The Unmet Needs of Hepatitis E Virus Diagnosis in Suspected Drug-Induced Liver Injury in Limited Resource Setting.

Mohamed A El-Mokhtar,Marwa M Thabet,Amer Ali Abd El-Hafeez,Ibrahim M Sayed,Magdy Fouad,Elsayed A Elgohary,Alaa S Abd-Elkader,Haidi Karam-Allah Ramadan,Mohammad M Sallam,Mona Embarek Mohamed

doi:10.3389/fmicb.2021.737486

Abstract

Background: Currently, there are no specific biomarkers for drug-induced liver injury (DILI), and the diagnosis of DILI is based mainly on the exclusion of other causes of liver dysfunction and the recognition of potential causative drugs. Hepatitis E virus (HEV) diagnosis is not routinely enrolled in many countries, and HEV infection could be misdiagnosed as DILI.Methodology: We retrospectively analyzed plasma samples (n = 80) collected from suspected DILI for HEV markers such as anti-HEV IgM, anti-HEV IgG, and HEV RNA. Anti-HEV antibodies were assessed using commercial ELISA kits. HEV RNA was tested by RT-qPCR targeting HEV ORF2/3, the receiver operating characteristic (ROC) curve was plotted, and a putative threshold for liver function parameters was determined.Results: Out of 80 samples, 12 samples were positive for anti-HEV IgM and anti-HEV IgG, and HEV RNA was detected in seven samples. The median viral load was 3.46 × 103 IU/ml, and the isolated viruses belonged to HEV genotype 1. The level of liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST), but not alkaline phosphatase (ALP), was significantly higher in HEV confirmed cases than in non-HEV confirmed cases. We identified a plasma ALT level of at least 415.5 U/L and AST level of at least 332 U/L; ALT/ALP ratio of at least 5.08 could be used as a guide for the patients diagnosed as DILI to be tested for HEV infection. The previous liver function parameters showed high sensitivity and good specificity.Conclusion: Hepatitis E virus was detected in suspected DILI cases. The diagnosis of DILI is not secure until HEV testing is done. Liver function parameters can be used as a guide for HEV testing in suspected DILI cases in countries with limited resources.

Highlights

Hepatitis E virus (HEV) is a positive-sense, single-stranded RNA virus that causes acute viral hepatitis globally (Rein et al, 2012; Sayed et al, 2015)
Sequencing analysis was successful in four cases, and the isolated viruses belonged to HEV genotype 1
We found that diclofenac was associated with 17.5% (14/80) of the suspected drug-induced liver injury (DILI), five out of 14 (35.7%) were positive to HEV markers, and nine samples (64.3%) tested negative for HEV markers (Table 2)

Summary

Introduction

Hepatitis E virus (HEV) is a positive-sense, single-stranded RNA virus that causes acute viral hepatitis globally (Rein et al, 2012; Sayed et al, 2015). HEV isolates that cause infections to humans belong to the genus Orthohepevirus A, in the Hepeviridae family (Smith et al, 2020). There are eight HEV genotypes (HEV 1– 8); five of them are associated with human infections (Smith et al, 2016, 2020). HEV-1 and HEV-2 are common in developing countries where the infection is mainly transmitted by the fecal– oral route (World Health Organization [WHO]., 2011; Rein et al, 2012). HEV-8 was identified in a Bactrian camel, and its role in human infection is still under investigation (Woo et al, 2016). Hepatitis E virus (HEV) diagnosis is not routinely enrolled in many countries, and HEV infection could be misdiagnosed as DILI

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