Rudolph's Pediatrics, 22nd Ed.

CHAPTER 308. Viral Hepatitis

Henry Pollack and William Borkowsky

Many viruses can infect the liver (Table 308-1). Often, infection occurs as part of a disseminated viremia. In this chapter, we focus mainly on the 5 viruses whose primary target is the liver: the hepatitis viruses A through E (HAV, HBV, HCV, HDV, and HEV).

Hepatitis is both a clinical and a laboratory diagnosis. The best measure of liver injury is the enzyme alanine aminotransferase (ALT), which is primarily released by hepatocytes during injury or death. Inflammation of the liver can result from a variety of causes. In the evaluation of a patient with hepatitis, it is also necessary to consider nonviral diseases of the liver that can cause similar symptoms (see Chapter 419). Because of the large number of potential viral causes of hepatitis, the evaluation of a patient can be confusing and complicated. The clinical context in which disease presents is the key to directing the work-up (see Table 308-1). If just the transaminases are mildly elevated, then waiting and repeating these test might avoid an extensive and costly evaluation. Identifying the causative agent may not be critical for an asymptomatic transient elevation of transaminases. In symptomatic disease, it is impossible to establish the causative agent from symptoms alone.

Table 308-1. Viral Causes of Hepatitis Based on Epidemiology and Clinical Presentation

Epidemic: Generally HAV or HEV

Classical clinical features: HAV, HBV, HCV

Sporadic: HBV, HCV

Clustering within a family: HBV, HCV, inherited

Birth, travel, or blood exposure in country where infection is endemic: East/Southeast Asia (HBV); Africa (HBV); Caribbean and South America, especially Amazon region (HBV); eastern Europe (HBV, HCV); South Asia (HBV, [Pakistan HCV > HBV]); foreign travel (HAV > HBV > HEV); injection use (HCV > HBV); transfusion (HCV > HBV)

Fulminant: HAV > HBV

Age: Newborn and infant (CMV > HSV, HHV-6, enterovirus, LCM, rubella), child or adolescent (EBV, CMV)

Transient: Enteroviruses, influenza, viremias (HSV, varicella, HHV-6, HHV-7), parvovirus, adenoviruses, rubella, rubeola

Persistent: EBV, CMV, HIV, congenital (rubella, CMV, HSV), LCM

Chronic: HBV, HCV, HDV

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; HHV, human herpes virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LCM, lymphocytic choriomeningitis virus.


HAV is a single-stranded ribonucleic acid (RNA) virus that is classified as a picorna virus. First identified in the 1970s, it is the major cause of infectious hepatitis. There are several genotypes but only 1 known serotype. HAV causes acute hepatitis and asymptomatic infection but never chronic infection.


HAV is the most frequent cause of epidemic hepatitis in the United States with rates highest in the western United States. Approximately 5000 to 10,000 cases are reported each year. This number represents only 10% of the estimated new cases. Approximately one fifth of cases occur in children under the age of 15. Infection occurs primarily via the fecal-oral route because the virus is relatively resistant to gastric acidity, making it an extremely efficient gastrointestinal pathogen. Infection can also occur by percutaneous exposure to blood (intravenous drug use) or exceptionally by transfusion. In 50% of cases, no source is identified. HAV is highly contagious within families and close contacts (sexual partners). Men who have sex with men are also at high risk of infection. The rates of HAV infection have declined dramatically, especially in children, with the introduction of the HAV vaccine in 1995.1Epidemics are generally caused by person-to-person transmission or by contaminated food or water products. Daycare outbreaks and community-wide outbreaks were common before the introduction of the vaccine. Travel to countries where HAV is endemic is also a frequent cause of sporadic infection. In countries where it is endemic, infection is usually acquired in childhood and is often asymptomatic.


HAV replicates in the liver; it is excreted in the bile and shed in the stool. The incubation period is between 2 and 6 weeks (average 4 weeks). A period of viremia precedes the presence of virus in stool and continues through the period of elevated liver enzymes.2 Clinical disease occurs after shedding in stool has begun (Fig. 308-1). The period of peak infectivity is during the 2 weeks prior to jaundice or elevated ALT and alkaline phosphatase. Shedding of virus can persist for several months in young children.


The frequency of clinical symptomatology is a function of age, ranging from less than 10% in young children to approximately 50% in older children and more than 80% in adults. Symptomatic acute infection usually begins abruptly with fever, nausea, abdominal pain, malaise, fatigue, anorexia, jaundice, and dark urine. Symptoms generally subside by 2 months. The severity of disease increases with age. Fulminant infection occurs in 1% to 2% of cases and is associated with a mortality as high as 50% even with liver transplantation.


The diagnosis is made serologically by the detection of HAV IgM during the acute phase of infection. Lifelong immunity is conferred by HAV IgG, a marker of prior infection. The virus can also be recovered by polymerase chain reaction in the blood or stool. Complications include severe hepatitis and prolonged cholestatic hepatitis and are more common in adolescents, adults, and persons with chronic liver diseases.

In the absence of specific treatment of acute HAV, supportive care remains the only treatment option. Symptoms generally subside after a few weeks. In the case of fulminant hepatitis, early referral for liver transplantation is critical. In most cases, the prognosis is excellent. Occasionally, relapsing hepatitis lasting up to 6 months may occur. Recovery provides lifelong protection from reinfection.


Improved sanitation, purified water, and better hygiene are key strategies in reducing environmental exposure to HAV and preventing large-scale epidemics. An individual can be protected from acquiring disease after exposure to HAV by the use of either gamma globulin injections (intramuscularly) or the HAV vaccine,3 which has been licensed since 1995. Immunization against HAV is now recommended starting at age 12 months.4

FIGURE 308-1. Time course of virologic, serologic, and clinical events during acute hepatitis A infection. ALT, alanine aminotransferase; IgG, immunoglobulin G; IgM, immunoglobulin M.


HBV is the smallest (3.2 kb) and one of the most successful human viruses, having been present among humans for at least 3000 years. HBV, a DNA virus, goes through an RNA-polymerase cycle that is responsible for a high rate of mutation as well as for the virus’s sensitivity to nucleosides and nucleotides that act also on retroviral reverse transcriptase.


HBV infects more than 1 billion people and chronically infects 300 million to 400 million persons, making it one of the most common viral infections worldwide. It is responsible for 80% of the cases of primary liver cancer worldwide that claim an estimated 500,000 lives each year. Transmission occurs percutaneously, sexually, via mucous membranes, and vertically from mother to infant. Infection acquired in infancy, when chronic infection is most likely to occur, accounts for the largest portion of chronic HBV worldwide. Areas of high prevalence (> 2%) include Asia, Africa, Eastern Europe, and South America. The seroprevalence in the United States is low, and new cases of acute HBV have declined dramatically since the introduction of the hepatitis B vaccine. By contrast, the number of cases of chronic infection has increased to 1.4 million with the influx of immigrants from countries of high prevalence. This accounts for most of the cases of chronic HBV in children seen in the United States. In addition, there are an estimated 20,000 chronically infected pregnant women who deliver each year, but very few of their children develop chronic HBV since the implementation of universal perinatal HBV prophylaxis in the United States in 1991. Even with adequate prophylaxis, up to 25% of infants born to mothers whose viral load is higher than 109copies/ml will become infected.5 Asian Pacific Islanders account for approximately 60% of the cases of chronic HBV in the United States, and overall, they are more than a 30 times as likely as Caucasians to be infected with HBV than Caucasians. Other groups with high prevalence are Africans, Eastern Europeans, Haitians, and South Americans from the Amazon Basin. Other groups of children who have higher rates of chronic HBV are adolescent males who have sex with males and intravenous drug users. Genotype distribution varies by geography. The most common genotype among non-Asians in the United States is genotype A, whereas it is genotype B and C among Asian Pacific Islanders.


HBV is found in extremely high amounts in blood but also can be found in high titers in urine and saliva, directly correlating with blood levels. The risk of infection is related to the dose of virus in the donor and the volume of the infectious exposure. In the case of neonates exposed to E antigen (eAg)-positive (which correlate with 106-12 viral particles/mL of blood) mothers, the risk of infection exceeds 90% but is less than 30% when born to eAg-negative (correlating with < 106 particles/mL) mothers. After exposure, there is local replication, uptake by dendritic cells, then viremia and infection of almost all hepatocytes where active replication occurs. The incubation period is 6 weeks to 6 months.

Whether a person develops chronic infection depends mostly on the age at the time of exposure (from > 90% at birth, 40% up to age 5, < 2% in adolescence and young adults), genetic factors (HLA class II genes and tumor necrosis factor-polymorphisms) and the competence of the immune system. Even after resolution of acute infection, HBV can be found in the liver by polymerase chain reaction and, like varicella, can recrudesce after immune suppression or during periods of incompetence. Resolution of infection after exposure involves T cell–mediated immunity, either cytokine-mediated or via cytolytic mechanism. The stronger the cytolytic response, the greater will be the severity of the clinical manifestations. HBV by itself is nonnecrotizing and does not cause obvious hepatotoxicity or ALT release. Therefore, the clinical course can range from asymptomatic infection to fulminant infection wherein most of the host’s hepatocytes are destroyed by the person’s own cytotoxic T cells. Chronic infection often is accompanied by repeated episodes of T cell–mediated immunity against infected hepatocytes that leads to flares of ALT and, over time, fibrosis, scarring, and cirrhosis. ALT rises are surrogate markers of the patient’s immune response to the virus. Resolution of infection is marked by the disappearance of the circulating viral surface antigen (HBsAg) and the appearance of antibody to the antigen (HBsAb) (Fig. 308-2A). If infection persists for longer than 6 months, the patient is considered to have chronic infection.

While the hallmark of chronic infection is the presence of HBsAg, the staging of infection requires a more complete laboratory analysis. A core-related antigen (HBeAg) that correlates with viral load was used as a marker of high viral activity, but mutations can abolish eAg production (eAg-HBV) yet sustain high viral activity, rendering it unreliable for this purpose. The most important determinant of long-term outcome of both hepatocellular carcinoma (HCC) and cirrhosis is viral load, with marked increased risk with viral loads greater than 104 copies/mL.6Integration of HBV genome in host DNA is responsible in part for the risk of HCC. In chronic HBV infection, HCC can occur without cirrhosis, distinct from HCC resulting from chronic HCV. This has implications for the different monitoring strategies for HCC in these 2 infections.


The symptoms of acute HBV and chronic HBV infection can sometimes overlap. Usually, however, the syndromes are quite distinct. Acute infection can be asymptomatic or clinically apparent, with resolution. Severe, acute, and fulminant hepatitis leading to rapid liver failure (bleeding, encephalopathy, low glucose) occurs in about 1% of clinically apparent infections, which is less common than in acute HAV infection and often requires liver transplant for survival. The severity of severe disease is related to viral (mainly precore and core promoter mutations) and host factors. Although rare in incidence, the most common cause of fulminant HBV in neonates and infants eAg mutants.7

There are usually at least 4 phases of chronic HBV infection (Fig. 308-2B). Initially, the patient goes through an immunotolerant phase characterized by high viral load and normal ALT. At this stage, the infection is usually completely asymptomatic. This phase can last several decades, especially if infection occurred vertically or during early childhood. Viral loads are generally in the 108 to 1010 copies/mL range. The beginning of an immune response is heralded by a rise in ALT. This begins the phase of immune recognition. If the immune response is effective, the viral load will begin to decline and eAg clearance may occur during the phase of immune clearance. During this phase, flares in ALT more than 10 times the upper limit of normal may occur, and occasionally they will be accompanied by jaundice and other symptoms of acute HBV infection. These flares are self-limited, but if they occur often enough, they may lead to marked fibrosis and cirrhosis. In children, these 2 phases most frequently occur during adolescence, often after puberty when the rates of eAg clearance can be as high as 15% per year. HBsAg may clear, signaling that the infection has resolved, but this is much less likely (only about 1% per year), and even after clearance, it can be detected in the liver by polymerase chain reaction.

Because of the time it takes to develop cirrhosis, it is much less common in children (< 5%), as is end-stage liver disease and hepatomas. Most commonly, they occur after 4 to 6 decades, especially in men 40 to 55 years of age.

FIGURE 308-2. A: Time course of virologic, serologic, and clinical events during the course of acute hepatitis B infection. B: Time course of virologic, serologic, and clinical events during the course of chronic hepatitis B infection. Conceptual stages of infection are included in pink. HBc, hepatitis B core antigen; HBe, hepatitis B e antigen; HBs, hepatitis B surface antigen.


The diagnosis of acute HBV infection is generally based on the presence of IgM antibody to the HBV core protein (IgM HBcAb). In the early “window” period of infection, HBsAg may be negative, but HBV DNA can be detected. HBsAg will become positive over time and then disappear with the appearance of surface antibody to HBV (HBsAb) as the infection resolves. IgG antibody to HBV core protein will also become positive and remain positive, and HBcIgM will disappear (see Fig. 308-2A).

The initial evaluation of a child with chronic HBV includes liver enzymes, HBV viral load (quantitative DNA), HBe antigen, and HBeAb. The patient should also be tested for HCV antibody and either vaccinated against HAV or tested for HAV antibody if from a resource-poor country where HAV is usually acquired during childhood. Human immunodeficiency virus (HIV) testing should be obtained, especially when there are specific risk factors. A baseline liver ultrasound is often obtained to eliminate other liver pathology and hepatomas but there is no consensus in children how often ultrasounds should be repeated. α-Feto-protein, a marker for HCC, should be obtained periodically. Genotyping can be done for prognostic purposes and deciding on a specific treatment. Liver biopsy will usually show little if any fibrosis and is generally only helpful in deciding to treat an older adolescent with normal ALT. Hepatic complications are cirrhosis, end-stage liver disease manifestations, and HCC. Extrahepatic manifestations may occur in children but are uncommon. Glomerulonephritis (membranous) is the one of the most common manifestations, being the most frequent etiology in Asia for acute glomerulonephritis, and occurring in about 1% to 2% of children with chronic HBV infection. Other extrahepatic manifestations are periarteritis nodosa and Giannoti Crosti acrodermatitis (Fig. 308-3).


The treatment of acute HBV is supportive. The role of antivirals in treating acute uncomplicated HBV is unknown. In fulminant HBV, treatment with lamivudine has been shown to decrease mortality and reduce the need for liver transplant. Similarly, lamivudine has been used to prevent and treat acute reactivation of HBV after liver transplant.

There are currently 2 approved treatments for chronic HBV in children: α-interferon, which needs to be given parenterally, and the nucleoside analog lamivudine (Epivir), given orally. Resistance to lamivudine can develop with the emergence of tyrosine-methionineaspartate-aspartate (YMDD) mutation in the polymerase locus of the virus.8 In children 16 years or older, entecavir is also approved. There are ongoing clinical trials of the oral HBV drugs adefovir (nucleotide), entecavir, and tenofovir (nucleotide), which may be effective in viruses resistant to lamivudine. Tenofovir is approved for children with HIV infection but is not yet approved for the treatment of HBV. Interferon therapy is often accompanied by flulike symptoms, weight loss, neutropenia, behavioral and mood changes, and outright depression. Pegylated interferon, which provides for prolonged blood levels, is approved for adults in whom it has been shown to be more effective, but there are no trials in children with chronic HBV.

The endpoint of treatment is to achieve a durable viral suppression to prevent the long-term complications of HBV. Guidelines for treatment in adults have been developed by the American Association for the Study of Liver Disease, but there is no consensus for treatment of children. In general, there is no need to rush into treatment unless early or confirmed cirrhosis is noted. The goal should be to suppress viral load low enough to achieve eAg clearance, which increases the chances of withdrawing drug and retaining effective viral suppression. This avoids long-term treatment and prevents the development of resistance. Treatment response is dependent on ALT level and viral load at the time of treatment. When the ALT is more than 5-fold above the upper limit of normal, the chance of eAg clearance is greater than 50%.9 The duration of treatment varies by agent: For nucleosides, treatment continues for 6 months after eAg clearance; interferon therapy should continue for 6 months (pegylated interferon for 1 year).

FIGURE 308-3. Gianotti-Crosti syndrome. Flat papules on the cheek of a 5-year-old girl. Similar papules were also present symmetrically on forearms, elbows, and the ventral aspects of the legs. (Source: Wolff K, Johnson RA. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill; 2009.)

The prognosis of chronic HBV during childhood is generally good. The incidence of HCC and cirrhosis related to HBV infection in childhood is low but can occur.10 Without eventual treatment, approximately 10% to 25% of persons with chronic HBV acquired at birth or during early childhood will die from cirrhosis or HCC, especially males with a family history of HCC, exposure to aflatoxin, and chronic alcohol use. This typically occurs between ages 40 and 60.


HBV infection can be prevented by proper hygiene, proper sterilization of medical equipment, the use of barrier methods during sexual intercourse, and single-use syringes (syringe exchange). Human hepatitis B–specific immunoglobulin (HBIG) has also been used to prevent HBV infection, either preexposure or postexposure. By far the most effective way to prevent infection is through vaccination, which has been the key to successfully decreasing the incidence of acute and chronic HBV in children in the United States. Universal vaccination of newborns was first recommended in 1991. This was followed by recommendations for catch-up vaccinations in older children and adolescents and, then, in 2006, by the vaccinating all children at the time (see Chapter 244).

Perinatal prophylaxis combines vaccine and HBIG. The failure rate is less than 5%, mostly a result of high viral load, although mutations in the surface antigen can also lead to failure of binding of antibody.

Postexposure, HBIG and vaccine are necessary. HBV vaccine alone is adequate before exposure unless there is insufficient time to receive several doses, necessitating the concomitant use of HBIG. Lamivudine is used in the face of cancer chemotherapy and other inducers of immunosuppression to prevent relapse.


HCV, originally labeled as non-A, non-B hepatitis, is a 9.5-kb single-stranded RNA. The virus is transcribed as a single polypeptide that is subsequently cleaved into viral proteins, including the envelope, core, polymerase, serine protease, and helicase proteins. These last 2 proteins are important targets for antivirals. There are 6 different genotypes of HCV. Their importance is largely related to differences in the response to treatment.


HCV is transmitted primarily through blood transfusions or percutaneously (including tattoos). Sexual transmission is inefficient (< 5%) but can be enhanced if the host is immuno-compromised. Similarly, vertical transmission occurs in approximately 5% of cases but may be increased 3- to 4-fold if the mother is HIV infected, particularly when the child also is HIV infected.11 The mother’s HCV viral load is also a predictor of transmission, occurring at higher frequency when the viral load is greater than 106 copies/mL. The benefit of cesarean section in preventing vertical transmission has been controversial, but most studies show no benefit. While HCV can be detected in breast milk at low titer, it is generally felt that transmission does not occur through this route and present recommendations are not to stop breast-feeding.

Almost 50% of children infected with HCV will spontaneously resolve infection.14 If this occurs, it is usually within the first few years of infection. HCV generally takes decades to become symptomatic; less than 5% will develop cirrhosis before adulthood. There are an estimated 200 million cases of chronic HCV worldwide and almost 4 million in the United States. Genotype 1 accounts for approximately 70% of cases of HCV in the United States. The seroprevalence in children under 12 years of age is estimated to be 0.2% and 0.4% for adolescents based on the 1994 National Health and Nutritional Examination Survey data,12 or approximately 60,000 to 100,000 children.13 The rate of new infections has been declining in the United States as a result of testing of blood for HCV since 1990. The major route of new infection in young children in the United States today is perinatal infection. Because of declining rates of infection in women of childbearing age, the number of infants infected is expected to also decline. In adolescents and young adults, transmission by injection or tattooing is the main source of infection. In resource-poor countries, the major route of infection by transfusion and reuse of unsterilized needles remains an important continued source of infection for children.


During acute HCV infection, ALT generally rises with the period of initial viremia. In about 50% of cases, viremia resolves within 6 months as a result of cell-mediated immune responses (mediated by CD4, CD8, and natural killer T cells) that control acute infection (Fig. 308-4A). Broad multiepitope responses, in particular, are associated with resolution of infection. When viremia is not controlled during this phase, long-term infection results (Fig. 308-4B). The cirrhosis risk for infants who acquired infection by transfusion is generally less than 5% by age 2014 but may be higher for vertically infected, and HIV-coin-fected children. HCC always occurs after cirrhosis and is very rare in children.


Acute HCV infection can either be asymptomatic or present with the classical symptoms of hepatitis, including fever, nausea, vomiting, abdominal pain, diarrhea, and jaundice. Symptomatic infection is more likely to be seen in adolescents, often after percutaneous exposure from intravenous drug use or tattooing.

Chronic HCV infection during childhood is usually clinically silent. Fatigue may accompany chronic infection. Extrahepatic symptoms include arthralgias, arthritis, and thrombocytopenia. Cryoglobulinemia, a complication seen in adults, is unusual in children. The most common finding is elevated ALT, which is present in about half of the cases. The disease course is milder than in adults, and cirrhosis or severe fibrosis is uncommon.13

FIGURE 308-4. A: Time course of virologic, serologic, and clinical events during a typical course of acute hepatitis C infection. B: Time course of virologic, serologic, and clinical events during chronic hepatitis C infection, showing fluctuations in viremia and transaminases.


Diagnostic testing begins with HCV antibody testing, but this may be absent in the early phase of acute infection (Fig. 308-4A). At this stage, HCV RNA may be required to diagnose infection. The newest generation of enzyme-linked immunosorbent assays (ELISAs) is very sensitive. Specificity was originally determined by the recombinant immunoblot assay (RIBA), similar to a western blot but with recombinant proteins. A positive RIBA or enhanced ELISA means that infection with HCV occurred. To determine whether infection is still ongoing or active and not resolved, a quantitative polymerase chain reaction should be performed. Because of fluctuations in levels of viremia, a single negative RNA test is generally not sufficient to exclude ongoing infection.

Long-term complications include cirrhosis, end-stage liver disease, and HCC. The latter almost always occurs after and as a result of liver cirrhosis.


There are 2 approved treatments of chronic HCV in children: α-interferon and α-interferon with ribavirin. They are approved for children 3 years of age and older. Treatment regimens and outcomes are dependent on the viral genotype, the magnitude of viremia, and the duration of infection. Age may also be a factor. Combination interferon-ribavirin is generally more potent. For genotype 1, sustained viral response is seen in approximately 40% of treated children, whereas in genotypes 2 and 3, sustained viral response is as high as 80% to 90%.15 Pegylated interferon has been approved in adults and has been shown to provide higher response rates for genotype 1. As of 2008, there are ongoing trials of pegylated-interferon-alpha2b combined with ribovarin in children; preliminary results indicate that the response rates are at least as good as, if not higher than, those reported in adults with fewer reported serious side effects. Side effects of interferon include flulike symptoms, neutropenia, hair loss, hypothyroidism, behavioral problems, and depression. The major side effect of ribavirin is anemia. Newer, promising HCV-specific antiviral treatments directed against the protease and helicase proteins, which are effective against genotype 1 viruses, are currently in phase I and II trials in adults.

Recent trials have shown a much higher sustained viral response (∼ 90%) when treatment is begun within the first year of infection, regardless of genotype.16,17 Early treatment should be considered in someone with clear evidence of acute HCV. This situation would arise mainly in adolescents or young adults.

In chronic HCV infection, the desired endpoint of treatment is to achieve complete viral suppression, which will halt and even reverse clinical progression. If viral suppression is sustained, eradication and cure of HCV is achievable. By convention, if the viral load remains undetectable for 6 months after treatment is discontinued, the patient is considered cured.

Deciding on who and when to treat is complicated and must take into consideration the patient’s symptomatology, degree of hepatic fibrosis, genotype, viral load, age, convenience, and risks from side effects. If the patient has severe fibrosis (stage 3) or cirrhosis (rare in children), treatment should be initiated to prevent further complications. In most other circumstances, treatment can be deferred to a time when it is convenient and expedient for the patient and family. Given the high cure rate for genotypes 2 and 3 (70–90%) and the shorter duration of treatment (6 months vs 12 months), there is little reason to delay treatment. Because of the difficulty of treating genotype 1 and the promising new HCV antivirals in clinical trial, delaying treatment as long as possible may be a reasonable strategy. If treatment is undertaken, it should be discontinued if the response after 12 weeks of therapy is suboptimal. For genotype 1 HCV, a liver biopsy may be useful, although newer serum surrogate markers of fibrosis as well as newer technology that measure liver compliance may obviate their use.

FIGURE 308-5. Time course of virologic, serologic, and clinical events occurring after superinfection with hepatitis D in a patient with existing chronic hepatitis B infection.

Persons with chronic HCV should be vaccinated against HAV and HBV if they are not already immunized.


No vaccine is currently available for HCV. Development of a vaccine that induces neutralizing antibodies has been hampered by the extraordinary ability of the virus to mutate its envelope. The use of intravenous gamma globulin has not been found to be effective in preventing vertical transmission or infection after percutaneous exposure.

While interferon may prevent infection if administered after exposure, the cost and side effects of its use are not warranted, especially given the general low probability of infection occurring and becoming chronic. The effect of waiting until a diagnosis is made does not decrease the effectiveness of early treatment of acute HCV infection, which may be effective in close to 90% of cases.

There are currently no means of preventing vertical transmission. Interferon is proscribed during pregnancy and may have serious side effects when given to young infants; newer antivirals may one day find a role, but given that they are still in clinical trial in adults, the prospect of their use in pregnant women or infants over the next few years is remote.


HDV is a defective virus that is dependent on concurrent infection with HBV to function.

It is found in approximately 5% of chronic HBV infected individuals, predominantly in Mediterranean countries, the Middle East, South America, Russia, and South Asia. It is very uncommon in North America, northern Europe, and East and Southeast Asia. It is generally more common in adults but has also been reported in a large proportion of HBV-infected children in Russia and South Asia (4– 40%). It can be transmitted percutaneously, sexually, and by close family contact either together with HBV (coinfection) or to a person already infected with HBV (superinfection). Vertical transmission is rare if it occurs at all. Infection usually results in the downregulation of HBV replication but increases the risk of cirrhosis and HCC through a direct pathogenic effect on hepatocytes, in contradistinction to HBV.


HDV infection can present as a fulminant hepatitis, usually when coinfection with HBV takes place. More commonly, it presents as an exacerbation of hepatitis in a person already infected with HBV (Fig. 308-5). HDV infection is associated with a greater chance of developing cirrhosis or HCC. Infection can resolve spontaneously, especially if there is resolution of chronic HBV, with conversion to Hepatitis B surface antigen negative status.


Diagnosis is made by serology: either anti-HDV antibody (IgM or IgG) or HDV antigen. Active infection is diagnosed by RNA polymerase chain reaction.

Treatment for HDV has generally been ineffective. It is not sensitive to anti-HBV nucleosides but has shown some responsiveness to interferon and more so to pegylated interferon when treatment is given for a year. Effective treatment requires resolution of HBV.


HDV accelerates the rate of cirrhosis and HCC. Prevention of HBV infection through vaccination and the treatment of chronic HBV. The fate of infection depends on resolution of HBV infection. There is no vaccine for HDV.

FIGURE 308-6. Time course of virologic, serologic, and clinical events occurring during infection with hepatitis E virus.


HEV is caused by a single-stranded RNA virus that has been recently reclassified as a hepevirus, closely related to the togavirus and calicivirus. It is the major cause of enterically transmitted non-A, non-B hepatitis.18 It is usually transmitted through the fecal-oral route from contaminated water or food. It may be zoonotic, transmitted from pigs and rats. It is found mostly in South Asia, the Middle East, East Africa, and Central America, although its range has been increasing recently, and sporadic outbreaks have occurred in the United States. The incubation period is between 15 and 60 days (mean 40 days). Most cases (80%) are asymptomatic. It is the cause of massive epidemics of acute hepatitis in Asia. It is usually a self-limited infection, lasting a few weeks, followed by complete recovery (Fig. 308-6). There is no chronic disease. Its major importance is in the high mortality it causes in pregnant women (20–60%) from fulminant hepatic failure (encephalopathy, hemorrhage with disseminated intravascular coagulation, or renal failure).19 Vertical infection in viremic pregnant women is estimated to occur in 50% to 100% of cases, and clinical symptoms are found in neonate. Most neonates recover and clear virus, although as many as 20%, those with early severe symptoms, may die from fulminant infection.20 Diagnosis is made by serology (anti-HEV IgM antibody) or polymerase chain reaction (in research labs). There is currently no treatment except supportive care for HEV. Several promising vaccines are currently in clinical trials.