Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries.

Hepatitis E Virus Infection

Hepatitis E virus (HEV) infection causes severe liver disease in pregnant women. In a case series of 220 pregnant women with jaundice and acute viral hepatitis, women with HEV infection died more o...

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Maternal and Fetal Outcomes in Pregnant Women with Acute Hepatitis E Virus Infection

Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale epidemics of acute viral hepatitis, particularly in developing countries. In men and non-pregnant women, the disease is usually self-limited and has a case-fatality rate of less than <0.1%. However, in pregnant women, particularly from certain geographical areas in India, HEV infection is more severe, often leading to fulminant hepatic failure and death in a significant proportion of patients. In contrast, reports from Egypt, Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in non-pregnant women. The reasons for this geographical difference are not clear. The high mortality rate in pregnancy has been thought to be secondary to the associated hormonal (oestrogen and progesterone) changes during pregnancy and consequent immunological changes. These immunological changes include downregulation of the p65 component of nuclear factor (NF-kappaB) with a predominant T-helper type 2 (Th2) bias in the T-cell response along with host susceptibility factors, mediated by human leucocyte antigen expression. Thus far, researchers were unable to explain the high HEV morbidity in pregnancy, why it is different from other hepatitis viruses such as hepatitis A with similar epidemiological features and the reason behind the difference in HEV morbidity in pregnant women in different geographical regions. The recent developments in understanding the immune response to HEV have encouraged us to review the possible mechanisms for these differences. Further research in the immunology of HEV and pregnancy is required to conquer this disease in the near future.

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Hepatitis E and pregnancy: understanding the pathogenesis.

Hepatitis E virus (HEV) infection can lead to acute and chronic hepatitis as well as to extrahepatic manifestations such as neurological and renal disease; it is the most common cause of acute viral hepatitis worldwide. Four genotypes are responsible for most infection in humans, of which HEV genotypes 1 and 2 are obligate human pathogens and HEV genotypes 3 and 4 are mostly zoonotic. Until quite recently, HEV was considered to be mainly responsible for epidemics of acute hepatitis in developing regions owing to contamination of drinking water supplies with human faeces. However, HEV is increasingly being recognized as endemic in some developed regions. In this setting, infections occur through zoonotic transmission or contaminated blood products and can cause chronic hepatitis in immunocompromised individuals. HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool. Although an effective HEV vaccine exists, it is only licensed for use in China. Acute hepatitis E is usually self-limiting and does not require specific treatment. Management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin.

Hepatitis E virus infection.

Hepatitis E, caused by infection with hepatitis E virus (HEV), is a common cause of acute hepatitis in areas with poor sanitation. The virus has four genotypes with one serotype: genotypes 1 and 2 exclusively infect humans, whereas genotypes 3 and 4 also infect other animals, particularly pigs. In endemic areas, both large outbreaks of acute hepatitis as well as sporadic cases occur frequently. These cases are usually due to genotype 1 or 2 HEV and are predominantly caused by fecal-oral transmission, usually through contamination of drinking water; contaminated food, materno-fetal (vertical spread) and parenteral routes are less common modes of infection. The acute hepatitis caused by this virus has the highest attack rates in young adults and the disease is particularly severe among pregnant women. HEV superinfection can occur among persons with pre-existing chronic liver disease. In non-endemic regions, locally acquired disease was believed to be extremely uncommon. However, in recent years, an increasing number of cases, due mostly due to genotype 3 or 4 HEV, have been recognized. These are more often elderly men who have other coexisting illnesses, and appear to be related to zoonotic transmission from pigs, wild boars and deer, either food-borne or otherwise. Also, chronic infection with genotype 3 HEV has been reported among immunosuppressed persons in these regions. A subunit vaccine has been shown to be effective in preventing clinical disease, but is not yet commercially available. Our understanding of hepatitis E epidemiology has undergone major changes in recent years, and the future may hold even more surprises.

Epidemiology of hepatitis E: Current status

Background: Infection with hepatitis E virus (HEV) is a major cause of acute viral hepatitis in several developing countries. Although usually self-limiting and benign, the disease is particularly severe among pregnant women, with mortality rates reaching 15–20%.

Methods:  Immune parameters among pregnant women with acute hepatitis E (P-HEV) were investigated and compared with those in non-pregnant patients with hepatitis E (N-HEV), and healthy pregnant (PC) and non-pregnant (NPC) women.

Results:  Peripheral blood mononuclear cells (PBMC) from P-HEV patients had lower lymphocyte proliferation response to phytohemagglutinin (PHA) than those in the PC and NPC groups. A positive lymphocyte proliferation response to HEV antigen (HEVAg), a mixture of eight peptides derived from HEV proteins, was observed in 7/19 (37%) P-HEV patients, 3/9 (33%) N-HEV patients and only 2/21 (10%) PC and 2/14 (14%) NPC subjects; the stimulation indices in the P-HEV group were similar to the N-HEV group and higher than the PC group. Measurement of cytokine production by PBMC in response to PHA and HEVAg showed a reduction in production of T-helper 1 (Th1) cytokines and an increase in that of Th2 cytokines in the P-HEV group. Cytokine mRNA levels showed similar changes.

Conclusion:  These results show the existence of a Th2 bias in pregnant women with acute hepatitis E. The role of this Th2 bias in the greater severity of hepatitis E among pregnant women needs further investigation.

Vineeta Das

Papers

Immunological alterations in pregnant women with acute hepatitis E