ACP medicine, 3rd Edition


Acute Viral Hepatitis

Marlyn Mayo MD1

1Assistant Professor of Medicine, University of Texas Southwestern Medical Center at Dallas

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

June 2007

Acute viral hepatitis most commonly results from infection with hepatitis A, B, or C viruses, although a number of other viruses may also cause this disease, including hepatitis D and E viruses [see Table 1]. Hepatitis G virus and torque teno virus1 have been identified but do not appear to cause acute hepatitis. Acute hepatitis with serum aminotransferase levels greater than 1,000 units/L may also be caused by hepatic ischemia, exposure to hepatotoxins, and massive replacement of the liver with malignancy.

Table 1 Causes of Acute Viral Hepatitis

Hepatitis A virus


Hepatitis B virus


Hepatitis C virus


Hepatitis D virus

Yellow fever virus

Hepatitis E virus

Measles (rubeola) virus

Herpes simplex virus

Rubella virus

Varicella-zoster virus

Coxsackievirus B

Epstein-Barr virus


The incidence of acute viral hepatitis has been declining in the United States [see Figure 1]. The last peak of acute hepatitis A was in 1995, and in 2004 (the most recent year for which statistics are available), the number of cases reached a record low of fewer than 6,000.2 The incidence of acute hepatitis B has fallen more than 80% since 1985.2 Rates have been declining most rapidly in the pediatric population, thanks to targeted vaccination of children. In addition, donated blood is now carefully screened for serologic or virologic evidence of hepatitis virus infection. Plasma-derived products undergo viral inactivation. Nevertheless, about 13,000 cases of acute viral hepatitis are reported annually in the United States, and this number is likely a gross undercount, because of lack of reporting and unrecognized infections.


Figure 1Annual incidence of acute viral hepatitis A, B, and C (formerly non-A non-B [NANB] hepatitis) in the United States.2

Hepatitis A


Hepatitis A virus (HAV) is a small, positive-stranded RNA virus in the Picornoviridae family that is usually spread by the fecal-oral route, either person-to-person or by ingestion of contaminated food or water. HAV is stable in the environment for months but can be inactivated by a 1:100 solution of household bleach. Rare cases of infection via blood product transfusion have been reported.3

The incubation period of hepatitis A lasts from 15 to 45 days. HAV RNA is present in serum and shed in the stool throughout most of this period, then usually disappears from serum and stool shortly after the onset of symptoms. Patients can be assumed to be no longer infectious once 3 weeks have elapsed since the onset of clinical illness. By the time a patient presents to a physician's office, transmission to unvaccinated contacts likely has already occurred. Thus, person-to-person transmission is the most common known mode of inoculation [see Table 2]. Improved sanitation has increased the typical age of exposure to HAV in the United States to adulthood.

Table 2 Modes of Hepatitis A Transmission2


Percentage of Patients

Contact with hepatitis A patient


International travel


Day care center contact


Injection drug use


Food/water outbreak


Male-male sexual contact


No risk factor identified


*In the period from 2 to 6 weeks before presentation.
N = 5,571; multiple risk factors may have been reported from a single case.
Sexual, household, or other contact.


Inactivated vaccines for HAV are safe and effective and provide long-lasting immunity. Although a single vaccine dose produces an excellent short-term antibody response, two doses 6 to 18 months apart are recommended to ensure long-term protection. None of the HAV vaccines are licensed for children younger than 12 months. In the past, United States surveillance data indicated that over 50% of HAV cases occurred in specific communities (e.g., Alaska Native, American Indian, and Hispanic populations). For that reason, vaccination strategy in the United States initially targeted members of specific high-risk groups and children living in areas with a higher incidence of hepatitis A [see Table 3]. Although the incidence of acute hepatitis A used to be higher in Western states, rates have declined since 2001, when routine childhood vaccination was emphasized in these states. In 2006, the Advisory Committee on Immunization Practices (ACIP) extended the recommendation for vaccination against HAV to all United States children 1 to 2 years of age.4 Unfortunately, food-borne outbreaks continue to be a major problem that circumvents the targeted immunization strategy, and a universal vaccination program is currently being considered.

Table 3 Populations That Should Receive the Hepatitis A Vaccine in the United States4

All children 1–2 years old

Persons with chronic liver disease

Persons with HIV infection

Illicit drug users

Persons with clotting factor disorders

Laboratory workers who handle hepatitis A virus

Travelers to endemic areas*

Adoptive families of children from endemic areas

Men who have sex with men

Workers in high-risk environments (e.g., day care)

Inhabitants of communities with high or intermediate rates of hepatitis A

Children in Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, and Washington (states with > 20 cases/100,000 persons); immunization may be considered for children in Arkansas, Colorado, Missouri, Montana, Texas, and Wyoming (states with 10 to 20 cases/100,000 persons)

*Endemic areas for hepatitis A include most of Africa, Asia, and South and Central America; a detailed map is available on the Centers for Disease Control and Prevention Web site (
The following persons are not considered at high risk: health care workers, sewage/sanitation workers, food service workers, children attending day care, and nursing home patients.


Clinical Course

Asymptomatic infection is common in children younger than 5 years. Adults 50 years of age and older have a higher risk of fatal outcome. Persons with underlying chronic hepatitis B or C or alcoholic hepatitis are also more likely to progress to fulminant liver failure.5,6,7 Most patients (72%) will become jaundiced after a nonspecific viral prodrome that includes fatigue; weakness; anorexia; nausea and vomiting; fever; diarrhea; headache; abdominal pain; and myalgias, arthralgias, or both. One third of patients will require hospitalization, but most will eventually recover. The overall mortality is only 0.6%. In the United States, 3% of all cases of acute liver failure are attributed to acute HAV infection.8

Acute HAV infection does not evolve into chronic hepatitis. Acute relapsing cholestatic hepatitis A is a rare condition consisting of two or more bouts of acute HAV infection occurring over a period of 6 to 10 weeks. Recovery from acute HAV infection leads to lifelong immunity.

Serologic Markers

Immunoglobulin M antibodies to HAV (anti-HAV IgM) are present at the onset of symptoms in 95% of patients. Repeat testing may be needed to detect anti-HAV IgM in the other 5%. Anti-HAV IgM remains detectable for 3 to 6 months after acute infection. The total anti-HAV titer (i.e., IgM plus IgG) remains positive for many years, often for life. Anti-HAV IgG confers immunity to reinfection. In the third National Health and Nutrition Examination Survey (NHANES III), which was conducted from 1988 to 1994, approximately one third of the United States population had serologic evidence of immunity to HAV.9 The prevalence of infection increased with age; over 75% of persons 70 years of age or older had positive total anti-HAV titers. Anti-HAV IgG becomes detectable within 2 to 4 weeks of the initial dose of the HAV vaccine, and 99% of individuals who complete the vaccine series remain anti-HAV positive 5 years later.

There are no commercially available HAV RNA assays in the United States. HAV reverse transcription polymerase chain reaction (RT-PCR) and stool viral antigen tests are used as research tools.


Prevention through appropriate vaccination is the most effective strategy to reduce morbidity and mortality from hepatitis A. In community outbreaks, vaccination has been effective in limiting spread of the disease. For persons with known recent exposure to HAV, immune globulin is administered intramuscularly at a dose of 0.02 mg/kg. When given within 2 weeks after exposure, immune globulin is 85% effective at preventing acute HAV infection. Immunity lasts for 1 to 3 months. When given later than 2 weeks after exposure, immune globulin can attenuate the clinical course of illness. Unlike HAV vaccine, immune globulin can be administered to infants.

Patients who present with symptomatic HAV infection require supportive care. No specific antiviral medication is available. Hospitalization and referral for liver transplantation may be needed in severe cases.

Hepatitis B


Hepatitis B virus (HBV) is a partially double-stranded DNA virus belonging to the family Hepadnaviridae. It is a highly infectious virus, transmitted through exchange of body fluids. The incidence of acute HBV infection (unlike that of HAV) shows little geographic variation within the United States; however, rates are slightly higher in males and in African Americans. Most newly identified cases of hepatitis B in the United States are actually not acute infections; rather, they are chronic infections identified in persons who have recently emigrated from endemic areas. Acute HBV infection in the United States occurs principally in adults who have acquired the virus through sexual contact [see Table 4].

Table 4 Modes of Hepatitis B Transmission2


Percentage of Patients

Multiple homosexual or bisexual partners


Multiple heterosexual partners


Injection drug use


Sexual contact with known hepatitis B patient




Percutaneous injury (e.g., needle stick)


Household contact with known hepatitis B patient


Blood transfusion




No risk factor identified


*In the period from 6 weeks to 6 months before presentation.
N = 6,104; multiple risk factors may have been reported from a single case.


Recombinant vaccines against HBV are safe and highly effective. The rapid decline in hepatitis B cases in the United States over the past decade coincides with the implementation of the current vaccine strategy, which aims to vaccinate all children, all adolescents, and high-risk adults [see Table 5].10,11

Table 5 Populations That Should Receive the Hepatitis B Vaccine in the United States10,11

All infants at birth (babies born to HbsAg+ mothers also receive HBIG)

All previously unvaccinated children and adolescents

Persons with chronic liver disease not from hepatitis B

Persons with a recent history of multiple sexual partners or a sexually transmitted disease

Injection drug users

Persons receiving certain blood products or transplanted organs

Health care workers

Hemodialysis patients

Household or sexual contacts of known hepatitis B patients

Men who have sex with men

HBIG—hepatitis B immune globulin   HBsAg—hepatitis B surface antigen


Clinical Course

The clinical presentation of acute hepatitis B is indistinguishable from that of hepatitis A, with jaundice developing after a nonspecific viral prodrome [see Hepatitis A, Diagnosis, Clinical Course, above]. Among hepatitis B cases reported to the Centers for Disease Control and Prevention in 2004, 76% of patients had jaundice, 39% had to be hospitalized, and 0.5% died. The likelihood of needing hospitalization increases with age. Complete recovery is usually expected, however. In less than 1% of patients does the disease progress to acute liver failure. In the United States Acute Liver Failure Study, HBV was the second most common virus associated with acute liver failure (after HAV), accounting for 7% of all cases.8

The rate of progression from acute to chronic hepatitis B varies with the maturity and strength of the persons's immune system at the time of initial infection. Approximately 90% of neonates, 5% to 10% of immunocompromised adults, and 1% to 3% of healthy immunocompetent adults experience progression to chronic infection. The acute HBV syndrome usually results from de novo infection, but it may also represent a reactivation of chronic HBV infection. An acute reactivation flare of chronic disease is often precipitated by a period of immunosuppression, such as chemotherapy treatment.

Fibrosing cholestatic hepatitis B is a rare histologic variant that is characterized by very high levels of HBV replication, cholestasis, and rapid progression to cirrhosis. It is more commonly seen in reactivation of chronic HBV infection in immunosuppressed recipients of transplanted organs.

Serologic and Virologic Markers

HBV has several proteins that induce antibody responses, including surface antigen (HBsAg), envelope antigen (HBeAg), and core antigen (HBcAg). The appearance of these antigens and antibodies in the serum, and their disappearance from it, follows a relatively predictable pattern; thus, serologic studies can be used to identify where in the course of acute HBV an individual patient is situated [see Figure 2]. Surface antigen is the first of these proteins to be produced, about 1 to 3 months after exposure; HBsAg is produced in great excess of what is needed to coat the virions and is therefore easily detected in the serum. The earliest antibody response is the IgM antibody to core protein (IgM anti-HBc), which becomes detectable about 1 to 2 months after exposure, approximately the same time that serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are rising. Thus, almost all patients who present with jaundice and elevated serum aminotransferase levels from acute HBV infection will have positive HBsAg and IgM anti-HBc titers. Rarely, patients with very active chronic HBV infection will also test positive for both HBsAg and IgM anti-HBc, and the distinction between new infection and flare of an old infection must be made by history. The IgM anti-HBc titer is typically lower in flares of chronic disease than in acute hepatitis B.


Figure 2Increases and decreases in serum levels of hepatitis B virus (HBV) proteins and their corresponding antibodies follow a predictable pattern. HBV surface antigen (HBsAg) is the first of these proteins to be produced, about 1 to 3 months after exposure. The earliest antibody response is the IgM antibody to HBV core protein (IgM anti-HBc), which reaches the detection threshold about 1 to 2 months after exposure, approximately the same time that serum alanine aminotransferase (ALT) levels are rising. IgM anti-HBc is eventually replaced by IgG anti-HBc, resulting in a negative IgM anti-HBc but a positive total anti-HBc titer. Although levels below the detection threshold can be measured, commercial laboratories report such results as indeterminate or negative, to ensure the reliability and clinical significance of positive reports.

A falling HBsAg level signals the road to recovery in acute HBV infection. HBsAg will eventually be replaced by HBsAb; this process typically occurs 3 to 6 months after a person becomes infected with HBV, but may take more than a year. Some persons clear HBsAg before HBsAb levels have risen to the detection threshold. During this period, which is called the core window, a positive IgM anti-HBc titer alone is sufficient for the diagnosis of acute HBV infection, in the proper clinical setting.

IgM anti-HBc is eventually replaced by IgG anti-HBc, resulting in a negative IgM anti-HBc titer but a positive total anti-HBc titer. Both the HBsAb and total anti-HBc antibody responses are long-lived. After many years (usually 10 or more), the HBsAb titer will decline to undetectable levels, although the total anti-HBc titer will often remain positive for life. HBsAb confers immunity to reinfection; however, persons who have recovered from acute hepatitis B and lost their HBsAb are also able to mount an effective immune response when rechallenged with the virus. Use of the word “cured” is avoided in HBV infection because the virus may remain present at very low levels in a relatively dormant form, even after the patient appears to have recovered from the acute illness. This tiny amount of viral replication goes unrecognized by the immune system and does not lead to clinical disease, but the infection can become reactivated if the individual becomes immunosuppressed.

Patients who do not recover from acute HBV infection will continue to have elevated levels of HBsAg and total anti-HBc. These patients will progress through varying stages of chronic HBV infection, including viral replication and dormancy, immune activation, and tolerance. Rare mutant viruses that do not make HBsAg (identified by a negative HBsAg titer but a positive HBV DNA level) have been described, although such viruses have been identified primarily in patients who received HBV immune globulin after a liver transplant. About 2% of patients with chronic HBV infection make nonprotective HBsAb, and for that reason, they have simultaneously positive HBsAb and HBsAg titers.

Testing for HBeAg and HBeAb is of limited value in the setting of acute hepatitis B. Such tests are primarily useful in elucidating the status of chronic infection and the response to antiviral therapy. HBeAg is produced when infectious virions are being made, and therefore it is a good marker of active viral replication. However, newer DNA testing is a more sensitive and quantitative marker of viral replication. Conversion from HBeAg positivity to HBeAb positivity is an early marker of successful treatment of chronic HBV infection. The HBeAg and HBcAg are produced by overlapping regions of DNA. Some viruses have a mutation in the so-called pre-core region, which enables them to make HBcAg but not HBeAg.

There are seven genotypes of HBV, designated A through G. HBV A and D are the most common genotypes in the United States. Although HBV genotype has important implications for chronic HBV infection and progression to hepatocellular carcinoma, genotyping is not generally indicated in acute HBV infection.


Most cases of acute hepatitis B will resolve spontaneously, and thus only supportive care is needed. Patients should be counseled on transmission of HBV. All persons who have had very close contact with the patient in the previous 6 months and who have not already received HBV vaccine should be vaccinated. Intimate contacts of patients with acute hepatitis B (as well as infants born to HBsAg-positive mothers) should receive HBV immune globulin in addition to the vaccine.

Antiviral Medication

Several case series have suggested that treatment during the acute stage of HBV infection with antiviral medication (e.g., lamivudine) may shorten the duration of illness and prevent progression to liver failure.12,13,14,15 Other researchers have reported failure of antiviral therapy to prevent a fatal outcome.16 No controlled trials have directly demonstrated that treatment of acute HBV infection improves survival or reduces progression to chronic disease. Because the stakes of severe hepatitis B are high and the overall incidence of acute HBV infection is declining, it is unlikely that large randomized trials will be completed. It is reasonable to consider using antiviral therapy in patients with severe acute HBV infection (i.e., those with coagulopathy, encephalopathy, or severe jaundice), although this practice is not yet the standard of care. Lamivudine appears to be very well tolerated in decompensated patients, even in those with fulminant disease. Patients with fulminant liver failure should also be considered for liver transplantation. The long-term outcome of patients with acute hepatitis B treated with antiviral therapy is not yet known. Thus, with mild cases of acute hepatitis B, letting the disease run its course remains the prudent response. Prophylaxis against reactivation of chronic HBV infection with an antiviral agent (e.g., lamivudine) should be given to HBV-infected patients (even if HBV DNA is below the limit of detection) before planned immunosuppression, such as chemotherapy.

Hepatitis C

Transmission and Prevention

Hepatitis C virus (HCV) is an RNA virus of the Flaviridae family. HCV is transmitted parenterally. Before universal screening of the blood supply in the United States, which began in 1990, HCV was the most common cause of posttransfusion hepatitis. Currently, the risk of acquiring HCV through transfusion of a unit of blood in the United States is estimated to be between 0.01% and 0.001%.17 In 2004, most cases of acute HCV infection in the United States occurred in injection drug users [see Table 6]. The second most common risk factor for acute HCV infection is multiple sexual partners. The risk of transmission from an HCV-positive individual to an HCV-negative partner in a monogamous relationship is about 4% to 5% over 20 years.18 Because this transmission rate is considered low, sexual barrier precautions are not routinely recommended for monogamous couples. Although 5% to 6% of patients with acute hepatitis C report household contact with person known to be infected with HCV, it is not clear how (or whether) such transmission may occur. The sharing of blood-contaminated toiletries (e.g., razors, toothbrushes) has been proposed but not proved to be a transmission source. Perinatal transmission occurs in 4% of cases; the risk is proportional to maternal HCV viral load. Pregnant women who are coinfected with HIV and have high HCV viral burdens have a 25% risk of perinatal HCV transmission.19

Table 6 Modes of Hepatitis C Transmission2


Percentage of Patients

Injection drug use


Multiple sexual partners




Sexual contact with known hepatitis C patient


Household contact with known hepatitis C patient


Percutaneous injury (e.g., needle stick)


Health care worker




Blood transfusion


No risk factor identified


*In the period from 6 weeks to 6 months before presentation.
N = 755; multiple risk factors may have been reported from a single case.

The risk of HCV transmission from a single needle stick averages 1.8% (range, 0% to 7%).17 The United States Public Health Service does not recommend the use of immune globulin or antiviral agents for postexposure prophylaxis of hepatitis C. Health care workers who experience occupational exposure to the blood of an HCV-infected patient should undergo follow-up HCV testing to determine whether infection has occurred.20

Unfortunately, no effective HCV vaccine has been developed. The only prevention strategies are the practices of universal precautions, blood screening, blood product purification, and risk-reduction counseling. Despite the lack of an effective vaccine, the rates of acute HCV infection in the United States are declining, for uncertain reasons. Screening of the blood supply is one possible factor. Among injection drug users—the group in which acute HCV infection has shown the most rapid decline—improved needle practices after the onset of the HIV epidemic may be responsible.


Clinical Course

In adults, acute HCV infection is more likely to be asymptomatic than is acute HAV or HBV infection. Only 10% to 20% of patients with acute HCV infection develop jaundice, and only 20% to 30% have nonspecific symptoms of fatigue, nausea, or vomiting. In patients who do become jaundiced, the bilirubin level usually peaks at less than 10 to 15 mg/dl, and peak serum aminotransferase levels are usually under 1,000 units/L. Progression to fulminant liver failure is exceedingly rare. In the 1,033 patients enrolled in the United States Acute Liver Failure Study between 1998 and 2006, only one case of liver failure was attributed to acute HCV infection.8

Most untreated cases of acute hepatitis C (50% to 84%) will evolve into chronic HCV infection.21 Spontaneous recovery is more likely to occur in patients who have an icteric illness, those infected with HCV genotype 2 or 3,22 young females who are not African American, and those who experience rapid decline in HCV RNA levels during the first 4 weeks.23,24 When spontaneous recovery occurs, it usually does so within the first 3 to 4 months of infection.

Serologic and Virologic Markers

HCV RNA can be detected in the blood by RT-PCR or transcription-mediated amplification (TMA) within 2 weeks of acute infection, usually before the patient becomes symptomatic or develops an elevated serum ALT level. HCV PCR assays, although not approved by the Food and Drug Administration for diagnosis in the acute setting, have been standardized and are often used for this purpose. The presence of HCV RNA in the plasma defines active HCV infection.

Antibodies to HCV develop gradually after the initial infection. A series of enzyme-linked immunosorbent assays (ELISAs) have been developed to detect anti-HCV antibodies. The current third-generation ELISA detects antibodies an average of 7 to 8 weeks after infection,25but antibodies may not be detectable in some individuals until 12 weeks after infection. Distinguishing between IgM and IgG anti-HCV has not proved clinically useful for differentiating acute from chronic infection. Antibody titers will rise over weeks to months in acute infection and will slowly fall in persons in whom the virus has been cleared, ultimately becoming negative in 5% of 10% of patients.26 Although more sensitive than the second-generation assays, the third-generation HCV ELISA is slightly less specific. A confirmatory test is sometimes needed, particularly if no risk factors can be identified. A positive HCV RNA level confirms the presence of the virus. Recombinant immunoblot assays (RIBA) are useful for differentiating cases in which the infection has resolved from cases in which an antibody test result is falsely positive. RIBA assesses reactivity to four individual HCV antigens and includes a superoxide dismutase (SOD) control. SOD detects antibodies to yeast proteins that may produce false positive results in the ELISA assay (the recombinant HCV antigens are made from yeast). RIBA is positive within 7 months in 85% of cases of acute HCV.21

There are six major genotypes of HCV, which can be identified by several methodologies, all of which are accurate. Genomic amplification and sequencing is the gold standard, but PCR with genotype-specific primers, restriction fragment length polymorphism of amplified sequences, and line probe assays compare favorably.


Because liver failure from acute HCV infection is practically nonexistent, the primary goal of treatment of patients with acute HCV infection is to prevent progression to chronic HCV. Several studies have now indicated that antiviral therapy given during the acute phase of HCV infection significantly decreases the evolution to chronic disease.27,28 Moreover, response rates for treatment of acute HCV infection are much better than for chronic liver disease (90% versus 50%),27 providing another incentive for treatment during the acute phase. However, because treatment trials have used different methodologies, the optimal timing and treatment regimen for acute HCV infection is still uncertain. A plummet in the number of new HCV infections has also made further studies difficult to complete.

Initiation of therapy for new HCV infections is usually delayed until 4 to 12 weeks after the onset of symptoms, for two reasons. First, 15% to 50% of acute infections will resolve naturally.23 Therapy is unnecessary in these patients, and natural clearance will generate protective memory T cell responses. Second, delaying treatment for up to 12 weeks does not appear to compromise therapeutic efficacy. One study, however, found that delaying treatment for 20 weeks did decrease response rates, from 92% to 76%.29 Response rates to treatment with both regular and pegylated interferon are excellent, but the latter is both easier to administer and possibly more effective. Ribavirin cotherapy is not necessary to achieve high sustained response rates. Treatment with pegylated interferon alpha-2b (1.5 µg/kg weekly) for a duration of 8 weeks is effective for infection with HCV genotypes 2, 3, and 4. However, genotype 1 infection requires 24 weeks of therapy.28

The long-term follow-up of patients treated for acute HCV infection is limited, but the response appears to be durable. Of 31 patients followed for a median of 2.6 years after eradication of the virus (defined as undetectable RNA levels 6 months after therapy), all remained free of the virus. Of possible concern, however, was that only 35% of these patients retained HCV-specific CD4+ T cell responses, a feature that has been previously considered necessary to prevent relapse and protect from a second infection.30,31

Hepatitis D

Hepatitis D virus (HDV) is a very small RNA virus, the sole member of the Deltavirus family. HDV can infect only persons with simultaneous HBV infection; HDV does not produce its own capsid, and instead uses the HBsAg protein to coat its virions and bind to hepatocytes.

Transmission and Prevention

HDV is transmitted parenterally. However, unlike its helper virus, HBV, the most common route of transmission in the United States is through intravenous drug use rather than sexual contact. The incidence of HDV infection in North America is low, and it is falling precipitously in other previously endemic areas of the world, such as the Mediterranean basin, because of the implementation of HBV vaccine programs. HDV infection can be prevented by vaccination for HBV. There is no HDV vaccine to protect HBsAg carriers. HDV may be acquired as a superinfection or coinfection with HBV; however, the HBV replication must be established first. In cases of HBV-HDV-HCV coinfection, one virus is usually dominant over the others.32,33


Clinical Course

Acute HDV infection may be asymptomatic, but patients often present with jaundice, and the clinical course is often severe. Approximately 10% to 15% of cases follow an indolent course, whereas 40% progress to cirrhosis within 2 to 6 years. HDV infection increases the risk of progression to cirrhosis and development of hepatocellular carcinoma in patients with HBV.34 HDV is also an important cause of fulminant liver failure worldwide, although no cases have yet been reported by the United States Acute Liver Failure Study Group.8

Serologic and Virologic Markers

HDV antigen is present early in HDV infection but becomes rapidly undetectable as it becomes bound by HDV antibody; thus, it is rarely used for diagnostic testing. HDV RNA, however, is detectable throughout infection. HDV IgM antibody becomes detectable days to weeks after the onset of illness, after which HDV IgG becomes detectable. If the infection resolves, HDV IgM will disappear after a few months. HDV IgG persists longer but usually decreases in titer and may also disappear. Patients who are HBsAg positive and who develop an acute hepatitis infection but are HBc IgM negative should be tested for possible HDV superinfection.


There are no currently no studies of treatment of acute hepatitis D. Several small studies have evaluated the use of interferon, lami vudine, or both for chronic HDV infection, but very few patients in these studies have shown sustained virologic responses.35,36,37

Hepatitis E

Transmission and Prevention

Hepatitis E virus (HEV) is an RNA virus that is transmitted through the fecal-oral route. Contaminated water sources are responsible for most large outbreaks. Thus, hepatitis E is endemic in developing areas with warm climates, such as India, Asia, Central America, Africa, and the Middle East. Epidemics often follow flooding from the monsoon season. HEV is not a common cause of acute hepatitis in North America, but it should be considered in travelers to endemic areas. The classification of HEV is still being debated, but HEV shares features with Norwalk agent, rubella, and HAV. No vaccine for HEV is available as of yet, but good sanitation and personal hygiene may help curtail outbreaks.


Clinical Course

The incubation period of HEV infection is 28 to 40 days. Serum aminotransferase levels peak 42 to 46 days after exposure.38 As with other forms of viral hepatitis, a viral prodrome of flulike symptoms lasting 1 to 5 days precedes the development of jaundice. Hepatosplenomegaly and pruritus are not uncommon.39 Acute hepatitis E may progress to fulminant liver failure. The overall mortality is less than 1%.40 In the United States Acute Liver Failure Study, one of 1,033 cases was attributed to acute HEV infection.8 For unknown reasons, the mortality from hepatitis E is much higher in pregnant women, and it increases with the duration of pregnancy. Maternal mortality is about 1% to 2% in the first trimester, 8% to 10% in the second trimester, and 20% in the third trimester.41 Patients with underlying chronic liver disease also have very high mortality (up to 67%).42 Survivors of hepatitis E do not develop chronic infection.

Serologic and Virologic Markers

Development of HEV IgM usually is accompanied by an elevation in the serum ALT level. HEV IgM may not be detectible until just before the ALT level peaks, and it persists until about 6 months after the illness resolves. Thus, if the HEV IgM titer is negative early in the course of illness, the assay may need to be repeated if clinical suspicion is high. HEV RNA is detectible in the serum about 2 weeks after exposure. However, HEV RT-PCR tests are not widely available. HEV IgG becomes detectable shortly after HEV IgM does and persists longer, although the average duration is not known (the period has been estimated to be 1 to 14 years). Likewise, the period of immunity that follows an initial infection is not known. Studies of serologic prevalence suggest that some persons who become infected with HEV remain asymptomatic. However, these seroepidemiologic studies are complicated by the fact that different ELISAs vary widely in their sensitivity and specificity.


Immune globulin is not helpful in acute HEV infection. Even immune globulin produced in endemic areas has very low levels of IgG HEV and does not offer protection from the acute illness. Supportive care and referral for liver transplantation if necessary constitute the mainstay of therapy.

Nonhepatotropic Viruses

In addition to hepatitis viruses A through E, several other viruses may cause liver inflammation, even though the liver is not the primary site of viral replication [see Table 1]. With the exception of herpes simplex virus (HSV) and varicella-zoster virus (VZV), these viruses typically cause a milder acute hepatitis, with a twofold to 10-fold elevation in serum aminotransferase levels and an increase in serum bilirubin levels of up to 10 mg/dl.

Herpes Simplex Virus

Both HSV-1 and HSV-2 can cause an acute hepatitis syndrome if the infection is disseminated. Disseminated infection usually occurs in immunocompromised persons, but it may also occur in immunocompetent individuals, particularly during pregnancy, and in neonates. Concomitant skin and mucous membrane lesions are found in about 40% of cases. HSV hepatitis often takes a severe and rapidly fatal course if acyclovir is not started early. Thus, if HSV hepatitis is suspected, acyclovir (10 to 30 mg/kg/day every 8 hours) should be started while a diagnosis is being confirmed. In patients with HSV hepatitis, an HSV DNA PCR serum assay is usually positive. Liver biopsy reveals focal areas of necrosis, sometimes with intranuclear inclusions in the hepatocytes. In immunocompetent adults, liver transplantation may be considered.

Varicella-Zoster Virus

Primary VZV infection (chickenpox) may cause an acute hepatitis. In children, this is usually manifest as a mild elevation in serum aminotransferase levels, but in adults, the aminotransferase level may increase to over 1,000 units/L, and the disease may progress to fulminant liver failure. Hepatic involvement in reactivation of zoster (shingles) is rare but may occur in immunocompromised persons. The diagnosis is best confirmed by detecting the virus in the serum by PCR. The liver biopsy result may resemble that of HSV hepatitis, with focal coagulative necrosis and intranuclear inclusions. VSV typically incites more of an inflammatory response in the liver. Treatment is with acyclovir, 30 mg/kg/day every 8 hours for 7 to 10 days.

Epstein-Barr Virus

Epstein-Barr virus (EBV) is a lymphotropic DNA virus that involves the liver, the spleen, or both organs in 10% to 15% of symptomatic infections. EBV is transmitted through oral secretions (hence the popular term, kissing disease), and usually remains in the body for life. Over 90% of the world's population is infected with EBV; many primary infections occur in childhood. Primary EBV infections in adults older than 30 years are more likely to result in hepatitis and jaundice.43 The typical presentation of liver involvement is mild jaundice and hepatomegaly. The most common findings overall are pharyngitis, cervical lymphadenopathy, splenomegaly, and lymphocytosis. Thrombocytopenia is often present. The heterophile antibody (i.e., Mono spot) test is sensitive but not entirely specific. Confirmation with an EBV antibody assay is suggested. If a liver biopsy is done, the atypical lymphocytes may be seen infiltrating the sinusoids.

There is no specific treatment of EBV hepatitis. It is usually a mild, self-limited disease; there are only rare reports of liver failure.


Like EBV, cytomegalovirus (CMV) is a common lymphotropic DNA virus (CMV is found in up to 70% of the population); it persists in a dormant state after acute infection. CMV hepatitis may occur with the primary infection or, more commonly, with reactivation. Immunocompetent patients may have mild jaundice, mild to moderately elevated serum aminotransferase and alkaline phosphatase levels, and hepatosplenomegaly. In immunocompromised individuals, however, the disease can follow a severe, life-threatening course; immunocompromised patients should be started on gancyclovir or foscarnet. The diagnosis is best made on the basis of a positive CMV early antigen or DNA polymerase assay. A CMV IgM assay may also be positive. Liver biopsy may show so-called owl's eye nuclear inclusions, but it will usually show giant multinuclear cells and focal necrosis.

Human Parvovirus B19

Human parvovirus B19 is a small DNA virus that causes a wide variety of clinical diseases, most commonly, the childhood illness erythema infectiosum (fifth disease). Mild elevation of serum aminotransferase levels may occur during the course of fifth disease. Human parvovirus B19 is specifically associated with aplastic anemia. The virus has been found in 50% to 67% of cases of cryptogenic acute liver failure, including many involving aplastic anemia, suggesting that human parvovirus B19 may cause either very mild or very severe liver disease.44Therapy is supportive, and liver transplantation may be considered.


Infections with adenoviruses are extremely common, but hepatic involvement is unusual. Adenoviruses are DNA viruses and usually cause a mild upper respiratory illness or a gastrointestinal syndrome. However, several cases of fulminant liver failure from adenovirus infection in immunocompromised patients have been reported.45 Therapy is supportive.

Yellow Fever

Yellow fever virus is one of the RNA hemorrhagic fever viruses. It is a member of the Flaviviridae family, along with HCV. It is transmitted by either mosquitoes or person-to-person in tropical areas (exclusive of the tropical areas of North America). Early in the disease course, patients may develop jaundice and abnormal serum aminotransferase levels. The mild form of yellow fever may resolve spontaneously, but 20% of patients will progress to multiorgan failure and death. No specific therapy is available, but a live attenuated vaccine provides protection and should be offered to travelers to endemic areas.

Rubella (German Measles) and Rubeola (Measles)

Mild elevations in the serum aminotransferase level may accompany rubella or rubeola. However, since initiation of very effective childhood vaccines in the United States, very few cases have been reported.

Coxsackievirus B

Coxsackievirus B is an enterovirus that predominantly affects children younger than 2 years, although it can be passed to older children and adults. In the vast majority of new infections (> 95%), patients are either asymptomatic or experience a brief upper respiratory illness. Infection can, however, lead to encephalitis, meningitis, myopericarditis, rash (hand, foot, and mouth disease), and sometimes hepatitis. In neonates, the disease may progress to a sepsis syndrome with liver failure. The diagnosis of coxsackievirus B infection is best made by RT-PCR of the enterovirus RNA. No specific antiviral medication is helpful.


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Editors: Dale, David C.; Federman, Daniel D.