The Dual Threat of Hepatitis E

Rowen K. Zetterman, MD


October 30, 2013

In This Article

Hepatitis E Virus Infection

Hepatitis E virus (HEV) disease is a worldwide health problem.[1] HEV is the most common cause of acute hepatitis in developing countries,[2] and one third of the world's population may already be infected.[3] HEV poses different threats in developing and developed countries -- the former being associated with large outbreaks of severe disease, and the latter with sporadic cases of mild or even asymptomatic disease.

One of the largest outbreaks of acute hepatitis E occurred in 1955 in New Delhi following contamination of drinking water during a flood.[4] As many as 30,000 people developed jaundice. Although it was initially believed to be an outbreak of hepatitis A, the large number of cases in adults and the high risk for death from fulminant hepatitis in pregnant women made that conclusion unlikely.[5]

In highly endemic areas, enterically transmitted HEV has caused acute hepatitis epidemics. Outbreaks of HEV disease have been documented in the Indian subcontinent, Africa, the Middle East, China, and Mexico. Subsequently, sporadic cases of HEV disease caused by ingestion of undercooked or uncooked meat have occurred in industrialized countries.[6] No large-scale epidemics have been associated with zoonotic transmission.

HEV infection was initially thought to occur only in highly endemic areas, such as the Indian subcontinent, and cases recognized in the United States were seen primarily in travelers from these areas. We now know that HEV is also endemic in the United States. As a cause of mild acute viral hepatitis, HEV infection can sometimes be confused with drug-induced hepatitis.

Hepatitis E Virology

HEV is a nonenveloped, single-strand, 7.2-kDa, spherical 27- to 30-nm RNA virus that replicates in the liver cell cytoplasm using 3 open reading frames that code for both structural and nonstructural proteins.[7] The HEV genus is Hepevirus of the family Hepeviridae, which includes animal viruses similar to HEV.

The 4 genotypes of HEV differ in both worldwide distribution and clinical manifestations of infection.[8] Genotypes 1 and 2 are human viruses, and genotypes 3 and 4 are swine viruses that can infect humans (zoonoses). There are at least 24 subtypes of hepatitis E. The 4 genotypes have a common serotype, and antibodies developing in response to infection with 1 genotype will cross-react with the others. The epidemics that occur in the developing world are largely of genotype 1.

Genotype 1 occurs in the Indian subcontinent, Middle East, Africa, and Russia. Genotype 2 has been identified in Africa and Mexico and has a 75% homology with genotype 1. Genotypes 1 and 2 have a limited host range, and infection appears to be restricted to humans and primates. Genotype 3 occurs in the United States, South America, Mexico, Europe, Australia, New Zealand, and East Asia. In the United States, this virus is found in both pigs and humans and has a 75% homology to genotypes 1 and 2. Genotype 4 has been identified in swine and humans in Japan and China.

Severity of illness depends on genotype.[9] Genotype 1 causes more severe disease, whereas infection caused by genotypes 3 and 4 is clinically less severe, although genotype 4 is more likely to cause clinical illness than genotype 3.[10] An additional genotype has been documented in birds -- avian HEV[11] -- which has a shorter genome and a 50% sequence homology to the other genotypes.


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