Hepatitis E virus

Hepatitis E (HEV) is an important public health disease in many developing countries of Asia and Africa and occurs also sporadically in some industrialized countries. The disease mainly affects young adults and has a relatively high mortality of up to 25% in affected pregnant women ( Emerson et al., 2003).

Structure:

HEV is a non enveloped, icosahedral, single stranded and positive sense RNA virus of approximately 7200 bases in length. It is a polyadenylated single strand RNA molecule that contains of short 5′ and 3′ untranslated regions (UTRs), and three partially overlapping open reading frames (ORF):
ORF1: Encodes a methyltransferase, protease, helicase and replicase.
ORF2: Encodes the capsid protein.
ORF3: Encodes a protein of undefined function.
A three-dimensional, atomic-resolution structure of the capsid protein in the context of a virus-like particle has been described ( Guu et al., 2009).

Figure 1: Genome organization and proteins of HEV.

Genotypes:
HEV genotype is dominant in a given geographic area, but not limited to it. HEV strains are classified into 4 genotypes, and it was recently proposed that HEV genotypes are divided into 24 subtypes. Although genotypes 1 and 2 have been found exclusively in humans, genotypes 3 and 4 have been found in humans and animals such as pigs, boars, and deer.

• Genotypes1 and 2 have been isolated in tropical and subtropical countries in Asia, Africa, and America.
• Genotype 3 has been identified almost worldwide, but the distribution of its 10 subtypes varies greatly. Subtypes 3a and 3j strains have been mainly identified in North America; 3b, 3d, and 3g strains in Asia; and 3c, 3e, 3f, 3h, and 3i strains in Europe.
• Genotype 4 has been found only in Asia. ( Lu et al., 2006).
Swine HEV isolates belong to either genotype 3 or 4 ( Feagins et al., 2007), but recently genotype 1 was detected in a pig in Cambodia ( Caron et al., 2006). The avian HEV was proposed to belong to a new genotype 5 ( Huang et al., 2004), but this has not yet been confirmed.


Transmission:

HEV is a water borne infection in developing countries and is believed to spread zoonotically in industrialized countries ( Emerson et al., 2003).
The highest rates of infection occur in regions with poor sanitation and low socioeconomic status. Minor modes of transmission in endemic areas could be vertical and through blood transfusions ( Khuroo et al., 2004). Person to person contact transmission is inefficient ( Somani et al., 2003).
Animals as a reservoir:
Domestic animals have been reported as a reservoir for the HEV, with some surveys showing infection rates exceeding 95% among domestic pigs (Satou et al., 2007).
Transmission after consumption of wild boar meat and uncooked deer meat has been reported as well ( Li et al., 2005). The rate of transmission to humans by this route and the public health importance of this are however still unclear ( Kuniholm et al., 2008).
An avian virus has been described that is associated with Hepatitis-Splenomegaly syndrome in chickens. This virus is genetically and antigenically related to mammalian HEV and probably represents a new genus in the family.
The zoonotic transmission of HEV is a serious issue in developed countries. Though a majority of infections are asymptomatic, sustained transmission can lead to the evolution of virulent strains in future (
HEV genotype 3 infections have become more common in the United Kingdom, like genotype 4 did in China in the past decade ( Ijaz et al., 2005). Genotype 3 is widely distributed and evolution of virulent strains has more far consequences.


Clinical presentation and pathogenesis:

The HEV target population is young to middle aged adults, 15 to 40 years of age. The clinical symptoms are typical of acute viral hepatitis and include jaundice, malaise, anorexia, nausea, abdominal pain, fever and hepatomegaly; anicteric hepatitis is also observed ( Smith, 2001).
The disease is self limiting and no chronic sequelae have been reported in general. However, two recent reports present biochemical, histological and genetic evidence of chronic HEV infection in transplant patients
HEV has a mortality rate of 0.2–1% in the general population. Increased morbidity and mortality is observed in chronic liver diseased patients superinfected with HEV .

HEV account for 62.5% of viral hepatitis during pregnancy. It has 12% maternal mortality and high maternal morbidity including premature delivery, intrauterine fetal death, intrauterine growth retardation, fulminant hepatitis leading to encephalopathy and multiorgan dysfunction syndrome



Laboratory diagnosis:

Animal models and in vitro culture:


HEV transmission studies have mostly been done in non-human primates. These have provided important information regarding the biology and pathogenesis of HEV, and are indispensable tools for vaccination and drug testing ( Kamili et al., 2004).
Recently, HEV genotype 3 from a high titer stool suspension has successfully been passaged for multiple generations in PLC/PRF/5 cells and these cells were used to assess the infectivity of HEV shed in patients’ stools




Host immune response, detection and prophylaxis:


Studies on experimentally infected macaques first defined the clinical and serological course of HEV infection. In those studies, serum anti-HEV immunoglobulin G (IgG) appeared around 3-4 weeks post inoculation at the peak of ALT elevation.

A human volunteer study showed:
• Anti-HEV IgM to peak in the symptomatic period and then declined to baseline within 3-6 months of illness.
• Anti-HEV IgG levels continued to rise during the symptomatic phase and were detectable in the convalescent phase for 2 years. In other studies anti-HEV IgG persisted for up to 13 years. These have been reviewed earlier.

The detection of HEV infection is based on serological and nucleic acid tests. The former detects serum antibodies against HEV and the latter detects and quantitate HEV RNA in serum, bile and/or faeces. An acute HEV infection is generally positive for both IgM and IgG anti-HEV, while only the latter is positive for past infection. Thus, in an endemic area, the IgM anti-HEV test is of value in deciding acute infection while the IgG test has more value in seroprevalence studies. Recently, an ELISA for detecting putative neutralizing antibody responses to HEV genotypes 1 to 4 has been developed, which may be useful in future trials of candidate HEV vaccines .
Figure 2: Hepatitis E viral antigens and antibodies detectable in the blood following infection.

Prevention:
Improving sanitation is the most important measure, which consists of proper treatment and disposal of human waste, higher standards for public water supplies, improved personal hygiene procedures and sanitary food preparation. Thus, prevention strategies of this disease are similar to those of many others that plague developing nations, and they require large-scale international financing of water supply and water treatment projects. A vaccine based on recombinant viral proteins has been developed and recently tested in a high risk population (military personnel of a developing country). The vaccine appears to be effective and safe, but further studies are needed to assess the long-term protection and the cost-effectiveness of hepatitis E vaccination.
Treatment:
HEV is a self-limiting disease that attracts little active management in endemic areas. Thus, fulminant cases are poorly managed and have high rates of mortality.There is no way of effectively treating the symptoms of any acute hepatitis, including hepatitis E. During acute infection, a patient should take a balanced diet and rest in bed as needed