Features of hepatitis E virus infection in humans and animals in Japan

In Japan, hepatitis E had long been considered to be a rare liver disease which can be accidentally imported from endemic countries in Asia and Africa, where the sanitation conditions are suboptimal. However, since the identification of the first autochthonous hepatitis E case and hepatitis E viremic domestic pigs in Japan in 2001, our understanding of hepatitis E virus (HEV) infection in this country has been changing markedly. This has largely been due to the development of serological and gene‐based diagnostic assays, the accumulation of molecular epidemiological findings on HEV infection in humans and animals (as potential reservoirs for HEV in humans) and the recognition of the importance of zoonotic food‐borne and other routes of transmission of HEV, including blood‐borne transmission. Although it is now evident that autochthonous hepatitis E in Japan is far more common than was previously thought, clinical and subclinical HEV infections indigenous to Japan remain underdiagnosed and their prevalence is still underestimated due to the presence of unknown transmission routes and a low awareness of the infection status by many physicians in Japan. This review focuses on the features of HEV infection in humans and animals, as definitive or potential reservoirs for HEV, in Japan, and updates the current knowledge on the routes of transmission, including zoonotic routes, which are important for the maintenance and spread of HEV in Japan.     

Hepatitis E in new zealand

Background and Aim: Locally acquired hepatitis E virus (HEV) infection has been described in a number of developed countries and is thought to be zoonotic from pigs. Little is known about hepatitis E in humans in New Zealand (NZ) but 90% of NZ pigs show evidence of HEV infection. The aim of this study was to investigate the epidemiology of hepatitis E infection in NZ by documenting HEV immunoglobulin (Ig) G seroprevalence in NZ blood donors, testing patients with unexplained hepatitis for HEV, and comparing genetic sequences of human HEV with local porcine isolates. Methods: In total, 265 blood donors were tested for HEV IgG and 77 patients with unexplained hepatitis were tested for HEV. Viral sequences were compared with known HEV isolates including those from NZ pigs. Results: The HEV IgG seroprevalence was 4%. HEV genotype 3 was isolated in four patients with unexplained hepatitis. Clinical and sequencing data suggest that two cases were acquired in Europe and two in NZ. All cases were in elderly patients, one of whom was asymptomatic and initially misdiagnosed as a drug reaction. The NZ‐acquired cases were most similar to HEV from Japan, and bore little sequence homology to HEV isolated from NZ pigs. Conclusions: Hepatitis E does occur in NZ in patients who have not traveled to endemic areas and seems to affect the elderly. The seroprevalence data suggest that subclinical/unrecognized infection is common. Sequencing data suggest that some reservoir other than pigs could be the source of HEV in NZ. It is recommend that all patients with unexplained hepatitis, whatever their age or travel history, are tested for HEV.     

Hepatitis E,what’s the real issue?

Hepatitis E Virus (HEV) infection is a worldwide disease and the primary cause of acute viral hepatitis in the world with an estimated 20 million cases every year and 70 000 deaths. Hepatitis E is a waterborne infection in the developing countries. In these countries, HEV genotypes 1 and 2 cause large outbreaks and affect young subjects, resulting in significant mortality in pregnant women and patients with cirrhosis. In the developed countries, HEV genotypes 3 and 4 are responsible for autochthonous, sporadic hepatitis and transmission is zoonotic. Parenteral transmission by the transfusion of blood products has been identified as a potential new mode of transmission. The prevalence of positive HEV viraemia in blood donors in Europe ranges from 1/600 to 1/2500 in highly endemic European countries. HEV can cause neurological disorders and chronic infections in immunocompromised patients. The progression of acute hepatitis E is usually asymptomatic and resolves spontaneously. Diagnostic tools include anti‐HEV IgM antibodies in serum and/or viral RNA detection in the blood or the stools by PCR. Ribavirin is used to treat chronic infection. A vaccine has been developed in China.     

Lack of hepatitis E virus infection in HIV patients with advanced immunodeficiency or idiopathic liver enzyme elevations

Summary.  Hepatitis E virus (HEV) is an enterically transmissible RNA agent that causes self-limited acute hepatitis. Recent reports have highlighted that organ-transplant recipients may develop chronic hepatitis E and progress to cirrhosis. Similar cases could occur in HIV patients. We have investigated 50 HIV-infected individuals with CD4 counts <200 cells/mm³ and 43 with cryptogenic hepatitis. None of them showed HEV viremia. Thus, HEV infection does not seem to be prevalent in the HIV population and accordingly universal HEV vaccination is not warranted in these patients.     

Autochthonous sporadic acute hepatitis E caused by two distinct subgenotype 3b hepatitis E virus strains with only 90% nucleotide identity

Hepatitis E, which is caused by hepatitis E virus (HEV), is a public health concern in Japan, where the zoonotic food-borne transmission of HEV from domestic pigs and wild boars plays an important role. A 44-year-old Japanese man with autochthonous sporadic acute hepatitis E was admitted with general fatigue and moderate liver dysfunction. In the present study, two distinct HEV strains were recovered from the patient, who had consumed the raw or undercooked pig liver and intestine two or three times per week for 3 months before the disease onset. The recovered HEV strains were segregated into two clusters within subgenotype 3b, the open reading frame (ORF)1 and ORF2 sequences of which each showed ~10% difference, indicating HEV mixed infection. Because most notified patients with clinical HEV infection in Japan are diagnosed based on the detection of IgA-class HEV antibodies and because serum samples from only a limited number of HEV-infected patients are subjected to HEV RNA detection and nucleotide sequencing, it is very likely that patients with HEV mixed infection remain largely overlooked. The identification of sources of autochthonous HEV infection remains an important goal. Continued efforts to trace the sources of acute or chronic autochthonous HEV infection are warranted.     

Hepatitis E: an emerging global disease – from discovery towards control and cure

Hepatitis E is a systemic disease affecting the liver predominantly and caused by infection with the hepatitis E virus (HEV). HEV has marked genetic heterogeneity and is known to infect several animal species including pigs, boar, deer, mongoose, rabbit, camel, chicken, rats, ferret, bats and cutthroat trout. HEV is the sole member of the family Hepeviridae and has been divided into 2 genera: Orthohepevirus (mammalian and avian HEV) and Piscihepevirus (trout HEV). Human HEVs included within the genus Orthohepevirus are designated Orthohepevirus A (isolates from human, pig, wild boar, deer, mongoose, rabbit and camel). Hepatitis E is an important public health concern, and an estimated one‐third of the world population has been infected with HEV. In recent years, autochthonous hepatitis E is recognized as a clinical problem in industrialized countries. Several animal species especially domestic swine, wild boar and wild deer are reservoirs of genotype HEV‐3 and HEV‐4 in these countries. Human infections occur through intake of uncooked or undercooked meat of the infected animals and pig livers or sausages made from these livers and sold in supermarkets. HEV can be transmitted through blood and blood component transfusions, and donor screening for HEV is under serious consideration. Chronic hepatitis E resulting in rapidly progressive liver cirrhosis and end‐stage liver disease has been described in organ transplant patients. Ribavirin monotherapy attains sustained virological response in most patients. HEV 239 vaccine has been marketed in China and its long‐term efficacy over four and a half years reported.     

Sporadic acute hepatitis E in the united kingdom: an underdiagnosed phenomenon?

BACKGROUND: Hepatitis E (HEV) is the primary cause of enterically transmitted non-A non-B hepatitis worldwide. Case reports of HEV in individuals in the United Kingdom relate to travel to endemic areas or contact with individuals who have visited these areas. CASE REPORTS: Four individuals presented with acute hepatitis to a hepatology clinic in a teaching hospital. Serology confirmed acute hepatitis E in all four. Investigation by the Communicable Disease Control Department established no links between the cases, no travel to an endemic area, and no contacts. CONCLUSION: Contrary to current belief, community acquired hepatitis E virus infection occurs sporadically in the United Kingdom and should be considered as a cause of seronegative hepatitis.     

Sporadic cases of acute autochthonous hepatitis E in Spain

BACKGROUND/AIMS: In industrialized countries hepatitis E virus (HEV) infection is rare and its diagnosis is difficult because the utility of available tests is not well established. METHODS: We studied the presence of acute HEV infection markers in a cluster of 11 cases of acute hepatitis with IgG anti-HEV antibodies. RESULTS: Three cases were confirmed as acute hepatitis E and 8 as presumptive hepatitis E, two as a past HEV infection and one could not be determined. Three different HEV strains were identified in serum from 3 patients. Two strains belonged to genotype 3, the predominant genotype found in local urban sewage and the other strain belonged to genotype 1 and was considered an imported strain. CONCLUSIONS: Our findings demonstrate the presence of some autochthonous, sporadic acute hepatitis E cases as well as an imported case in our area and the transitory nature of virological and serological markers for HEV.     

Contribution of HEV and HCV in causing fulminant non-A, non-B hepatitis in western India

Summary. During 1990, 38 patients with fulminant non-A, non-B hepatitis (NANB) died in Government Medical College Hospital, Aurangabad. Serum samples from these patients were tested for antibodies to hepatitis C virus (anti-HCV) and IgM antibodies to hepatitis E virus (IgM-anti-HEV). All samples were also subjected to polymerase chain reaction (PCR) for the detection of HBV DNA, HCV RNA and HEV RNA. None of the patients had circulating anti-HCV antibodies; three had HCV RNA. Based on anti-HEV-IgM positivity 14 patients (37%) could be diagnosed as suffering from hepatitis E. None was positive for HEV RNA. In the absence of serological markers, HBV DNA was present in three cases. None of the HBV DNA positive patients had anti-δ antibodies. Dual infections (HBV with HEV, and HBV with HCV) were seen in two cases. The aetiology of half of the NANB cases could not be assigned to the known hepatitis viruses using current techniques.     

Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation

Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid‐organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV‐RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.     

警惕输血引起的慢性戊型肝炎

戊型肝炎主要是HEV经粪-口传播引起的病毒性肝炎,然而近年来陆续报道了一些通过输血传播的病例。虽然通常情况下戊型肝炎为急性自限性疾病,但患者如处于免疫抑制状态（如器官移植、肿瘤化疗或HIV感染等）,感染HEV后会发展为慢性肝炎,并有可能迅速发展为肝纤维化和肝硬化。由于这些患者常常需要多次输血,更加大了感染HEV的风险。本文总结了全球献血员的HEV流行情况、经输血传播HEV的病例及免疫缺陷患者感染HEV后的危害等,提示应警惕输血引起的慢性戊型肝炎。     

Acute hepatitis E of a man who consumed wild boar meat prior to the onset of illness in Nagasaki, Japan.

Zoonotic infection of hepatitis E virus (HEV) has been suggested. To date, pigs, deer, and wild boar have been implicated as reservoirs of HEV in Japan. However, it is not known to what extent zoonotic transmission of HEV play roles of causing HEV transmission. In the present report, we describe a case of acute hepatitis E in which a transmission of HEV by a zoonotic transmission is strongly suggested. The patient had eaten grilled wild boar meat 59 days prior to onset of acute hepatitis. Although the meat was not stored, one of the two people who ate boar meat with the patient at the same time showed high levels of HEV-IgM and -IgG and normal levels of liver enzymes, suggesting a subclinical infection of HEV. Accumulating evidence suggests that eating wild boars is associated with a high risk of acquiring hepatitis E infection.     

Severe hepatitis E infection during pregnancy

In areas with endemic hepatitis E virus (HEV), acute liver failure secondary to hepatitis E infection is common in pregnancy and associated with a mortality rate of up to 20%. However, there is little information on the clinical course of severe hepatitis E infection during pregnancy in non-endemic areas such as the UK. Here we describe two cases of severe hepatitis E in pregnancy in patients returning from the Indian subcontinent. These cases were diagnosed by the detection of IgM anti-HEV antibody using an enzyme immunoassay with recombinant hepatitis E viral antigens. The first case describes acute hepatic failure, with coagulopathy and encephalopathy, warranting intensive therapy and elective ventilation. In the other case, the patient had severe hepatitis with coagulopathy. Both cases spontaneously resolved with no foetal loss. These cases highlight the need for suspicion of HEV infection in patients returning from endemic areas and presenting with acute non-A non-B hepatitis, especially when pregnant. Furthermore, the intensive treatment of acute liver failure caused by HEV may reduce the high mortality reported in Asia.     

Severe hepatitis E infection during pregnancy

In areas with endemic hepatitis E virus (HEV), acute liver failure secondary to hepatitis E infection is common in pregnancy and associated with a mortality rate of up to 20%. However, there is little information on the clinical course of severe hepatitis E infection during pregnancy in non-endemic areas such as the UK. Here we describe two cases of severe hepatitis E in pregnancy in patients returning from the Indian subcontinent. These cases were diagnosed by the detection of IgM anti-HEV antibody using an enzyme immunoassay with recombinant hepatitis E viral antigens. The first case describes acute hepatic failure, with coagulopathy and encephalopathy, warranting intensive therapy and elective ventilation. In the other case, the patient had severe hepatitis with coagulopathy. Both cases spontaneously resolved with no foetal loss. These cases highlight the need for suspicion of HEV infection in patients returning from endemic areas and presenting with acute non-A non-B hepatitis, especially when pregnant. Furthermore, the intensive treatment of acute liver failure caused by HEV may reduce the high mortality reported in Asia.     

戊型肝炎的研究现状和展望

戊型肝炎是戊型肝炎病毒感染引起的急性病毒性肝炎,随着80年代戊型肝炎病毒的被证实,近20余年来,人们对戊型肝炎的研究更加深入。本文从戊型肝炎病毒的结构、戊型肝炎病毒的基因分型（基因1型,2型,3型及4型,其中基因3型及基因4型为人畜共患）、戊型肝炎的流行病学及诊断治疗、预防等方面对戊型肝炎的研究现状进行阐述并对戊型肝炎未来的研究作出展望。值得一提的是,我国研制的戊型肝炎疫苗的上市为戊型肝炎的防控带来曙光。     

Non-travel-associated hepatitis E in England and Wales: demographic, clinical, and molecular epidemiological characteristics

Between 1996 and 2003, 186 cases of hepatitis E were serologically diagnosed. Of these, 17 (9%) were not associated with recent travel abroad. Patients were >55 years old (range, 56-82 years old) and tended to be male (76%). Two patients presented with fulminant hepatitis. A total of 129 (69%) cases were associated with recent travel to countries where hepatitis E virus (HEV) is hyperendemic. Compared with patients with travel-associated disease, patients with non-travel-associated disease were more likely to be older, living in coastal or estuarine areas, not of South Asian ethnicity, and infected by genotype 3 strains of HEV. The genotype 3 subgenomic nucleotide sequences were unique and closely related to those from British pigs. Patients infected by HEV indigenous to England and Wales tended to belong to a distinct demographic group, there were multiple sources of infection, and pigs might have been a viral reservoir.     

Hepatitis E: An Underdiagnosed,Emerging Infection in Nonendemic Regions

Although hepatitis E virus (HEV) is the primary cause of enterically transmitted acute hepatitis and jaundice in developing countries, locally acquired HEV infections are increasing in nonendemic countries. As such, HEV is emerging as an underdiagnosed cause of infection. This report describes three clinically variable cases of HEV infection with unusual clinical presentations. These cases highlight the fact that HEV should be considered in the differential diagnosis of patients with unexplained hepatitis (acute or chronic) with or without extrahepatic manifestations. HEV should also be considered in patients with persistently elevated liver enzymes who have not travelled to known HEV-endemic regions. Lack of knowledge among physicians and an absence of standardized diagnostic tests may result in increased morbidity and mortality from HEV infection.     

Hepatitis E: Dimensión del problema en España

Hepatitis E virus (HEV) infection is one of the most frequent causes of acute hepatitis worldwide. However, in Spain, HEV causes only a tiny number of cases of acute hepatitis, the most prevalent cause being hepatitis A. Most cases of HEV in Spain are “imported”, being acquired through travel to areas where this infection is endemic. Nevertheless, in the last few years a growing number of “autochthonous cases” have been reported in persons with no history of travelling to HEV-endemic areas. The prevalence of IgG antibodies against HEV, indicating exposure to this virus, is approximately 0.6-7.3% in the general population in Spain and is 19% in persons with risk factors such as exposure to pigs.