Acute non-A, non-B, non-C hepatitis differences and similarities between hepatitis E virus infection and autoimmune hepatitis, with phylogenetic analysis of hepatitis E virus in humans and wild boars

Abstract

Background: Hepatitis E virus (HEV) infection incidence is increasing in Europe, accounting for the majority of acute hepatitis cases. We investigated the prevalence and clinical characteristics of acute hepatitis E (AHE) in patients with acute non-A/B/C hepatitis from central Greece, their differences from acute autoimmune hepatitis (AIH) patients and the molecular similarity of human strains to local HEV strains in wild boars.

Methods: Sera from 20 patients with non-A/B/C acute hepatitis (2015-2017) were tested prospectively for anti-HEV IgM, IgG antibodies and HEV-RNA. Sera from patients diagnosed with acute AIH (2000-2015; n=56) were tested retrospectively. Liver tissue samples from 40 wild boars were tested for HEV-RNA. Positive wild boar and patients' samples were sequenced and phylogenetically analyzed.

Results: Twelve of the 76 (16%) patients were diagnosed with AHE: HEV-RNA 11.5x10⁴ (38.7-39.7x10⁶) IU/mL; 11/20 (55%) acute non-A/B/C hepatitis and 1/56 (2%) AIH patients. Patients with AHE were older than those without, predominately men, with higher alanine aminotransferase but lower IgG levels (P=0.005 and P=0.002, respectively), and had high titers of smooth muscle antibodies. Liver biopsies, performed in 6/12 patients with HEV infection, revealed histology compatible with AIH. HEV strains from both patients and wild boars belonged to genotype 3.

Conclusions: Approximately one sixth of patients with acute non-A/B/C hepatitis had autochthonous HEV infection with AIH features. Therefore, a careful workup to exclude HEV should be carried out in all acute hepatitis cases before a definite diagnosis of AIH is established. Wild boars seem to be an important reservoir of HEV in Greece.

Keywords: Hepatitis E virus; acute autoimmune hepatitis; genotyping; wild boars.

Figure 1

Phylogenetic tree constructed with maximum-likelihood method. Analysis was performed by using 10 nucleotide sequences of Greek strains of hepatitis E virus (HEV), 4 from patients (OM654048-51) and 6 from wild boars (OM654052-57), and 27 HEV sequences of genotypes 1,2,3 and 4 retrieved from the GenBank database. Bootstrap values (expressed as percentages of 1000 replications) are shown at the branch points; only values over 50% are indicated. Greek strains are marked with ♦