Hepatitis E virus in acute liver failure: An unusual suspect?
Authors: Ibrahim M. Sayed, Ann‐Sofie Vercouter, Philip Meuleman
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. See Article on Page 1870 Acute liver failure (ALF) is a life‐threatening illness that involves rapid deterioration of liver function, mostly in healthy people without known prior liver disease. The clinical presentation of ALF usually includes loss of liver metabolic function, coagulopathy, hepatic encephalopathy, and multiorgan failure. The main etiologies of ALF are infection with hepatitis viruses and drug toxicity.1 The hepatitis E virus (HEV) is the most common cause of acute viral hepatitis and ALF in developing countries such as India and Bangladesh, whereas in the United States and western Europe most ALFs are caused by drug‐induced liver injury (DILI). Yet up to 20% of ALF cases in developed countries have an indeterminate cause. It is speculated that the involvement of HEV in ALF is largely underestimated due to lack of screening, use of insensitive assays, and misdiagnosis. HEV has become an important pathogen in industrialized countries.2 There are at least four HEV genotypes (gt1‐4) that can cause infection in humans. HEV gt1 is responsible for acute HEV (AHE) infection in developing countries where the fecal‐oral route is the principal mode of transmission. Patients with AHE usually develop flu‐like myalgia, arthralgia, weakness, abdominal pain, vomiting, jaundice, darkened urine, and elevated liver enzymes and bilirubin. About 20%‐40% of AHE patients in developing countries may progress to ALF, and this percentage is increased among pregnant women. HEV cases of gt3 and gt4 are zoonotic and account for most autochthonous HEV infections in industrialized countries, where animals such as pigs and wild boar are the main reservoir. Consumption of raw or undercooked, infected meat products and transfusion of contaminated blood are well‐established routes of transmission. Infection with HEV gt3 is usually asymptomatic in immunocompetent persons, while the infection can evolve to chronicity in immunocompromised patients. In this issue, Fontana et al. describe the rate of acute HEV infection in ALF cases in North American patients.3 Serum samples from nearly 700 ALF cases of different etiologies were collected during the period 1998‐2011 and retrospectively analyzed for signs of acute HEV infection. Initially all samples were screened by in‐house enzyme‐linked immunosorbent assay (ELISA) for the presence of HEV‐specific immunoglobulin M (IgM). Positive samples were confirmed using the commercially available Wantai HEV IgM assay and assessed for the presence of HEV RNA using in‐house reverse‐transcription quantitative polymerase chain reaction. Using this strategy, only 3 of 681 (0.4%) ALF cases could be linked to AHE infection. Anti‐HEV IgM was repetitively detected in these three cases using the in‐house ELISA and/or the more sensitive Wantai assay, while HEV RNA repeatedly tested negative. The initial diagnoses of the three cases before HEV testing were DILI (n = 2) and fulminant hepatitis B infection (n = 1). All three suspected HEV cases in this study were non‐Hispanic, Caucasian men.3 The rate of ALF instigated by HEV reported by Fontana and colleagues is considerably lower than a previous report from the United States. Davern et al. demonstrated that 9 of 318 (3%) suspected DILI cases identified in the United States during the period 2004‐2009 were in fact AHE infections. Anti‐HEV IgM was detectable in all cases, and 4 had detectable HEV RNA using nested reverse‐transcription polymerase chain reaction. Eight out of 9 cases in this study were non‐Hispanic white men. None of the cases had a history of travel to an endemic area or of eating undercooked pork or wild game.4 Because both aforementioned US studies used the same ELISA, the difference in HEV infection rate in ALF patients (0.4% versus 3%) may be due to differences in demographic and genetic characteristics of the tested subjects. Interestingly, HEV‐infected cases in the two previous studies were predominantly white men. A recent study showed that American non‐Hispanic blacks are more protected from primary HEV infection than non‐Hispanic whites and Mexican Americans. This protective effect was mainly associated with the presence of apolipoprotein E alleles ϵ3 and ϵ4.5 Another recent US study showed that HEV does not contribute to hepatic decompensation among patients with advanced chronic hepatitis C.6 In contrast to the United States, European studies highlight a more pronounced role of HEV in ALF. According to a recent study, acute HEV infection contributed to 10% of ALF cases in Germany.7 Dalton et al. reported that 6 of 47 (13%) ALF cases in the United Kingdom were HEV‐related and previously misdiagnosed as DILI.8 In a Scottish liver transplant unit, HEV was responsible for 4 out of 80 ALF cases (5%). Two of these were previously erroneously ascribed to acetaminophen overdose.9 The prominent role of HEV in ALF in developing countries is most likely related to the higher pathogenicity of gt1 viruses compared to gt3 viruses. Using a humanized mouse model, we recently showed that gt1 viruses replicate to much higher levels than gt3 viruses.10 This, perhaps in combination with distinct tropism, could explain why HEV‐related complications during pregnancy seem to be limited to gt1 viruses. The difference in HEV‐related ALF between the United States and Europe is more difficult to explain because only gt3 viruses are endemic in these regions. Nevertheless, several aspects could play a role. One could argue that the US studies are still underestimating the role of HEV in ALF because of differences in HEV diagnosis. Indeed, the US studies mentioned above solely rely on the detection of HEV‐specific IgM measured with in‐house ELISA, while reverse‐transcription polymerase chain reaction is only applied on IgM‐positive serum samples. In European studies HEV IgM usually is evaluated with a more sensitive commercial ELISA in combination with independent highly sensitive molecular amplification of viral RNA. Manka et al. reported three cases that tested positive on polymerase chain reaction, while virus‐specific IgM remained under the limit of detection.7 Such cases will undoubtedly also exist in the United States. There is no doubt that HEV is present in the United States. There is ample evidence that the virus circulates among US pig herds, and the presence of virus‐specific IgG denotes zoonotic exposure. It is conceivable that US strains are less pathogenic than the European ones. However, a recent study could not identify any specific genetic signature in European isolates that was associated with symptomatic HEV infection.11 A difference in dietary lifestyle between Europeans and Americans could be another contributing factor. Consumption of raw, dried, and undercooked pork meat and sausages is more common in European countries, which increases the risk of HEV exposure. Recently, it was demonstrated that Chinese cows may become infected with HEV and that infectious viral particles can be present in fresh and pasteurized milk.12 Further research is needed to ascertain whether this potential new transmission route is of importance in Europe and the United States. One of the main limitations of all of the above‐mentioned ALF studies is the limited availability of samples. In all retrospective studies, only serum/plasma samples were available for analysis. A recent study from our group showed that the HEV RNA load in fecal samples is about 10‐fold to 100‐fold higher than in corresponding plasma samples collected from HEV‐infected human liver chimeric mice.10 It is therefore advisable that fecal samples are used for the diagnosis of acute HEV infection. Undoubtedly, more acute HEV cases may be identified, which now remain under the radar. In summary, it is clear that HEV is one of the causative agents of ALF in developed countries, but more studies using the most sensitive diagnostic tools and most appropriate samples are needed to conclusively determine its actual contribution. Nevertheless, even when taking HEV into account, a considerable fraction of ALF cases in developed and developing countries continue to have an unknown cause. The quest for additional yet unidentified contributing factors and/or agents therefore continues. Author names in bold designate shared co‐first authorship.