Global Alert and Response (GAR)

Hepatitis E

The disease

- Diagnosis
- Host immune response
- Prevalence
- Pathogenesis
- Transmission
- Risk groups

Hepatitis E virus causes acute sporadic and epidemic viral hepatitis. Symptomatic HEV infection is most common in young adults aged 15-40 years and is uncommon in children. Although HEV infection is frequent in children, it is mostly asymptomatic and anicteric.5

The clinical presentation of hepatitis E is comparable to hepatitis A.

The incubation period following exposure to HEV ranges from 3 to 8 weeks, with a mean of 40 days.29, 40, 41

Typical signs and symptoms of hepatitis include jaundice, anorexia, hepatomegaly, abdominal pain and tenderness, nausea and vomiting, and fever, although the disease may range in severity from subclinical to fulminant.10, 29

Peak viremia and peak shedding of HEV into the faeces occurs during the incubation period and early acute phase of disease. Detection of HEV antigens in the liver generally parallels viremia and faecal shedding of virus.41, 52

The highest rate of clinically evident disease is typically observed in young to middle-age adults. Lower disease rates in younger age groups may be the result of anicteric or/and subclinical HEV infections.18

The severity of an HEV infection is generally greater than the severity of an HAV infection.41

In general, hepatitis E is a self-limiting viral infection followed by recovery.

Occasionally, a fulminant form of hepatitis develops, with mortality rates ranging between 0.5% - 4.0% of the overall population of patients.

Fulminant hepatitis cases in pregnancy may reach a mortality rate of 20% in the 3rd trimester. Premature deliveries with high infant mortality of up to 33% are also observed.10, 29, 40, 41, 48 The reason for this high mortality is not clear yet. Some of the complications of pregnancy are toxemia with hypertension, proteinuria, edema, and kidney lesions. By directly or indirectly affecting the kidneys, HEV might precipitate eclampsia and lead to increased mortality in pregnant women.6

Common cholestatic jaundice can persist for several weeks.

No evidence of chronic inflammation or of a healthy chronic carrier state has been detected, and no recurrence of hepatitis E has been reported.29, 40, 41

Association with hepatocellular carcinoma or persistent viremia are not features of HEV infection.48

Coinfection of young children with HEV and HAV may lead to severe forms of disease, including acute liver failure.

Since cases of hepatitis E are not clinically distinguishable from other types of acute viral hepatitis, diagnosis is made by biochemical assessment of liver function (laboratory evaluation of: urine bilirubin and urobilinogen, total and direct serum bilirubin, ALT and AST, alkaline phosphatase, prothrombin time, total protein, albumin, IgG, IgA, IgM, complete blood count). Acute hepatitis E is diagnosed when the presence of IgM anti-HEV is detected.41, 52

Storage of serum samples is acceptable for several days at 4°C, although anti-HEV will be preserved at -20°C, and a temperature of £-70°C should be preferred when viremia is suspected.42

Hepatitis E should be suspected in outbreaks of waterborne hepatitis occurring in developing countries, especially if the disease is more severe in pregnant women, or if hepatitis A has been excluded. If laboratory tests are not available, epidemiologic evidence can help in establishing a diagnosis.18

HEV RNA can be detected in acute phase faeces by PCR in approximately 50% of cases. Immune electron microscopy is positive in only about 10% of cases.41

The viral proteins pORF2 and pORF3 have been expressed in various recombinant systems and form the basis for diagnostic tests and vaccine studies. To confirm the results of EIA or ELISA tests, Western blot assays to detect IgM and IgG anti-HEV in serum can be used, along with polymerase chain reaction (PCR) tests for the detection of HEV RNA in serum and stool, immunofluorescent antibody blocking assays to detect antibody to HEV antigen in serum and liver, and immune electron microscopy to visualize viral particles in faeces.9, 18, 19, 22, 30, 36, 41, 48, 52, 55, 56

Host immune response
Viremia in bile and serum and shedding of HEV in faeces reach their peak during the incubation period and keep constant levels in the acute phase of the disease. At the same time, HEV antigens can be detected in the liver.

The period of infectivity after acute infection has not been determined, but virus excretion in faeces has been demonstrated up to 14 days after onset of jaundice.

Viremia precedes the major peak in ALT activity.

Virus excretion in stools continues for up to 14 days after onset of illness, then disappears during the recovery phase.

Antibodies to HEV (IgM and IgG) develop at the time symptoms occur, usually before the development of jaundice.41, 48 IgM anti-HEV precedes the IgG anti-HEV by a few days.4

Viremia may persist after appearance of serum antibodies.

IgM anti-HEV titres decline rapidly during early convalescence.48

IgG anti-HEV have been shown to persist for long periods of time (>14 yrs) and provide protection against subsequent infections.27, 29

Monkeys infected with human HEV are protected against new challenge with homologous or heterologous strains from Asian and African countries. However, the immunity is incomplete since only the clinical disease seems to be prevented, while the virus is still excreted in stools.38

Click here for: Typical serologic course

The highest prevalence of infection occurs in regions where low standards of sanitation promote the transmission of the virus.29

The prevalence of antibody to HEV in suspected or documented endemic regions has been much lower than expected (3 - 26%).41

Screening of blood donors in central Europe and North America has shown a prevalence of anti-HEV antibodies of 1.4 - 2.5%, in South Africa of 1.4%, in Thailand of 2.8%, in Saudi Arabia of 9.5%, and in Egypt of 24.0%.

The prevalence of antibody to HEV in non endemic regions (like the US) has been much higher than anticipated (1 - 3%).41, 51

HEV infections account for >50% of acute sporadic hepatitis in some high endemic areas.


In monkeys, viral replication apparently causes liver damage. The immune response successfully eliminates viremia and shedding of virus in faeces, while not inducing much damage to the liver. Seroconversion marks the clearing of virus from faeces and blood and is correlated with resolution of disease.54

As with hepatitis A, virus is detected in bile, liver and faeces before the onset of liver function abnormalities.48

Severe or fulminant cases may show submassive and massive hepatic necrosis.10, 48

HEV is spread by the oral-faecal route. This enterically transmitted virus has been implicated in several food and waterborne outbreaks.40

Consumption of faecally contaminated drinking water has given rise to epidemic cases, and the ingestion of raw or uncooked shellfish has been the source of sporadic cases in endemic areas.41

The low amount of intact HEV particles present in patient stools accounts for the generally lower rate of person-to-person transmission of hepatitis E when compared with that of hepatitis A.10

Naturally acquired HEV antibodies have been detected in primates, rodents and swine.26, 41 Swine HEV cross-reacts with antibodies to the human HEV capsid antigen.33

Human hepatitis E has been transmitted under laboratory conditions to various species of primates, domestic pigs, lambs and laboratory rats.9, 32, 41, 54, 57

Species specific HEV has been demonstrated in pigs with the identification of swine HEV. Swine HEV is distinct, but closely related to human HEV strains. While specific-pathogen-free pigs can be experimentally infected with the US-2 strain of human HEV, it is still not known whether swine HEV can infect humans, although it can infect chimpanzees under experimental conditions. Until then, swine HEV raises a potential public health concern for zoonosis and xenozoonosis following xenotransplantation with pig organs.32, 33

A zoonotic spread of HEV is not excluded, since monkeys, pigs, cows, rodents, sheep and goats are susceptible to infection with HEV (possible non-human reservoir of virus).14, 18, 26, 41, 53, 54

Although hepatitis E is not endemic in the US and other developed countries, anti-HEV has been found in a significant proportion, up to 28% in some areas, of healthy individuals in these countries.51 Subclinical infection of humans with swine HEV (possible non-human reservoir of virus) might explain the relatively high prevalence of anti-HEV in healthy individuals in areas where hepatitis E is not endemic.33, 60

Most cases of acute hepatitis E in the US, central and western Europe have been reported among travellers returning from high HEV-endemic areas, although a few have occurred in individuals who have not left their country. It appears, therefore, that some HEV is imported into industrialized countries and some is probably endemic, possibly as a zoonosis.29

The occurrence of sporadic HEV infections in humans may maintain transmission during inter epidemic periods.

Regardless of whether HEV is endemic in the respective human population, hepatitis E is enzootic in pigs, probably worldwide.34

There is no evidence for sexual transmission or for transmission by transfusion.4

Risk groups
Here is a list of groups of people who are at risk of contracting HEV:

  • persons residing in areas where extended community outbreaks exist
  • international travellers to regions of the world where HEV is endemic
  • refugees residing in overcrowded temporary camps following catastrophies, especially in Sudan, Somalia, Kenya and Ethiopia
  • persons who have chronic liver disease
  • possibly persons working with non-human primates, pigs, cows, sheep and goats

Typical serologic course

From: Robertson BH and Bradley DW. Enterically transmitted hepatitis. In: Lennette EH, Lennette DA, and Lennette ET, eds. Diagnostic Procedures for Viral, Rickettsial, and Chlamydial Infections, 7th ed. Washington, DC, American Public Health Association, 1995:361-373,45 "Copyright (1995) American Public Health Association", with permission.

Summary of clinical, biochemical, and serologic findings in acute hepatitis E.