Cite this asParvez MK (2017) Hepatitis E: Diagnostic and Therapeutic Challenges. Arch Hepat Res 3(1): 010-012 DOI: 10.17352/ahr.000009
HEV infection may be symptomatic or asymptomatic that has affected about one-third of world population with a case fatality rate of 1-2%, including 20-30% of infected pregnant women [3-5]. Though inherently hepatotropic causing fulminant liver failure and cirrhosis, HEV has recently evolved with extra hepatic manifestations where biochemical/serological evidence of infection is often modest or absent [6-8].
HEV is a non-enveloped virus with a positive single-strand RNA genome (~7.2 kb) with three partially overlapped open reading frames (ORF1, ORF2 and ORF3) . Of the several recognized genotypes, HEV1 and HEV2 are known to infect humans only while HEV3, HEV4 and HEV7 are infectious to humans and other mammalian species, such as swine, boar and dear . On the other hand, genotypes HEV5 and HEV6 have been detected in animals only, and their transmission to humans are not established . Further, while HEV1 is endemic in Asia and Middle East, HEV2 is prevalent in African and South American countries. Contrarily, HEV3 and HEV4 are less pathogenic, and are mainly confined to Eastern Asian countries, Eastern and Western Europe, and North America . Notably, in the Western countries, autochthonous HEV3 infection is attributed to sporadic cases of acute hepatitis, potentially linked to pork consumption . In addition, HEV3 is also associated with chronic course of infection in solid organ transplant or blood transfusion patients where immunosuppressive drugs, like tacrolimus is considered as the main predictive factor for the disease severity .
In acute hepatitis E, both anti-HEV IgM and IgG antibodies rise simultaneously in the narrow window of detectable HEV RNA. In general, seropositivity for anti-HEV IgG indicates previous HEV infection and occasionally, an ongoing infection. On the other hand, the positive anti-HEV IgM test indicates acute or recent infection. Several diagnostic assays for anti-HEV IgG and IgM are available; however, the use of anti-HEV IgM assays is still doubtful because of their unreliable specificity and sensitivity. While in Europe and Asia, many such anti-HEV assays are commonly used, none of these has been approved by the USA authorities. However, HEV testing is limited to few specialized centers and therefore, the hepatitis E diagnosis is often delayed in the USA . Nonetheless, it still needs to be determined, which commercial assay has the greatest specificity and sensitivity. Recently, a new Wantai anti-HEV IgG assay kit (Wantai Biological Pharmacy Enterprise Co., Ltd, Beijing, China) has been preferred by many laboratories, worldwide for its consistent sensitivity and specificity compared to others . Nonetheless, the universal gold standard for detecting ongoing HEV infection is the HEV-RNA tests in stool or blood samples by RT-PCR method. Recently, a WHO standard of HEV-RNA has been evaluated, which allows a comparison of qualitative and quantitative RT-PCR assays among different laboratories across the globe .
The timely and proper diagnosis of hepatitis E is technically very challenging. In the absence of an approved algorithm, the consistency of serological tests and RNA quantification in terms of sensitivity and specificity are the limiting factors. Consequently, most of the ‘first-generation’ anti-HEV IgG assays-based studies had a very low seroprevalence (<5%) in developed countries. It was mistaken that these positive individuals had either been exposed to HEV whilst visiting an endemic country or simply had non-specific cross-reactivity.
Prior to the knowledge of chronic HEV infection in immunosuppressed transplant recipients, it was frequently misdiagnosed as graft-versus-host disease, chronic rejection or drug-induced liver injury. Notably, acute hepatitis E is frequently misdiagnosed as drug-induced hepatotoxicity where the correct diagnosis is not secure without first excluding hepatitis E infection . Moreover, the anti-HEV IgM false-positivity was later shown because of past immunization against herpes viruses, like cytomegalovirus (CMV) and Epstein-Barr virus (EBV) . Recently, a retrospective analysis of HEV serology has shown a high degree of cross-reactivity where approximately 33.3 and 24.2% of HEV IgM positive samples were also positive for EBV and CMV IgM, respectively . Further, a case report has also revealed markers of past CMV and EBV infections in a hepatitis E patient with high fever, rash, arthralgia or AOSD-like symptoms . Similarly, a chronic hepatitis E patient with systemic lupus erythematosus has been reported recently who was on immunosuppressant drugs therapy for 40 years . While HEV diagnosis was based on persistent elevation of liver transaminases (ALT/AST) and progressive liver fibrosis, the patient’s immunologic profiles, like total lymphocyte count, CD4+, CD8+, and CD3+ T cell counts, including anti-HEV specific T-3 cell response were ignored to conclude the etiology. Therefore, the diagnosis of HEV infection should be based on clinical presentations, elevated ALT/AST, serology, and confirmatory RNA test.
Although one of the effective HEV vaccines [20,21], is approved in China, it is still not available in other countries, including the USA and Europe. Since HEV3 has been associated with the chronic infection, it is still unclear if this vaccine can prevent HEV3 in industrialized nations. Needlessly so far, there has been no established treatment for self-limiting acute hepatitis E. However, in recent times, pegylated interferon-α-2a (pegIFN-α-2a) and ribavirin (RBV) are shown effective drugs for treating acute liver failure and chronic patients. Though, RBV effectively inhibits the HEV replication and induce a sustained virological response (SVR) in chronic patients , drug-resistance or non-response associated viral mutations lead to therapeutic failure in a proportion of patients [23,24].
Genetically, HEV also exists as a heterogeneous population within infected individuals. The drug (RBV) pressure in chronic patients may thus result in virus eradication as well as selection of replication competent quasi-species . Recently, the correlation of RBV failure and disease severity with the detection of classical G1634R mutant, including new variants (K1383N, D1384G, K1398R, V1479I and Y1587Fl) in the RNA polymerase region of HEV ORF1 gene has been described . Interestingly, the emergence of K1383N mutations and their association with an overall increase in viral heterogeneity in several patients, is shown reversible upon RBV cessation [24,26].
Hepatitis E is a life-threatening infection in pregnant and immunosuppressed individuals where a proportion of patients fail to achieve SVR during RBV treatment. Nonetheless, the molecular mechanism of non-response or failure to RBV monotherapy in such cases still remains elusive. Several HEV false-positive results due to cross-reactivity have indicated the unreliability of the serological diagnosis of acute hepatitis E. Therefore, the diagnosis of HEV infection should be based on clinical presentation, biochemistry, serology and confirmatory viral RNA testing. Though within the last few years, a novel assay for the detection of HEV-antigen has been developed, its diagnostic fidelity still needs to be established prospectively in larger cohorts. In addition, a comprehensive clinical, virological and molecular data are needed to understand and control the viral paradigm shift of pathogenicity.
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