Experimental non-A,non-B hepatitis in chimpanzees: Light,electron and immune microscopical observations

ABSTRACT— Two chimpanzees (Pan troglodytes) were inoculated and cross-challenged with a fibrinogen and factor VIII preparation, respectively. Successful non-A, non-B (NANB) infection was documented by biphasic elevations of aminotransferases (ALT), concomitant hepatitic reactions and typical electron microscopic alterations, the most consistent being dilatation of the endoplasmic reticulum, as well as tubular and sponge-like cytoplasmic inclusions in the absence of nuclear virus-like particles. An anti-nuclear (anti-DNA) antibody of the IgM class in one of the chimpanzees simulating an antiviral antibody is described.     

丙型肝炎疫苗研究的新理念、挑战与策略

丙型肝炎病毒（HCV）感染是引起慢性肝病的主要原因之一,严重危害人类健康,目前抗病毒治疗的标准方案为聚乙二醇干扰素α（PEG-IFN-α）联合利巴韦林,其有效率仅为50%70%,且疫苗研究进展缓慢,已成为严峻的公共卫生问题。近10多年来,对HCV感染发病机制、保护性免疫应答和病毒持续感染机制的认识取得了很大进展,中和抗体以及CD4＋和CD8＋T细胞在内的强烈的T细胞免疫应答已被证明与HCV的清除相关,这将是研制丙型肝炎疫苗的希望所在。当前HCV疫苗的研究主要集中在多肽疫苗、核酸疫苗、病毒载体疫苗、重组多表位疫苗、以抗原递呈细胞为载体的树突状细胞（DC）疫苗等,已有多种疫苗正在研制并进行进入临床试验前的测试。我们结合多年来对HCV的研究基础,通过与国内外同行交流,提出变＂单纯预防＂为＂防治结合,以诱导持续免疫应答和维持病毒抑制状态为基本目标＂的HCV疫苗研究新理念,发展以诱导细胞免疫为主的预防和治疗性疫苗,尤其是既能在体内有效激发HCV特异性细胞毒性T淋巴细胞（CTL）反应,又能维持CD4＋记忆T细胞功能的治疗性细胞疫苗。本文综述关于HCV保护性免疫应答及持续感染的机制,HCV疫苗研究新理念,目前面临的挑战以及研究策略。     

Human non-A,non-B hepatitis: ultrastructural alterations in hepatocytes

ABSTRACT— Ultrastructural investigation of liver biopsies from two patients with non-A, non-B hepatitis revealed cytoplasmic and nuclear alterations in the hepatocytes. The lesions in both patients, one with acute and one with chronic hepatitis, were similar and distinct from those previously described in other forms of hepatitis. These findings are compared with the reported findings in chimpanzee liver after inoculation with non-A, non-B infective material. The intranuclear findings are similar to the aggregations of 20–27 nm particles described in some infected chimpanzees, and the cytoplasmic alterations seem to be similar to the cytoplasmic structures and tubular arrangements reported in other inoculated chimpanzees. A striking finding of this study is the presence of both alterations together in the same biopsy in two different patients, suggesting that they represent a different stage of viral infection or different parts of the viral agent. It still remains to be proved that the ultrastructural particles indeed contain antigen(s) of the non-A, non-B hepatitis virus. The nuclear and cytoplasmic alterations are, however, characteristic for non-A, non-B hepatitis and are useful as ultrastructural hallmarks of this form of hepatitis.     

Sequence variability of hepatitis C virus and its clinical relevance

SUMMARY. Chronic type C hepatitis is a potentially serious disease that can lead to cirrhosis and hepatocelluler carcinoma. This complex disease is caused by the hepatitis C virus (HCV), a positive sense, single-stranded RNA virus. HCV has been assigned to a separate genus within the Flaviviridae, and shares a close relationship to the pestiviruses. Nucleotide sequence variation has been observed in genomes amplified from serum of patients with HCV infection, and cloning of RNA amplified from patients infected with HCV has confirmed the heterogeneity of the agent responsible for post-transfusion and sporadic hepatitis C. The variability of HCV is structured in a way that immediately suggests a two tiered classification: this nomenclature comprises 'types' corresponding to the major branches in a phylogenetic tree of sequences from genomic or subgenomic regions of the genome, and 'subtypes', corresponding to the more closely related sequences within some of the major groups. This genotyping designation has provided an epidemiological tool for studying geographical differences in hepatitis C infection. Clearly discernible patterns of genotype distribution have been found in those countries that have been studied so far. In many European countries genotype distributions vary with the age of patients, reflecting rapid changes in genotype distribution with time within a single geographical area. Unfortunately we know very little about modes of transmission within different communities. There is considerable interest in the clinical significance of different HCV genotypes, and the intriguing question of whether these differences may affect the spectrum of the disease associated with hepatitis C. These data also have implications for diagnosis and treatment of acute and chronic hepatitis C. A uniform typing scheme and nomenclature will facilitate our understanding of the disease caused by this virus worldwide.     

New ultrastructural marker in hepatocytes in non-A,non-B viral hepatitis

ABSTRACT— A new ultrastructural cytoplasmic marker designated as type 2, and distinct from type 1 previously associated with NA-NB hepatitis in chimpanzees, was found in hepatocytes of two patients and of one experimentally infected chimpanzee. These cases represent a minority of all cases we studied as presumed NA-NB viral hepatitis. Type 2 marker consists of tubular structures composed of an assembly of ring-like units coated with smaller uniform fragments, accumulated in different patterns in dilated cisternae of the endoplasmic reticulum. Preliminary data using immunofluorescence with NA-NB hepatitis convalescent serum and antiserum against fibrinogen are reported. Type 2 marker may represent a different agent or a different reaction pattern to one agent of NA-NB viral hepatitis. Its features are compared with those of hepatitis B.     

Transmission of viral hepatitis by blood and blood derivatives: current risks, past heritage

For more than 40 years in the history of transfusion medicine, transmission of viral hepatitis from infected donors to recipients has been a frequent and serious adverse effect of the administration of blood components and plasma derivatives. This epidemic is now over, at least in developed and resource-rich countries. Hence, the attention of clinicians and investigators now focuses mainly on the measures to reduce the residual risk, on the possible emergence of novel or undiscovered agents causing post-transfusion hepatitis, and on the long-term outcome of patients who became infected more than ten years ago. The present article reviews these issues.     

Hepatitis E: source and route of infection,clinical manifestations and new developments

Hepatitis E was previously thought to be a disease of developing countries causing significant morbidity and mortality in young adults, particularly among pregnant women and patients with pre‐existing chronic liver disease. Recent studies have shown that hepatitis E is also an issue in developed countries. In this setting, hepatitis E is a zoonotic infection and causes acute infection mainly in middle‐aged and elderly men; and chronic infection in the immunosuppressed. The scope and burden of disease are still emerging. The diagnosis of hepatitis E should be considered in any patient with hepatitis, irrespective of their age or travel history.     

Acute hepatitis non-A,non-B; are there any specific light microscopic features?

ABSTRACT— Coded examination of liver biopsies from a total of 24 patients with acute hepatitis non-A, non-B revealed two main histological trends: (a) acute viral hepatitis with confluent necrosis (sublobular and bridging) carrying a relatively good prognosis and taking a chronic course in only four out of 14 patients (29%); and (b) acute viral hepatitis with severe portal infiltration rich in lymphocytes and plasma cells, lymph follicles with germinal centers and bile duct lesions, as described by Poulsen & Christoffersen. The latter group showed a very high tendency to transition to chronic hepatitis (six out of seven patients, 86%) or a course characterized by one or multiple acute relapses (one out of seven patients, 14%). Bile duct lesions, if present in biopsies of patients with acute hepatitis, are of diagnostic and prognostic value. They point to the etiological possibility of a hepatitis non-A, non-B and, at the same time, they indicate a high likelihood of evolution to chronic liver disease.     

Aiming for the elimination of viral hepatitis in Australia,New Zealand,and the Pacific Islands and Territories: Where are we now and barriers to meeting World Health Organization targets by 2030

Viral hepatitis affects more than 320 million people globally, leading to significant morbidity and mortality due to liver failure and hepatocellular carcinoma (HCC). More than 248 million people (3.2% globally) are chronically infected with hepatitis B virus (HBV), and an estimated 80 million people (1.1% globally) are chronically infected with hepatitis C virus (HCV). In 2015, more than 700 000 deaths were directly attributable to HBV, and nearly 500 000 deaths were attributable to HCV infection; 2–5% of HBV‐infected people develop HCC per annum irrespective of the presence of cirrhosis, whereas 1–5% HCV‐infected people with advanced fibrosis develop HCC per annum. The rapidly escalating global mortality related to HBV and HCV related viral hepatitis to be the 7th leading cause of death worldwide in 2013, from 10th leading cause in 1990. Australia, New Zealand, and Pacific Island Countries and Territories fall within the World Health Organization Western Pacific Region, which has a high prevalence of viral hepatitis and related morbidity, particularly HBV. Remarkably, in this region, HBV‐related mortality is greater than for tuberculosis, HIV infection, and malaria combined. The region provides a unique contrast in viral hepatitis prevalence, health system resources, and approaches taken to achieve World Health Organization global elimination targets for HBV and HCV infection. This review highlights the latest evidence in viral hepatitis epidemiology and explores the health resources available to combat viral hepatitis, focusing on the major challenges and critical needs to achieve elimination in Australia, New Zealand, and Pacific Island Countries and Territories.     

microRNA在乙型、丙型肝炎中的作用

近年来,作为基因表达的重要调节因子microRNA(miRNA),以及与这些miRNA关联或调控的各种肝脏疾病,如肝炎、肝纤维化和肝细胞癌(HCC)等方面的研究取得了新进展.许多编码miRNA的基因及其靶标被发现,它们与肝脏疾病的直接或间接的关联性也通过大量的实验研究(包括人体组织)得到确证.病毒性肝炎是由多种不同肝炎病毒引起的一组以肝脏损伤为主的传染病,根据病原学诊断,肝炎病毒至少有5种,但目前最常见的是HBV和HCV感染.本文就miRNA与病毒性肝炎的关系研究进展作一综述.     

Non-A,non-B fulminant viral hepatitis in France in returnees from Asia and Africa

Among 61 patients admitted for non-A, non-B fulminant viral hepatitis to Hôpital Beaujon, 10 had returned from Asia or Africa, and 51 had not been outside France, within the month preceding jaundice. This suggests that hepatitis might have been contracted in Asia or Africa in the former, and in France in the latter. The interval between the onset of jaundice and the onset of hepatic encephalopathy was 10 days in the former and 26 days in the latter (P<0.03). The serum of the patient returning from Asia contained, and the sera of the nine patients returning from Africa did not contain, antibodies to a virus isolated from the stools of patients suffering from an epidemic fecal-oral non-A, non-B viral hepatitis in Central Asia. It is concluded that infection with Asian-African non-A, non-B viruses can be the cause of fulminant hepatitis in persons returning from these countries, that the course of this type of non-A, non-B fulminant viral hepatitis is shorter than that of non-A, non-B fulminant hepatitis contracted in France, and that different viruses might be responsible for non-A, non-B hepatitis in Asia and Africa.     

A population-based study of reported hepatitis C diagnoses from 1998 to 2018 in immigrants and nonimmigrants in Quebec,Canada

Immigrants living in low hepatitis C (HCV) prevalence countries bear a disproportionate HCV burden, but there are limited HCV population-based studies focussed on this population. We estimated rates and trends of reported HCV diagnoses over a 20-year period in Quebec, Canada, to investigate subgroups with the highest rates and changes over time. A population-based cohort of all reported HCV diagnoses in Quebec (1998–2018) linked to health administrative and immigration databases. HCV rates, rate ratios (RR) and trends overall and stratified by immigrant status and country of birth were estimated using Poisson regression. Among 38,348 HCV diagnoses, 14% occurred in immigrants, a median of 7.5 years after arrival. The average annual HCV rate/100,000 decreased for immigrants and nonimmigrants, but the risk (RR) among immigrants increased over the study period [35.7 vs. 34.5 (RR = 1.03) and 18.4 vs. 12.7 (1.45) between 1998–2008 and 2009–2018]. Immigrants from middle-income Europe & Central Asia [55.8 (RR = 4.39)], sub-Saharan Africa [51.7 (RR = 4.06)] and South Asia [32.8 (RR = 2.58)] had the highest rates between 2009 and 2018. Annual HCV rates decreased more slowly among immigrants vs. nonimmigrants (−5.9% vs. −8.9%, p < 0.001), resulting in a 2.5-fold (9%–21%) increase in the proportion of HCV diagnoses among immigrants (1998–2018). The slower decline in HCV rates among immigrants over the study period highlights the need for targeted screening for this population, particularly those from sub-Saharan Africa, Asia and middle-income Europe. These data can inform micro-elimination efforts in Canada and other low-HCV-prevalence countries.     

PREVALENCE AND CLINICAL SIGNIFICANCE OF HEPATITIS G VIRUS INFECTION IN ADULT BETA-THALASSAEMIA MAJOR PATIENTS

The risk of polytransfused patients for hepatitis C virus (HCV) infection is likely to extend to another recently identified member of the Flaviviridae, hepatitis G virus (HGV). We investigated the prevalence of HGV in 40 adult Italian patients with transfusion-dependent thalassaemia and evaluated the clinical significance of HGV infection. HGV-RNA was detected in 9/40 patients (22.5%). HGV infection was significantly associated with HCV viraemia ( P  =0.0012), with all patients positive for HGV being also viraemic for HCV. Overall, the clinical picture of patients with HCV/HGV co-infection was not different from that of patients with isolated HCV. However, patients co-infected with both viruses had lower values of alanine-transferase ( P  =0035) and a lower titre of HCV viraemia ( P  =0042) in the absence of other evident factors which could influence the clinical expression of HCV infection. In conclusion, HGV is highly prevalent among Italian polytransfused patients. No evidence of a clinically significant pathogenic role for HGV in liver disease could be found in these patients. In a subset of cases a possible interference of HGV with HCV infection was observed.     

健康人群和肝病患者中检测TTV的意义

目的了解新型肝炎病毒－ＴＴＶ的致病性和在健康人群和肝病患者中的流行情况．方法收集１８０份健康体检患者血清和１５６份不同类型肝病患者血清,采用ＰＣＲ方法检测ＴＴＶ的ＤＮＡ．同时检测ＨＡＶ,ＨＢＶ,ＨＣＶ,ＨＥＶ和ＨＧＶ感染标志,比较分析ＴＴＶ在健康人群和不同类型肝病患者中流行情况及其致病性．结果健康体检人群和肝病患者中,ＴＴＶＤＮＡ检出率分别为２２％和４５％,两组间无显著性差异（Ｐ＞００５）．体检人群中,ＡＬＴ正常和升高者的检出率分别为１７％和１４３％．急性肝炎,慢性肝炎和肝硬变者的检出率分别为４８％,４３％和４７％．１１例阳性患者中,３例ＡＬＴ正常,８例ＡＬＴ异常．在８例ＡＬＴ异常患者中,６例为ＨＢＶ现行感染,１例为ＨＣＶ现行感染,仅１例为ＮＡ－Ｇ肝炎患者．结论在中国健康体检人群和肝病患者中能检出低水平的ＴＴＶ现行感染．但似乎仅引起个别患者的转氨酶轻度升高．ＴＴＶ的致病性可能较弱或需要其他因素协同致病．     

严重乙型肝炎活动进展为肝衰竭的预后因素分析

目的 旨在探讨影响严重肝炎活动预后的因素。方法 应用Logistic回归分析69例严重肝炎活动患者,探讨可能与进展成肝衰竭相关的临床和病毒学指标,包括HBV基因型、PC(G1896A)及BCP(A1762T/G1764A)变异;筛选出独立预测因素。结果 严重活动性肝炎患者中,33例(47.8%)进展成肝衰竭。多因素分析筛选出总胆红素升高(TB>256 μmol/dL, P=0.008)及凝血功能异常(PTA<40%, P<0.001)是严重肝炎活动进展为肝衰竭的危险因素。HBeAg阴性(P=0.065)、PC变异(P=0.090)与病情恶化有一定相关性。结论 血清总胆红素水平、凝血功能、HBeAg状态及PC变异在预测HBV相关的严重肝炎活动进展为肝衰竭中有预测价值。