Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 2008;358:811–817. (Reprinted with permission.)
Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.
Hepatitis E, caused by infection with hepatitis E virus (HEV), is endemic in several developing countries.1 The disease was originally believed to be rare in the United States and Europe, occurring only in those who had traveled to disease-endemic regions. However, in recent years, many cases of hepatitis E have been reported from the United States and Europe.2
Based on phylogenetic analysis, HEV isolates have been classified into four genotypes.3, 4 Genotype 1 is the most prevalent and is widespread in regions where hepatitis E epidemics are common, including most parts of Asia and northern Africa. Genotype 2, initially identified from cases during an epidemic in Mexico during the 1980s, has also caused some cases in western Africa. Genotype 3 virus has been isolated most often from sporadic cases of hepatitis E in nonendemic regions (the United States, Europe, South America, Japan). Genotype 4 has been found in specimens from a few cases of human disease in China, Taiwan, Japan, and Vietnam. Genotype 3 and 4 HEV has also been found in swine and occasionally in other animals in several countries around the world.2 In areas with sporadic human cases due to genotype 3 or 4 HEV, swine have shown HEV from the same genotypes. On the other hand, in HEV-endemic countries with genotype 1 virus, such as India, HEV isolates from swine have belonged to a different genotype (i.e., genotype 4).5
HEV infection is most often transmitted by the fecal-oral route, usually through contaminated drinking water. The infection is self-limiting in nature, although some affected persons develop fulminant hepatic failure. Characteristically, in pregnant women, the illness is particularly severe and carries a high case fatality rate.
In the report by Kamar et al.,6 the authors investigated 217 French solid-organ transplant recipients receiving immunosuppressive drugs who had a recent onset of elevated aminotransferase levels, but no detectable serological markers of infection with other hepatitis viruses, for evidence of HEV infection. They found detectable HEV RNA in 14 (6.5%) patients. Of these, seven were asymptomatic and seven had symptoms like fatigue, arthralgias, and myalgias. Sequencing analysis in 12 patients revealed genotype 3 HEV infection in all. There was no correlation between HEV RNA concentration and aminotransferase levels. Liver biopsy during the acute phase (n = 9) showed liver inflammation and mild fibrosis. On follow-up for 10-24 months, 8 of 14 patients had persistent HEV viremia and liver enzyme elevation, indicating evolution to chronic hepatitis. Liver biopsies at this stage (n = 6) showed portal hepatitis with dense lymphocytic infiltrate, variable degrees of piecemeal necrosis and fibrosis, with mean Metavir activity and fibrosis scores of 2.0 ± 1.0 and 1.8 ± 0.8, respectively.
The patients with chronic hepatitis E had a significantly shorter time from transplantation to the development of HEV infection, and thus had lower total lymphocyte, and CD2, CD3, and CD4 lymphocyte counts than those with resolving HEV infection; the other demographic and clinical features and immunosuppressive regimens used were similar in the two groups.
In another recent report, Gérolami et al. described a kidney transplant recipient with prolonged aminotransferase elevation, persistent viremia with genotype 3 HEV, and active chronic hepatitis and cirrhosis on liver biopsy, and proposed that chronic HEV infection may lead to liver cirrhosis.7 In addition, Haagsma et al. have recently reported two patients who underwent liver transplantation who developed chronic HEV infection (both genotype 3) with progressive liver injury.8 Both these patients had persistent HEV RNA in serum and liver tissue and histological evidence of chronic hepatitis, including liver cirrhosis in one patient. These reports suggest that chronic HEV infection may occur in solid organ transplant recipients and may have important clinical consequences.
How do these recent data relate to the existing knowledge? Until recently, HEV infection was believed to be self-limiting. The first recorded epidemic of hepatitis E occurred in Delhi, India, during 1955-1956. Chuttani et al.9 followed a group of those affected during this epidemic and showed that there were no long-term consequences. Serial follow-up of cases with hepatitis E, albeit in limited numbers, showed clearance of viremia and viral excretion in all individuals over a few weeks.10 Similar findings have been reported in experimental animals infected with HEV. The first indication of chronic infection with HEV was a recent report describing a Japanese patient with T cell lymphoma receiving chemotherapy who was found to have persistent HEV viremia.11 The report by Kamar et al.6 and the other recent reports referred to above expand on this information and indicate that chronic infection with HEV can occur.
However, several issues deserve consideration before we add chronic hepatitis to the spectrum of disease associated with HEV infection. First, the persistent HEV infection was observed in organ transplant recipients who were receiving immunosuppressive drugs. Such patients are known to have persistence of viral agents which are associated with a self-limited course in otherwise healthy persons, such as Epstein-Barr virus and cytomegalovirus. Immunosuppression is also known to reactivate latent viral infections such as varicella-zoster infection. Even persons who are presumed to have eradicated an infection by conventional criteria (e.g., clearance of hepatitis B virus with development of antibodies against hepatitis B surface antigen) may develop active viral multiplication and disease following institution of immunosuppressive drug therapy. Thus, occurrence of chronic HEV infection in the transplant recipients, as observed by Kamar et al., may reflect a similar phenomenon, and may not occur in non-immunosuppressed individuals.
Second, the study enrolled transplant recipients with known ALT elevation and looked for evidence of HEV viremia. Finding persistent HEV viremia in such patients does not necessarily imply that HEV infection led to ALT elevation. These findings would in fact elicit a sense of déjà vu in those familiar with the “hepatitis G virus/hepatitis GB virus” (HGV) story. A nucleic acid sequence was identified from clinical specimens obtained from a patient with post-transfusion hepatitis, and was also detected in sera from a large proportion of patients with post-transfusion hepatitis who tested negative for hepatitis B and C viruses.12 Thus, the ALT elevation and liver injury in these transfusion recipients was ascribed to the presence of this genomic marker of infection with a novel agent, which was provisionally named as HGV. However, the entire HGV edifice crumbled shortly thereafter when it was shown that the “HGV” sequences could be detected equally frequently in sera from blood transfusion recipients without post-transfusion hepatitis and in those with post-transfusion hepatitis C.13 Thus, future studies on persistent HEV infection in transplant recipients should not only include patients with ALT elevation but also those with immunosuppression but normal ALT, with the latter group serving as a comparison group to clarify the role of HEV infection in causing liver injury.
Finally, all the subjects with chronic HEV infection in the study by Kamar et al. who underwent viral genotyping had infection with genotype 3 HEV. Infection with genotype 3 HEV differs in several respects from infections with genotypes 1 and 2 virus. It has been associated usually with an illness of varying severity in elderly men with coexisting diseases, as opposed to HEV genotype 1, which mainly affects younger people with no underlying disease.14 Also, the genotype 3 HEV infection in humans appears to be most often a zoonotic infection which has been acquired from animals, whereas genotype 1 and 2 HEV have not yet been found to infect nonprimate mammals. Thus, it appears that genotype 1 and 2 HEV are primarily human pathogens. In contrast, genotype 3 HEV appears to be primarily an animal virus that occasionally crosses the species barrier. Thus, genotype 3 HEV may be an opportunistic human pathogen, causing infection and disease in humans only if body resistance is low, such as in the elderly or the immunosuppressed. The course of such infection may differ from that of infection with genotypes associated with endemic disease. Infection with genotype 3 HEV is responsible for only a minor proportion of acute hepatitis E cases around the world. Thus, the real test of “chronic hepatitis E” will lie in finding whether persistent infection occurs with genotype 1 HEV, which is responsible for most of disease burden due to hepatitis E.