Review Article

Hepatitis E—A Concise Review of Virology, Epidemiology, Clinical Presentation and Therapy

M. C. Donnelly; L. Scobie; C. L. Crossan; H. Dalton; P. C. Hayes; K. J. Simpson


Aliment Pharmacol Ther. 2017;46(2):126-141. 

In This Article

Diagnosis of HEV Infection

Clinically, cases of HEV infection are indistinguishable from other causes of acute viral hepatitis. HEV infection can be diagnosed either indirectly by the demonstration of anti-HEV antibodies or directly by detecting HEV RNA using a quantitative reverse transcription polymerase chain reaction in serum, plasma or stool samples. During acute HEV infection, anti-HEV IgM becomes detectable in the days prior to the onset of symptomatic illness and becomes undetectable again at 4–6 months. Anti-HEV IgG becomes detectable soon after the presence of anti-HEV IgM, and persists for many years, even lifelong in some patients. In 95% of patients, anti-HEV IgG is detectable at time of first clinical presentation.[115] Nucleic acid testing is essential to exclude HEV infection in the immunosuppressed population in view of the poor antibody response in such individuals.

There is currently no consensus across laboratories for HEV testing, and the sensitivity and specificity of HEV assays vary widely. This may at least in part account for the differences in reported rates of anti-HEV antibody in various populations. For example, within one country (UK), the prevalence of anti-HEV antibody in the blood donor population was 3.6% as detected by one assay, compared with 16.2% with the use of an alternative.[62] In the recent meta-analysis of HEV seroprevalence in Europe by Hartl, seroprevalence again varied depending upon the assay used, with the Wantai assay reporting significantly higher seroprevalence rates across all cohorts tested.[60] As a result, it can be difficult and unreliable to compare data from different populations obtained by different laboratory methods. Several serological methods are available for diagnosis of HEV, including enzyme immunoassay and immunochromatography. Anti-HEV IgM can be difficult to detect, which may hinder the diagnosis of acute HEV infection, Abravanel reported upon the performance of a HEV IgM rapid test from Wantai in detecting anti-HEV IgM in both immunocompetent and immunocompromised patients.[116] The rapid Wantai assay is a relatively new, immunochromatographic assay which can rapidly detect anti-HEV IgM. Abravanel identified that the sensitivity of this assay was higher in immunocompetent patients (sensitivity: 97.7%; 95% CI: 87.9%-99.9%) compared with the immunocompromised (sensitivity: 85%; 95% CI: 70.2%-94.3%).

In an attempt to harmonise HEV PCR techniques and standards, the World Health Organisation initiated the production of international standards for anti-HEV IgG and HEV RNA.[117] This work involved 23 laboratories from 10 countries; in summary the World Health Organisation established a genotype 3a HEV strain as the International Standard strain for HEV RNA, with an assigned a unitage of 250 000 IU/mL. With regard to serology, there are no World Health Organisation reference materials available at present but this work is in progress.

Serum anti-HEV IgM and IgG may be negative in the presence of active HEV infection, and this may be as a result of the sensitivity of assays used, and/or the immunocompetence status of the patient. There have been reports of false positive results from anti-HEV IgM assays in cases of Epstein-Barr virus and cytomegalovirus infection.[118] Therefore, HEV RNA PCR is the favoured diagnostic test, particularly in the immunocompromised. If the patient has undergone liver biopsy for investigation of acute or chronic hepatitis, histology commonly demonstrates a nonspecific hepatitis which may easily be attributed to an alternative cause, and the diagnosis must be confirmed with HEV Ag immunohistochemistry. However, the availability of this technique is limited.