukopenia with or without a relative lymphocytosis
Acute liver failure (see Ch. 2) 1 2 3 4
Striking coagulopathy Leukocytosis, hyponatremia, and hypokalemia common Hypoglycemia Marked elevations of serum bilirubin and aminotransferases, but the latter may decline towards normal despite disease progression.
Cholestatic disease 1 Serum bilirubin levels may exceed 20 mg/dL
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Diagnosis
2 Serum aminotransferase levels may decline toward normal despite cholestasis 3 Variable elevation of serum alkaline phosphatase
Relapsing hepatitis 1 After apparent normalization or near-normalization of serum aminotransferase and bilirubin levels during convalescence, both may rise again 2 Infrequently peak levels may exceed those of initial bout
Histology Liver biopsy is rarely performed in acute self-limited viral hepatitis.
Self-limited disease 1 Major hepatocyte injury • focal hepatocyte necrosis • loss of hepatocytes (cell dropout) • ballooning degeneration • apoptosis with Councilman-like bodies (mummified, hyalinized, necrotic hepatocytes, extruded into a hepatic sinusoid) 2 Endophlebitis, affecting the central vein 3 Diffuse mononuclear cell (CD8+ and natural killer cell) infiltrate • within widened portal tracts • segmental erosion of the limiting plate • within hepatic parenchyma • Kupffer’s cells enlarged, hyperplastic, with lipofuscin pigment and debris; remnants of injured hepatocytes
Acute liver failure 1 2 3 4 5
Liver biopsy usually precluded by coagulopathy Extensive confluent hepatocyte dropout (disappearance) Collapse of reticulin framework Lobular inflammation Variable cholestasis
Cholestatic disease 1 Hepatocyte degeneration, inflammation as in self-limited hepatitis 2 Prominence of bile plugs in dilated hepatocyte canaliculi and bilirubin staining of hepatocytes 3 Hepatocytes form multiple, scattered, duct-like structures (pseudoglandular transformation)
Relapsing hepatitis Changes similar to those in self-limited disease.
Diagnosis Differential diagnosis 1 2 3 4 5
Drug- and toxin-induced liver disease (see Ch. 8) Ischemic hepatitis (see Ch. 20) Autoimmune hepatitis (see Ch. 5) Alcoholic hepatitis (see Ch. 6) Acute biliary tract obstruction (see Ch. 33)
Acute viral hepatitis
Table 3.1: Serologic patterns in the diagnosis of acute viral hepatitis Agent
Acute phase
Convalescence
HAV
Total anti-HAV positive IgM anti-HAV positive
Development of IgG anti-HAV Disappearance of IgM anti-HAV
HEV
IgM anti-HEV positive and/or HEV RNA (in stool) IgG anti-HEV may be present
Loss of HEV RNA; development of IgG anti-HEV Loss of IgM anti-HEV
HBV
HBsAg positive and IgM anti-HBc positive
Loss of HBsAg; later loss of IgM anti-HBc; development of IgG anti-HBc; late development of anti-HBs
HDV
HDV RNA positive or HDV antigen positive or IgM anti-HDV positive in HBsAg-positive patient HDV/HBV coinfection: IgM anti-HBc positive HDV/HBV superinfection: IgG anti-HBc positive
Loss of HDV RNA or antigen; development of IgG anti-HDV or loss of anti-HDV Above plus usual loss of HBsAg Above usually without loss of HBsAg
HCV
Early presence of HCV RNA; presence of or development of anti-HCV
Loss of HCV RNA (in a minor proportion of patients); anti-HCV persistence for decades
Fig. 3.1 Serologic course of HAV
Fecal HAV
IgM anti-HAV
IgG anti-HAV
Titer Jaundice Symptoms ↑ALT HAV in serum
0
4
8
12
16
20
Weeks after exposure
Serologic diagnosis For serologic diagnosis, see Table 3.1. 1 Enterically transmitted infections a HAV (see Fig. 3.1) • IgM antibody to HAV (IgM anti-HAV) is detected during acute phase and for 3–6 months thereafter • presence of positive anti-HAV without IgM anti-HAV indicates past infection
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Diagnosis
b HEV • there are no Food and Drug Administration (FDA)-approved commercial serologic assays available • IgM and IgG antibodies to HEV (anti-HEV) detected early by research assays • IgM anti-HEV may persist for at least 6 weeks after peak of illness • IgG anti-HEV may remain detectable for as long as 20 months 2 Blood-borne infections a HBV (see Fig. 3.2) • serologic diagnosis is established by detection of presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) and HBsAg: – both are usually present at onset of symptoms – IgM anti-HBc is usually preceded by HBsAg – HBsAg is first routinely measured serologic marker of HBV infection to appear – HBsAg may disappear, usually within several weeks to months after appearance, before loss of IgM anti-HBc • HBeAg and HBV DNA: – HBV DNA in serum is first detectable marker of HBV infection but not routinely measured – HBeAg is usually detectable after appearance of HBsAg – both markers disappear after weeks to months in self-limited infection; corresponding antibodies anti-HBs and anti-HBe persist – not necessary for routine diagnosis • IgG anti-HBc: – replaces IgM anti-HBc in resolving infection – indicative of past or continuing infection – not induced by HBV vaccine • antibody to HBsAg (anti-HBs): – last antibody to appear – a neutralizing antibody
Fig. 3.2 Serologic course of HBV
HBeAg
IgG anti-HBc
AntiHBs
Titer
HBeAg
0
4
Jaundice Symptoms ↑ALT Anti-HBe HBV DNA
8 12 16 18 20 24 28 32 36 40 52 Weeks after exposure
IgM antiHBc
Acute viral hepatitis Fig. 3.3 Serologic course of HCV
Serum ALT
Anti-HCV Titer
Symptoms/Jaundice HCV RNA in serum
Normal 0
1
2
3
4
5
6
12
Months after exposure
b •
•
•
• c •
•
– generally indicative of recovery and immunity to reinfection – elicited by HBV vaccine HDV HBsAg-positive individual with: – antibody to HDV (anti-HDV) and/or circulating HDV RNA (assays are unapproved in USA) – IgM anti-HDV may be present transiently HBV/HDV coinfection: – HBsAg positivity – IgM anti-HBc-positive – anti-HDV and/or HDV RNA HDV superinfection of HBV carrier: – HBsAg positivity – IgG anti-HBc positive – anti-HDV and/or HDV RNA anti-HDV titers decline to undetectable levels with resolution of infection HCV (see Fig. 3.3) serologic diagnosis: – detection of antibodies to recombinant HCV antigens (anti-HCV) – third-generation assays include antigens from structural and nonstructural regions – anti-HCV is detected in about 60% of patients during acute phase of illness; anti-HCV appears weeks to months later in about 35% – <5% of infected patients do not develop anti-HCV (a higher percentage of HIV-infected patients do not develop anti-HCV) – assays for IgM anti-HCV under development (not FDA-approved) – anti-HCV generally persists for prolonged periods following acute infection, in both self-limited and chronic HCV infections HCV RNA: – the earliest marker of acute HCV infection – appears within a few weeks of exposure
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Natural history and outcome
– expensive, not routinely used for diagnosis except when HCV suspected in anti-HCV negative individual – present in chronic HCV infection
Natural History and Outcome Enterically transmitted infections (HAV and HEV) 1 Complete clinical, histologic, and biochemical recovery within 3–6 months 2 Occasional instances of acute liver failure • age-dependent fatalities in HAV infection (increased risk after age 40 years) • increased risk in pregnant women with HEV infection • increased risk in those with pre-existing liver disease 3 No chronic liver disease or prolonged carriage of virus
Blood-borne infections (HBV, HDV and HCV) 1 HBV a Risk of persistent infection: age dependent and declines progressively with increasing age: • 90% of infected neonates become carriers • 1–5% of adult patients develop chronic HBV infection b Acute liver failure in <1% of acute infections c Persistent infection (HBsAg positive with or without active HBV replication) • asymptomatic carrier with normal or nonspecific liver histologic changes • chronic hepatitis, cirrhosis, hepatocellular carcinoma • associated with membranous glomerulonephritis, polyarteritis nodosa, and, less certainly, mixed cryoglobulinemia 2 HDV a HDV/HBV coinfections usually self-limited and resolve without sequelae b Acute liver failure more often in HDV superinfection of HBV-infected individuals than in coinfection c HDV superinfection of HBV-infected individuals may lead to chronic HDV infection superimposed on chronic HBV infection with development of severe chronic hepatitis and cirrhosis 3 HCV a Self-limited infections in 15–45% b Very rarely associated with acute liver failure c Persistent HCV infections with prolonged viremia and elevated or fluctuating serum aminotransferase levels are common d Histology in persistent HCV infection • chronic hepatitis – mild, moderate, or severe inflammation • portal, periportal, bridging fibrosis, or cirrhosis e Risk of hepatocellular carcinoma limited to those with cirrhosis f Associated with: • mixed cryoglobulinemia • cutaneous vasculitis • membranoproliferative glomerulonephritis • porphyria cutanea tarda
Acute viral hepatitis
Treatment Self-limited infection 1 Outpatient care unless persistent vomiting or severe anorexia leads to dehydration 2 Maintenance of adequate caloric and fluid intake • no specific dietary recommendations • a large breakfast may be best-tolerated meal • prohibition of alcohol during acute phase 3 Vigorous or prolonged physical activity should be avoided 4 Limitation of daily activities and rest periods determined by severity of fatigue and malaise 5 No specific drug treatment for hepatitis A, E, D; interferon alfa in acute hepatitis C may reduce risk of chronic infection; role of lamivudine or adefovir in acute hepatitis B uncertain; corticosteroids of no value 6 All nonessential drugs discontinued
Acute liver failure (see Ch. 2) 1 Hospitalization required • as soon as diagnosis made • management best undertaken in a center with a liver transplantation program 2 No specific therapy has proved effective 3 Goals • continuous monitoring and supportive measures while awaiting spontaneous resolution of infection and restoration of hepatic function • early recognition and treatment of life-threatening complications • maintenance of vital functions • preparation for liver transplantation if recovery appears unlikely 4 Survival rates of about 65–75% are achieved by early referral for liver transplantation
Cholestatic hepatitis 1 Course may be shortened by short-term treatment with prednisone or ursodeoxycholic acid, but no clinical trials available 2 Pruritus may be controlled with cholestyramine
Relapsing hepatitis 1 Management identical to that of self-limited infection
Prevention of Enterically Transmitted Infections HAV Immunoprophylaxis is the cornerstone of preventive efforts. 1 Pre-exposure immunoprophylaxis • inactivated HAV vaccine – highly effective (protective efficacy rate 95–100%) – highly immunogenic (nearly 100% in healthy subjects) – protective antibodies induced in 15 days in 85–90% – safe, well tolerated – estimated duration of protection: 20–50 years – injection site soreness is major adverse event
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Prevention blood-borne infections
• inactivated HAV vaccine (HAVRIX and VAQTA) doses and schedules: – Adults 19 years of age or older: two-dose (1440 ELISA Units) regimen of HAVRIX (GlaxoSmithKline), with second dose at 6–12 months after first – Children over 2 years of age: three-dose regimen of HAVRIX (360 ELISA Units), 0, 1, and 6–12 months or two-dose regimen (720 ELISA Units), 0 and 6–12 months – Adults 18 years of age or older: two-dose (50 units) regimen of VAQTA (Merck) with second dose at 6 months after first – Children over 2 years of age: two-dose (25 units) regimen of VAQTA (Merck) with second dose 6–18 months after first • indications for inactivated HAV vaccine – travelers to high-risk areas (for those leaving immediately, immune globulin may be given simultaneously, at a different site, although vaccine alone may be sufficient) – homosexual and bisexual men and adolescents – injecting drug users – native peoples of the Americas and Alaska – children and young adults in communities experiencing community-wide outbreaks – children in regions, counties, states with HAV attack rates above the national average – susceptible patients with chronic liver disease – laboratory workers handling HAV – food-handlers when deemed cost-effective by local health officials – ?staff in day care centers, sewage and waste water treatment workers 2 Post-exposure immunoprophylaxis • efficacy of HAV vaccine in the postexposure setting is not established but is possible (more data needed) • efficacy of immune globulin is well established but imperfect Immune globulin schedule and dose – 0.02 mL/kg body weight, deltoid injection, as early as possible after exposure – well tolerated, injection site soreness – indications: household and intimate contacts of individuals with acute HAV infection
HEV The presence of lgG anti-HEV in contacts of patients with hepatitis E may be protective, but efficacy of immune globulin containing anti-HEV is uncertain. • ?development of high-titer, hyperimmune globulin • HEV vaccine is undergoing clinical trials in endemic areas
Prevention of Blood-borne Infections HBV The cornerstone of immunoprophylaxis is the pre-exposure administration of HBV vaccine. 1 Pre-exposure immunoprophylaxis with HBV vaccine a Recombinant yeast-derived vaccines • contain HBsAg as the immunogen • highly immunogenic, inducing protective levels of anti-HBs in >95% of healthy young (under 40 years of age) recipients after all three doses • 85–95% effective in preventing HBV infection or clinical hepatitis B • principal side-effects
Acute viral hepatitis
– transient pain at injection site in 10–25% – short-lived, mild fever in fewer than 3% • boosters not recommended even as long as 15 years after initial immunization (?may provide lifelong protection) • boosters only for immunocompromised individuals if anti-HBs titer below 10 mU/mL • immunotherapeutic value in the individual with established HBV infection is under study b HBV vaccine doses and schedules: • intramuscular (deltoid) injection of Engerix-B (GlaxoSmithKline) in a dose of 20 μg of HBsAg protein for adults; infants and children through age 19 years receive 10 μg doses; repeated 1 and 6 months later • intramuscular (deltoid) injection of Recombivax HB (Merck) in a dose of 10 μg of HBsAg protein for adults and 5 μg doses for children up to age 19 years; repeated 1 and 6 months later • children between ages 11 and 15 years may receive 10 μg of Recombivax HB initially with a single booster at 4–6 months c Indications • universal infant immunization recommended shortly after birth • catch-up vaccination of adolescents through 19 years of age (if not previously vaccinated) • targeted high-risk groups: – household and spouse contacts of HBV carriers – Alaskan natives, Pacific Islanders – health care and other workers exposed to blood (includes first-responders) – injecting drug users – homosexual and bisexual men – individuals with multiple sexual partners – workers in institutions for the developmentally disadvantaged – recipients of high-risk blood products – maintenance hemodialysis patients – inmates of prisons (in which injecting drug use and homosexual behavior may occur) – individuals with pre-existing liver disease (e.g., chronic hepatitis C) 2 Post-exposure immunoprophylaxis with HBV vaccine and hepatitis B immune globulin (a preparation of immune globulin containing high titers of anti-HBs) a Indications: • susceptible sexual contacts of acutely HBV-infected individuals – 0.04–0.07 mL/kg HBIG as early as possible after exposure – First of three HBV vaccine doses given at another site (deltoid) at the same time or within days – Second and third vaccine doses given 1 and 6 months later • neonates of HBsAg-positive mothers identified during pregnancy – A dose of 0.5 mL of HBIG given within 12 h of birth into the anterolateral muscle of the thigh – HBV vaccine, in doses of 5–10 μg, given within 12 h of birth (at another site in the anterolateral muscle), repeated at 1 and 6 months – protective efficacy exceeds 95%
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Combined vaccine for the prevention of hepatitis A and B
b HDV • neither specific high-titer anti-HDV containing immune globulin nor HDV vaccine is available • immunoprophylaxis is dependent on the prevention of HBV by use of HBV vaccine c HCV • immunoprophylaxis of HCV infection not available, although neutralizing antibodies identified; work on HCV vaccine in progress • anti-HCV screening and nucleic acid testing for HCV RNA of blood and improved donor selection have reduced risk of transfusion-associated hepatitis C dramatically in the USA (<1:2 000 000 units transfused) • safe sexual practice for contacts of HCV-infected individuals may be appropriate
Combined Vaccine for the Prevention of Hepatitis A and B A combination vaccine (Twinrix–GlaxoSmithKline) containing 20 μg of HBsAg protein (Engerix-B) and >720 Elisa Units of inactivated hepatitis A virus (Havrix) provides dual protection with three injections spaced at 0, 1, and 6 months. • Indicated for previously susceptible individuals with risk of both HAV and HBV infections
Further Reading Aggarwal R, Suni D, Sofat S, et al. Duration of viraemia and faecal viral excretion in acute hepatitis E. Lancet 2000; 356:1081–1082. Bower WA, Nainan OV, Han X, Margolis HS. Duration of viremia in hepatitis A infection. J Infect Dis 2000; 182:12–17. CDC. Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR 2001; 50:1–42. Goldstein ST, Alter MJ, Williams IT, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982–1998: implications for vaccination programs. J Infect Dis 2002; 185:713–719. Harpaz R, McMahon BJ, Margolis HS, et al. Elimination of new chronic hepatitis B virus infections: results of the Alaska immunization program. J Infect Dis 2000; 181:413–418. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001; 345:1452–1457. Koff RS. Hepatitis A and E. In: Zakim D, Boyer TD, eds. Hepatology. A Textbook of Liver Disease, 4th edn. Philadelphia: Saunders; 2002:939. Koff RS. Hepatitis A, hepatitis B, and bivalent hepatitis vaccines for immunoprophylaxis: an update. Dig Dis Sciences 2002; 47:1183–1194. Koff RS. Hepatitis vaccines. In: Schiff E, Sorrell M, Maddrey W, eds. Diseases of the Liver, 9th edn. Philadelphia: Lippincott–Raven; 2002:971–983. Mahoney FJ. Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev 1999; 12:351–366. Meyerhoff AS, Jacobs RJ. Transmission of hepatitis A through household contact. J Viral Hepatitis 2001; 8:454–458. Teo E-K, Ostapowicz G, Hussain M, et al. Hepatitis B infection in patients with acute liver failure in the United States. Hepatology 2001; 33:972–976. Thimme R, Oldach D, Chang K-M, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194:1395–1406. Vento S, Garofani T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998; 338:286–290. Vryheid RE, Kane MA, Muller N, et al. Infant and adolescent hepatitis B immunization up to 1999: a global review. Vaccine 2001; 19:1026–1037. Whalley SA, Murray JM, Brown D, et al. Kinetics of acute hepatitis B virus infection in humans. J Exp Med 2001; 193:847–853. Worm HC, Van der Poel WHM, Brandstatter G. Hepatitis E: an overview. Microbes Infect 2002; 4:657–666.
Acute viral hepatitis
Raymond S. Koff,
MD
Key Points 1 Acute viral hepatitis is the most common cause of liver disease in the world; it and its sequelae are responsible for 1–2 million deaths annually. 2 The nonenveloped, enterically transmitted hepatitis viruses (HAV and HEV), in general, are self-limited infections, but severe hepatitis may develop in some cases; the blood-borne hepatitis viruses (HBV, HDV, and HCV) are enveloped agents associated with persistent infection, prolonged viremia, and the development of chronic liver disease and its sequelae. 3 A wide spectrum of clinical illness is well documented, ranging from asymptomatic, anicteric infection to acute liver failure (fulminant hepatitis); with the exception of acute hepatitis C, no specific treatment of acute viral hepatitis is available; liver transplantation is indicated in acute liver failure when recovery seems unlikely. 4 Highly effective and safe vaccines are available for pre-exposure immunoprophylaxis of HAV and HBV infection; for post-exposure immunoprophylaxis of HAV, immune globulin is used, while for post-exposure immunoprophylaxis of HBV both HBIG and HBV vaccine are used. 5 Neither immune globulin preparations nor vaccines are available for the prevention of HEV or HCV. HBV vaccination prevents HDV infection, but for persons with established HBV infection vaccines to prevent HDV superinfection are not available.
Acute Viral Hepatitis: Importance • • • •
worldwide, hepatitis virus infections are the most common cause of liver disease many hepatitis episodes are anicteric, inapparent, or subclinical globally, viral hepatitis is the major cause of persistent viremia with its sequelae, viral hepatitis is responsible for 1–2 million deaths annually
The Agents of Viral Hepatitis The agents of acute viral hepatitis can be broadly classified into two groups: the enterically transmitted and the blood-borne agents.
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The agents of viral hepatitis
Enterically transmitted agents These agents, namely hepatitis A virus (HAV), hepatitis E virus (HEV): – are nonenveloped viruses – survive intact when exposed to bile – are shed in feces – are not linked to chronic liver disease – do not result in a prolonged viremic or intestinal carrier state A third enterically transmitted hepatitis virus may exist 1 HAV • classified as a picornavirus, subclassified as a ‘hepatovirus’ • 27–28 nm in diameter with cubic symmetry • single-stranded, linear RNA molecule, 7.5 kb • one serotype in human beings; three or more genotypes • contains a single immunodominant neutralization site • contains three or four virion polypeptides in capsomere • replication in cytoplasm of infected hepatocyte; no definitive evidence of replication in intestine • propagated in nonhuman primate and human cell lines 2 HEV • tentatively classified in a separate family called hepatitis E-like viruses • 27–34 nm in diameter • linear RNA molecule, 7.2 kb • RNA genome with three overlapping open reading frames encoding structural proteins and nonstructural proteins involved in HEV replication: – RNA-dependent RNA polymerase (RNA replicase) – helicase – cysteine protease – methyltransferase • only one serotype identified in human beings; four to nine main genotypes • immunodominant neutralization site on structural protein encoded by second open reading frame • can be propagated in human embryo lung diploid cells • replication in vivo limited to hepatocytes 3 Other enterically transmitted agents • occasional outbreaks of other enterically transmitted hepatitis, without serologic markers of HAV or HEV
Blood-borne agents These agents, namely hepatitis B virus (HBV), hepatitis D virus (HDV), and hepatitis C virus (HCV), are: – enveloped viruses – disrupted by exposure to bile/detergents – not shed in feces – linked to chronic liver disease – associated with persistent viremia 1 HBV • human-infecting member of hepatotropic DNA-containing viruses, the ‘Hepadnaviridae’
Acute viral hepatitis
• eight genotypes (A through H): ?relationship to severity, response to therapy • 42-nm spherical particle with: – a 27-nm diameter, electron-dense, nucleocapsid core – a 7-nm thick outer lipoprotein envelope • HBV core contains circular, partially double-stranded DNA (3.2 kb in length) and: – DNA polymerase protein with reverse transcriptase activity – hepatitis B core antigen (HBcAg), a structural protein – hepatitis B e antigen (HBeAg), a nonstructural protein that correlates imperfectly with active HBV replication • HBV outer lipoprotein envelope contains: – hepatitis B surface antigen (HBsAg), with three envelope proteins: major, large, and middle proteins – minor lipid and carbohydrate components – HBsAg present in 22-nm spherical or tubular noninfectious particles, in excess of intact HBV particles • one major serotype; many subtypes based on HBsAg protein diversity • HBV mutant viruses are a consequence of poor proof-reading ability of reverse transcriptase or emergence of resistance; these include: – HBeAg-negative precore/core mutant (uncommon in USA) – HBV vaccine-induced escape mutant (rare) – lamivudine-induced YMDD mutant • liver is major but not only site of HBV replication 2 HDV • a defective RNA virus, requiring helper function of HBV for its expression and pathogenicity but not for its replication • only one serotype recognized, three genotypes • 35–37-nm spherical particle, enveloped by HBV lipoprotein coat (HBsAg) – 19-nm core-like structure • contains an antigenic nuclear phosphoprotein (HDV antigen) – binds RNA – exists in two isoforms: smaller 195 amino acid and larger 214 amino acid proteins – smaller HDV antigen transports RNA into the nucleus: essential for HDV replication – larger HDV antigen is prenylated: inhibits HDV RNA replication and participates in HDV assembly • HDV RNA is single stranded, covalently closed, and circular • HDV antigenome is a genome complementary, circular RNA found in infected hepatocyte and, to a lesser extent, in purified HDV particles • with slightly less than 1680 nucleotides, HDV RNA is the smallest RNA genome among the animal viruses; HDV resembles plant satellite viruses • RNA genome can form an unbranched rod-like structure by folding on itself through intramolecular base pairing • replication limited to hepatocyte • cell lines transfected with HDV cDNA constructs express HDV RNA and HDV antigens 3 HCV • a glycoprotein enveloped, single-stranded RNA virus • 55-nm spherical particle; 33-nm nucleocapsid core • classified among the Flaviviridae, in genus termed ‘hepacivirus’ • HCV genome comprises about 9400 nucleotides encoding a large polyprotein of about 3000 amino acid residues
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Epidemiology and risk factors
– one-third of the polyprotein comprises a series of structural proteins (an internal nucleocapsid or core (C) protein and two glycosylated envelope proteins, termed E1 and E2, present in the lipid-containing envelope of the virus) – envelope proteins may generate neutralizing antibodies – a hypervariable region is localized in E2 – remaining two-thirds of the polyprotein consists of nonstructural proteins (termed NS2, NS3, NS4A, NS4B, NS5A, and NS5B) involved in HCV replication; these are a zinc-dependent metalloproteinase in NS2/3, a nucleotide triphosphatase/helicase in NS3, a chymotrypsin-like serine protease in NS3, and RNA-dependent RNA polymerase in NS5B • only one HCV serotype identified; multiple HCV genotypes exist; genotypes are variably distributed throughout the world • genotypes correlated with likelihood of response of chronic infection to antiviral therapy
Epidemiology and Risk Factors HAV 1 Incubation period: 15–50 days (average 30 days) 2 Worldwide distribution; highly endemic in developing countries 3 HAV is excreted in the stools of infected persons for 1–2 weeks before and for at least 1 week after onset of illness 4 Viremia is short lived (usually no longer than 3 weeks); occasionally up to 90 days in protracted or relapsing infection 5 Prolonged fecal excretion (months) reported in infected neonates; frequency, level of virus in stool, and epidemiological importance are uncertain 6 Enteric (fecal-oral) transmission predominantly via person-to-person household spread; occasional outbreaks linked to common-source vehicles: • contaminated food, bivalve mollusks, water 7 Other risk factors include exposure: • in day care centers for infants, diapered children • in institutions for developmentally disadvantaged • via international travel to developing countries • via oral-anal homosexual behavior • via shared equipment by injection drug users 8 No evidence for maternal-neonatal transmission 9 Prevalence correlates with sanitary standards and large household size 10 Transmission via blood transfusion: very rare 11 Overall seroprevalence in USA: 30% and declining
HEV 1 2 3 4 5 6 7 8
Incubation period averages about 40 days Widely distributed; epidemic and endemic forms but rare in USA HEV RNA in serum and stool during acute phase The most common form of sporadic hepatitis in young adults in the developing world Largely water-borne epidemic disease Intrafamilial, secondary cases: uncommon Maternal-neonatal transmission has been documented In the USA imported cases in returning travelers, in recent immigrants from endemic regions; sporadic cases extremely rare
Acute viral hepatitis
9 Prolonged viremia or fecal shedding unusual 10 Zoonosis: swine, other animals
HBV 1 Incubation period ranges from 15 to 180 days (average 60–90 days) 2 HBV viremia lasts for weeks to months after acute infection 3 1–5% of adults, 90% of infected neonates, and 50% of infants develop chronic infection and persistent viremia 4 Persistent infection linked with chronic hepatitis, cirrhosis, hepatocellular carcinoma 5 Worldwide distribution: HBV carrier prevalence <1% in USA, 5–15% in Asia 6 HBV is present in blood, semen, cervicovaginal secretions, saliva, other body fluids 7 Modes of transmission: a Blood-borne • recipients of multiple blood products • injecting drug users • hemodialysis patients • health care and other workers exposed to blood b Sexual transmission c Tissue penetrations (percutaneous) or permucosal transfer • needlestick accidents • re-use of contaminated medical equipment • shared razor-blades • tattoos • acupuncture, body-piercing • shared toothbrushes d Maternal-neonatal, maternal-infant transmission e No evidence for fecal-oral spread
HDV 1 Incubation period is estimated to be 4–7 weeks 2 Endemic in Mediterranean basin, Balkan peninsula, European parts of former Soviet Union, parts of Africa, Middle East, and Amazon basin 3 Declining incidence with increasing use of HBV vaccine 4 Viremia short lived (acute infection) or prolonged (chronic infection) 5 HDV infections occur solely in individuals at risk for HBV infection (coinfections or superinfections) • injecting drug abusers • homosexual or bisexual adolescents and men • recipients of high-risk blood products • sexual partners 6 Modes of transmission a Blood-borne b Sexual transmission c Maternal-neonatal spread
HCV 1 Incubation period ranges from 15 to 160 days (major peak at about 50 days) 2 Prolonged viremia and persistent infection common (55–85%); wide geographic distribution 3 Persistent infection etiologically linked with chronic hepatitis, cirrhosis, hepatocellular carcinoma
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Clinical features
4 Seroprevalence of past/present infection 1.8% in USA; approaches 20% in some communities in Italy, Japan 5 Modes of transmission a Blood-borne (the predominant mode) • injecting drug use and tissue penetrations • recipients of blood/blood products (exceedingly rare in USA with estimated risk now 1:2 000 000 transfused units) b Sexual transmission: low efficiency, low frequency c Maternal-neonatal: low efficiency, low frequency d No evidence of fecal–oral transmission
Pathophysiology 1 Cell-mediated immune mechanisms largely responsible for hepatocyte injury • involves CD8+ and CD4+ T-cell responses • production of cytokines in liver and systemically 2 Direct viral cytopathic effect • postulated in immunosuppressed patients with exceedingly high levels of viral replication, but no direct evidence
Clinical Features Self-limited disease 1 Spectrum of severity ranges from asymptomatic, inapparent infection to fatal acute liver failure 2 Similar clinical syndromes for all agents beginning with nonspecific prodromal constitutional and gastrointestinal symptoms: • malaise, anorexia, nausea, and vomiting • flu-like symptoms of pharyngitis, cough, coryza, photophobia, headache, and myalgias 3 Onset of symptoms tends to be abrupt for HAV and HEV; in the others onset is usually insidious 4 Fever is uncommon except in HAV infection 5 Immune-complex-mediated, serum-sickness-like syndrome in less than 10% of patients with HBV infection; rarely in others 6 Prodromal symptoms abate or disappear with onset of jaundice, although anorexia, malaise, and weakness may persist 7 Jaundice heralded by the appearance of dark urine; pruritus (usually mild and transient) may occur as jaundice increases 8 Physical examination reveals mild enlargement and slight tenderness of the liver 9 Mild splenomegaly and posterior cervical lymphadenopathy in 15–20% of patients
Acute liver failure (see Ch. 2) 1 Characterized by changes in mental status (encephalopathy) • lethargy, drowsiness, coma • reversal of sleep patterns • personality changes 2 Cerebral edema (usually without papilledema) 3 Coagulopathy (prolongation of the prothrombin time) 4 Multiple organ failure • acute respiratory distress syndrome
Acute viral hepatitis
5 6 7 8
• cardiac arrhythmias • hepatorenal syndrome • metabolic acidosis • sepsis • gastrointestinal bleeding • hypotension Development of ascites, anasarca Case fatality rate: about 60% Serial physical examination shows: shrinking liver Extraordinarily high frequency, approaching 10–20%, in pregnant women with hepatitis E, particularly during the third trimester
Cholestatic hepatitis 1 2 3 4 5
Jaundice may be striking and persist for several months prior to complete resolution Pruritus may be prominent Persistent anorexia and diarrhea in a few patients Excellent prognosis for complete resolution Most commonly seen in HAV infection
Relapsing hepatitis 1 Symptoms and liver test abnormalities recur weeks to months after improvement or apparent recovery 2 Most commonly seen in HAV infection – IgM anti-HAV may remain positive, and HAV may once again be shed in stool 3 Arthritis, vasculitis, and cryoglobulinemia may be seen 4 Prognosis is excellent for complete recovery even after multiple relapses (particularly common in children)
Laboratory Features Self-limited disease 1 Most prominent biochemical feature is: marked elevation of serum alanine and aspartate aminotransferase levels (ALT and AST, respectively) 2 Peak aminotransferases (ALT and AST): vary from 500 to 5000 U/L 3 Serum bilirubin level uncommonly above 10 mg/dL, except in cholestatic hepatitis (see later) 4 Serum alkaline phosphatase normal or mildly elevated 5 Prothrombin time normal or increased by 1–3 s 6 Serum albumin normal or minimally depressed 7 Peripheral blood counts: normal or mild leukopenia with or without a relative lymphocytosis
Acute liver failure (see Ch. 2) 1 2 3 4
Striking coagulopathy Leukocytosis, hyponatremia, and hypokalemia common Hypoglycemia Marked elevations of serum bilirubin and aminotransferases, but the latter may decline towards normal despite disease progression.
Cholestatic disease 1 Serum bilirubin levels may exceed 20 mg/dL
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Diagnosis
2 Serum aminotransferase levels may decline toward normal despite cholestasis 3 Variable elevation of serum alkaline phosphatase
Relapsing hepatitis 1 After apparent normalization or near-normalization of serum aminotransferase and bilirubin levels during convalescence, both may rise again 2 Infrequently peak levels may exceed those of initial bout
Histology Liver biopsy is rarely performed in acute self-limited viral hepatitis.
Self-limited disease 1 Major hepatocyte injury • focal hepatocyte necrosis • loss of hepatocytes (cell dropout) • ballooning degeneration • apoptosis with Councilman-like bodies (mummified, hyalinized, necrotic hepatocytes, extruded into a hepatic sinusoid) 2 Endophlebitis, affecting the central vein 3 Diffuse mononuclear cell (CD8+ and natural killer cell) infiltrate • within widened portal tracts • segmental erosion of the limiting plate • within hepatic parenchyma • Kupffer’s cells enlarged, hyperplastic, with lipofuscin pigment and debris; remnants of injured hepatocytes
Acute liver failure 1 2 3 4 5
Liver biopsy usually precluded by coagulopathy Extensive confluent hepatocyte dropout (disappearance) Collapse of reticulin framework Lobular inflammation Variable cholestasis
Cholestatic disease 1 Hepatocyte degeneration, inflammation as in self-limited hepatitis 2 Prominence of bile plugs in dilated hepatocyte canaliculi and bilirubin staining of hepatocytes 3 Hepatocytes form multiple, scattered, duct-like structures (pseudoglandular transformation)
Relapsing hepatitis Changes similar to those in self-limited disease.
Diagnosis Differential diagnosis 1 2 3 4 5
Drug- and toxin-induced liver disease (see Ch. 8) Ischemic hepatitis (see Ch. 20) Autoimmune hepatitis (see Ch. 5) Alcoholic hepatitis (see Ch. 6) Acute biliary tract obstruction (see Ch. 33)
Acute viral hepatitis
Table 3.1: Serologic patterns in the diagnosis of acute viral hepatitis Agent
Acute phase
Convalescence
HAV
Total anti-HAV positive IgM anti-HAV positive
Development of IgG anti-HAV Disappearance of IgM anti-HAV
HEV
IgM anti-HEV positive and/or HEV RNA (in stool) IgG anti-HEV may be present
Loss of HEV RNA; development of IgG anti-HEV Loss of IgM anti-HEV
HBV
HBsAg positive and IgM anti-HBc positive
Loss of HBsAg; later loss of IgM anti-HBc; development of IgG anti-HBc; late development of anti-HBs
HDV
HDV RNA positive or HDV antigen positive or IgM anti-HDV positive in HBsAg-positive patient HDV/HBV coinfection: IgM anti-HBc positive HDV/HBV superinfection: IgG anti-HBc positive
Loss of HDV RNA or antigen; development of IgG anti-HDV or loss of anti-HDV Above plus usual loss of HBsAg Above usually without loss of HBsAg
HCV
Early presence of HCV RNA; presence of or development of anti-HCV
Loss of HCV RNA (in a minor proportion of patients); anti-HCV persistence for decades
Fig. 3.1 Serologic course of HAV
Fecal HAV
IgM anti-HAV
IgG anti-HAV
Titer Jaundice Symptoms ↑ALT HAV in serum
0
4
8
12
16
20
Weeks after exposure
Serologic diagnosis For serologic diagnosis, see Table 3.1. 1 Enterically transmitted infections a HAV (see Fig. 3.1) • IgM antibody to HAV (IgM anti-HAV) is detected during acute phase and for 3–6 months thereafter • presence of positive anti-HAV without IgM anti-HAV indicates past infection
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Diagnosis
b HEV • there are no Food and Drug Administration (FDA)-approved commercial serologic assays available • IgM and IgG antibodies to HEV (anti-HEV) detected early by research assays • IgM anti-HEV may persist for at least 6 weeks after peak of illness • IgG anti-HEV may remain detectable for as long as 20 months 2 Blood-borne infections a HBV (see Fig. 3.2) • serologic diagnosis is established by detection of presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) and HBsAg: – both are usually present at onset of symptoms – IgM anti-HBc is usually preceded by HBsAg – HBsAg is first routinely measured serologic marker of HBV infection to appear – HBsAg may disappear, usually within several weeks to months after appearance, before loss of IgM anti-HBc • HBeAg and HBV DNA: – HBV DNA in serum is first detectable marker of HBV infection but not routinely measured – HBeAg is usually detectable after appearance of HBsAg – both markers disappear after weeks to months in self-limited infection; corresponding antibodies anti-HBs and anti-HBe persist – not necessary for routine diagnosis • IgG anti-HBc: – replaces IgM anti-HBc in resolving infection – indicative of past or continuing infection – not induced by HBV vaccine • antibody to HBsAg (anti-HBs): – last antibody to appear – a neutralizing antibody
Fig. 3.2 Serologic course of HBV
HBeAg
IgG anti-HBc
AntiHBs
Titer
HBeAg
0
4
Jaundice Symptoms ↑ALT Anti-HBe HBV DNA
8 12 16 18 20 24 28 32 36 40 52 Weeks after exposure
IgM antiHBc
Acute viral hepatitis Fig. 3.3 Serologic course of HCV
Serum ALT
Anti-HCV Titer
Symptoms/Jaundice HCV RNA in serum
Normal 0
1
2
3
4
5
6
12
Months after exposure
b •
•
•
• c •
•
– generally indicative of recovery and immunity to reinfection – elicited by HBV vaccine HDV HBsAg-positive individual with: – antibody to HDV (anti-HDV) and/or circulating HDV RNA (assays are unapproved in USA) – IgM anti-HDV may be present transiently HBV/HDV coinfection: – HBsAg positivity – IgM anti-HBc-positive – anti-HDV and/or HDV RNA HDV superinfection of HBV carrier: – HBsAg positivity – IgG anti-HBc positive – anti-HDV and/or HDV RNA anti-HDV titers decline to undetectable levels with resolution of infection HCV (see Fig. 3.3) serologic diagnosis: – detection of antibodies to recombinant HCV antigens (anti-HCV) – third-generation assays include antigens from structural and nonstructural regions – anti-HCV is detected in about 60% of patients during acute phase of illness; anti-HCV appears weeks to months later in about 35% – <5% of infected patients do not develop anti-HCV (a higher percentage of HIV-infected patients do not develop anti-HCV) – assays for IgM anti-HCV under development (not FDA-approved) – anti-HCV generally persists for prolonged periods following acute infection, in both self-limited and chronic HCV infections HCV RNA: – the earliest marker of acute HCV infection – appears within a few weeks of exposure
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Natural history and outcome
– expensive, not routinely used for diagnosis except when HCV suspected in anti-HCV negative individual – present in chronic HCV infection
Natural History and Outcome Enterically transmitted infections (HAV and HEV) 1 Complete clinical, histologic, and biochemical recovery within 3–6 months 2 Occasional instances of acute liver failure • age-dependent fatalities in HAV infection (increased risk after age 40 years) • increased risk in pregnant women with HEV infection • increased risk in those with pre-existing liver disease 3 No chronic liver disease or prolonged carriage of virus
Blood-borne infections (HBV, HDV and HCV) 1 HBV a Risk of persistent infection: age dependent and declines progressively with increasing age: • 90% of infected neonates become carriers • 1–5% of adult patients develop chronic HBV infection b Acute liver failure in <1% of acute infections c Persistent infection (HBsAg positive with or without active HBV replication) • asymptomatic carrier with normal or nonspecific liver histologic changes • chronic hepatitis, cirrhosis, hepatocellular carcinoma • associated with membranous glomerulonephritis, polyarteritis nodosa, and, less certainly, mixed cryoglobulinemia 2 HDV a HDV/HBV coinfections usually self-limited and resolve without sequelae b Acute liver failure more often in HDV superinfection of HBV-infected individuals than in coinfection c HDV superinfection of HBV-infected individuals may lead to chronic HDV infection superimposed on chronic HBV infection with development of severe chronic hepatitis and cirrhosis 3 HCV a Self-limited infections in 15–45% b Very rarely associated with acute liver failure c Persistent HCV infections with prolonged viremia and elevated or fluctuating serum aminotransferase levels are common d Histology in persistent HCV infection • chronic hepatitis – mild, moderate, or severe inflammation • portal, periportal, bridging fibrosis, or cirrhosis e Risk of hepatocellular carcinoma limited to those with cirrhosis f Associated with: • mixed cryoglobulinemia • cutaneous vasculitis • membranoproliferative glomerulonephritis • porphyria cutanea tarda
Acute viral hepatitis
Treatment Self-limited infection 1 Outpatient care unless persistent vomiting or severe anorexia leads to dehydration 2 Maintenance of adequate caloric and fluid intake • no specific dietary recommendations • a large breakfast may be best-tolerated meal • prohibition of alcohol during acute phase 3 Vigorous or prolonged physical activity should be avoided 4 Limitation of daily activities and rest periods determined by severity of fatigue and malaise 5 No specific drug treatment for hepatitis A, E, D; interferon alfa in acute hepatitis C may reduce risk of chronic infection; role of lamivudine or adefovir in acute hepatitis B uncertain; corticosteroids of no value 6 All nonessential drugs discontinued
Acute liver failure (see Ch. 2) 1 Hospitalization required • as soon as diagnosis made • management best undertaken in a center with a liver transplantation program 2 No specific therapy has proved effective 3 Goals • continuous monitoring and supportive measures while awaiting spontaneous resolution of infection and restoration of hepatic function • early recognition and treatment of life-threatening complications • maintenance of vital functions • preparation for liver transplantation if recovery appears unlikely 4 Survival rates of about 65–75% are achieved by early referral for liver transplantation
Cholestatic hepatitis 1 Course may be shortened by short-term treatment with prednisone or ursodeoxycholic acid, but no clinical trials available 2 Pruritus may be controlled with cholestyramine
Relapsing hepatitis 1 Management identical to that of self-limited infection
Prevention of Enterically Transmitted Infections HAV Immunoprophylaxis is the cornerstone of preventive efforts. 1 Pre-exposure immunoprophylaxis • inactivated HAV vaccine – highly effective (protective efficacy rate 95–100%) – highly immunogenic (nearly 100% in healthy subjects) – protective antibodies induced in 15 days in 85–90% – safe, well tolerated – estimated duration of protection: 20–50 years – injection site soreness is major adverse event
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Prevention blood-borne infections
• inactivated HAV vaccine (HAVRIX and VAQTA) doses and schedules: – Adults 19 years of age or older: two-dose (1440 ELISA Units) regimen of HAVRIX (GlaxoSmithKline), with second dose at 6–12 months after first – Children over 2 years of age: three-dose regimen of HAVRIX (360 ELISA Units), 0, 1, and 6–12 months or two-dose regimen (720 ELISA Units), 0 and 6–12 months – Adults 18 years of age or older: two-dose (50 units) regimen of VAQTA (Merck) with second dose at 6 months after first – Children over 2 years of age: two-dose (25 units) regimen of VAQTA (Merck) with second dose 6–18 months after first • indications for inactivated HAV vaccine – travelers to high-risk areas (for those leaving immediately, immune globulin may be given simultaneously, at a different site, although vaccine alone may be sufficient) – homosexual and bisexual men and adolescents – injecting drug users – native peoples of the Americas and Alaska – children and young adults in communities experiencing community-wide outbreaks – children in regions, counties, states with HAV attack rates above the national average – susceptible patients with chronic liver disease – laboratory workers handling HAV – food-handlers when deemed cost-effective by local health officials – ?staff in day care centers, sewage and waste water treatment workers 2 Post-exposure immunoprophylaxis • efficacy of HAV vaccine in the postexposure setting is not established but is possible (more data needed) • efficacy of immune globulin is well established but imperfect Immune globulin schedule and dose – 0.02 mL/kg body weight, deltoid injection, as early as possible after exposure – well tolerated, injection site soreness – indications: household and intimate contacts of individuals with acute HAV infection
HEV The presence of lgG anti-HEV in contacts of patients with hepatitis E may be protective, but efficacy of immune globulin containing anti-HEV is uncertain. • ?development of high-titer, hyperimmune globulin • HEV vaccine is undergoing clinical trials in endemic areas
Prevention of Blood-borne Infections HBV The cornerstone of immunoprophylaxis is the pre-exposure administration of HBV vaccine. 1 Pre-exposure immunoprophylaxis with HBV vaccine a Recombinant yeast-derived vaccines • contain HBsAg as the immunogen • highly immunogenic, inducing protective levels of anti-HBs in >95% of healthy young (under 40 years of age) recipients after all three doses • 85–95% effective in preventing HBV infection or clinical hepatitis B • principal side-effects
Acute viral hepatitis
– transient pain at injection site in 10–25% – short-lived, mild fever in fewer than 3% • boosters not recommended even as long as 15 years after initial immunization (?may provide lifelong protection) • boosters only for immunocompromised individuals if anti-HBs titer below 10 mU/mL • immunotherapeutic value in the individual with established HBV infection is under study b HBV vaccine doses and schedules: • intramuscular (deltoid) injection of Engerix-B (GlaxoSmithKline) in a dose of 20 μg of HBsAg protein for adults; infants and children through age 19 years receive 10 μg doses; repeated 1 and 6 months later • intramuscular (deltoid) injection of Recombivax HB (Merck) in a dose of 10 μg of HBsAg protein for adults and 5 μg doses for children up to age 19 years; repeated 1 and 6 months later • children between ages 11 and 15 years may receive 10 μg of Recombivax HB initially with a single booster at 4–6 months c Indications • universal infant immunization recommended shortly after birth • catch-up vaccination of adolescents through 19 years of age (if not previously vaccinated) • targeted high-risk groups: – household and spouse contacts of HBV carriers – Alaskan natives, Pacific Islanders – health care and other workers exposed to blood (includes first-responders) – injecting drug users – homosexual and bisexual men – individuals with multiple sexual partners – workers in institutions for the developmentally disadvantaged – recipients of high-risk blood products – maintenance hemodialysis patients – inmates of prisons (in which injecting drug use and homosexual behavior may occur) – individuals with pre-existing liver disease (e.g., chronic hepatitis C) 2 Post-exposure immunoprophylaxis with HBV vaccine and hepatitis B immune globulin (a preparation of immune globulin containing high titers of anti-HBs) a Indications: • susceptible sexual contacts of acutely HBV-infected individuals – 0.04–0.07 mL/kg HBIG as early as possible after exposure – First of three HBV vaccine doses given at another site (deltoid) at the same time or within days – Second and third vaccine doses given 1 and 6 months later • neonates of HBsAg-positive mothers identified during pregnancy – A dose of 0.5 mL of HBIG given within 12 h of birth into the anterolateral muscle of the thigh – HBV vaccine, in doses of 5–10 μg, given within 12 h of birth (at another site in the anterolateral muscle), repeated at 1 and 6 months – protective efficacy exceeds 95%
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Combined vaccine for the prevention of hepatitis A and B
b HDV • neither specific high-titer anti-HDV containing immune globulin nor HDV vaccine is available • immunoprophylaxis is dependent on the prevention of HBV by use of HBV vaccine c HCV • immunoprophylaxis of HCV infection not available, although neutralizing antibodies identified; work on HCV vaccine in progress • anti-HCV screening and nucleic acid testing for HCV RNA of blood and improved donor selection have reduced risk of transfusion-associated hepatitis C dramatically in the USA (<1:2 000 000 units transfused) • safe sexual practice for contacts of HCV-infected individuals may be appropriate
Combined Vaccine for the Prevention of Hepatitis A and B A combination vaccine (Twinrix–GlaxoSmithKline) containing 20 μg of HBsAg protein (Engerix-B) and >720 Elisa Units of inactivated hepatitis A virus (Havrix) provides dual protection with three injections spaced at 0, 1, and 6 months. • Indicated for previously susceptible individuals with risk of both HAV and HBV infections
Further Reading Aggarwal R, Suni D, Sofat S, et al. Duration of viraemia and faecal viral excretion in acute hepatitis E. Lancet 2000; 356:1081–1082. Bower WA, Nainan OV, Han X, Margolis HS. Duration of viremia in hepatitis A infection. J Infect Dis 2000; 182:12–17. CDC. Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR 2001; 50:1–42. Goldstein ST, Alter MJ, Williams IT, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982–1998: implications for vaccination programs. J Infect Dis 2002; 185:713–719. Harpaz R, McMahon BJ, Margolis HS, et al. Elimination of new chronic hepatitis B virus infections: results of the Alaska immunization program. J Infect Dis 2000; 181:413–418. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001; 345:1452–1457. Koff RS. Hepatitis A and E. In: Zakim D, Boyer TD, eds. Hepatology. A Textbook of Liver Disease, 4th edn. Philadelphia: Saunders; 2002:939. Koff RS. Hepatitis A, hepatitis B, and bivalent hepatitis vaccines for immunoprophylaxis: an update. Dig Dis Sciences 2002; 47:1183–1194. Koff RS. Hepatitis vaccines. In: Schiff E, Sorrell M, Maddrey W, eds. Diseases of the Liver, 9th edn. Philadelphia: Lippincott–Raven; 2002:971–983. Mahoney FJ. Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev 1999; 12:351–366. Meyerhoff AS, Jacobs RJ. Transmission of hepatitis A through household contact. J Viral Hepatitis 2001; 8:454–458. Teo E-K, Ostapowicz G, Hussain M, et al. Hepatitis B infection in patients with acute liver failure in the United States. Hepatology 2001; 33:972–976. Thimme R, Oldach D, Chang K-M, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194:1395–1406. Vento S, Garofani T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998; 338:286–290. Vryheid RE, Kane MA, Muller N, et al. Infant and adolescent hepatitis B immunization up to 1999: a global review. Vaccine 2001; 19:1026–1037. Whalley SA, Murray JM, Brown D, et al. Kinetics of acute hepatitis B virus infection in humans. J Exp Med 2001; 193:847–853. Worm HC, Van der Poel WHM, Brandstatter G. Hepatitis E: an overview. Microbes Infect 2002; 4:657–666.