The histology of acute autochthonous hepatitis E virus infection

AIM: To document the histological appearances of liver biopsies in autochthonous hepatitis E virus (HEV) infection. METHODS AND RESULTS: Four patients were serologically positive for HEV; three had no traditional risk factors, the fourth had recently returned from China. All four consumed meat products. Liver histology of the three autochthonous (locally acquired) cases showed portal tracts expanded by a severe mixed polymorph and lymphocytic inflammatory infiltrate, with a geographical distribution of polymorphs at the interface and lymphocytes centrally. Moderate to severe interface hepatitis and cholangiolitis were present. There was a striking acinar mixed inflammatory infiltrate made up of polymorphs, lymphocytes and macrophages; frequent apoptotic hepatocytes, focal necrosis, cholestatic rosettes and zone 3 canalicular and cytoplasmic bilirubinostasis were noted. Significant steatosis, megamitochondria and Mallory bodies were not present. There was no evidence of iron, copper or alpha(1)-antitrypsin accumulation. By contrast, the histology of the imported case of HEV infection showed less intense portal and acinar inflammation, no cholangiolitis and no geographical distribution of the portal inflammatory infiltrate. CONCLUSION: The histological appearances of autochthonous HEV infection are sufficiently distinctive to consider the diagnosis in an acute setting and possibly to differentiate it from the endemic form of the disease.     

Sporadic cases of acute autochthonous hepatitis E virus infection in Southwest Germany

Hepatitis E infection is usually a self-limiting disease and an important cause of acute hepatitis in tropical and subtropical regions where the virus is endemic. In industrialized countries, sporadic cases of acute hepatitis E virus (HEV) infections have been described and the number of documented autochthonous infections seems to be increasing. We report three sporadic cases of autochthonous hepatitis E infections in Southwestern Germany which presented at our university hospital within two years. All cases were men who presented with acute hepatitis, icterus and elevated liver. In case 1 and case 2, liver biopsy revealed acute hepatitis, both patients were positive for anti-HEV antibodies, case 1 was also positive for HEV RNA with a viral load of 3.0 × 10³ copies/ml in serum. In case 3, anti-HEV antibodies were detectable and HEV RNA was detected in serum (4.3 × 10³ copies/ml) and stool (1.4 × 10⁶ copies/ml). None of the patients had a recent travel history outside Germany and close contact to animals has been denied. HEV sequence analysis of two patients revealed genotype 3 with homologies to other European isolates and isolates from swine. Thus the source of infection remains unclear. Hepatitis E should be considered in differential diagnosis in patients with unexplained hepatitis and patients with acute hepatitis, whatever their age or travel history might be, should be tested for HEV.     

First report of a human autochthonous hepatitis E virus infection in Brazil

BackgroundSporadic acute hepatitis E cases occurring in non-endemic areas have been associated to genotypes 3 and 4 of hepatitis E virus. Several studies have demonstrated the relationship among human and animals strains, mostly pigs and deers, from respective areas characterizing zoonosis. Circulation of genotype 3 of HEV in Brazilian swine herds have already been demonstrated. Nevertheless, no confirmed human cases have been reported to date in Brazil.ObjectivesA study was developed to attempt the identification of hepatitis E acute cases in Brazil.Study designA retrospective study carried out with 64 serum samples from patients with acute non-A–C hepatitis was performed to identify human cases of acute hepatitis E.ResultsWe could identify a confirmed case of acute hepatitis E. The patient seroconverted to hepatitis E virus-specific IgM and IgG antibody, HEV-RNA was amplified from serum, and the analysis of the sequence of a 242 nucleotide fragment from the ORF1 genome region classified the strain within genotype 3 and subgenotype 3b. Investigation of risk factors and results from phylogenetic analysis suggested a likely zoonotic origin for the infection.ConclusionsThe first report of a human autochthonous in Brazil contributes with new information for hepatitis E epidemiology in Latin America and to considerate further broadly epidemiological studies.     

散发性戊型肝炎病毒感染的诊断

用基因工程重组的戊型肝炎病毒基因结构区第二码框架和第二读码框架具有免疫表位的嵌合抗原，建立了间接酶联免疫法，检测散发性急性肝炎病人血清中抗－ＨＥＶＩｇＧ和ＩｇＭ抗体。在４６例急性肝炎病人中出抗－ＨＥＶＩｇＧ抗体阳性７例，阳性率为１５．２２％，７例ＩｇＧ抗体阳性中，有５例ＩｇＭ抗体也阳性，占７１．４％。     

Imported and autochthonous hepatitis E virus strains in Spain

Hepatitis E virus (HEV) causes hepatitis E, an acute liver disease displaying diverse epidemiological patterns that correlate with the genetic diversity of the virus. Only a few strains have been characterized to date from cases of hepatitis E in Spain. Using three sets of new, HEV‐specific primers, viral genome fragments were amplified from serum samples from 13 patients with acute hepatitis in different regions of Spain. Direct sequencing of these fragments and analysis of sequences lead to identify six genotype 1, six genotype 3, and one genotype 4 viral strains. Genotype 1 sequences were found in the clade with subtype 1a strains, and were amplified from travelers from India and Bangladesh, and from an African immigrant. Genotype 3 sequences were found in the clade with subtype 3f strains, were always amplified from patients who did not travel abroad recently, and were closely related to sequences from swine strains isolated in Spain. Patients infected by these strains lived in different regions and were mainly men aged above 50 years. The single genotype 4 sequence detected was amplified from a traveler returning from Vietnam. Hepatitis E is both an imported and an autochthonous disease in Spain, and closely related HEV genotype 3f strains are responsible for infections acquired locally in different regions of the country within a given time. Studies involving a significant number of human, swine, and environmental viral strains collected prospectively are, however, required in order to confirm a swine origin for autochthonous HEV genotype 3 human infections. J. Med. Virol. 81:1743–1749, 2009. © 2009 Wiley‐Liss, Inc.     

Severe thrombocytopenia associated with acute hepatitis E virus infection

We describe here what is, to the best of our knowledge, the third reported case of severe thrombocytopenia associated with acute hepatitis E virus infection. The patient was a 72-year-old French woman. It seems likely that the cause of the thrombocytopenia was acute hepatitis E virus infection, possibly occurring via an immune mechanism. No complications were noted, in contrast to the two previous reports.     

A search for RNA of hepatitis E virus autochthonous for Russia in the most probable sources of infection

The research that has been carried out in the 30 years since the discovery of hepatitis E virus (HEV) has proven that autochthonous HEV is present in nonepidemic areas: Europe and Russia. Monitoring of the HEV antibodies (anti-HEV) among the Russian population has discovered regions with increased seroprevalence, which testifies to a high probability of local HEV infection in these areas. Coming into contact with HEV is especially dangerous for patients in risk groups. In this work, blood-sera testing was carried out to assess the presence of anti-HEV among these contingents (groups). Seropositive sera from patients from regions with high anti-HEV seroprevalence, patients in risk groups, samples with high probability of HEV occurrence including the animals as possible reservoir, have been used for RNA extraction. A system has been developed of HEV RNA detection both in real-time RT-PCR and in a nested PCR variant has confirmed its sensitivity to the synthetic reference templates and positive control samples in a commercial test system (Genesis, United Kingdom). HEV RNA was absent in all tested samples. This indicates a low frequency of the autochthonous HEV carriage occurrence. Sampling enlargement to tens of thousands persons is necessary for significant HEV RN detection.     

Molecular investigation of hepatitis E virus infection in patients with acute hepatitis in Kathmandu,Nepal

One hundred fifty-four consecutive patients with sporadic acute hepatitis, who were seen at a city hospital in the Kathmandu valley of Nepal in 1997, were studied. IgM antibodies to hepatitis A virus were detected in four patients (3%), IgM antibodies to hepatitis B core in four patients (3%), hepatitis B surface antigen in 20 (13%), and hepatitis C virus RNA in four patients (3%). IgM antibodies to hepatitis E virus (HEV) (anti-HEV IgM) and HEV RNA were detected in 77 (50%) and 48 (31%), respectively. Consequently, 86 patients (56%) including nine HEV-viremic patients without anti-HEV IgM, were diagnosed with hepatitis E. The cause of hepatitis was not known in 53 patients (34%). All 48 HEV RNA-positive samples were genotyped as 1, and subtyped further as 1a in 17 (35%), 1c in 29 (60%), and mixed infection of 1a and 1c in 2 (4%). A seasonal difference in the prevalence of HEV subtypes was recognized. Before the rainy season (January to July), both 1a and 1c isolates were found: the intrasubtypic difference was up to 9.0% and 1.7%, respectively, in the 412-nucleotide sequence of open reading frame 2. During the rainy season (August), only 1c isolates (n = 17) with 99.5-100% identity were found; 13 of 17 isolates had the same sequence, being identical to the 3 isolates that emerged at the end of July. These results suggest that a particular HEV 1c strain spread widely during the rainy season and was implicated in a small epidemic in the Kathmandu valley in August 1997.     

非甲-非戊型慢性病毒性肝炎患者隐匿性HBV感染的研究

目的 观察非甲-非戊型慢性病毒性肝炎患者隐匿性HBV感染的状况,探讨荧光定量聚合酶链反应(FQ-PCR)技术对隐匿性HBV感染的诊断价值.方法 应用FQ-PCR技术对57例非甲-非戊型慢性病毒性肝炎患者进行了血清、肝组织HBV-DNA定量检测,并将肝组织HBV DNA定量水平与肝脏炎症活动度的关系进行了分析.结果 血清、肝组织HBV DrqA定量阳性分别为13例(22.81%)、22例(38.60%).13例血清HBV DNA定量阳性患者其肝组织定量亦均阳性,但9例肝组织HBV DrqA定量阳性患者其血清定量为阴性,差异有统计学意义(P<0.01);同时13例血清与肝组织定量均阳性患者比较.显示肝组织HBV DNA定量水平显著高于血清定量水平[(6.62±1.21)拷贝,gvs.(4.03±1.06)拷贝/ml,(P<0.01)].肝组织HBV DNA水平与肝脏炎症活动度并无相关性,10例G2,7例G3,5例G4患者HB'q DNA定量分别为(6.13±1.65)拷贝/g、(5.92±1.81)拷贝,g、(5.83±1.89)拷贝/g,(P0.05),但HBV DNA定量阳性患者均为活动性肝脏病变.结论 HBV隐匿性感染是部分非甲-非戊型慢性病毒性肝炎患者的病因.单纯检测血清免疫学标志物对HBV感染诊断存在漏诊,对非甲-非戊型慢性病毒性肝炎患者应用FQ-PCR技术开展血清定量尤其是肝组织中HBV DNA定量检测可提高HBV感染的诊断.对隐匿性HBV感染的慢性病毒性肝炎亦应给予有效的抗病毒治疗.     

Spectrum of hepatitis E virus infection in India

A solid phase enzyme linked immunosorbent assay (ELISA) that detects IgM and IgG to hepatitis E virus (HEV) was used to study seroepidemiology in 40 healthy subjects and 227 consecutive patients with liver diseases in an endemic area. Fifty-two of the liver diseases patients (22.9 percent) had acute hepatitis E. In contrast, none of the 40 healthy subjects were positive for IgM anti-HEV, validating the ELISA assay. Twenty-three of 25 (92%) patients with epidemic non-A, non-B hepatitis were confirmed as having acute hepatitis E. Only 1 of the 10 patients with sporadic, fulminant hepatic failuire of non-A, non-B, non-C etiology was positive for IgM anti-HEV. Five (31.2%) of the 16 patients with acute hepatitis in HBsAg carriers were positive for IgM anti-HEV. One patient with acute hepatitis B wascoinfected with acute hepatitis E. Acute hepatitis was a disease of the adult population, with peak attack rates in the second and third decades of life. This disease was seen in only 4 (16%) of the 25 patients with acute viral hepatitis occurring below 14 years of age. Cholestasis was predominant in 25% of patients, enzyme elevation was monophasic, and all patients had clinical and biochemical recovery from the disease. The data suggest that the majority of patients with acute sporadic non-A, non-B, non-C hepatitis in India have hepatitis E. However, fulminant hepatic failure to sporadic nature is rarely from hepatitis E. © 1994 Wiley-Liss, Inc.     

Serological diagnostics of hepatitis E virus infection

Development of accurate diagnostic assays for the detection of serological markers of hepatitis E virus (HEV) infection remains challenging. In the course of nearly 20 years after the discovery of HEV, significant progress has been made in characterizing the antigenic structure of HEV proteins, engineering highly immunoreactive diagnostic antigens, and devising efficient serological assays. However, many outstanding issues related to sensitivity and specificity of these assays in clinical and epidemiological settings remain to be resolved. Complexity of antigenic composition, viral genetic heterogeneity and varying epidemiological patterns of hepatitis E in different parts of the world present challenges to the refinement of HEV serological diagnostic assays. Development of antigens specially designed for the identification of serological markers specific to acute infection and of IgG anti-HEV specific to the convalescent phase of infection would greatly facilitate accurate identification of active, recent and past HEV infections.     

戊型肝炎病毒黑猩猩动物模型的建立

目的为了建立戊型肝炎病毒感染模型。方法两只性别不同的黑猩猩用戊型肝炎病毒接种，检测丙氨酸转氨酶，戊型肝炎病毒ＩｇＭ及ＩｇＧ抗体。结果感染后的黑猩猩均在１个月内发生典型的肝炎症状。结论本实验资料为阐明戊型肝炎病毒感染的规律提供了证据。     

Autoimmune liver disease-associated serologic profiling in Chinese patients with acute hepatitis E virus infection

The association between hepatitis E virus (HEV) and autoimmune liver diseases has been well-researched; however, the focus has been on autoimmune hepatitis (AIH) and not primary biliary cholangitis (PBC). Therefore, we aimed to investigate the prevalence and evolution of AIH- and PBC-related autoantibodies in Chinese patients with HEV infection. In this retrospective study, 164 patients with acute HEV were included, specifically those whose liver autoantibody results were available and who had no pre-existing liver disease at the time of HEV diagnosis. Positive liver autoimmune serology was present in 69 (42.1%) patients and 21 (12.8%) had at least two autoantibodies at diagnosis. Greater age and alkaline phosphatase levels were independent risk factors for autoantibody positivity. Follow-up serologic tests, which were available for 27 of the 69 autoantibody-positive patients, showed that although antinuclear antibodies disappeared in 11/20 (55.0%) and antimitochondrial antibodies disappeared in 4/5 (80%) patients, 16 still remained positive for autoantibodies and two of them even developed new PBC-related antibodies, as described below. One patient developed a rim-like ANA pattern, accompanied by an enhancement of anti-gp210 positivity; and the other was diagnosed as PBC, based on chronic elevation of cholestatic enzymes and presentation with de novo AMA-M2, 18 months after HEV clearance. In conclusion, AIH- and PBC-related autoantibodies are frequently present during acute HEV infection, indicating that HEV should be excluded before diagnosing AIH and/or PBC. Importantly, some cases maintained or developed autoantibodies after viral clearance, and one patient subsequently developed PBC, highlighting that these individuals warrant long-term follow-up.

     

High seroprevalence against hepatitis E virus in patients with chronic hepatitis C virus infection

BackgroundHepatitis E virus (HEV) genotype 3 is endemic in Europe. Superinfection with HEV in patients with underlying chronic liver disease can cause hepatic decompensation leading to increased morbidity and mortality.ObjectivesThe prevalence of anti-HEV antibodies was investigated in 204 patients with chronic hepatitis C virus (HCV) infection and different stages of fibrosis.Study designSera were analyzed for anti-HEV IgG, IgM and HEV RNA.ResultsThe median age of the patients was 55 years (IQR 40–62 years); 126 (62%) were men. Ninety-eight (48%) patients had a METAVIR fibrosis stage F2 or higher. The prevalence of anti-HEV IgG was 30% (62/204), which was significantly higher than among Swedish blood donors (17%, p < 0.01). The prevalence of anti-HEV antibodies was associated with higher age (OR 1.08 (1.05–1.11); p < 0.01). It was also higher for patients with a prior history of blood transfusion (48%) as compared to intravenous drug use (IDU; 26%) as the risk factor for acquisition of the HCV infection (OR 2.72 (1.2–6.19); p < 0.02). The prevalence of anti-HEV IgG was also significantly higher in patients with significant fibrosis, i.e. ≥F2 (38%; OR 2.04 (1.11–3.76); p = 0.02) and/or neoplasm (72%; OR 7.27 (2.46–21.44); p < 0.01).ConclusionsWhen adjusted for age, the prevalence of anti-HEV antibodies was significantly higher in patients with previous or current malignant liver disease compared to blood donors. The lack of significant correlation between HCV and HEV infections indicate low level of transmission of HEV by IDU. HEV infections warrant more attention, especially in patients with preexisting liver disease.     

Leucocyte hepatitis B virus DNA in acute and chronic hepatitis B virus infection

In the present study we have investigated 53 patients with a spectrum of acute and chronic hepatitis B virus (HBV) infection for the presence of leucocyte HBV-DNA with the aid of molecular techniques. HBV-DNA was detected in peripheral blood mononuclear cells of 31 of 45 (69%) of chronic HBsAg carriers and 2 of 8 (25%) patients with acute hepatitis B. Although HBV-DNA was detected more frequently in leucocytes from those HBsAg carriers seropositive for HBeAg (79%), 50% of those with anti-HBe in serum had leucocytes positive for HBV-DNA independent of the presence of serum HBV-DNA. Examination of various leucocyte subpopulations showed the presence of HBV-DNA in polymorphonuclear leucocytes as well as T- and non-T-enriched mononuclear cell fractions. The HBV-DNA identified was predominantly 3.2-kilobase (kb), while higher molecular weight sequences were rarely detected, and lower molecular weight sequences indicative of active viral replication were not observed. These data indicate that although leucocytes do not actively support viral replication, they frequently harbour 3.2-kb HBV-DNA and may act as a reservoir for infection and, more importantly, since leucocytes contaminate several body secretions, may be involved in virus transmission.