Genetic susceptibility to hepatitis E viral infection: An enigmatic virus gives up a secret
Authors: Ivo Ditah, Michael Charlton
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article on Page 1346 Although something of a microbial Sasquatch in the United States (seen by few in the flesh but frequently described), hepatitis E viral (HEV) infection is the most common cause of acute viral hepatitis and jaundice worldwide and a major public health problem in developing nations, with associated high morbidity and mortality among pregnant women, infants <2 years old, and solid organ transplant recipients.1 The last decade has seen paradigm shifts in our understanding of the epidemiology of HEV in developed nations, where the prevalence and impact of HEV are increasingly recognized. Advances in our understanding of the epidemiology of HEV infection have followed a steady evolution in the performance of HEV diagnostic tests. The most recent analysis of the National Health and Nutrition Education Survey (NHANES), which is a robust population‐based representative sample of the noninstitutionalized US population, reported the seroprevalence of HEV in the United Sates to be ∼6% (95% confidence interval 5.12%‐6.94%), equating to one in 15 people having been infected with HEV.3 Although rarely invoked as a source of clinical events, HEV is clearly prevalent. Factors associated with HEV seropositivity in the United States are increasing age, birth outside of the United States, Hispanic race, and higher frequency of "meat" (e.g., sausage) consumption (>10 times/month).3 The most recent studies have shown that most cases of HEV infection in developed countries are locally acquired (autochthonous), possibly related to zoonotic transmission,2 with HEV genotype 3 being the most commonly associated with zoonotic (swine and rabbits) transmission. Unfortunately, because serological and target amplification tests for HEV are not widely available, the clinical burden of HEV infection in the developed world is poorly defined. Among persons tested in the NHANES cohort, one in 2000 with anti‐HEV had evidence of recent exposure (immunoglobulin M–positive).3 This would translate to over 120,000 people in the United Sates with recent HEV infection at any given time, severalfold greater than hepatitis C. Part of the enigma of HEV infection lies in the subclinical nature of the great majority of cases, with only the very tip of the HEV infection burden ever being suspected or diagnosed. The threshold for suspicion of and the clinical burden related to HEV infection are changing as the list of clinical manifestations of HEV infection grows. In addition to hepatitis, HEV infection is a recognized cause of nonspecific symptoms, such as rash and arthralgia, and distinct extrahepatic clinical syndromes including Guillain‐Barre syndrome, myasthenia gravis, bilateral brachial neuritis, peripheral neuralgia with meningitis, seizures, nerve palsies, and pseudotumor cerebri.4 The risk of liver‐related mortality for patients with HEV infection is known to be high in patients with chronic liver disease, the elderly, pregnant women, and the immunosuppressed.2 The impact of HEV in developed countries is thus already substantial and likely to be greatly underestimated. The ever increasing number of individuals with fatty liver disease, organ transplant recipients, and the elderly in developed countries is likely to increase the impact of HEV infection and mandates greater urgency in increasing our understanding of the pathophysiological mechanisms that underlie the host–virus interaction during HEV infection. While epidemiological data from analyses of the NHANES has identified environmental and demographic factors that may predispose to HEV infection, no data exist on genetic factors that may play a role in HEV infection. The variability in the prevalence of serological markers of HEV infection between ethnic groups suggests the possibility of a genetic basis for susceptibility. In this issue of hepatology, Zhang et al. provide an article entitled "Apolipoprotein E and protection against hepatitis E virus infection in American, non‐Hispanic blacks."6 This exciting work opens a new chapter of evidence in our understanding of the epidemiology of HEV infection and may offer insights into the pathobiology of HEV infection. The authors used data from the NHANES database to assess the association between anti‐HEV immunoglobulin G seropositivity and human genetic variants among three racial/ethnic groups in the United States. The study included a representative sample of 6272 subjects. The main finding of the study is that apolipoprotein E (APOE) ε3 and ε4 are protective against HEV infection in persons of non‐Hispanic black ethnicity. The magnitude of the protective effect was substantial, with the alleles APOA4 rs5110‐A and APOE rs7412‐C being associated with 80% (odds ratio = 0.2, 95% confidence interval 0.1‐0.5; P = 0.007) and 40% (odds ratio = 0.6, 95% confidence interval 0.5‐0.8; P = 0.02) lower odds of seropositivity, respectively. This finding provides, at least in part, a genetic basis for the observed racial distribution of anti‐HEV seropositivity in the US population; and this is the first report of any kind to identify a genetic association with susceptibility to or protection from HEV infection. A recent analysis of the same NHANES data set on the current epidemiology of HEV infection in the United States found that Hispanic ethnicity is associated with a higher seroprevalence of HEV compared to non‐Hispanic blacks and non‐Hispanic whites.3 The finding by Zhang et al. that lower levels of APOE ε3 and ε4 are protective in non‐Hispanic blacks may partially account for lower seroprevalence of HEV in this racial group. While the basis of the protective effect of APOE ε3 and ε4 cannot be determined from the study by Zhang et al., roles of APOE ε3 and ε4 in hepatitis E viral entry/assembly and/or in determining immune response to HEV infection are raised. APOE expression is known to be differentially expressed in the development of HEV infection in swine.7 Swine HEV is thought to be responsible for the majority of human infection seen in the United States. Current treatments for HEV infection (reduction in immunosuppression when appropriate and ribavirin for ∼3 months) are partially effective. The most advanced HCV vaccine programs have demonstrated 80%‐100% efficacy in phase 3 trials conducted in China.8 Proven efficacy is, however, limited to HEV genotypes 1 and 4. Efficacy against HEV genotype 3, the most common in the United States, is unknown. In the most recent vaccine study, all the participants in the vaccine group in whom HEV infection developed had antibodies with high or moderate avidity during the acute phase, suggesting susceptibility to HEV infection on the basis of host factors other than antibody levels.8 The results of the study by Zhang et al., in this issue of hepatology, provide a potential basis for the observations made in vaccine clinical trials and may serve to identify individuals who may benefit from distinct prevention and treatment strategies. In the era of individualized medicine, the report by Zhang et al. of a protective effect of APOA4 rs5110‐A and APOE rs7412‐C alleles is particularly timely. Certainly, more data are needed, and the implications for clinical practice remain to be determined. Future studies should explore the prevalence and relationship of these APOE variants to clinical and serological response to HEV infection and vaccination in endemic settings. The findings by Zhang et al. are likely to be an important advance in our understanding of the biology and management of HEV infection.