Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury

Abstract

Background & aims: The diagnosis of drug-induced liver injury relies on exclusion of other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of HEV infection among patients with drug-induced liver injury in the United States.

Methods: The Drug-Induced Liver Injury Network (DILIN) is a prospective study of patients with suspected drug-induced liver injury; clinical information and biological samples are collected to investigate pathogenesis and disease progression. We analyzed serum samples, collected from patients enrolled in DILIN, for immunoglobulin (Ig) G and IgM against HEV; selected samples were tested for HEV RNA.

Results: Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive for anti-HEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM (collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients who had anti-HEV IgM were mostly older men (89%; mean age, 67 years), and 2 were human immunodeficiency virus positive. Clinical reassessment of the 9 patients with anti-HEV IgM indicated that acute hepatitis E was the most likely diagnosis for 7 and might be the primary diagnosis for 2.

Conclusions: HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected to be drug induced. Serologic testing for HEV infection should be performed, particularly if clinical features are compatible with acute viral hepatitis.

Figure 1. Liver injury initially attributed to nevirapine (Case #2) and later considered probably due to chronic HEV infection

a. The portal area is expanded by a chronic inflammatory infiltrate with interface hepatitis indicative of chronic hepatitis. Several eosinophils are present (H&E, 400x). b. There is portal fibrotic expansion with early bridging fibrosis. Ductular reaction is present at the edges of the portal areas (Masson trichrome, 200x).

Figure 2. Acute liver injury attributed to nevirapine (Case #7) and later considered due to hepatitis E

a. The biopsy shows an acute hepatitis pattern with mild canalicular cholestasis. There portal inflammation with many plasma cells and a few eosinophils and moderate interface hepatitis. The parenchyma shows and numerous foci of lobular inflammation with acidophil bodies (H&E, 200x). b. There is early periportal fibrosis and mild ductular reaction (Masson trichrome, 200x).