Review Article

Hepatitis E—A Concise Review of Virology, Epidemiology, Clinical Presentation and Therapy

M. C. Donnelly; L. Scobie; C. L. Crossan; H. Dalton; P. C. Hayes; K. J. Simpson


Aliment Pharmacol Ther. 2017;46(2):126-141. 

In This Article

Genotype 1 and 2 HEV Infection


Genotype 1 and 2 cause a waterborne, epidemic hepatitis with the virus being transmitted via the faeco-oral route. Recent and novel work using human liver chimeric mice as a model of HEV infection demonstrated that HEV genotype 1 infection was established after intravenous injection of stool derived HEV virions, whereas intraperitoneal or intravenous injection of HEV-positive patient serum did not lead to active HEV infection.[33] This finding suggests that at least for HEV genotype 1, stool derived HEV virions are more infectious than virions derived from serum. HEV genotypes 1 and 2 are endemic in developing countries; HEV genotype 1 is a common cause of acute hepatitis in Asia (in particular India), whereas genotype 2 is prevalent in Central America, Mexico and Africa. These genotypes are restricted to humans (Figure 1).

The World Health Organization estimates that there are 20 million HEV infections worldwide, leading to an estimated 3.3 million symptomatic cases of HEV,[3] and 56 600 HEV related deaths.[2] However, this estimate was based on data from only nine of 21 of the Global Disease Burden areas worldwide, and it is likely that the true burden of disease is much higher. The majority of these infections are genotype 1 and 2, affecting patients in the developing world; imported cases are also observed in developed countries. Case fatality rates in epidemics range from 0.2% to 4%.[49] However, mortality rates are significantly higher in particular populations; reportedly up to 20% of infected pregnant patients in endemic countries.[50]

Hepatitis E Infection and Pregnancy. HEV infection during pregnancy (particularly during the third trimester) leads to a worsening in both maternal and foetal outcomes compared with other acute viral hepatitides, however, the pathogenesis of HEV infection in pregnant females, and the resultant high mortality rate, is incompletely understood. The high mortality rate is likely to be a result of a number of complex and interacting factors, including viral, host, hormonal and immunological factors. Potential important contributing factors include high viral load,[51] dysregulation of the progesterone receptor signalling pathway and other hormonal changes in pregnancy.[52] In pregnant women with genotype 1 HEV infection, a significantly higher viral load is seen in patients with acute liver failure compared with acute hepatitis, and higher viral loads were observed in patients with foetal death compared with patients without foetal death.[51] Defective monocyte-macrophage function occurs in pregnant patients with HEV-induced acute liver failure compared with HEV-induced acute liver injury, with reduced toll-like receptor 3 and toll-like receptor 7 expression and concomitant reduction in toll-like receptor downstream signalling.[53] This suggests an inadequate trigger for the innate immune response contributes to the development and severity of HEV-induced acute liver failure in pregnancy. Pregnancy is associated with a high level of steroid hormones, which may promote viral replication and suppress CD4 cells.[54] HEV-infected women with acute liver failure have lower CD4 counts and higher CD8 counts. Pregnant women with HEV acute liver failure have also been shown to have higher levels of oestrogen, progesterone and B-HCG compared with HEV negative patients or control healthy pregnant women.[54] The role of herbal medicines has also been debated, with one group suggesting that HEV-infected pregnant women may be more likely to take herbal medicines, which could also contribute to the high mortality in certain geographical regions.[55]

In addition, in Central Asia and eastern Africa, high mortality rates have also been reported amongst HEV-infected children aged under 2 years.[56,57]

Clinical features

The majority of acute HEV infections are asymptomatic; if present (in 20% of those with genotype 1 or 2 HEV infection),[3] symptoms are often nonspecific and include anorexia, nausea, fatigue, myalgia and jaundice. Laboratory tests show elevated serum bilirubin levels and a marked rise in liver enzymes. The mean incubation period is 40 days (range: 15–60 days). Most acute infections resolve spontaneously, with symptoms disappearing within 4–6 weeks. However, acute HEV infection can cause acute liver failure, most commonly in pregnant females in the developing world as described above. Although acute HEV infection can cause severe acute liver injury in the Western world, it rarely causes acute liver failure. Genotype 1 and 2 infections have also been implicated in the development of acute-on-chronic liver failure/decompensated liver disease. In countries where HEV is endemic, the number of cases of acute-on-chronic liver failure secondary to HEV is variable (ranging from 4% to 75%) with a median short-term mortality rate of 34% (range: 0%-100%).[58] One study from India reported a 70% 12-month mortality rate in patients with HEV infection superimposed upon chronic liver disease and interestingly, HEV infection was associated with a higher mortality rate than decompensation due to any other cause.[59]