115

SECTION N HEPATITIS

Acute Viral Hepatitis

MICHAEL P. CURRY | SANJIV CHOPRA 1983 by immune electron microscopy in his feces after he infected himself with fecal material of a person suspected of having enterically transmitted NANB hepatitis, and the virus was named hepatitis E in 1988.22 The virus was subsequently cloned in 1990, and diagnostic tests were available the following year.23

Historical Perspective
Hippocrates rst described the existence of epidemic jaundice as early as 400 bc. Further outbreaks of jaundice were documented in Europe in the 17th and 18th centuries, notably during periods of conict. From then until World War II, the existence of viruses as the major cause of liver disease was unknown. The distinction between infectious and serum hepatitis by Krugman and colleagues in 1967 and the discovery of the Australia antigen by Blumberg and co-workers later that year were landmark events that led to a major increase in our knowledge of viral hepatitis.1,2 Epidemics of infectious hepatitis acquired from contaminated food and water were linked to hepatitis A virus (HAV) infection. In 1973, Feinstone and associates detected HAV in stool utilizing the technique of immune electron microscopy.3 Subsequently, HAV was identied as a 27-nm particle resembling an enterovirus, transmission of the infection to marmosets and chimpanzees was recorded, and specic complement xation and immune adherence antibody tests were developed.4-6 The use of the serologic marker, the Australia antigen, provided a means of characterizing the epidemiology of hepatitis B virus (HBV) infection.2,7,8 Further developments included the identication of the virus as a 42-nm particle (Dane particle) containing an outer coat, the hepatitis B surface antigen (HBsAg), and an inner core, the hepatitis B core antigen; the development of specic tests to detect the hepatitis B antigens and their respective antibodies9-11; the transmission of the infection to chimpanzees; and the development of a specic hepatitis B immune serum globulin.12,13 In 1975, Krugman produced a crude vaccine for HBV infection by boiling the serum of a patient with HBV and was able to prevent transmission of hepatitis B in human subjects.14 Subsequently, a new antigen found in liver specimens from some patients with HBV infection led to the identication of the delta virus or hepatitis D virus (HDV) in 1977.15 HDV was seen in only a fraction of patients with HBV and was often associated with a more severe or fulminant course of disease. Recognition of an infectious agent distinct from that resulting in hepatitis A or B was now possible, and it became apparent that there existed another or other agents responsible for what was termed non-A, non-B (NANB) hepatitis. In 1974, Prince and colleagues and Feinstone and co-workers independently observed that some cases of post-transfusion hepatitis were not caused by HAV or HBV.16,17 The development of rened hepatitis B vaccines can be considered one of the major achievements of modern medicine. The initial use of rst-generation vaccines derived from plasma HBsAg and subsequent use of recombinant HBV vaccines have resulted in the reduction of HBV carrier rates. Furthermore, the introduction of universal HBV vaccination in Taiwan has resulted in a 75% reduction in the incidence of HBV-related childhood hepatocellular carcinoma, and, hence, the hepatitis B vaccine can truly be called the rst anticancer vaccine.18 In 1978, Alter and colleagues demonstrated the potential for transmission of infection by inoculating chimpanzees with plasma from individuals with NANB hepatitis.19 Further advances in molecular biology led to the development of tests specic for hepatitis C virus (HCV) by Houghton and colleagues in 1989, and testing of large repositories of stored blood demonstrated that HCV was indeed the subsequent cause of NANB hepatitis.20 The existence of another enterically transmitted virus was suspected in 1980 when sera from people affected by a large waterborne epidemic in Delhi in 1955 were found to lack serologic markers for HAV and HBV infection.21 Viral particles were recognized by Mikhail Balayan in

Background
The hepatotropic viruses are a group of diverse pathogens that share a common ability to cause inammation and necrosis of the liver. The term viral hepatitis generally refers to disease caused by the ve well-described hepatotropic viruses, which are divided into enteral and parenteral groups on the basis of their mode of transmission. HAV and hepatitis E virus (HEV) are enterically transmitted by the fecaloral route. HAV does not exist in a chronic carrier state. HEV is normally thought to cause only acute hepatitis; however, some reports have documented cases of chronic HEV in immunocompromised solid organ transplant recipients (Table 115-1). Hepatitis B, C, and D viruses are parenterally transmitted, occur in both acute and chronic forms, and, when they persist in a chronic carrier state, serve as a reservoir for infection. They have the potential to cause chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Other viruses that can cause hepatic inammation include Epstein-Barr virus (EBV); herpes simplex virus (HSV); mumps, rubella, rubeola, varicella-zoster virus; yellow fever virus; coxsackie B virus, and adenovirus. Although these agents can cause diagnostic confusion by producing liver inammation and dysfunction, they are not primary causes of acute or chronic viral hepatitis. Novel technologies have further identied other viruses that were initially thought to cause post-transfusion hepatitis, namely, hepatitis G virus (HGV) or GB virus C (GBV-C) and the transfusion-transmitted virus (TTV), and SEN viruses, but these are not currently believed to be human pathogens. A small number of patients may present with a viral hepatitis-like syndrome without serologic evidence of viral infection. In these seronegative cases, other etiologies including autoimmune hepatitis, drug-induced hepatitis, vascular disease, or viruses not yet identied must be considered in the diagnosis. Acute viral hepatitis infection is a global public health concern associated with substantial morbidity and mortality. In the United States, the incidence of acute HAV, HBV, and HCV declined dramatically between 1995 and 2006. New cases of HAV and HBV are at the lowest levels ever recorded since the U.S. government began collecting data more than 40 years ago. The incidence of acute HAV infection declined 90% between 1995 and 2006 (1.2 cases per 100,000 population). The greatest decline in new infections was seen in children and reects the practice of routine vaccination of children that began in 1999. Similarly during the same time period, there was a signicant decline (81%) in the number of cases of acute HBV infection to the lowest level ever recorded of 1.6 cases per 100,000 population. Again, the greatest decline was seen in children younger than age 15 years, and this reects the universal vaccination at childbirth. The incidence of acute HCV infection also declined through the 1990s until 2003. This decline was attributable to the decrease in incidence among injection drug users, likely reecting changes in behavior and practices. However, since 2003, acute HCV infection rates have plateaued, and, indeed, there was a slight increase in reported cases in 2006 in injection drug users (Table 115-2).24 As a result of acute infection with these viruses, approximately 285 deaths from fulminant hepatitis occur annually100 from hepatitis A, 150 from hepatitis B, and 35 from HBV-HDV coinfection

1577

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115-1

TABLE

Hepatitis Type and Characteristics of Infection A Picornaviridae RNA 15-50 Yes Yes Rare No No B Hepadnaviridae DNA 28-160 Possible Yes Yes Yes Yes C Flaviviridae RNA 14-160 No Rare Yes Yes Yes D Deltaviridae RNA Variable No Yes Yes Yes With HBV E Caliciviridae RNA 15-45 Yes No No No No

Characteristic Virus family Nucleic acid Incubation period (days) Mode of transmission Orofecal Sexual Blood Chronic infection Cirrhosis and HCC

HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

or superinfection. The number of acute infections for HAV, HBV, and HCV likely represent underestimates of the true number of acute infections. The estimated actual number of new infections reported by the Centers for Disease Control and Prevention (CDC) for 2006 was 32,000 for HAV, 46,000 for HBV, and 19,000 for HCV (Figs. 115-1 and 115-2 and Table 115-2). The difference between the number of cases reported to the National Notiable Disease Surveillance System (NNDSS) and the actual number of cases estimated to have occurred by the CDC is largely due to underreporting of cases, incomplete reporting of cases, and nonreporting of asymptomatic cases of acute viral hepatitis. The estimated data on actual number of acute infections are believed to be accurate because studies have estimated that for each case of acute hepatitis reported to the NNDSS, two to ve cases are not reported; available evidence suggests that no systematic changes have occurred in reporting patterns since 1990; and, lastly, the national trends that document the decline in acute viral hepatitis are mirrored in the CDCs Sentinel Counties Study of Acute Viral Hepatitis, in which the accuracy and completeness of reporting were assessed. VIRUSES BEYOND A TO E Approximately 15% to 17% of hepatitis infections remain unexplained. Acute hepatitis and chronic hepatitis occur sporadically, after transfusion and in organ transplant recipients. Some such cases result in the development of fulminant liver failure. The causative agents for non-A to E hepatitis continue to be sought. Candidate viruses include hepatitis F virus (HFV), HGV, TTV, and SEN virus. HFV was initially identied as a putative hepatitis virus spread by the fecal-oral route; however, there is insufcient evidence to corroborate this, and the identity of HFV is in doubt.25 Two viral agents related to hepatitis have been identied and designated. HGV is also known as hepatitis-GB virus (HGBV) (so named after the initials of the patient from whom the virus was isolated). There is considerable homology between HGV and HGBV. Three different viruses were isolated and designated GBV-A, GBV-B, and GBV-C. The role of HGV and GBV-C in human disease, if any, remains unestablished.

16 14 12 10 8 6 4 2 0

Incidence (per 100,000) of acute HAV infection per year United States (19822006)

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006

A
14 12 10 8 6 4 2

Year Incidence (per 100,000) of acute HBV infection per year United States (19822006)

115-2

TABLE

Estimated Disease Burden of Viral Hepatitis in the United States, 2006 HAV 3,579 1.2 32,000 HBV 4,713 1.6 46,000 HCV 802 0.3 19,000

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006

Year

Characteristic Number of reported acute infections Rate of reported cases (per 100,000 population) Actual number of acute infections

HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus.

Figure 115-1 Incidence of acute hepatitis A virus (HAV) and hepatitis B virus (HBV) infection in the United States from 1982 to 2006. (From Wasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitisUnited States, 2006. MMWR Surveill Summ. 2008: 57[SS02]:1-24.)

115 Acute Viral Hepatitis

1579

2.5 2.0 1.5 1.0 0.5 0

Incidence (per 100,000) of acute HCV infection per year United States (19922006)

1992

1994

1996

1998

2000

2002

2004

2006

Year Figure 115-2 Estimated number of cases of acute hepatitis C virus (HCV) from 1992 to 2006. Cases of hepatitis C reported to the National Notiable Disease Surveillance System are unreliable for monitoring trends because these reports include cases based only on a positive laboratory test for anti-HCV; most positive tests are likely to represent chronic HCV infection. (From Wasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitisUnited States, 2006. MMWR Surveill Summ. 2008:57[SS02]:1-24.)

SPECTRUM OF CLINICAL DISEASE Acute viral hepatitis may be asymptomatic, marked only by a rise in aminotransaminase levels; symptomatic with or without jaundice; subfulminant; or fulminant. Asymptomatic infections are 10 to 30 times more common than symptomatic infections. In addition, there are several different types of illness associated with HAV infection, including protracted or cholestatic and relapsing HAV infection. Asymptomatic hepatitis is recognized by the detection of a rise in liver function tests and the detection of serologic markers of viral infections in an individual often being evaluated for nonspecic constitutional symptoms. Acute asymptomatic infection may also occur with only a minimal rise in liver function tests, as is the case in neonatal HBV infection, in which there appears to be tolerance to the infection. In general, the younger the patient, the milder the clinical form of hepatitis. Asymptomatic HBV infections are detected in 90% of Eskimo children younger than 4 years but are found in only two thirds of adults older than 30 years. The case-fatality rate with acute HAV infection is also directly proportional to the age of the infected individual. The overall case-fatality ratio among cases of acute HAV reported to the NNDSS is 0.3% to 0.6% but increases to 1.8% among adults older than 50 years.26 Clinical features of acute symptomatic viral hepatitis are common to all forms of viral hepatitis. There are no clinical features that unequivocally distinguish the individual types of hepatitis from each other; however, there are certain epidemiologic patterns of transmission that may suggest a particular virus. The illness of acute viral hepatitis can be divided into the following broad categories: the incubation period, the preicteric phase, the icteric phase, and the convalescent phase. The incubation period is the time immediately after acquisition of infection to the time of rst symptoms and varies from a few weeks to as long as 6 months, depending on the type of the viral infection. During this time, the patient is well and without symptoms. The earliest symptoms are nonspecic and predominantly constitutional. Symptoms include malaise, joint pain, myalgia, fatigue, anorexia, nausea and vomiting, and abdominal or right upper quadrant discomfort. Approximately 25% of patients describe their initial symptoms as an inuenza-like illness. The symptoms of pharyngitis,

cough, coryza, and photophobia generally last only 1 to 3 days and are replaced by the more typical symptoms of malaise and anorexia. Malaise is the most common symptom, occurring in 95% of those with symptomatic disease; it is sometimes profound and may increase later in the day. Anorexia is common but is typically one of the rst symptoms to resolve. Patients may give a history of distaste for alcohol and tobacco smoke; however, this dysgeusia is not specic for viral hepatitis and is sometimes seen with other forms of acute hepatitis. Nausea and vomiting are common, are rarely severe, and can increase in severity as the day continues. Abdominal discomfort is experienced by 60% of patients with symptomatic disease. HAV infection is generally associated with an abrupt onset of illness and fever.27,28 High temperature and rigors should prompt the physician to look for other causes of liver dysfunction such as cholangitis. Aseptic meningitis and meningoencephalomyelitis are rare complications of acute viral hepatitis.29 These prodromal symptoms usually last a few days but can persist for 2 or 3 weeks. In the absence of jaundice, these symptoms may be passed off as an inuenza-like illness unless a specic exposure or risk is elicited in the history. Jaundice may occur with varying severity and last from a few days to several weeks. It is usually preceded by dark urine reecting bilirubinuria caused by the rising concentrations of conjugated serum bilirubin. Jaundice is rst noted in the sclera and is usually accompanied by pale stool, reecting the absence of bile pigment in the stool. Pruritus, which is reported by 40% of jaundiced patients, is usually mild and transient unless a cholestatic illness is present, as is sometimes the case with HAV infection. At this stage, the low-grade fever may abate. However, anorexia, malaise, and weakness may persist. Complete clinical recovery may take up to 6 months after the onset of symptoms, and fatigue and weakness can persist for some weeks after apparent biochemical recovery. A small percentage of patients develop a serum sickness-like illness characterized by fever, urticarial skin rash, and arthritis. These signs, which usually occur at the onset of the illness, are thought to be due to circulating immune complexes and are most common with acute HBV infection.30 HBV infection in childhood can be associated with a nonrelapsing, nonitching erythematous papular dermatitis involving the face, arms, buttocks, and legs, with enlarged lymph nodes in the axillary and inguinal regions. This is known as Gianotti-Crosti syndrome.31,32 This presentation is not exclusively caused by HBV infection and can also occur after infection and reactivation of EBV.33,34 Relapsing or biphasic hepatitis has been described with HAV infection. The rate of relapse of HAV varies from 1.5% to 11.9%. It occurs at an interval of 4 to 15 weeks after the original illness, and the severity of symptoms and biochemical abnormalities is generally similar to that seen with the initial illness. Rarely, more severe cholestasis is seen with the second episode.35 One or more relapses may occur. Of note, there is no association between the severity of the initial illness and the development of a relapse. Occasionally, immune-mediated phenomena such as arthritis or cryoglobulinemia occur during a relapse. HAV does not cause chronic liver disease, and liver function tests invariably return to normal within 12 months. Cholestatic variants of viral hepatitis have also been described. In acute HAV infection, a protracted cholestatic course of HAV infection with pruritus occurs in 8% of cases. This was rst described in 1984 after the advent of diagnostic testing.36 Severe pruritus, diarrhea, weight loss, and malabsorption may accompany the cholestasis. The pathogenic mechanisms underlying cholestatic hepatitis A are unknown. However, prolonged viral shedding has been noted in patients with persistent elevation of alanine aminotransaminase (ALT), indicating that the enterohepatic cycling of HAV may contribute to relapsing or protracted infection. These patients must be considered potentially infectious. As with relapsing HAV infection, all patients recover completely. Fibrosing cholestatic hepatitis (FCH) is another cholestatic liver injury associated with viral hepatitis. It usually arises acutely in immunosuppressed individuals with chronic viral infection. In 1991, Davies

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and coauthors described a rapidly progressive and fatal form of recurrent HBV infection occurring in patients undergoing liver transplantation for HBV infection without prophylaxis for reinfection.37 It is characterized by balloon degeneration of hepatocytes, mild or absent inammation, sinusoidal brosis, and cholestasis. Subsequently, others have demonstrated prominent expression of HBsAg, enhanced HBV transcription, and high levels of HBV DNA. Similar forms of disease have been reported with HCV in both organ transplant recipients and human immunodeciency virus (HIV)-infected patients.38,39 Unlike cholestatic HAV infection, FCH caused by HBV or HCV leads to liver failure and death unless successful antiviral therapy is instituted. Fulminant hepatic failure, dened as severe liver failure that develops within 8 weeks of the onset of symptoms, is the most serious manifestation of viral hepatitis. It is fortunately a rare complication that occurs in only 0.14% to 0.35% of hospitalized cases of HAV infection.40,41 Because the hospitalized cases of HAV infection are only a proportion of all cases of HAV infection, the true prevalence of HAV fulminant hepatic failure is considerably lower. The incidence of fulminant hepatic failure in acute HBV infection is 1% to 4% of hospitalized patients, and the risk increases when there is associated HDV infection.42 The presence of HBsAg in the blood at the time of presentation does not necessarily implicate HBV as the cause. The risk of acute liver failure as a consequence of acute hepatitis C appears to be very low, but it may be more common in patients with underlying chronic HBV infection.43 Reports from Japan suggest a higher incidence, but the high rate of positivity in this population may reect chronic exposure rather than causality. However, the risk of acute liver failure in patients with HCV who become superinfected with HAV is not insignicant. Vento and co-workers prospectively observed patients with chronic HBV and HCV for acute superimposed HAV infection and found that acute liver failure occurred more frequently in patients with chronic HCV infection than in patients with chronic HBV.44 Cases such as these have led the National Institutes of Health to recommend that all nonimmune patients with chronic HCV be vaccinated against HAV and HBV. The CDC has made the same recommendation for hepatitis A but is somewhat guarded about vaccination against hepatitis B unless risk factors for HBV infection are present.45 Acute liver failure secondary to HEV infection varies from 0.6% to 2.8% in men to 20% in pregnant women.46,47 Because HEV infection is common in areas of Asia and Africa, a history of recent travel may be helpful in considering the diagnosis. No evidence has emerged to implicate hepatitis F or G as a causative agent in fulminant hepatic failure. The term fulminant hepatic failure was introduced in the 1960s to dene a disease that is characterized by severe sudden liver cell dysfunction leading to coagulopathy and hepatic encephalopathy in people with no underlying liver disease. It was dened as fulminant hepatic failure when severe liver failure (dened as the presence of encephalopathy) developed within 8 weeks of the onset of symptoms.40 Subsequently, nomenclature was proposed to achieve closer alignment with outcome. The term acute liver failure is used to describe the onset of encephalopathy within 12 weeks of the onset of jaundice. Hyperacute refers to the development within 7 days, and subacute refers to an onset between 5 and 12 weeks.41 The denition excludes patients with preexisting liver disease but allows the inclusion of subclinical disease related to Wilsons disease and some patients with hepatitis B-related liver failure. There are considerable geographic variations in the etiology of acute liver failure. The most common causes in Japan and Asia are related to viral hepatitis. Hepatitis E is the leading cause in India, and HBV infections are the leading cause in France and Japan. Drug-induced (acetaminophen toxicity) fulminant hepatic failure is most common in the United Kingdom and has become the leading cause of liver failure in the United States.48 Viral hepatitis was identied in only 12% of cases. HBV and HAV infections accounted for 7% and 4%, respectively, in a multicenter study reported by Lee and colleagues.49,50

PHYSICAL FINDINGS The physical ndings in acute viral hepatitis are generally nonspecic and are not helpful in differentiating one type from another. Vital signs are usually normal. However, low-grade fever is usually present. Bradycardia, a feature of obstructive jaundice, can occur in acute viral hepatitis if the patient is signicantly icteric. The bradycardia correlates with the level of serum bilirubin and is attributed to the effects of bile salts on the sinoatrial node. Jaundice is more common in adults than children. Pruritus associated with jaundice may lead to excoriations. Features such as spider angiomas are rarely seen in acute liver disease. Urticaria and dermatographism may be seen in patients with an underlying immunemediated phenomenon. Lymphadenopathy is found in 5%, splenomegaly in approximately 15%, and hepatomegaly in 85% of patients with acute viral hepatitis.28 Features such as pharyngitis or conjunctival suffusions may provide clues to a specic diagnosis of EBV or leptospirosis. HISTOPATHOLOGY A liver biopsy is not indicated in patients with acute, self-limited hepatitis. In difcult cases, such as those with protracted or cholestatic disease, liver biopsy may be helpful in establishing the diagnosis, differentiating it from other etiologies, and aiding therapeutic decisions. In cases of fulminant liver failure, liver biopsy is seldom indicated and is often precluded by coagulopathy and thrombocytopenia. The degree of hepatocyte necrosis seen on liver biopsy is not associated with either the need for liver transplantation or mortality. The absence of a specic diagnosis does not preclude the performance of liver transplantation in such cases. The typical histologic ndings in acute viral hepatitis include lobular disarray, apoptosis of hepatocytes, mononuclear cell inltration of the portal and periportal areas, and cholestasis. Hepatocellular changes range from minor degrees of cell swelling characterized by granular cytoplasm to severe ballooning degeneration and cell death. Hepatocyte nuclei show prominent nucleoli and increased variation in size. Apoptosis, which is thought to be the predominant method of cell death caused by hepatotropic viruses, is evident by shrinking of hepatocytes and the presence of eosinophilic material. Apoptotic bodies may also contain pyknotic nuclear remnants. Hepatocyte loss, liver cell dropout, and anisocytosis coupled with regeneration of hepatocytes result in loss of the orderly pattern of hepatic sinusoidal cords and disarray of the lobule. Cholestasis in the form of bile thrombi in the canaliculi generally correlates with the serum bilirubin level. It is common in acute hepatitis but rare in chronic hepatitis and therefore is of some diagnostic importance. The bile ducts are normal in appearance. Unlike the ndings in classic acute inammation, the inammatory components of acute viral hepatitis are characterized predominantly by inltration of lymphocytes rather than polymorphonuclear inammatory cells. These lymphocytes are seen in the lobule and the portal tracts. In acute hepatitis, the most conspicuous inammation is seen in zone 3 of the hepatic acinus. The extent of the inammation is variable, and portal tracts may be normal or expanded. Inammatory cells in the lobule give the appearance of spotty necrosis and consist of T cells and macrophages. More extensive necrosis between the terminal venule and the portal tract is called bridging necrosis and is a severe manifestation of acute hepatitis. In a minority of patients with acute hepatitis, the necrosis extends throughout the entire lobule or acinus and is referred to as panacinar necrosis. In these cases, the hepatic parenchyma is replaced by collapsed stroma, inammatory cells, and activated macrophages. Around the surviving portal tracts there is proliferation of bile ducts as a regenerative response. The hepatitic process may also involve the hepatic sinusoids and central vein. Swelling of the sinusoidal endothelial cells and disruption of the terminal venular cells by lymphocytic inltration are not uncommon. In contrast to chronic hepatitis, the inammatory changes

115 Acute Viral Hepatitis

1581

in the hepatic lobule usually predominate over those in the portal areas, but portal inammation is nevertheless present. The density of the inammatory inltrate is variable. With the advent of specic serologic and molecular tests for infectious agents, liver biopsy is neither necessary nor able to differentiate the likely viral agents. However, it may help in suggesting a diagnosis of autoimmune hepatitis or establishing a diagnosis of Wilsons disease.

Hepatitis A
HAV is the most common cause of viral hepatitis worldwide, and it is one of the most frequently reported notiable diseases in the United States (see also Chapter 173).24 It is a member of the picornavirus family and is an icosahedral particle 27 to 32 nm in diameter. Only one serotype exists, but multiple genotypes have been dened on the basis of sequence comparisons. These distinct genotypes can be found in different geographic regions, and six (formerly seven) HAV genotypes have been identied worldwide, including three human genotypes (I, II, and III ) and three simian strains (IV, V, and VI). The three human genotypes have a nucleotide sequence variation of 15% to 25%.51,52 However, they are antigenically closely related, do not appear to have biologically signicant differences, and infection with one genotype confers immunity to other strains. The HAV genome is a single-stranded, positive-sense, linear RNA approximately 7.5 kb in length. It encodes one open reading frame (ORF) that produces a polyprotein 2235 amino acid residues long. The polyprotein is divided into three main functional domains: P1, P2, and P3. P1 encodes the viral capsid proteins, and P2 and P3 encode the nonstructural proteins including the RNA helicase, protease, and RNA polymerase. The viral capsid comprises 32 subunits, each of which has four major polypeptides termed VP1 to VP4. The polyprotein is anked at either end by 5 and 3 untranslated regions (UTRs). The 5 UTR is the most conserved and contains an internal ribosomal entry site for initiation of protein synthesis. Fewer nucleotide substitutions in the 5 UTR have been reported in cases of fulminant and severe hepatitis compared with self-limiting hepatitis.53 HAV infection is spread predominantly by direct person-to-person contact by the orofecal route or by the ingestion of contaminated food or water.54 In 2006, 65% of the cases reported to the CDC had no identiable risk factor. In cases with known risk factors, the most frequent was international travel (15%). Seventy-two percent of these individuals reported travel to Mexico and Central/South America (Table 115-3).24 It is highly contagious, with a secondary attack rate of 15% to 20%, and it spreads rapidly between individuals in prolonged close contact, in schools, institutions, and army camps. Sexual and household contact of an individual with acute HAV is among the most frequently identied risk factors (see Table 115-3). Because the majority of children have asymptomatic or unrecognized infections, they play a key role in HAV transmission and serve as a source of infection for others. In studies of adults without an identied source of infection, 52% lived in a house with a child younger than 6 years of age,

and 25% to 40% of contacts younger than 6 years of age had serologic evidence of acute HAV infection.55,56 Infection may also occur by consumption of contaminated ice water or by ingestion of uncooked or undercooked foods that have been washed in contaminated water. Waterborne outbreaks are infrequent in developed countries. Raw shellsh are a particularly common source of infection. Higher sero prevalence rates of HAV infection are seen in men who have sex with men (MSM), and in recent years the proportion of cases reported among MSM has increased from 3% to 9%.24,57 Sexual transmission through seminal or vaginal secretions does not appear to be signicant. Transmission through blood products is possible, as documented in hemophiliacs who receive products from pooled donors.58-60 Blood transfusion is rarely associated with transmission.61 In addition, intravenous drug users are at higher risk for acquiring HAV infection. Improvements in sanitation and hygiene have resulted in a reduction in the rate of childhood exposure in Sweden and Hong Kong. HAV is a worldwide virus but is highly endemic in developing countries. Patterns of endemicity have been identied as low, medium, and high. In areas of high endemicity, such as Asia, India, the Far East, and areas of South America, infection is almost universal in early childhood and results in a high level of immunity among adults. Within the United States, there is a different epidemiology of HAV infection. The overall seropositivity is 38% and ranges from 11% in children younger than 5 years to 74% in people older than 50 years. There is considerable variation over time and with geographic location and ethnicity in the United States (Fig. 115-3). Historically, the highest rates of infection were reported in the western regions; however, the incidence in the west has declined substantially since the recommendation for widespread routine childhood vaccination such that the rates in the west are approximately equal to those in other regions in the United States. Similarly, the rates of HAV infection have differed by race and ethnicity, with the highest rates having occurred in Native Americans/ Alaska Natives and the lowest rates among Asians/Pacic Islanders. Hispanics have also consistently had higher rates of infection than non-Hispanics. With the widespread use of vaccine, rates of infection in Native Americans/Alaska Natives have declined to levels lower than those for any other race, and although the rates of infection have similarly declined for Hispanics since 1997, they remain higher than those for non-Hispanics.24 HAV has an incubation period of 15 to 50 days, with a mean period of 30 days. It is excreted in the stools of infected people for 1 or 2 weeks before and for at least 1 week after the onset of illness. After ingestion, the virus passes through the gastrointestinal mucosa and reaches the

130 120 Rate per 100,000 110 30 20 10 0 10.3 4.6 Total Asian 5.5 6.4 20.7 121.2

115-3

TABLE

Risk Factors Associated with Reported Hepatitis A in the United States, 2006 % 65.2 10.2 9.3 12.7 2.1 4.3 14.7 7.5 4.2

Risk Factor Unknown Sexual or household contact Men who have sex with men Other contact Injection drug use Contact of child or employee in day care International traveler Suspected food- or waterborne infection Child or employee in day care

NonNon- Hispanic Native Hispanic Hispanic American/ black white Alaska Native

Figure 115-3 Hepatitis A rates by race or ethnicity. The highest rates occurred among Native Americans/Alaska Natives and the lowest rates among Asians; rates among Hispanics were higher than those among non-Hispanics. Racial or ethnic differences in rates most likely reected differences in risk factors for infection, such as socioeconomic levels and resultant living conditions and more frequent contact with people from countries where hepatitis A is endemic.

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115-4

TABLE

Symptoms and Signs in Epidemic and Sporadic Hepatitis A % 71-85 67-79 76-80 18-58 19-73 26-54 68-94 52-58 8-19 Signs Hepatomegaly Hepatic tenderness Splenomegaly Jaundice Bradycardia Lymphadenopathy Skin rash % 14-78 39-46 3-13 40-80 17 4 14

HAV viremia Fecal shedding Clinical illness ALT

Symptoms Anorexia Nausea, vomiting Malaise Fever Headache Abdominal pain Dark urine Pale stool Arthralgia

IgG anti-HAV Infection IgM anti-HAV

liver.62 The virus enters the hepatocytes through receptors, sheds its capsid, and begins replicating. The virus replicates exclusively in the liver. After replication, the new virions pass into the bile canaliculi and are excreted in the bile. Hepatitis A is an acute self-limiting disease that rarely causes death and is characterized by a spectrum of severity ranging from asymptomatic, inapparent infection to fulminant fatal disease. Jaundice is very unusual in children younger than 4 years, and in the age group from 4 to 6 years, 90% are anicteric. In contrast, jaundice is present in 40% to 70% of those older than 15 years. A prodromal phase of infection is abrupt in onset and develops in 85% of the patients who ultimately become jaundiced (Table 115-4).27 The development of jaundice is typically associated with improvement in the prodromal symptoms. Jaundice resolves within 2 weeks in the majority of individuals. Extrahepatic manifestations include cutaneous vasculitis involving the buttocks and lower extremities, renal failure, pancreatitis, bradycardia, prolongation of PR and QT intervals, T wave changes, and left axis deviation. Rarely, convulsions, mononeuritis multiplex, Guillain-Barr syndrome, transverse myelitis, and aplastic anemia have been described with acute HAV infection.63 The clinical, serologic, and virologic course of an acute HAV infection is shown in Figure 115-4. In the majority of people, antibodies to HAV become detectable 5 to 10 days before the onset of symptoms. Initially, the antibody consists of both immunoglobulin G (IgG) and IgM; however, after 3 to 12 months, IgM disappears from the serum and IgG persists, conferring lifelong immunity. Two serological tests are licensed for the detection of HAV antibodies: (1) IgM anti-HAV and (2) total anti-AV (IgM and IgG). A diagnosis of acute HAV is made by nding IgM antibody to the capsid protein of HAV in an individual with either symptoms or biochemical evidence of hepatitis. In the majority of patients, IgM anti-HAV declines to undetectable levels within 6 months after infection; however, there are reported cases in which IgM anti-HAV persists for more than 1 year as well as false-positive IgM anti-HAV in people without clinical or biochemical evidence of HAV infection.

6 7 Weeks

9 10 11 12 13

HBV viremia HBeAg Clinical illness ALT Total anti-HBc Anti-HBe

HBsAg

IgM anti-HBc

anti-HBs

Infection

12

16

20

24 28 32 36 Weeks

52

100

Figure 115-4 The clinical, virologic, and serologic course of acute hepatitis A virus (HAV) infection and acute hepatitis B virus (HBV) infection. ALT, alanine aminotransferase; HBc, hepatitis B core; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; IgG, immunoglobulin G; IgM, immunoglobulin M.

Hepatitis B
HBV (also see Chapter 146) and related viruses are classied in the family of hepadnaviruses. The complete virion or Dane particle is a double-shelled, 42-nm DNA virus.9 It consists of an envelope composed of virus-encoded proteins, host-derived lipid components, and a core particle made up of nucleocapsid protein, the viral genome, and the polymerase protein. HBV also produces 22-nm spheres and laments that contain only envelope proteins and are not infectious. The HBV genome is a circular, partially double-stranded DNA approximately 3200 base pairs in length. HBV infection is a global health problem, with an estimated 350 million HBV carriers worldwide and 500,000 deaths each year.64 Chronic HBV infection is endemic in most areas of sub-Saharan Africa, Southeast Asia, China, and Alaska, with a carrier rate of 8% to 20%. Intermediate prevalence rates (2% to 7%) are seen in Mediterranean countries, Japan, Central Asia, the Middle East, and South

America. Low rates of infection (0.1% to 2.0%) are seen in the United States, Canada, western Europe, Australia, and New Zealand.65 The wide range in the carrier rates in different areas of the world is largely related to the differences in age at the time of acquisition of infection. In highly endemic areas, most infections occur in the perinatal period or during early childhood, when the rate of progression from acute to chronic HBV infection is approximately 90%.66 Transmission takes place at the time of birth by maternal-fetal transfusion and exposure to maternal blood in the birth canal as well as in the postpartum period through close contact between mother and baby. Progression to chronic infection for those infected between the ages of 1 and 5 years is 20% to 50%, whereas it is less than 5% for adult-acquired infection (Table 115-5).67-69

115-5

TABLE

Endemic Patterns of Hepatitis B Virus Infection Low <2 4-6 Adult Moderate 2-7 20-50 Adults and children High >8 70-90 Neonates and children

Carrier rate (%) Current or past infection rate (%) Predominant age at infection

115 Acute Viral Hepatitis

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The prevalence rate in the United States is derived from a study (National Health and Nutrition Examination Survey III, 19981994) that excluded those at high risk, including incarcerated and homeless individuals, and may represent an underestimation of the actual prevalence rate. An estimated 5% of the civilian, noninstitutionalized U.S. population has serologic evidence of past or present infection; 0.42% have chronic infection and serve as the primary source of infection for others. The overall prevalence of HBV infection differs among racial and ethnic populations and is highest among people who have emigrated from areas with a high endemicity of HBV infection. Immigrants to the United States born in countries where HBV is endemic have higher prevalence rates. Between 1994 and 2003, approximately 40,000 immigrants with chronic HBV were admitted to the United States annually.70 The prevalence of infection among blacks is four times that seen in the white population (11.9% versus 2.65%). From 1995 to 2006, reported cases of symptomatic acute HBV in the United States declined by 81% to the lowest rate ever recorded (1.6/100,000 population). After aymptomatic infection and underreporting are taken into account, an estimated 46,000 new infections occurred in 2006. Disease incidence is highest in non-Hispanic blacks (2.3/100,000 population), followed by Hispanics (1.2/100,000) and non-Hispanic whites (1.1/100,000). HBV is transmitted by cutaneous and mucosal exposure to infectious blood or bodily uids.71,72 In the United States, hepatitis B occurs in people exposed to blood or bodily uid through contaminated needles and syringes and through multiple sexual partners.72 Data from the CDC indicate that in 2006, approximately one third of individuals reported at least one sexual risk factor and that injection drug use was reported by 16% of those with acute HBV.24 Employment in health care, receipt of a blood transfusion, and dialysis account for less than 3% of cases. Health care workers, particularly surgeons, pathologists, and hemodialysis staff, have a higher risk for HBV infection, but these account for a low proportion of those exposed.73 The risk of HBV infection after a needlestick injury is related to the hepatitis B early antigen (HBeAg) and HBV DNA status of the source patient. Several reports document outbreaks in dialysis units in 1994 as a consequence of failure to identify and isolate infected individuals and vaccinate susceptible patients.74,75 Improved infection control and vaccination of susceptible individuals in dialysis units have reduced the incidence of infection among dialysis patients from 3% in 1980 to 0.1% in 1993. In addition, there are reports of transmission from a cardiothoracic surgeon to patients despite awless infection control precautions.76 With the current screening of blood donors, elimination of those with high-risk behavior from the donor pool, screening for HBsAg and antibodies to the core antigen (anti-HBc), and the use of viral inactivation procedures, the risk of post-transfusion hepatitis B is estimated to be 0.0002 per transfusion recipient.71 More than half (56%) of the cases reported to the CDC in 2006 had no recognized risk factor (Fig. 115-5).24 In endemic areas, horizontal transmission among children may result from close contact leading to transfer of virus across minor skin breaks and mucous membranes. Various bodily uids have been reported to test positive for HBsAg, and semen and saliva have been consistently shown to harbor infectious virions.77 Despite this, there is no convincing evidence that HBV can be transmitted orally. Similarly, HBsAg and HBV DNA can be found in the breast milk of mothers with chronic HBV infection. In immunized children, there is no increased risk of transmission of HBV related to breast-feeding.78,79 Because HBV can persist for a long time outside the human body, transmission by contamination of surfaces and tools such as toothbrushes and razors may occur. The worldwide incidence of HBV infection is decreasing. In 1982, hepatitis B vaccines were licensed in the United States. Despite this, the incidence of acute HBV continued to rise until 1985, when vaccination programs for health care professionals were implemented. Further reductions in the incidence of acute infection were seen with routine infant immunization in 1991 and routine catch-up adolescent immunization in 1995. Since 1995, there have been further signicant declines in the incidence of acute infection. The most dramatic decline

Unknown 55.6%

Injection drug use 16.1%

Sexual contact with HBV patient 7.7% Household contact of HBV patient 1.3% Homosexual activitiy (male) 14.6% Medical employee exposure 0.5% Hemodialysis 0.2%

Blood transfusion 0.6% Surgery 10.2% Percutaneous injury 4.7%

>1 Sexual partner 34.4%

Figure 115-5 Risk factors for acute hepatitis B virus (HBV) infection in the United States, 2006. Epidemiologic characteristics of patients reported with HBV infection. (From Wasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitisUnited States 2006. MMWR Surveill Summ. 2008;57:1-24.)

has occurred in the cohort of children targeted for routine infant and adolescent vaccination. With the implementation of these vaccine practices, an estimated 6800 perinatal infections and 18,700 adolescent infections have been prevented annually. However, because hepatitis B incidence has declined among U.S.-born children, unvaccinated foreign-born children account for a high proportion of the new infections. Increased public awareness and education about sexual practices and risks have also contributed to the overall reduction in HBV infection. The diagnosis of acute HBV infection is based on serologic markers of HBV infection in a clinical setting consistent with an acute hepatitis. HBsAg is the hallmark of HBV infection and appears in the serum during the incubation period, usually 1 to 10 weeks after exposure and 2 to 7 weeks before the onset of symptoms (see Fig. 115-4). Approximately 95% of patients have detectable HBsAg at the onset of jaundice. Most patients who recover from HBV infection clear HBsAg within 6 months, and persistence of HBsAg in the serum beyond this time implies chronic infection. In some patients who demonstrate a vigorous immune response, HBsAg may be cleared rapidly from the serum, and in these cases specic antibody testing provides clues to the diagnosis. HBV infection is associated with the development of anti-HBc before the onset of symptoms and within 1 month after the appearance of HBsAg. HBsAg clearance is usually followed by the development of neutralizing anti-HBs antibodies that confer immunity. In some patients, the anti-HBs antibodies may not appear for several weeks to months. During this period, there is no detectable HBsAg or anti-HBs. The presence of an IgM anti-HBc is the only marker of acute HBV infection during the period between the disappearance of HBsAg and the appearance of anti-HBs. IgM anti-HBc is usually a marker of recent HBV infection. However, the titer of IgM anti-HBc can increase to detectable levels during exacerbations of chronic HBV infection and therefore be misleading. As the patient recovers from acute HBV infection, the IgM anti-HBc is replaced by IgG anti-HBc. The presence of anti-HBc and anti-HBs indicates resolved infection. Early in the course of acute infection, markers of active viral replication (HBeAg and HBV DNA) are also detectable in the serum. During acute HBV infection, HBeAg is rapidly cleared, before the disappearance of HBsAg. In chronic HBV infection, HBeAg may persist for years to decades, and seroconversion from HBeAg to anti-HBe is generally associated with a reduction or loss of HBV DNA and can be associated with a are of hepatitis. A small proportion of patients lose HBeAg but

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still have active HBV replication and liver damage. These patients generally have a pre-core mutant that prevents production of HBeAg. Chronic infection develops in a variable proportion of patients depending on the age of exposure. These patients remain positive for HBsAg and anti-HBc, and a variable proportion display HBeAg and HBV DNA positivity.

Hepatitis D
HDV (also see Chapter 146) is a defective virus of the Deltaviridae family that requires the presence of HBV for virion assembly but not for replication; therefore, HDV infection is closely related to HBV infection.80 The virus is 35 to 37nm in diameter with a single-stranded circular RNA and a delta antigen coated with the surface antigen of HBV. There is one recognized serotype and three genotypes with different geographic and disease associations. HDV genotype I prevails in the United States and Europe, where there is an increased risk of a fulminant course or a rapid progressive chronic liver disease. Genotype II, found in East Asia, is less frequently associated with fulminant disease or rapid progression to cirrhosis, and genotype III occurs in South America, where it is associated with outbreaks of fulminant and severe hepatitis among the Yucpa Indians of Venezuela and the Sierra Nevada de Santa Marta in Colombia.81-83 In the Amazon Basin, infection with HDV has been implicated as a cause of Labrea hepatitis or the so-called Amazon black fever. This condition is characterized by viral hepatitis and protein-calorie malnutrition.84 It is estimated that approximately 5% (15 million) of the HBV carriers worldwide are infected with HDV.85 Despite the fact that HDV is closely associated with HBV, the geographic distribution of HDV does not parallel that of HBV infection. Specic areas that have a high prevalence include the Amazon Basin in South America, central Africa, the Mediterranean basin, and the Middle East. It is generally spread by parenteral exposure.86 However, in some areas, intrafamilial spread has been reported.87 Infection in western countries is uncommon and predominantly conned to intravenous drug users and multiple transfused individuals. It is endemic in Italy, where it predominantly affects children and young adults and is probably spread through mucosal and parenteral routes. There has been a reduction in the prevalence in Italy because of improvement in socioeconomic conditions, reduction in high-risk sexual behaviors, and HBV vaccination programs.88 In the Far East, the prevalence among individuals with chronic HBV varies from 90% in the Pacic Islands to 5% in Japan. The clinical manifestations of acute HDV infection vary from benign acute hepatitis to fulminant liver failure. In the chronic setting, patients may be asymptomatic carriers or may progress more rapidly to cirrhosis and hepatocellular carcinoma. Acute infection occurs in two clinical scenarios: coinfection with acute HBV infection or superinfection in a patient chronically infected with HBV. Coinfection with HBV results in an acute hepatitis indistinguishable from acute HBV. It is usually severe, with a reported mortality of 2% to 20%. A high incidence of liver failure has been reported among drug addicts.89,90 Less than 5% of cases of acute coinfection with HDV and HBV result in chronic HDV infection. The disease may be biphasic with two peaks in serum aminotransaminases a few weeks apart; the rst is related to the peak of HBV replication and the second to the peak of HDV replication. In a small number of patients, HDV superinfection results in clearance of HBsAg. Clearance of HBV results in loss of HDV infection because of the dependence of virion assembly on the HBsAg. In others, this loss is temporary and HBsAg returns when the HDV replication decreases. In cases of superinfection in which HDV and HBV persist, there is usually a signicant exacerbation of preexisting HBV liver disease. The disease is severe, and there is an increased risk of fulminant liver failure or progression to cirrhosis. In patients who require liver transplantation for fulminant HDV superinfection, the risk of HBV recurrence is signicantly reduced.91 The diagnosis of HDV coinfection should be suspected in patients who have a severe fulminant course. Similarly, in patients with chronic HBV who develop an acute hepatitis or have a rapid progression of

their liver disease, testing for HDV should be employed. HBsAg must be present to support HDV infection, and IgM anti-HBc should be present to make a diagnosis of acute HBV-HDV coinfection. Total (IgM and IgG) anti-HDV antibody can be detected by enzyme-linked immunosorbent assay (ELISA), and such commercial assays are available in the United States. IgM anti-HDV is present only transiently in acute HDV infection, and commercial testing for clinical diagnosis is not available in the United States. IgG anti-HDV appears late in the course of acute infection and may not be detected unless the test is repeated later in the disease. If chronic disease occurs, high titers of both IgG and IgM anti-HDV are present, and the titer of IgM antiHDV correlates with the level of HDV replication and the severity of liver disease. Antibody titers of 1:1000 are indicative of ongoing infection. Serum HDV antigen and HDV RNA can be detected during acute infection. HDV antigen is present only transiently and may be missed. HDV RNA is present early and is readily detectable by polymerase chain reaction (PCR). The U.S. Food and Drug Administration has not approved testing procedures for serum HDV antigen. HDV antigen can be detected by direct immunouorescence or immunohistochemical staining of liver tissue. However, this is not practical for the diagnosis of acute infection because few patients undergo liver biopsy for evaluation of acute hepatitis. The detection of intrahepatic HDV antigen has been proposed as the gold standard for the diagnosis of HDV infection and is reasonable for consideration in a patient with chronic HBV and suspected HDV superinfection. With prolonged HDV infection, there may be loss of HDV antigen expression in hepatocytes, resulting in a false-negative test.

Hepatitis C
HCV is an RNA virus of the Flaviviridae family, previously known as NANB hepatitis, which is spread predominantly by parenteral routes (also see Chapter 154). It has a genome of 9379 base pairs and is a single-stranded, positive-sense RNA virus that has a single ORF encoding both structural and nonstructural proteins. An estimated 170 million people are infected worldwide, and HCV infection is now the leading cause for liver transplantation in the United States because of it propensity to cause chronic liver disease, cirrhosis, and hepatocellular carcinoma. Acute HCV infection accounts for 15% or 16% of cases of acute icteric hepatitis in the United States, ranking below hepatitis A and B. The incidence of acute HCV decreased steadily until 2005. In the 1980s, there were an estimated 230,000 cases per year, and there were 36,000 new cases in 1996.92 Rates appear to have plateaued between 2003 and 2005 and subsequently increased to 19,000 cases in 2006.24 The reasons for the decrease are multiple and include the disappearance of post-transfusion hepatitis, adoption of universal precautions, and a decrease in transmission by injection drug use. The incidence of new infections is highest in people age 25 to 39 years. In 2006, there was no difference in the rate of acute HCV infection across racial/ethnic populations.24,93 Currently, the majority of cases of acute HCV occur as a consequence of parenteral exposure through injection drug use (54%).24,94 However, 32% of cases reported to the CDC had no recent or readily identiable risk factor noted.24 The clinical symptoms resemble those of other forms of viral hepatitis, and the disease can be distinguished only by serologic testing. Fewer than 15% to 25% of cases of acute HCV infection result in the development of jaundice, and therefore there is a high rate of subclinical infection.95 The mean incubation period is 50 days (range, 14 to 120 days). The preicteric phase is dened by nonspecic symptoms of fatigue, poor appetite, right upper quadrant pain, and low-grade fever lasting 2 to 10 days. As with HBV, some patients develop a serum sickness-like syndrome characterized by rash, urticaria, and arthralgias resolving with the onset of jaundice or within a few days. Symptoms of jaundice last 1 or 2 weeks, and patients with a history of jaundice are less likely to progress to chronic disease. Patients with acute, selflimited disease appear to have truly recovered from infection, with normal serum aminotransaminases and the absence of HCV RNA and without long-term consequences. After infection with HCV, HCV

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RNA becomes detectable in the serum within days to 8 weeks.96 It is usually present in the blood before the development of jaundice, but the titer of the viral RNA may uctuate greatly, and some patients may be intermittently negative for the HCV RNA. The minimal interval after suspected exposure after which a persistently negative HCV PCR test excludes infection has not been denitely established. Anti-HCV ELISA tests become positive as early as 8 weeks after exposure. Approximately one half of patients with symptomatic acute infection have detectable antibodies to HCV detected by ELISA when they rst present for care. However, the development of HCV antibodies may be delayed in patients who have subclinical infection. A positive antiHCV ELISA does not distinguish between those who cleared the infection and those who are chronically infected. The diagnosis of acute HCV relies on a high index of suspicion, and it is necessary to perform an HCV RNA test early in the course of infection or repeated antibody tests later in the disease process. The serum aminotransaminases become elevated approximately 6 to 12 weeks after exposure (range, 1 to 26 weeks) and are very variable in concentration. In one series that included 44 patients, the mean ALT was 885U/L. Distinction of acute HCV from a newly discovered chronic HCV infection may not always be possible because HCV RNA and anti-HCV antibodies are present in both situations. A recent exposure history, a negative antibody test with a positive HCV RNA, the presence of symptoms suggestive of an acute hepatitis, and the level of serum aminotransaminases may provide some help. A liver biopsy documenting the presence of signicant brosis and features consistent with viral hepatitis suggests chronic disease. Because of the absence of symptoms associated with acute infection and the high propensity for the development of chronic disease (85%), HCV can persist in an indolent and often silent manner and arise decades later with manifestations of end-stage liver disease. As a result, periodic screening for infection may be warranted in patients who are at high risk for infection. Fulminant hepatic failure caused by acute HCV infection is rare but may be more common in patients with underlying chronic HBV infection.43

115-6

TABLE

Serial Epidemics of Hepatitis E Virus Infection Years 1955, 1975-1976, and 1991 1955-1956 1973 1976-1977 1980-1981 1983-1984 1985-1986 1986 1986-1988 1987

Country India USSR Nepal Burma Algeria Ivory Coast Eastern Sudan and Somalia Mexico China Borneo

Hepatitis E
Hepatitis E (also see Chapter 177), previously known as enterically transmitted NANB hepatitis, was rst recognized as a distinct clinical entity in the early 1980s when sera from people affected by a large waterborne epidemic of viral hepatitis in Delhi, India, were found to lack serologic markers for HAV and HBV infection.97 The virus was then identied by immune electron microscopy in the feces of a volunteer infected with NANB hepatitis.22 The virus was subsequently cloned in 1990.23 It has been accorded its own genus (Hepevirus) and its own family (Hepeviridae). HEV is composed of at least ve genotypes: Genotypes 1 and 2 are strictly human pathogens, genotypes 3 and 4 are of swine origin but can infect humans, and genotype 5 is of avian origin (chicken) and likely does not infect humans. The four mammalian strains (genotypes 1 through 4) all belong to the one serotype. It is endemic in the Indian subcontinent and Southeast and Central Asia and accounts for a substantial proportion of sporadic hepatitis in both children and adults.98 Serial epidemics have been reported (Table 115-6); the largest outbreak of HEV was reported in the Xinjiang province of China in 1986 to 1988 and aficted more than 100,000 people. Sporadic cases are common in areas in which the disease is endemic, such as India, where HEV infection accounts for 50% to 70% of all patients with sporadic hepatitis.99 Sporadic hepatitis cases are uncommon in nonendemic areas and are generally limited to travelers to endemic areas.100 However, HEV has been reported in Australia, Italy, Britain, the United States, Japan, and Greece in patients without any such travel history.101-103 HEV is transmitted by the fecaloral route, and most reported epidemics have been related to the consumption of contaminated drinking water.97,104 Person-to-person contact does not appear to be an efcient mode of transmission, and secondary attack rates among household contacts are only 0.7% to

2.2%, in contrast to the rate of 15% to 20% seen with HAV. In nonhuman primate models, the clinical response is dose dependent, and a low dose of virus usually results in an inapparent infection.105 The prevalence of anti-HEV antibodies among multiply transfused patients and injection drug users is similar to that of the general population, and there is no evidence to suggest parenteral or sexual transmission. The highest attack rate ranges from 1% to 15%, and infection occurs more commonly among young adults. Acute infection during pregnancy is associated with an inordinately high mortality rate for reasons that are unclear. Transmission from mother to fetus during pregnancy has been documented to occur with the development of a spectrum of diseases ranging from anicteric hepatitis to fulminant hepatic necrosis in the newborn.47,106 The source of infection in industrialized countries is unknown, but there is increasing evidence that it is a zoonotic infection. Studies suggest that HEV can be isolated from several animals, including swine, rodents, cats, dogs, and cows, in multiple countries, and molecular sequencing studies indicate that these isolates are phylogenetically related to those resulting in human infection.107-109 There are documented cases of transmission of HEV infection following consumption of wild boar meat and deer meat.110 The incidence of HEV infection is increasing in the United Kingdom. The number of cases diagnosed in England and Wales increased signicantly after 2004, with 329 cases diagnosed in 2005. Approximately 67 of these individuals had no travel history. The majority of patients were male Caucasians older than age 55 years, and 60% reported owning a pet. Antibodies to HEV have been detected in both dogs and cats.111 Despite a very low number of acute HEV infections reported in the United States, the age-specic prevalence of anti-HEV is much higher than expected. In a study of 468 veterinarians and 400 blood donors from eight states, anti-HEV was detected in one fourth of veterinarians and more than 17% of volunteer blood donors.112 These data suggest that these are reservoirs and that HEV is a zoonotic infection. Hepatitis E causes disease that is indistinguishable from HAV without serological testing. The incubation period of HEV infection ranges from 15 to 45 days and is on average 10 days longer than that for HAV infection. Malaise, anorexia, nausea, vomiting, abdominal pain, fever, and hepatomegaly usually accompany jaundice. Fulminant liver failure occurs in 0.5% to 3% of patients. However, the gure is approximately 25% in patients with HEV infection who are in the third trimester of pregnancy. Indeed, pregnant women are more frequently affected during HEV outbreaks than nonpregnant women, with attack rates of 8% to 19% from the rst to the third trimester compared with 2.8% for nonpregnant women.47 A cholestatic variant similar to that in HAV infection has been described with HEV infection and usually resolves within 2 to 6 months. The overall mortality rate associated with HEV infection is higher than that of HAV and is reported to be 0.5% to 4% in hospitalized patients and 0.07% to 0.6% in population studies.110,113 It is not clear whether the mortality rate associated with HEV infection is age dependent. HEV infection does not commonly cause chronic liver disease or cirrhosis; however, there are rare reports of chronic infection of the immunocompromised host. Hepatic

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decompensation can occur in patients with underlying chronic liver disease after acute HEV infection.114 During acute HEV infection, IgM anti-HEV becomes detectable in the blood during the early phase of the infection and disappears over 4 to 6 months (Fig. 115-6). It is present in 90% of acutely infected patients between 1 and 8 weeks after the onset of illness. IgM precedes the development to IgG and is therefore useful in diagnosing acute HEV infection. The presence of IgG anti-HEV may represent the convalescent phase of an acute illness or previous exposure. In one study, IgG anti-HEV was present 14 years after the initial infection.115 Reverse transcriptasePCR (RT-PCR) testing allows detection of viral RNA in serum, stool, and some bodily uids.

Hepatitis G
HGV, also called GBV-C, is an RNA virus belonging to the Flaviviridae family. The virus was initially cloned from the plasma of a surgeon with acute hepatitis and is closely related to HCV. Like HCV infection, it is transmitted by parenteral exposure.116-118 HGV is distributed globally and has a high prevalence (1.7%) in the volunteer blood donor population in the United States. In a small study of volunteer blood donors with elevated ALT (>120U), HGV RNA was present in 4% of individuals, and anti-HGV antibodies were present in a further 10% of individuals.119 The prevalence of HGV infection is higher in patients infected with HIV or HCV, patients who have had multiple transfusions or organ transplantation, and patients who are receiving hemodialysis.120-125 HGV can be diagnosed by the presence of HGV RNA by PCR techniques. The appearance of anti-HGV appears to be associated with clearance of HGV RNA and with protective immunity.126 HGV RNA has been detected in patients with nonAE acute hepatitis, in patients with cryptogenic cirrhosis, and in patients with HCC; however, it is difcult to determine the exact role of HGV in these settings because coinfection with HCV is common. Thus, the exact role of HGV in producing liver disease in humans is unknown, and it has been frequently referred to as the orphan virus. Although HGV RNA has been detected in both acute and chronic liver disease, numerous lines of evidence suggest that it is not pathogenic. Seventy-ve percent of patients with detectable HGV RNA have normal liver function tests.116 In patients who have HCV infection or alcoholic liver
Acute phase Convalescent phase

disease, HGV infection does not appear to worsen the clinical or histopathologic stage of disease.127,128 In two studies investigating the cause of liver disease in patients with elevated aminotransferase levels, the prevalence of HGV was not different in the study and control groups.129,130 In liver transplant recipients with post-transplantation hepatitis of unknown cause, HGV is present in up to 58% of cases. The prevalence is not different from that in a control group of patients without post-transplantation hepatitis.131 Similarly, the presence of HGV coinfection in patients receiving transplants for HCV does not affect graft survival, the recurrence rate of HCV, or the severity of histologic recurrence of post-transplantation HCV disease.132 Early reports of HGV-induced fulminant hepatic failure are now controversial. Initial reports from Japan of HGV-associated fulminant hepatic failure have not been substantiated, and it appears that patients may have acquired the HGV after the diagnosis of fulminant hepatic failure through the use of therapeutic blood products.133-135

Pathogenesis
Viral hepatitis is characterized by a diffuse inammatory process resulting in acute or chronic liver injury, or both. The precise mechanism by which hepatocytes are injured is not known; however, it is known that antigen-specic and antigen-nonspecic cellular immunities contribute to hepatocyte injury in most types of viral hepatitis. HAV-associated liver injury is not completely understood, although the presence of HAV within hepatocytes before an increase in serum transaminases and the absence of direct cytopathic injury in cell culture models support a noncytopathic mechanism of injury. Only limited data are available on the immunology of HAV infection, and these studies have typically analyzed only the acute symptomatic phase of the infection in mild icteric cases. Immunohistochemical studies of liver tissue from acutely HAV-infected individuals have demonstrated the presence of CD45RO+ memory T cells, CD8+ T cells and B cells in the portal areas, and T cells and natural killer cells in the necrotic areas.136 In vitro cytotoxicity assays demonstrate that peripheral natural killer cells, lymphokine-activated killer cells, and human leukocyte antigen class I-dependent CD8+ T cells from HAV-infected individuals are capable of lysing cell lines infected with HAV more efciently than those cells from HAV antibody-negative individuals, suggesting that hepatocyte injury is immunologically mediated.137,138 Similarly, in HBV-associated liver disease, extensive human and animal studies suggest that the liver injury is mediated by a virusspecic cellular and humoral immune response. Although human immunological data of early intrahepatic immune responses are not available, animal studies have shown clearance of HBV DNA prior to the onset of symptoms of acute hepatitis, mediated by antiviral cytokines produced by cells of the innate and adaptive immune responses. In particular, interferon- (IFN-), tumor necrosis factor-, and interferon-/ (IFN-/) lead to a noncytopathic inhibition of HBV replication. Acute hepatitis is accompanied by a strong and transient expansion of CD4+ T cells directed against multiple HBV epitopes and an inux of these cells into the liver. HBc is the dominant antigen recognized by CD4+ T cells in most cases of acute resolving HBV infection. These HBc-specic CD4+ cells also contribute to the induction of virus-specic CD8+ T cells and help in the production of antibody to HBsAg.139,140 The appearance of CD8+ T cells coincides with the increase in serum aminotransaminases. Individuals who clear HBV infection, either spontaneously or after interferon therapy, maintain these broad and strong peripheral cytotoxic T lymphocyte responses against all HBV epitopes over time.141 In contrast, HDV infection may result in hepatocyte cell death through direct cytopathic mechanisms. Hepatocyte cell lines infected with plasmids containing the hepatitis D antigen (HDAg) gene demonstrated impairment of RNA synthesis and cell death, suggesting that HDV might be directly cytopathic to hepatocytes. In addition, microvesicular steatosis of hepatocytes has been observed in association with HDV infection, and recurrence after liver transplantation again suggests a direct cytopathic effect.142-144

HEV viremia HEV RNA in stool Clinical illness ALT

IgG anti-HEV

Infection

IgM anti-HEV

16 Weeks

20

24

28

Figure 115-6 Time course of clinical and serologic events during acute hepatitis E virus (HEV) infection. ALT, alanine aminotransferase; IgG, immunoglobulin G; IgM, immunoglobulin M.

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The mechanisms responsible for tissue injury in acute and chronic infection are not well understood. HCV is not directly cytopathic. This premise is based on the following observations: (1) Some transgenic animals expressing HCV proteins do not develop cytopathic changes or liver inammation, (2) cell lines expressing HCV under the control of inducible promoters do not develop cytopathic changes when HCV expression is turned on, and (3) there are no classic cytopathic features on liver biopsy. Clinical observations suggest that interaction between the virus and the immune response in the rst few weeks after the infection may determine the outcome of HCV infection. Resolution of acute HCV infection has been associated with vigorous, polyclonal and sustained HCV-specic CD4+ T-cell response.145-148 In the chimpanzee model, the appearance of this CD4+ T-cell response in the liver is associated with a decrease in viral load. Analysis of the cytokine prole of bulk cultures and peripheral CD4+ T-cell clones from individuals with acute self-limiting HCV infection reveals that viral clearance is more common in cases with secretion of IFN- and interleukin-2 (IL-2) than in individuals with a predominantly IL-10 cytokine prole. CD8+ T cells are responsible for cytotoxicity and production of cytokines that lead to viral clearance. Signicant CD8+ T-cell responses directed against multiple class I-restricted HCV epitopes of structural and nonstructural regions of the HCV polyprotein have been shown to correlate with elimination of the virus during the acute illness.149 INF- inhibits HCV replication in the replicon model system. No data on the mechanism of liver injury in acute HEV infection are available.

Differential Diagnosis
A number of disorders enter into the differential diagnosis of an acute hepatitis. These include a number of viruses in addition to the classic hepatotropic viruses, nonviral infectious agents, drug-induced liver injury, ischemic hepatitis (shock liver), severe autoimmune chronic active hepatitis, acute Budd-Chiari syndrome, Wilsons disease, and syndromes unique to pregnancy such as acute fatty liver of pregnancy and the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) (Table 115-7). Rarely, patients with a common bile duct stone and massive tumor replacement of the liver have a biochemical prole suggesting acute hepatitis. It should also be noted that patients with chronic hepatitis B infection can have an acute hepatitis picture with substantial elevations in aminotransferases in a number of settings. These include superimposed HDV (delta) infection and the phase of hepatitis B e antigen to hepatitis B e antibody seroconversion when spontaneous reactivation occurs. There is considerable variation in the extent to which other viruses cause hepatitis. EBV is a common cause of acute hepatitis, with subclinical hepatitis noted in 90% of patients with heterophile-positive mononucleosis (see Chapter 139). Most often, the serum aminotransferase levels are two to ve times the upper limit of normal.150 Splenomegaly is present in 50% of individuals. Hepatomegaly and jaundice

115-7

TABLE

Differential Diagnosis of Acute Hepatitis Noninfectious Drug-induced hepatitis Autoimmune hepatitis Ischemic hepatitis Acute fatty liver of pregnancy Acute Budd-Chiari syndrome Wilsons disease

Infectious Epstein-Barr virus Cytomegalovirus Herpes simplex virus Yellow fever Leptospirosis Q fever Human immunodeciency virus Brucellosis Lyme disease Syphilis

are uncommon. Generally, this syndrome is easily distinguished from acute viral hepatitis. On rare occasions, however, infection with EBV arises as acute icteric hepatitis without the usual telltale signs of fever, lymphadenopathy, and pharyngitis characteristic of mononucleosis. The diagnosis of EBV-induced acute hepatitis is established by the presence of a positive heterophile test and serologic exclusion of other causes of acute viral hepatitis. Fulminant liver failure may occur as a consequence of EBV infection.151 X-linked lymphoproliferative disease (Duncans syndrome) is characterized by the development of severe liver failure in young males. This rare disease is characterized by a family history of liver failure, lymphoma, immunoglobulin deciency, or pancytopenia complicating EBV infection. It is usually fatal.152 Cytomegalovirus (CMV) infection is often subclinical in healthy children and adults (see Chapter 138). Among neonates, the infection can be mild and subclinical or fatal. The classic syndrome in neonates consists of hepatomegaly, jaundice, hemolytic anemia, thrombocytopenic purpura, and central nervous system damage with periventricular calcication and microcephaly arising at or soon after birth.153 The most common syndrome in immunocompetent adults is CMV mononucleosis and is characterized by protracted fever, lassitude, anorexia, malaise, pharyngitis, splenomegaly, and lymphadenopathy. Jaundice is present in less than 10% of patients.154 Patients characteristically have an absolute lymphocytosis with greater than 50% mononuclear cells and greater than 10% atypical lymphocytes. In immunocompromised patients, CMV infection may lead to serious illness. The most common clinical pictures are pneumonia, retinitis, hepatitis, polyradiculopathy, encephalitis, gastrointestinal tract disease, and adrenal involvement; cases of myocarditis, pancreatitis, and genitourinary localizations are less common.155 HSV can cause a generalized infection that is usually associated with hepatic dysfunction. It is most common among neonates and immunocompromised children (also see Chapter 136). Most cases of HSV-associated hepatitis in adults also occur in immunosuppressed individuals, often in the post-transplantation setting. Patients present with fever, mild jaundice, and marked elevations in aminotransferases. Occasionally, patients can develop fulminant hepatic failure associated with HSV infection.156 Fulminant hepatitis has also been reported in otherwise healthy individuals including pregnant women.156 In a review of 21 cases of disseminated HSV in pregnancy by Gelven and colleagues,157 most patients had nonspecic symptoms and many did not have mucocutaneous lesions. They were usually febrile and anicteric and had markedly elevated aminotransferase values without a corresponding elevation in bilirubin level. Prompt initiation of acyclovir therapy resulted in 100% survival. Delayed or no therapy was associated with a 63% mortality rate. Yellow fever is enzootic in central Africa, Central America, and South America. More than 90% of cases occur in Africa (see Chapter 153). Yellow fever is characterized by an incubation period (3 to 7 days) much shorter than that of hepatitis A, B, and C viruses. Patients can present with a severe hepatitis. Of note, the serum aspartate aminotransferase (AST) is characteristically higher than the serum ALT, probably because of skeletal or myocardial injury, or both. In severe cases, it may be greater than 2000IU.158 The serum bilirubin levels are most often in the range of 5 to 10 mg/dL.159 Yellow fever should be suspected in the recent traveler to enzootic areas who did not receive adequate immunization. The mortality rate in yellow fever approximates 20%. Patients with leptospirosis infection present with an abrupt onset of fever, chills, myalgias, and headache (see Chapter 240).160 They may have marked jaundice.161 On physical examination, prominent conjunctival suffusion is often noted. Leukocytosis, which is uncommon in acute viral hepatitis, may be prominent and together with urinary ndings of proteinuria, hematuria, and anuria should raise the suspicion of leptospirosis. The serum creatine phosphokinase is elevated in 50% of patients. Marked jaundice accompanied by renal dysfunction in a febrile patient with leukocytosis should raise the possibility of Weils syndrome, a severe form of leptospirosis.161

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Q fever is caused by the rickettsial agent Coxiella burnetii and is uncommon in the United States. Patients present with fever, chills, and pneumonitis. Mild elevations in ALT and AST (two to ve times normal) are noted in 85% of patients. Hyperbilirubinemia and marked elevations of serum alkaline phosphatase can be present. Patients may have a prolonged febrile illness. Epidemiologic features linking exposure to farm or wild animals and the nding of unique hepatic granulomas (brin-ring granulomas are suggestive but not pathognomonic) should lead the clinician to suspect Q fever.162 A myriad of drugs can cause an acute hepatitis simulating acute viral hepatitis. The spectrum of acute liver injury ranges from mild hepatic dysfunction to fulminant hepatic failure. Common medications associated with severe hepatic toxicity include commonly prescribed analgesics such as acetaminophen and aspirin, antitubercular drugs including isoniazid and rifampin, and the anticonvulsant phenytoin. In addition, there has been recognition of acute hepatitis caused by a number of herbal agents. These products are aggressively promoted, and many individuals consider these natural herbal remedies to be completely devoid of unwanted side effects. Herbal medications documented to produce severe hepatotoxicity including fulminant hepatic failure include germander (Teucrium chamaedrys), chaparral (Larrea tridentata), pennyroyal oil (Mentha pulegium), mistletoe (Viscum album), kava (Piper methysticum), jin bu huan (Lycopodium serratum), and ma-huang (Ephedra sinica). This is by no means a complete list. Patients and their families should be specically interrogated regarding the use of any unconventional medications because they are often unaware that over-the-counter medications and herbal agents can have toxic potential. Alcohol is an important cause of hepatic injury. Patients with severe alcoholic hepatitis (those with hyperbilirubinemia and a marked prolongation of the prothrombin time [PT]) have a mortality rate of 50%. However, even in these severely ill patients the serum aminotransferases are almost always less than 300 IU, and characteristically the serum AST:ALT ratio is greater than 2:1. Patients with acute alcoholic hepatitis may also have prominent leukocytosis and, occasionally, even a leukemoid reaction. Hence, acute alcoholic hepatitis should seldom be confused with acute viral hepatitis. Autoimmune hepatitis may arise with an acute hepatitis-like picture with jaundice, marked elevations in serum ALT and AST, and a signicant prolongation of the PT. The aminotransferase levels can be in excess of 2000IU/L. Characteristic laboratory ndings include positive antinuclear antibody, smooth muscle antibody, and striking elevations of serum IgG.163 At histology, the liver biopsy specimens reveal prominent interface hepatitis with or without signicant brosis. Plasma cells may be prominent. Indeed, this disease has been referred to as plasma cell hepatitis. After exclusion of viral hepatitis by appropriate serologic tests, patients are treated with corticosteroids and usually have a dramatic benet. Ischemic hepatitis results from prolonged hypotension or severe left- or right-sided heart failure, and patients may present with a syndrome simulating acute viral hepatitis. Most patients with anoxic liver injury (ischemic hepatitis and shock liver) are admitted to an intensive care unit, trauma unit, or burn unit and have obvious hemodynamic alterations that result in severe centrilobular necrosis of the liver often accompanied by pre-renal azotemia. Within the rst 12 to 24 hours after the hypotensive episode, patients have dramatic elevations in serum ALT and AST at levels comparable to those seen with acute viral hepatitis. The serum bilirubin may be elevated but is usually less than 10mg/dL. The correct diagnosis can be condently made by recognition of the appropriate clinical setting and the characteristic rapid resolution of the dramatic ALT and AST elevations to normal levels within a few days after correction of the underlying hemodynamic insult.164 Acute fatty liver of pregnancy and the HELLP syndrome are encountered in women in the third trimester of pregnancy.165 Preeclampsia is common, and patients may have multiple gestations. Acute fatty liver of pregnancy has an approximate prevalence of 1 in 7000 to 1 in 16,000 deliveries. Affected women may have an inherited defect in mitochon-

drial beta oxidation of fatty acids that predisposes to this unique disorder. Accumulation of long-chain 3-hydroxyacyl metabolites produced by the fetus or placenta is probably toxic to the liver and the cause of the liver disease. Fetuses of some women affected with the HELLP syndrome also have long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deciency.166 Hence, these two syndromes may have a common basis. The differential diagnosis includes acute viral hepatitis and drug-induced hepatic dysfunction because the serum ALT and AST elevations can be greater than 10 times the upper limit of normal. Hepatic failure may occur in both acute fatty liver of pregnancy and the HELLP syndrome. In one series of 46 pregnant women who developed liver disease severe enough to require admission to a liver failure unit, 70% had acute fatty liver and 15% had the HELLP syndrome.167 Recognition of these syndromes is critically important because the treatment is inducing labor and delivering the newborn, which signicantly curtails both maternal and fetal mortality. Acute Budd-Chiari syndrome (hepatic vein occlusion) can arise as a severe and even fulminant hepatitis with marked elevations in serum ALT and AST, bilirubin, and PT.168 More than 90% of patients have ascites. The causes of acute Budd-Chiari syndrome include clotting disorders (such as polycythemia vera, paroxysmal nocturnal hemoglobinuria, protein C deciency, protein S deciency, antithrombin III deciency, prothrombin gene mutation, and occult myeloproliferative disorders), primary hepatocellular carcinoma, hypernephroma, the use of contraceptive pills, pregnancy, and congenital webs of the inferior vena cava. A rare and fulminant cause of Budd-Chiari syndrome is Behets disease, in which in addition to hepatic vein occlusion there is often accompanying inferior vena cava thrombosis.169 Wilsons disease (hepatolenticular degeneration) is a rare autosomal recessive defect of cellular copper export. Reduced biliary excretion of copper leads to accumulation in the liver and other organs, including the brain, kidneys, and eyes. Patients with Wilsons disease can present with an acute and even fulminant hepatitis-like picture with marked elevations in serum ALT, AST, and bilirubin, together with dramatic elevations in the PT.170 Diagnostic clues to Wilsons disease include low levels of serum uric acid, serum alkaline phosphatase, and serum ceruloplasmin. The diagnosis can be established by documenting the presence of a Kayser-Fleischer ring (a slit-lamp examination by an ophthalmologist is often necessary) in a patient with low serum ceruloplasmin. It is critically important to exclude Wilsons disease in a patient with unexplained acute hepatitis, chronic active hepatitis, liver disease and hemolytic anemia, or liver disease with neurologic manifestations because treatment with d-penicillamine is lifesaving.

Management
There is little specic therapy that can be offered for the treatment of acute viral hepatitis apart from symptomatic management and good supportive care with avoidance of further injuries. One of the most important tasks for the physician is to identify the patient who is likely to experience fulminant hepatic failure and refer for early consultation and assessment. These patients are a minority, and indeed most patients with acute viral hepatitis do not require hospitalization. The latter should be reserved for patients who have dehydration because of inadequate uid intake related to persistent anorexia or vomiting, patients with a progressive prolongation of the PT, and any patient who displays clinical ndings compatible with liver failure such as mental status changes. Patients who have cholestatic hepatitis complicated by ascites, a shrinking liver size, and falling serum albumin levels are at risk for subacute liver failure and may also need access to liver transplantation services. The duration of hospitalization is variable and dependent on the speed of resolution of signs and symptoms. There is no need for patients to remain hospitalized until liver function tests return to normal; most patients can be discharged to recover at home. Bed rest is generally recommended for patients with acute viral hepatitis. Traditionally, it was recommended for all patients during the symptomatic phase of the illness. These therapeutic precepts were

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derived from observations of military personnel during the Korean War, and some soldiers with acute HAV infection were assigned to bed rest for 3 months. This concept was challenged by Chalmers and colleagues, who reported that patients returning to duty after a short convalescence period recovered more rapidly than soldiers who had prolonged best rest.171 Further controlled studies have shown that after symptoms have resolved, normal activity does not slow recovery, induce relapses, or increase the risk of chronic hepatitis.172 Dietary manipulation has not been shown to improve symptoms, shorten the duration of the illness, or improve outcome. High-calorie diets (3000 to 4000kcal/day) and the addition of vitamin supplements have not been shown to enhance recovery. Vitamins are frequently given, but none have been shown to affect disease severity. In patients with prolongation in PT, parenteral vitamin K can be administered to distinguish between severe hepatocellular dysfunction and vitamin K deciency. This is particularly important in patients with prolonged cholestasis. Well-balanced nutrition is advised, and antinausea medication can be employed in patients with anorexia or nausea to improve a general sense of well-being and prevent dehydration. In patients with mental status changes and those with severe reduction in dietary intake requiring hospitalization, blood sugar should be monitored frequently to treat hypoglycemia. Alcohol should be avoided in the acute illness. There is no evidence that alcohol consumption after recovery leads to relapse or to an increased risk of chronic infection. One study showed that consumption of up to 26g of alcohol per day was not harmful to patients with acute HAV infection.173 It is prudent to advise that alcohol be avoided during the symptomatic phase; however, imposing abstinence for 6 months is unnecessary. Drug therapy to control symptoms should be judicious, and avoidance of all narcotic and hypnotic medication is advised because of the risk of sedation and coma in those with severe disease. In general, all but clearly necessary medication should be stopped during the course of the acute illness. Pain should be managed with acetaminophen, which should not exceed 2g/day. Nausea can be managed with metoclopramide, and chlorpromazine should be avoided because it has the potential to cause cholestasis. Pruritus can be managed with cholesty ramine. Ursodeoxycholic acid was used in one pilot study of acute viral hepatitis. Patients were randomly assigned to receive ursodeoxycholic acid or placebo for 3 weeks, with no observed difference in the duration of the illness. However, markers of cholestasis were signicantly better in the patients receiving active drug.174 SPECIFIC DRUG THERAPY There are no specic drug therapies available for patients with acute HAV or HEV infection. Postexposure prophylaxis with HAV vaccine or immunoglobulin should be considered for individuals with recent contact with HAV (see Chapter 320). HAV is resistant to most currently available antiviral drugs. Corticosteroids are helpful in the cholestatic phase of HAV infection in decreasing the serum bilirubin, alleviating itch, and ameliorating the symptoms of fatigue. Prednisone at a dose of 40mg/day often reduces the serum bilirubin by 40% over 4 days and should be tapered over a period of 2 to 4 weeks. Corticosteroids have not been proved to be of any benet in fulminant hepatic failure secondary to acute viral hepatitis, and some studies have shown that adverse events outweigh any potential benets of such therapy.175 Studies addressing antiviral therapy for HBV, HDV, and HCV infection have largely involved patients with chronic disease. Pilot studies have addressed the use of IFN- in acute HBV infection with resultant liver failure and have shown some benet in preventing chronic HBV disease. In one study from India, patients with HBV infection for more than 12 weeks were treated with IFN- or placebo. Although this study included a small number of patients (N = 54), seroconversion (disappearance of HBsAg, HBeAg, and serum HBV DNA and the appearance of anti-HBe) was seen more commonly with IFN- treatment (80%) than with placebo (53%). Two more patients in the study group seroconverted after treatment stopped, increasing the rate of successful treatment to 90%.176 In patients who have fulminant hepatic failure

related to HBV infection, results of IFN- therapy are conicting, with one study from Israel showing survival of 3 of 5 patients treated with IFN-, whereas only 2 of 12 patients with fulminant HBV or HBV-HDV survived.177,178 Lamivudine has been studied in a number of case series of patients with acute severe HBV infection. These series have demonstrated that lamivudine is well tolerated and effective in reducing HBV DNA.179,180 Furthermore, a randomized placebo-controlled trial of lamivudine for acute HBV demonstrated safety and conrmed efcacy in reducing HBV; however, there was no signicant difference noted in improvement in ALT, international normalized ratio or serum bilirubin, HBsAg loss, HBeAg seroconversion, or the development of anti-HBs.181 Despite this, there is a role for antiviral therapy in patients with fulminant HBV infection in the pretransplant setting so as to reduce HBV replication or render the patient HBV DNA negative prior to transplantation to decrease the risk of post-transplant recurrence. Initial studies of treatment in acute HCV infection demonstrated that it was possible to prevent chronic HCV in a signicant number of patients. A study by Jaeckel and colleagues from Germany showed that aggressive treatment of acute HCV infection with IFN- resulted in clearance of the HCV infection in 98% of treated patients. No control group was included in the study. However, it is well documented that HCV infection becomes chronic in 50% to 85% of acutely infected individuals, and this study may have demonstrated prevention of the development of chronic HCV infection. Treatment was well tolerated, and only 1 of 44 patients discontinued therapy because of side effects.182 A subsequent randomized trial of pegylated IFN2b monotherapy versus no treatment was conducted in a cohort of patients that remained viremic 8 weeks after acute infection. Patients were randomized to commence treatment at 8, 12, or 20 weeks after infection and were treated for 12 weeks. Sustained virological response (SVR) was 95%, 92%, and 76% with treatment onset at 8, 12, and 20 weeks, respectively. Spontaneous resolution in the control group was 29%. Genotype 1 patients had a signicantly better chance of achieving SVR if treated at week 8 as opposed to week 12 and week 20.183 MANAGEMENT OF FULMINANT HEPATIC FAILURE Patients with acute viral hepatitis rarely develop fulminant hepatic failure. Patients with severe viral hepatitis should be monitored closely with twice-weekly assessment of clinical status, liver function tests, and PT. The development of a rising PT or mental status changes at any juncture should prompt referral to a liver center for evaluation. Management of acute liver failure is best performed in an intensive care unit setting by a multidisciplinary team with access to a transplant center. Supportive care includes intensive care unit observation, optimal management of hemodynamic status with intravenous uids, central venous access, and Swan-Ganz catheterization. Patients should be assessed frequently for signs of hepatic encephalopathy, and development of grade III encephalopathy should prompt elective intubation for airway protection. Monitoring for raised intracranial pressure by placement of an intracranial pressure monitor or clinical assessment is critical. Systemic infection is common in patients with fulminant hepatic failure, and the clinical features usually associated with infection, such as fever and elevated white blood count, are frequently absent.184 The use of prophylactic antibiotics is controversial; however, several randomized trials support their use.184,185 The most promising therapy for fulminant liver failure is liver transplantation. Acute liver failure accounts for approximately 5% of all transplantations in the United States and 11% in Europe. The overall success of liver transplantation for fulminant liver failure varies from 59% to 73% depending on the center. Factors that indicate a poor prognosis without liver transplantation include age younger than 10 or older than 40 years, seronegative or drug-induced hepatitis, serum creatinine greater than 300 mol/L or 2.3 mg/dL, and a PT greater than 50 seconds. Special consideration needs to be given to patients who receive transplants for acute HBV infection with fulminant liver failure. There is a risk of recurrent HBV infection in the graft, with resultant post-transplantation hepatitis and

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graft loss. The risk is less for patients with HDV coinfection and patients who receive transplants for fulminant liver failure than for those who receive transplants for chronic HBV. In these cases, patients need to be treated with hepatitis B immunoglobulin (HBIg) and/or nucleoside analogues to prevent graft infection and loss.

115-8

TABLE

Dosing Schedule for Immunoglobulin for Pre- and Postexposure Prophylaxis against Hepatitis A Virus Infection Duration of Coverage Short-term (1-2mo) Long-term (3-5mo) Immunoglobulin Dose (mL/kg) 0.02 0.06 0.02

Setting Postexposure Postexposure

Prevention
Prevention of viral hepatitis relies on improvements in sanitation and vaccination of children for HAV and HBV infection. Prevention measures for specic viruses are discussed in chapters dealing with the individual specic agents. The recommendation regarding prevention of acute hepatitis among close contacts is governed by the type of viral hepatitis and the timing of infection. There is often a delay in the diagnosis of acute viral hepatitis and in determining the causative agent. It is necessary to delay postexposure prophylaxis until the nature of the infection is known. In cases of HAV infection, close contacts should receive immunoglobulin within 2 weeks of coming in contact with the infected patient. The recommended dose of HAV immunoglobulin is 0.02mL/kg body weight by intramuscular injection (Table 115-8). When administered within 2 weeks after exposure to HAV, immunoglobulin is more than 85% effective in preventing hepatitis A.186 A study has demonstrated that postexposure prophylaxis can be achieved with a single dose of single antigen hepatitis A vaccine for individuals aged 12 months to 40 years at the age-appropriate dose or with immunoglobulin (IG) (0.02mL/kg) as soon as possible.187 The study only included individuals aged 12 months to 40 years and did not include immunocompromised individuals. In addition, HAV vaccine is not licensed for individuals younger than 12 months; hence, IG should be used for infants younger than 12 months, immunocompromised individuals, and those with chronic liver disease who have not received prior HAV vaccination.188 Vaccination against HAV is the mainstay of prevention of HAV infection. Currently, two inactivated vaccines are available in the United StatesVaqta and Havrix. Both vaccines are highly immunogenic and efcacious. Within 1 month of the rst dose of vaccine, 97% to 100% of children, adolescents, and adults have protective levels of antibody. For prevention of infection in travelers, it is preferable that the rst dose be given at least 4 weeks before traveling to the endemic area. Havrix is available in two formulations: for persons 12 months to 18 years of age, 720 ELISA units (ELU) per dose in a two-dose schedule, and for persons older than 18 years, 1440 ELU per dose in a two-dose schedule. Vaqta is also approved in two formulations: for persons 12 months to 18 years of age, 25IU in a two-dose schedule, and for persons older than 19 years, 50 IU per dose in a two-dose schedule. Prevention of HBV infection largely relies on vaccination of all children at birth with HBV vaccine. Two types of hepatitis B vaccine have been approved in the United States (Recombivax HB and EngerixB). The currently available vaccines are produced by recombinant DNA technology. The vaccination schedule most often used for adults is three intramuscular injections, administered at 0, 1, and 6 months (see Chapters 146 and 320 for detailed schedules for HBV vaccination

in different age groups). The recommended series of three intramuscular doses of hepatitis B vaccine induces a protective antibody response (anti-HBs > 10mIU/mL in more than 90% of healthy adults and in more than 95% of infants, children, and adolescents).189,190 Larger vaccine doses or an increased number of doses are required to induce protective antibody in a high proportion of hemodialysis patients and may also be necessary for other immunocompromised persons.191,192 Combination HAV and HBV vaccine is available in the United States for vaccination of at-risk individuals in the form of Twinrix. It is indicated for individuals older than age 18 years in a dosing schedule of 0-, 1-, and 6-months or as an accelerated four-dose schedule given on days 0, 7, 21, and 30 followed by a booster at 12 months. Each dose of Twinrix contains 720 ELU of inactive HAV and 20 g of recombinant HBsAg. For postexposure prophylaxis, appropriate immunoprophylactic treatment can effectively prevent infection. The mainstay of postexposure immunoprophylaxis is hepatitis B vaccine, but in some settings the addition of HBIg provides an increase in protection. Transmission of perinatal HBV infection can be effectively prevented if the HBsAgpositive mother is identied and if her infant receives appropriate immunoprophylaxis. Hepatitis B vaccination and one dose of HBIg, administered to the neonate within 24 hours after birth, are 85% to 95% effective in preventing both HBV infection and the chronic carrier state.193,194 Hepatitis B vaccine administered alone in either a three-dose or a four-dose schedule beginning within 24 hours after birth is 70% to 95% effective in preventing perinatal HBV infections.195,196 Prophylaxis for exposure other than perinatal exposure usually combines HBIg and HBV vaccination. HBIg is administered at a dose of 0.06mL/kg body weight intramuscularly as soon as possible after the exposure (preferably within 24 hours). The effectiveness of HBIg when administered more than 7 days after exposure is unknown. When HBV vaccine is indicated, it should also be administered as soon as possible (preferably within 24 hours) and can be administered simultaneously with HBIg at a separate site. There are no preventive strategies for acute HDV infection except to prevent HBV infection. Similarly, there is no available postexposure prophylaxis for HCV. Hepatitis C immunoglobulin is currently in development. There is no effective vaccine to prevent HCV infection. A recombinant HEV vaccine has completed a phase II study of safety and efcacy for the prevention of HEV infection. The vaccine is administered as a three-dose schedule and demonstrates a 95.5% efcacy after all three doses. Hepatitis E infection occurred in 0.3% of the vaccine group and 7.4% of the placebo group (P < .001).197 Future trials and further development of this vaccine are required.

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