Hepatitis E virus infections

Hepatitis E virus(HEV)infection is now endemic worldwide.Most patients with acute infection recover uneventfully.Outbreaks and sporadic cases,particularly in high-risk individuals are emerging increasingly.The patients with risk factors like pregnancy and pre-existing chronic liver disease,present with or progress rapidly to severe disease.Immuno-suppression in post-transplant patients is an additional risk factor.Standardized FDA-approved diagnostic tests are the need of the hour.Further studies are needed to establish guideline-based treatment regimen and outbreak preparedness for HEV to decrease global morbidity,mortality,and healthcare burden.Policies for screening donors and transplant cases are requi-red.

Animal models of hepatitis E infection: Advances and challenges

Hepatitis E virus(HEV)is one of the leading causes of acute viral hepatitis worldwide.Although most of HEV infections are asymptomatic,some patients will develop the symptoms,especially pregnant women,the elderly,and patients with preexisting liver diseases,who often experience anorexia,nausea,vom-iting,malaise,abdominal pain,and jaundice.HEV infection may become chronic in immunosuppressed individuals.In addition,HEV infection can also cause several extrahepatic manifestations.HEV exists in a wide range of hosts in nature and can be transmitted across species.Hence,animals susceptible to HEV can be used as models.The establishment of animal models is of great significance for studying HEV transmission,clinical symptoms,extrahepatic manifestations,and therapeutic strategies,which will help us understand the pathogenesis,prevention,and treatment of hepatitis E.This review summarized the animal models of HEV,including pigs,monkeys,rabbits,mice,rats,and other animals.For each animal species,we provided a concise summary of the HEV genotypes that they can be infected with,the cross-species transmission pathways,as well as their role in studying extrahepatic manifestations,prevention,and treatment of HEV infection.The advantages and disadvantages of these animal models were also emphasized.This review offers new perspectives to enhance the current understanding of the research landscape surrounding HEV animal models.

Subclinical hepatitis E virus genotype 1 infection:The concept of“dynamic human reservoir”

Hepatitis E virus(HEV)is hyperendemic in South Asia and Africa accounting for half of total Global HEV burden.There are eight genotypes of HEV.Among them,the four common ones known to infect humans,genotypes 1 and 2 are prevalent in the developing world and genotypes 3 and 4 are causing challenge in the industrialized world.Asymptomatic HEV viremia in the general population,especially among blood donors,has been reported in the literature worldwide.The clinical implications related to this asymptomatic viremia are unclear and need further exploration.Detection of viremia due to HEV genotype 1 infection,apparently among healthy blood donors is also reported without much knowledge about its infection rate.Similarly,while HEV genotype 3 is known to be transmitted via blood transfusion in humans and has been subjected to screening in many European nations,instances of transmission have also been documented albeit without significant clinical consequences.Epidemiology of HEV genotype 1 in endemic areas often show waxing and waning pattern.Occasional sporadic occurrence of HEV infection interrupted by outbreaks have been frequently seen.In absence of known animal reservoir,where HEV exists in between outbreak is a mystery that needs further exploration.However,occurrence of asymptomatic HEV viremia due to HEV genotype 1 during epidemiologically quiescent period may explain that this phenomenon may act as a dynamic reservoir.Since HEV genotype 1 infection cannot cause chronicity,subclinical transient infection and transmission of virus might be the reason it sustains in interepidemic period.This might be the similar phenomenon with SARS COVID-19 corona virus infection which is circulating worldwide in distinct phases with peaks and plateaus despite vaccination against it.In view of existing evidence,we propose the concept of“Dynamic Human Reservoir.”Quiescent subclinical infection of HEV without any clinical consequences and subsequent transmission may contribute to the existence of the virus in a community.The potential for transmitting HEV infection by asymptomatic HEV infected individuals by fecal shedding of virus has not been reported in literature.This missing link may be a key to Pandora's box in understanding epidemiology of HEV infection in genotype 1 predominant region.

Realm of hepatitis E:Challenges and opportunities

Hepatitis E virus(HEV),responsible for widespread viral hepatitis,infects approximately 2.3 billion individuals globally,with a significant mortality burden in Asia.The virus,primarily transmitted through contaminated water and undercooked meat,is often underdiagnosed,particularly in immunocompromised patients.Current HEV treatments,while effective,are limited by adverse effects,necessitating research into safer alternatives.Moreover,HEV’s extrahepatic manifestations,impacting the nervous and renal systems,remain poorly understood.This study underscores the imperative for enhanced HEV research,improved diagnostic methods,and more effective treatments,coupled with increased public health awareness and preventive strategies.

Pathogenesis and clinical features of severe hepatitis E virus infection

The hepatitis E virus(HEV),a member of the Hepeviridae family,is a small,non-enveloped icosahedral virus divided into eight distinct genotypes(HEV-1 to HEV-8).Only genotypes 1 to 4 are known to cause diseases in humans.Genotypes 1 and 2 commonly spread via fecal-oral transmission,often through the consum-ption of contaminated water.Genotypes 3 and 4 are known to infect pigs,deer,and wild boars,often transferring to humans through inadequately cooked meat.Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms,such as jaundice.However,in immunosup-pressed individuals,the disease can progress to chronic hepatitis and even escalate to cirrhosis.For pregnant women,an HEV infection can cause fulminant liver failure,with a potential mortality rate of 25%.Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection,which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease.As the prevalence of HEV infection continues to rise worldwide,highlighting the particular risks associated with severe HEV infection is of major medical interest.This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.

Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment

The hepatitis E virus(HEV)is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s.Globally,it is one of the most frequent causes of acute viral hepatitis.The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus.Among the eight different genotypes identified to date,HEV genotype 1(HEV1),HEV2,HEV3,and HEV4 are the most frequent genotypes causing infections in humans.HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies.They are also responsible for severe hepatitis in pregnant patients and infants.In contrast,HEV3 and HEV4 are zoonotic,and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals.Their main reservoir is the pig,and they are mostly encountered in developed countries.The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women,infants,older people,immunocompromised individuals,patients with underlying chronic liver diseases,and workers that come into close contact with HEV-infected animals.In the clinical perspective,HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis,acute-on-chronic liver disease,chronic hepatitis,cirrhosis,and liver failure.Although HEV mainly results in acute selflimiting infection,chronic HEV infection may occur among immunocompromised patients(e.g.,solid-organ transplant recipients).Additionally,HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade,although the causal link for many of them still needs to be proven.Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success.However,ribavirin is contraindicated in pregnant patients,and interferon-alpha cannot be used in most transplant recipients.Therefore,there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirinresistant HEV.In this review article,a literature search using PubMed and MEDLINE databases was performed,up to March 2020.Only the articles published in English were reviewed.

Neurological manifestations of hepatitis E virus infection:An overview

Hepatitis E virus(HEV)is an important cause of repeated waterborne outbreaks of acute hepatitis.Recently,several extrahepatic manifestations(EHMs)have been described in patients with HEV infection.Of these,neurological disorders are the most common EHM associated with HEV.The involvement of both the peripheral nervous system and central nervous system can occur together or in isolation.Patients can present with normal liver function tests,which can often be misleading for physicians.There is a paucity of data on HEV-related neurological manifestations;and these data are mostly described as case reports and case series.In this review,we analyzed data of 163 reported cases of HEV-related neurological disorders.The mechanisms of pathogenesis,clinico-demographic profile,and outcomes of the HEV-related neurological disorders are described in this article.Nerve root and plexus disorder were found to be the most commonly reported disease,followed by meningoencephalitis.

Open reading frame 3 protein of hepatitis E virus:Multi-function protein with endless potential

Hepatitis E virus (HEV), a fecal-orally transmitted foodborne viral pathogen,causes acute hepatitis in humans and is responsible for hepatitis E outbreaksworldwide. Since the identification of HEV as a zoonotic agent, this virus has beenisolated from a variety of hosts with an ever-expanding host range. HEV-openreading frame (ORF) 3, the smallest ORF in HEV genomes, initially had beenperceived as an unremarkable HEV accessory protein. However, as novel HEVORF3function has been discovered that is related to the existence of a putativethird virion structural form, referred to as “quasi-enveloped” HEV particles, HEVis challenging the conventional virion structure-based classification scheme,which assigns all viruses to two groups, “enveloped” or “non-enveloped”. In thisreview, we systematically describe recent progress that has identified multiplepathogenic roles of HEV-ORF3, including roles in HEV virion release, biogenesisof quasi-enveloped virus, regulation of the host innate immune response, andinterference with host signaling pathways. In addition, implications of HEVORF3-associated quasi-enveloped virions are discussed to guide futuredevelopment of improved vaccines against zoonotic HEV infection.

Hepatitis E in solid organ transplant recipients:A systematic review and meta-analysis

BACKGROUND Hepatitis E virus(HEV)infection is underdiagnosed due to the use of serological assays with low sensitivity.Although most patients with HEV recover completely,HEV infection among patients with pre-existing chronic liver disease and organ-transplant recipients on immunosuppressive therapy can result in decompensated liver disease and death.AIM To demonstrate the prevalence of HEV infection in solid organ transplant(SOT)recipients.METHODS We searched Ovid MEDLINE,EMBASE,and the Cochrane Library for eligible articles through October 2020.The inclusion criteria consisted of adult patients with history of SOT.HEV infection is confirmed by either HEV-immunoglobulin G,HEV-immunoglobulin M,or HEV RNA assay.RESULTS Of 563 citations,a total of 22 studies(n=4557)were included in this metaanalysis.The pooled estimated prevalence of HEV infection in SOT patients was 20.2%[95%confidence interval(CI):14.9-26.8].The pooled estimated prevalence of HEV infection for each organ transplant was as follows:liver(27.2%;95%CI:20.0-35.8),kidney(12.8%;95%CI:9.3-17.3),heart(12.8%;95%CI:9.3-17.3),and lung(5.6%;95%CI:1.6-17.9).Comparison across organ transplants demonstrated statistical significance(Q=16.721,P=0.002).The subgroup analyses showed that the prevalence of HEV infection among SOT recipients was significantly higher in middle-income countries compared to high-income countries.The pooled estimated prevalence of de novo HEV infection was 5.1%(95%CI:2.6-9.6)and the pooled estimated prevalence of acute HEV infection was 4.3%(95%CI:1.9-9.4).CONCLUSION HEV infection is common in SOT recipients,particularly in middle-income countries.The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants.More studies examining the clinical impacts of HEV infection in SOT recipients,such as graft failure,rejection,and mortality are warranted.

Hepatitis E in immunocompromised individuals

Hepatitis E virus(HEV)originally identified as a cause of acute icteric hepatitis in developing countries has grown to be a cause of zoonotic viral hepatitis in developed countries such as the United States.While there are eight identified genotypes to date,genotype 1(HEV1),HEV2,HEV3,HEV4 are the most common to infect humans.HEV1 and HEV2 are most common in developing countries including Latina America,Africa and Asia,and are commonly transmitted through contaminated water supplies leading to regional outbreaks.In contrast HEV3 and HEV4 circulate freely in many mammalian animals and can lead to occasional transmission to humans through fecal contamination or consumption of undercooked meat.The incidence and prevalence of HEV in the United States is undetermined given the absence of FDA approved serological assays and the lack of commercially available testing.In majority of cases,HEV infection is a selflimiting hepatitis requiring only symptomatic treatment.However,this is not the case in immunocompromised individuals,including those that have undergone solid organ or stem cell transplantation.In this subset of patients,chronic infection can be life threatening as hepatic insult can lead to inflammation and fibrosis with subsequent cirrhosis and death.The need for re-transplantation as a result of post-transplant hepatitis is of great concern.In addition,there have been many reported incidents of extrahepatic manifestations,for which the exact mechanisms remain to be elucidated.The cornerstone of treatment in immunocompromised solid organ transplant recipients is reduction of immunosuppressive therapies,while attempting to minimize the risk of organ rejection.Subsequent treatment options include ribavirin,and pegylated interferon alpha in those who have demonstrated ribavirin resistance.Further investigation assessing safety and efficacy of anti-viral therapy is imperative given the rising global health burden.Given this concern,vaccination has been approved in China with other investigations underway throughout the world.In this review we introduce the epidemiology,diagnosis,clinical manifestations,and treatment of HEV,with emphasis on immunocompromised individuals in the United States.

An Analysis of Epidemiological Characteristics and the Clinical Features of 394 Cases of Sporadic Acute Hepatitis E in Southwest China from 2008 to 2010

Background and Aims Recently, epidemiology studies of hepatitis E in different areas are attracted more attention. Extensive studies of prevalent status and clinical manifestations could help us to broaden our knowledge, so as to excellently prevent and treat hepatitis E. The study analyzed the epidemiological characteristics and clinical features of 394 cases of sporadic acute hepatitis E(AHE) in Southwest of China from 2008 to 2010. Methods The clinical data of 394 cases with sporadic AHE in Southwest of China from 2008 to 2010 were reviewed.Results In the 394 cases with sporadic AHE, the ratio of male/female was 1.432∶1, and the mean age was(31.53 ± 18.12) years. Totally, 94(23.86%) patients aged under 18, 271(68.78%) patients aged between 18 and 60, and 29(7.36%) patients aged above 60. The incidence rate was significantly increased in summer(P = 0.000), especially in May(14.72%) and July(13.71%). In addition, the characteristics of occupation and ethnic group distribution were migrant laborers(106/394, 26.90%) and Han people(365/394, 92.64%). The length of stay, incidence of jaundice, the peak value of total bilirubin and alanine aminotransferase in male patients were all higher than those in female patients significantly(P < 0.05). The prolonged length of stay, decreased levels of ALT/ALB/CHE, increased levels of TBil, and increased incidence of jaundice and fatigue were associated with older age significantly(P < 0.05). The differences in peak values of total bilirubin(TBil), total bile acid(TBA), glutamyltransferase(GGT), cholinesterase(CHE) between AHE group and the groups of AHE accompanied respectively by chronic hepatitis B(CHB), acute alcoholic fatty liver(AFL), nonalcoholic fatty liver disease(NAFLD) were significant(P < 0.05). In addition, no significant difference was found in length of stay and biochemical indexes among anti-HEV-Ig G positive group, anti-HEV-Ig M positive group and antiHEV-Ig M/Ig G both positive group(P > 0.05).Conclusions Four epidemiological characteristics, including aged between 18 and 60, male, summer and migrant laborers, are found to be associated with acute hepatitis E. The prognosis of AHE in the majority of patients was favorable, but aged above 60 years and coexistence with CHB, AFL and NAFLD could be considerede as the factors inducing the infaust prognosis.

Significance of serum IgA in patients with acute hepatitis E virus infection

AIM： To study the significance of serum anti-hepatitis E virus （HEV） IgA in patients with hepatitis E. METHODS： A new method was established to assay anti-HEY IgA, which could be detected in the middle phase of the infection. We compared anti-HEV IgA assay with anti-HEV IgM and anti-HEV IgG assay in sera from 60 patients with positive HEV-RNA. RESULTS： The 60 patients with positive HEV-RNA had both anti-HEV IgA and anti-HEV IgM and 410 patients with negative HEV-RNA were used as control. Periodic serum samples obtained from 60 patients with hepatitis E were tested for HEV RNA, anti-HEV IgM, anti-HEV IgA and anti-HEV IgG. Their HEV-RNA was detectable in the serum until 20 ±11 d. We used anti-HEV IgM and anti-HEV IgA assay to detect HEV infection and positive results were found in 90 ± 15 d and 120 ±23 d respectively, the positive rate of anti-HEV IgA was higher than that of anti-HEV IgM and HEV-RNA （P 〈0.05）. CONCLUSION： The duration of anti-HEV IgA in serum is longer than that of anti-HEV IgM, and anti-HEV IgA assay is a good method to detect HEV infection.

A truncated hepatitis E virus ORF2 protein expressed in tobacco plastids is immunogenic in mice

AIM： To cost-effectively express the 23-ku pE2, the most promising subunit vaccine encoded by the E2 fragment comprising of the 3＇-portion of hepatitis E virus （HEV） open reading frame 2 （ORF2） in plastids of tobacco （Nicotiana tabacum cv. SR1）, to investigate the transgene expression and pE2 accumulation in plastids, and to evaluate the antigenic effect of the plastid-derived pE2 in mice. METHODS： Plastid-targeting vector pRB94-E2 containing the E2 fragment driven by rice psbA promoter was constructed. Upon delivery into tobacco plastids, this construct could initiate homologous recombination in psaB-trnfM and trnG-psbC fragments in plastid genome, and result in transgene inserted between the two fragments. The pRB94-E2 was delivered with a biolistic particle bombardment method, and the plastid-transformed plants were obtained following the regeneration of the bombarded leaf tissues on a spectinomycin-supplemented medium. Transplastomic status of the regenerated plants was confirmed by PCR and Southern blot analysis, transgene expression was investigated by Northern blot analysis, and accumulation of pE2 was measured by ELISA. Furthermore, protein extracts were used to immunize mice, and the presence of the pE2-reactive antibodies in serum samples of the immunized mice was studied by ELISA. RESULTS： Transplastomic lines confirmed by PCR and Southern blot analysis could actively transcribe the E2 mRNA. The pE2 polypeptide was accumulated to a level as high as 13.27 μg/g fresh leaves. The pE2 could stimulate the immunized mice to generate pE2-specific antibodies. CONCLUSION： HEV-E2 fragment can be inserted into the plastid genome and the recombinant pE2 antigen derived is antigenic in mice. Hence, plastids may be a novel source for cost-effective production of HEV vaccines.

Transfusion-transmitted hepatitis E:What we know so far?

Hepatitis E virus(HEV)is a major cause of viral hepatitis globally.There is growing concern about transfusion-transmitted HEV(TT-HEV)as an emerging global health problem.HEV can potentially result in chronic infection in immunocompromised patients,leading to a higher risk of liver cirrhosis and even death.Between 0.0013%and 0.281%of asymptomatic blood donors around the world have HEV viremia,and 0.27%to 60.5%have anti-HEV immunoglobulin G.HEV is infectious even at very low blood concentrations of the virus.Immunosuppressed patients who develop persistent hepatitis E infection should have their immunosuppressant regimen reduced;ribavirin may be considered as treatment.Pegylated interferon can be considered in those who are refractory or intolerant to ribavirin.Sofosbuvir,a nucleotide analog,showed modest antiviral activity in some clinical studies but sustained viral response was not achieved.Therefore,rescue treatment remains an unmet need.The need for HEV screening of all blood donations remains controversial.Universal screening has been adopted in some countries after consideration of risk and resource availability.Various pathogen reduction methods have also been proposed to reduce the risk of TT-HEV.Future studies are needed to define the incidence of transmission through transfusion,their clinical features,outcomes and prognosis.

Genetic characteristics and pathogenicity of human hepatitis E virus in Nanjing,China

AIM： To investigate the genetic characteristics and pathogenicity of hepatitis E virus （HEV） and assess the potential risk factors for sporadic hepatitis E.

Hepatitis E virus chimeric DNA vaccine elicits immunologic response in mice

AIM： To construct the plasmid pcHEV23 containing fragments of HEV ORF2 and ORF3 chimeric gene and to assess its ability to elicit specific immunologic response in mice. METHODS： The gene encoding the structural protein of HEV ORF2 fragment and full-length ORF3 was amplified by PCR. The PCR products were cloned into an eucaryotic expression plasmid pcDNA3. The resulting plasmid pcHEV23 was used as a DNA vaccine to inoculate BALB/c mice intramuscularly thrice at a dose of 100 or 200 ug. Mice injected with empty pcDNA3 DNA or saline served as control and then specific immune responses in the mice were detected. RESULTS： After 2-3 times of inoculation, all mice injected with pcHEV23 had anti-HEV IgG seroconversion and specific T lymphocyte proliferation. The lymphocyte stimulation index in the group immunized with pcHEV23 （3.1＋0.49） was higher than that in the control group （0.787±0.12, P〈0.01）. None in the control group had a detectable level of anti-HEV IgG. CONCLUSION： DNA vaccine containing HEV ORF2 and ORF3 chimeric gene can successfully induce specific humoral and cellular immune response in mice.

Hepatitis E virus is a leading cause of acute-on-chronic liver disease:experience from a tertiary centre in Bangladesh

BACKGROUND:Acute-on-chronic liver failure(ACLF) is common in Bangladesh.Acute viral E hepatitis is sporadically encountered in this country each year,with a rising incidence in the rainy season.This study aimed to identify the etiology of ACLF in Bangladesh. METHODS:In this retrospective study,69 ACLF patients were included.They presented to our department at the Bangabandhu Sheikh Mujib Medical University in Dhaka.History of diseases was recorded and appropriate investigations were conducted in all patients. RESULTS:Acute hepatitis E virus(HEV)infection was positive in 21.7%(15/69)of the patients,while 14.5% (10/69)had septicemia.Upper gastrointestinal tract hemorrhage was seen in 4.3%of the patients(3/69),while another 4.3%(3/69)had a positive history for alcohol or drugs.None of the patients tested positive for hepatitis A virus infection and no evidence of hepatitis B virus flare was found in any patient.No specific cause for ACLF could be identified. CONCLUSIONS:Acute HEV infection is a leading cause of ACLF in Bangladesh.Many patients were thought to have decompensation of cirrhosis,but subsequently were recognized as having ACLF by a retrospective review according to the definition of the Asian Pacific Association for the Study of the Liver Working Party Meeting on ACLF in New Delhi in early 2008.

Detection of hepatitis E virus RNA in sera of patients with hepatitis E by polymerase chain reaction

BACKGROUND: The duration of viremia during hepatitis E virus (HEV) infection has rarely been reported. This study was undertaken to detect HEV RNA in sera of patients with hepatitis E and to understand the process of HEV infection more thoroughly. METHODS: HEV RNA was detected in the serum samples of hospitalized patients with acute hepatitis E by reverse transcriptase-nested polymerase chain reaction (RT-nPCR) using two pairs of primers from open reading frame (ORF) I of the HEV genome. RESULTS: The serum samples from 44 (70%) of 62 patients were positive for HEV RNA. Thirty-two of these patients, with 288 serial serum specimens, were followed up for the whole process, and 24 patients (75%) were positive for HEV RNA. The positive rates declined with the course of the disease, serum HEV RNA persisting for 20.6 days on average after onset of illness. Serum HEV RNA remained positive in 36 (81.8%) of the 44 patients at the time their alanine aminotransferase (ALT) began to decrease. There was no difference in HEV RNA positivity between serum with high levels of HEV antibody (peak P/N ratio >= 4.0) and that with low levels (peak P/N ratio 4.0), with 25 out of 35 and 19 out of 27 (71.4% vs. 70.4%, P>0.05), respectively. CONCLUSIONS: There is a relatively long period of HEV viremia in patients with hepatitis E. The proportion of HEV viremia and its duration are not directly related to serum ALT values or HEV antibody levels.

Seroprevalence and evolutionary dynamics of genotype 4 hepatitis E virus in Shandong Province,China

AIM: To investigate the seroprevalence and evolutionary dynamics of hepatitis E virus (HEV) and assess the ancestor of HEVs in China&#x02019;s Shandong Province.

Hepatitis E virus in patients with acute severe liver injury

AIM: To examine the incidence of hepatitis E(HepE) in individuals with acute liver injury severe enough to warrant treatment at a transplant unit.METHODS: Hepatitis E virus(HEV) is an emerging pathogen in developed countries causing severe illness, particularly in immunocompromised patients or those with underlying chronic liver disease. HepE infection isoften under diagnosed, as clinicians can be reluctant to test patients who have not travelled to regions traditionally considered hyperendemic for HepE. There are few data regarding the significance of HEV in patients with very severe acute liver injury in developed countries. Eighty patients with acute severe liver injury attending the Scottish Liver Transplant unit were tested for HEV and anti-HEV IgG and IgM. Severe acute liver injury was defined as a sudden deterioration in liver function confirmed by abnormal liver function tests and coagulopathy or presence of hepatic encephalopathy. Eighty percent of these patients were diagnosed with paracetomol overdose. No patients had a history of chronic or decompensated chronic liver disease at time of sampling. IgG positive samples were quantified against the World Health Organization anti-HEV IgG standard. Samples were screened for HEV viral RNA by quantitative reverse transcription polymerase chain reaction.RESULTS: Four cases of hepatitis E were identified. Three of the four cases were only diagnosed on retrospective testing and were initially erroneously ascribed to drug-induced liver injury and decompensated chronic liver disease, with the cause of the decompensation uncertain. One case was caused by HEV genotype 1 in a traveller returning from Asia, the other three were autochthonous and diagnosed on retrospective testing. In two of these cases(where RNA was detected) HEV was found to be genotype 3, the most prevalent genotype in developed countries. Three patients survived, two of whom had been misdiagnosed as having drug induced liver injury. The fourth patient died from sepsis and liver failure precipitated as a result of hepatitis E infection and previously undiagnosed cirrhosis. Histopathology data to date is limited to mainly that seen for endemic HepE. All patients, with the exception of patient 1, demonstrated characteristics of HepE infection, as seen in previously described locally acquired cases.CONCLUSION: In patients with acute severe liver injury, HEV testing should be part of the initial diagnostic investigation algorithm irrespective of suspected initial diagnosis, age or travel history.