The role of hepatitis E virus infection in adult Americans with acute liver failure

Abstract

Acute hepatitis E virus (HEV) infection is a leading cause of acute liver failure (ALF) in many developing countries, yet rarely identified in Western countries. Given that antibody testing for HEV infection is not routinely obtained, we hypothesized that HEV-related ALF might be present and unrecognized in North American ALF patients. Serum samples of 681 adults enrolled in the U.S. Acute Liver Failure Study Group were tested for anti-HEV immunoglobulin (Ig) M and anti-HEV IgG levels. Subjects with a detectable anti-HEV IgM also underwent testing for HEV RNA. Mean patient age was 41.8 years, 32.9% were male, and ALF etiologies included acetaminophen (APAP) hepatotoxicity (29%), indeterminate ALF (23%), idiosyncratic drug-induced liver injury DILI (22%), acute hepatitis B virus infection (12%), autoimmune hepatitis (12%), and pregnancy-related ALF (2%). Three men ages 36, 39, and 70 demonstrated repeatedly detectable anti-HEV IgM, but all were HEV-RNA negative and had other putative diagnoses. The latter 2 subjects died within 3 and 11 days of enrollment whereas the 36-year-old underwent emergency liver transplantation on study day 2. At admission, 294 (43.4%) of the ALF patients were anti-HEV IgG positive with the seroprevalence being highest in those from the Midwest (50%) and lowest in those from the Southeast (28%). Anti-HEV IgG+ subjects were significantly older, less likely to have APAP overdose, and had a lower overall 3-week survival compared to anti-HEV IgG- subjects (63% vs. 70%; P = 0.018).

Conclusion: Acute HEV infection is very rare in adult Americans with ALF (i.e., 0.4%) and could not be implicated in any indeterminate, autoimmune, or pregnancy-related ALF cases. Past exposure to HEV with detectable anti-HEV IgG was significantly more common in the ALF patients compared to the general U.S.

Population: (Hepatology 2016;64:1870-1880).

© 2016 by the American Association for the Study of Liver Diseases.

Figures

Figure 1. Overview of study population

Of the 699 ALFSG patients with serum that was tested for anti-HEV IgM, 681 had interpretable anti-HEV IgM results. There were 3 subjects who were repeatedly anti-HEV IgM + and anti-HEV IgG + as well. Among the 678 anti-HEV IgM − subjects, there were 56% who were anti-HEV IgG − and 44% anti-HEV IgG +.

Figure 2. Representative liver histopathology from an acute HEV patient

A & B) A transjugular liver biopsy demonstrates bridging and chicken-wire fibrosis as well as Mallory bodies on trichrome stain suggestive of antecedent non-alcoholic steatohepatitis (400 × magnification). Photomicrograph provided by Dr. Lan Peng of University of Texas Southwestern, Dallas.

Figure 3. Seroprevalence of anti-HEV IgG + ALF patients by site location

There were 28 sites in the US ALFSG who contributed samples to this study over a 13 year period. When the frequency of anti-HEV IgG + samples was analyzed by geographic location, patients enrolled in the 8 southeastern sites had a statistically significantly lower seroprevalence rate compared to the other regions of the US (28% vs 48% p

Figure 4. Initial and follow-up anti-HEV IgG levels in ALF patients over time

A) There were 6 patients with a positive anti-HEV IgG baseline serum sample that remained positive at their month 12 and or month 24 study visit. B) There were 14 patients who also had a positive anti-HEV IgG baseline serum sample that became negative with a level of