Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections

Abstract

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis throughout the world. Most infections are acute but they can become chronic in immunocompromised patients, such as solid organ transplant patients, patients with hematologic malignancy undergoing chemotherapy and those with a human immunodeficiency virus (HIV) infection. Extra-hepatic manifestations, especially neurological and renal diseases, have also been described. To date, four main genotypes of HEV (HEV1-4) were described. HEV1 and HEV2 only infect humans, while HEV3 and HEV4 can infect both humans and animals, like pigs, wild boar, deer and rabbits. The real epidemiology of HEV has been underestimated because most infections are asymptomatic. This review focuses on the recent advances in our understanding of the pathophysiology of acute HEV infections, including severe hepatitis in patients with pre-existing liver disease and pregnant women. It also examines the mechanisms leading to chronic infection in immunocompromised patients and extra-hepatic manifestations. Acute infections are usually self-limiting and do not require antiviral treatment. Conversely, a chronic HEV infection can be cleared by decreasing the dose of immunosuppressive drugs or by treating with ribavirin for 3 months. Nevertheless, new drugs are needed for those cases in which ribavirin treatment fails.

Keywords: acute hepatitis; chronic hepatitis; hepatitis E virus; neurological disorders; pregnancy; renal injury.

Figure 1

Hepatitis E virus (HEV) genome. Open reading frames (ORF1) (blue box) encodes nonstructural proteins. ORF4 has been found only in HEV1. 7 mG: 7-methylguanosine; Hel: helicase; MT: methyl transferase; polyA: polyadenylated tail; PPR: polyproline region; Pro: cysteine protease; RdRp: RNA polymerase; X: X domain; Y: Y domain.

Figure 2

Phylogenetic tree based on full-length sequences of HEV strains. Sequence alignment was performed using ClustalW (MEGA5) and BioEdit, version 7.0. The neighbor-joining method was used to create the phylogenetic tree, with a bootstrap of 100 replicates.

Figure 3

Interference of HEV with the innate antiviral response. HEV RNA is detected in the cytoplasm by the retinoic acid-inducible gene I (RIG-I), leading to type I and type III interferon (IFN) production. The protease domain (Pro) of the ORF1 protein inhibits signaling via RIG-I and prevents IFN induction by de-ubiquitining RIG-I and TANK binding kinase 1 (TBK-1). The X domain (X) inhibits the phosphorylation (P) of IFN regulatory protein 3 (IRF3). Conversely, the ORF3 protein stimulates the direct interaction of type I IFN with RIG-I, but ORF3 also binds to STAT1 to restrict its phosphorylation and activation of the downstream cascade, thus inhibiting the expression of the IFN-stimulated genes (ISGs), including the double stranded (ds)RNA-activated protein kinase (PKR) and 2′,5′-oligoadenylate synthetase (2′5′-OAS) or ISG15. IKKε: IκB-Kinase-epsilon; IRF9: IFN regulatory protein 9; ISRE: interferon stimulated response element; MAVS: mitochondrial antiviral-signaling protein; Ub: ubiquitin.

Figure 4

Course of an acute HEV infection. ALT: alanine aminotransferase activity.

Figure 5

Histology of liver biopsies from a chronically HEV-infected patient. (a) Initial liver biopsy, (b) inflammation after 15 months of infection, and (c) Cirrhosis after 38 months of infection (Masson’s trichrome, magnification 100×).