Acute hepatitis E is a form of icteric, self-limited viral hepatitis caused by the hepatitis E virus (HEV). The disease prevails in developing countries of southeast Asia, Indian subcontinent and Africa. Rather surprisingly, a number of solitary cases or small series of cases of acute hepatitis E were recently identified in various European countries, the U.S. and Japan, where epidemic outbreaks of hepatitis E have never been reported and single cases of hepatitis E were confined to travelers returning from virus-endemic regions.

Clinical manifestations of hepatitis E are similar to those observed in patients with acute hepatitis A or B (icteric hepatitis); the illness usually is insidious in onset with a prodromal phase lasting 1 to 4 days. Some of HEV-infected persons may exhibit only nonspecific symptoms resembling those of an acute viral febrile illness with serum alanine aminotransferase elevations but without jaundice (anicteric hepatitis), and some may remain entirely asymptomatic. A few patients may have a prolonged course with marked cholestasis (cholestatic hepatitis) lasting 2 to 6 months, ultimately with spontaneous resolution. In a small proportion of patients, the disease is severe and associated with subacute or fulminant hepatic failure. Population surveys during outbreaks have reported mortality rates of 0.07% to 0.6%.

Hepatitis E virus (HEV) was identified in 1983 by immune electron microscopy (1) and is classified in a separate genus named Hepevirus in family Hepeviridae (2). HEV is a small RNA virus, 32 to 34 nm in diameter, nonenveloped, and icosahedral. HEV RNA, cloned in 1990 and fully sequenced shortly thereafter, is approximately 7.2 kilobases in length, single- and positive-stranded, 5'-capped, and polyadenylated (3, 4). HEV genome contains three open reading frames (ORFs): ORF1 encodes nonstructural proteins, ORF2 encodes the viral capsid protein, and ORF3 encodes a protein of a little unknown function but essential for infectivity when tested in experimentally inoculated primates. Phylogenetic analysis of HEV isolates shows the existence of geographically distinct genotypes (see table adapted from (5)).

HEV infection is transmitted predominantly through the fecal-oral route; most reported outbreaks in disease endemic areas have been related to consumption of fecally contaminated drinking water. Several epidemics of hepatitis E affecting several hundred to several thousand persons have occurred on the Indian subcontinent and in southeast and central Asia, where this infection is endemic (6, 7). Outbreaks of hepatitis E have also been reported from the northern and western parts of Africa and the Middle East and the North America, where two small outbreaks in Mexico occurred in 1986 and 1987 (tab. 1). Overall attack rates range from 1% to 15% and are higher for adults (3% to 30%) than for children (0.2% to 10%). The male-to-female ratio among cases has ranged from 1:1 to 4:1 with a particularly high attack and mortality rates (up to 25%) among pregnant women. Recurrent epidemics in endemic regions are probably related to continuous fecal contamination of water because person-to-person transmission of hepatitis E seems to be uncommon, and secondary attack rates among household contacts are only 0.7% to 2.2%. Seroprevalence rates of anti-HEV are quite high among populations in endemic areas (10% to 40%), anti-HEV antibodies are uncommon in children and their rates increase during young adulthood to reach about 40% in adults (8). In contrast, antibodies are common in children in Egypt and seroprevalence rate reaches 70% or more in young adults (9) but epidemic outbreaks of hepatitis E are not known.

Virologic, serological and pathologic data significant for pathogenesis of the HEV infection derived from both patients and experimentally infected primates (cynomolgus macaques, rhesus monkeys, and chimpanzees). In human volunteers (1, 10), the incubation period after oral exposure was 4 to 5 weeks and HEV was detected in the stool approximately 1 week before the onset of illness and for up to 2 weeks thereafter. In clinical cases, the fecal shedding of the virus was observed until about 4 weeks after the onset of illness.

In serum, HEV RNA can be detected for 2 weeks after the onset of illness in virtually all patients. The diagnosis of human HEV infection is based on detection of either HEV RNA in stool and serum specimens using a reverse transcription–polymerase chain reaction assay or the virus-specific host immune response (humoral and cellular). IgM anti-HEV appears in the early phase of clinical illness, lasts 4 to 5 months, and can be detected in 80% to 100% of cases during outbreaks of acute hepatitis E. The titer of IgG anti-HEV increases during the convalescent phase and remains high for at least 1 to 4.5 years; the exact duration of persistence of IgG anti-HEV in serum is not known.

The presence IgM anti-HEV in serum of patients is helpful in diagnosis of acute infection, whereas detection of IgG anti-HEV alone may indicate the convalescent phase or past infection (fig. 1). Patients with acute hepatitis E show cellular immune responses to HEV proteins (11, 12) but the number of cytokine producing HEV-reactive CD8-cells is not increased among peripheral blood mononuclear cells (PBMCs). Th1/Th2 cytokine balance is biased towards Th2 in pregnant women (13), in whom hepatitis E is particularly severe. The onset of ALT elevation in the serum and of histopathologic changes in the liver generally corresponds to the appearance of anti-HEV in serum. The temporal concordance of HEV-specific immune response with the onset of liver pathology suggests that liver injury is immune-mediated; there is no evidence for cytopathic properties of HEV itself. Histopathologic features of hepatitis E are similar to those of other forms of acute hepatitis but approximately one half of patients with hepatitis E has morphlogic evidence of cholestatic hepatitis (14). Submassive or massive necrosis and collapse of liver parenchyma are found in patients with severe liver injury.

Fulminant hepatic failure in HEV-infected pregnant women, associated with an increased frequency of abortions, stillbirths, and neonatal deaths, is an explosive disease with short pre-encephalopathy period, rapid development of cerebral edema and high occurrence of disseminated intravascular coagulation. Pregnant women, particularly those in the second or third trimester, are more frequently affected during hepatitis E outbreaks than are others in the population and have a worse outcome, with mortality rates of 5% to 25% (15, 16). The pathogenetic elements leading to severe liver damage during pregnancy, especially during its last trimester remains unknown and require further studies. Severe liver injury during pregnancy complicated by HEV infection may be related to immune and hormonal factors changed during pregnancy, and also to genetic and environmental factors in developing countries.