Enterically Transmitted Non-A, Non-B Hepatitis and the Discovery of Hepatitis E Virus

Abstract

The recognition of hepatitis E as a discreet disease entity in the late 1970s followed the development of serological tests for hepatitis A and the discovery that large waterborne outbreaks of hepatitis in India were not caused by hepatitis A virus (HAV). These "enterically transmitted non-A, non-B hepatitis" outbreaks had distinctive epidemiologic features, including the highest attack rates among young adults, little secondary household transmission of infection, and severe disease in pregnant women. The responsible agent, hepatitis E virus (HEV), was identified several years later in extracts of feces from a self-inoculated virologist. Multiple genetically related HEV genotypes are now known to exist, two of which are common in domestic swine herds and the cause of sporadic cases of acute hepatitis in economically well-developed countries. HEV genotypes possess impressive genetic and biologic diversity, and present many unanswered questions concerning their natural host range, potential for zoonotic transmission, and disease pathogenesis.

Figure 1.

Mohammed Khuroo standing near an open source of drinking water in Sopore, at the time of the 1978–1979 winter outbreak of enterically transmitted non-A, non-B (ET-NANB) he investigated in Kashmir. (From Khuroo 2011; adapted, with permission, from Elsevier © 2011.)

Figure 2.

An undated photograph of Mikhail S. Balayan, the Russian virologist who first identified hepatitis E virus (HEV) particles in extracts of his stool following ingestion of a fecal extract prepared from Soviet soldiers afflicted with enterically transmitted non-A, non-B (ET-NANB). (Image provided by M. Mikhailov.)

Figure 3.

Immune electron microscopic image of hepatitis E virus (HEV) particles identified by Mikhail Balayan in his stool approximately 5 weeks after ingesting infectious material from patients with ET-NANB hepatitis. Scale bar, 100 nm. (From Balayan et al. 1983; adapted, with permission, from S. Karger AG © 1983.)

Figure 4.

Immune electron microscopic image of virus particles present in one of the fecal extracts used to prepare the inoculum for Balayan’s experiment. (Image provided by M. Mikhailov.)

Figure 5.

Genetic relatedness of hepatitis E virus (HEV) strains identified in U.S. residents with either autochthonously acquired genotype (gt)3 or travel-associated (gt1 and gt4) hepatitis E. The phylogenetic tree was generated using the neighbor-joining method, and includes gt3 swine HEV sequences and representative sequences of each of the four major Orthohepesvirus A genotypes. (From Drobeniuc et al. 2013; adapted courtesy of Public Domain material provided by the journal Emerging Infectious Diseases.)