慢性病毒性肝炎研究进展

近年,慢性病毒性肝炎研究领域有较大进展,慢性乙型肝炎病毒（HBV）感染,虽然有了应用广泛、历史较久、且效果较好的疫苗,但迄今仍是世界范围肝硬化和肝癌的主要诱因。传染途径可经产道、性接触和非肠道途径（包括静脉吸毒、血制品等）。成年病人有少有变慢性,但一岁以下患儿90％变成慢性肝炎。慢性肝损伤的临床表现可以是轻微的炎症重到晚期肝硬化,程度不等。α干扰素（IFNα）是治疗活动性肝炎的产宰药物,单核苷酸类药物（lamivudine和adefovir）也具有同样的疗效。晚期肝病和肝癌患者可进行移植,但异常伴发移植物的感染。乙型肝炎免疫球蛋白和新型抗病毒药物联合应用,可降低移植物感染的严重性。丙型肝炎病毒（HCV）在20世纪后期感染了大约1％的世界人口。这中RNA病毒非经口传播,绝大多数病人变成慢性肝炎,约20％逐渐演变成肝硬化或肝癌。用IFNα和病毒唑（Ribavirin）联合治疗,约40％病人的病理表现有所改善。肝移植对某些病例是适宜的,但移植物感染仍是悬而未决的问题,新发现的庚型肝炎病毒（HGV）和TT病毒目前认为并不引起严重的肝损害。     

Liver transplantation in patients with alcoholic cirrhosis: selection criteria and rates of survival and relapse.

OBJECTIVE--To evaluate the outcome of liver transplantation in patients with alcoholic cirrhosis with respect to selection criteria, survival, and evidence suggesting a return to harmful drinking. DESIGN--Nine year retrospective study. SETTING--Cambridge and King''s College Hospital liver transplant programme. SUBJECTS--24 Patients (three women, 21 men) with alcoholic cirrhosis. MAIN OUTCOME MEASURES--Survival, rehabilitation, and clinical and laboratory evidence of a return to harmful drinking after transplantation. RESULTS--15 Patients were selected for transplantation because of repeated admission to hospital for the complications of advanced portal hypertension despite abstinence, and six because they had a hepatocellular carcinoma superimposed on alcoholic cirrhosis. Three patients who were not abstinent received transplants. The one year survival rate was 66%, and of the 18 patients surviving at least three months, 17 had been rehabilitated. In three patients laboratory variables and histological examination of the liver suggested a return to drinking, though they did not admit to taking alcohol. These patients represented the only cases in the series that were not abstinent before transplantation. CONCLUSIONS--The survival and rehabilitation of patients who received transplants for alcoholic cirrhosis compared favourably with those of patients who received transplants for cirrhosis of other aetiology. The criteria for selection for liver transplantation in patients with alcoholic cirrhosis should include recurrent complications related to severe portal hypertension despite maximum medical treatment in addition to a minimum period of six months of abstinence before transplantation.     

Integration of HBV-DNA into liver and hepatocellular carcinoma cells during persistent HBV infection

The hepatitis B virus carrier state (persistent HBV infection) is characterized by the presence of viral surface antigen (HBsAg) and virion particles (Dane particles) in the blood. From 1% to 10% of carriers develop chronic liver disease and/or hepatocellular carcinoma. Recent studies have demonstrated integrated HBV-DNA in hepatocellular carcinomas and in several human hepatoma cell lines. In hepatoma patients, integrated HBV-DNA has been found in all HBsAg carriers. Nontumorous liver also revealed integrated HBV-DNA with the same or a different hybridization pattern from that observed in the tumor. To explore when integration occurs, carriers of short-term (less than 2 years) or long-term (greater than 8-10 years) were evaluated. DNA extracts from percutaneous (needle) liver biopsies showed free viral DNA with no specific integration bands in short-term carriers. In long-term carriers, HBV-DNA was integrated into the host genome with either a diffuse or a unique hybridization pattern. HBV-DNA integration correlated with the duration of the carrier state and absence of virions in the serum but did not correlate with histologic evidence of chronic hepatitis. These studies suggest that integration of HBV-DNA occurs during persistent HBV infection irrespective of liver disease and precedes development of hepatocellular carcinoma.     

S-腺苷蛋氨酸治疗胆汁淤积性肝病伴抑郁／焦虑的临床效果研究

目的：研究s-腺苷蛋氨酸治疗胆汁淤积性肝病伴抑郁／焦虑患者的临床效果。方法：选择2011年3月-2013年3月我院收治的51例不同病因的胆汁淤积性肝病（药物性肝损害13例、慢性乙型肝硬化14例、酒精性肝硬化11例、自身免疫性肝病6例、肝癌5例、胆管癌2例）并抑郁／焦虑的患者,予s-腺苷蛋氨酸1．0g治疗2周,应用SDS／SAS量表分别评估和比较治疗前后各组患者抑郁／焦虑程度的评分情况。结果：S-腺苷蛋氨酸治疗后,所有组别胆汁淤积性肝病肝病改善的临床总有效率94．12％,其中药物性肝损害、慢性乙型肝硬化、酒精性肝硬化、自身免疫性肝硬化总有效率均为100．00％,肝癌的有效率为60．00％,胆管癌的有效率为50．00％,药物性肝损害患者临床疗效与其他各组有差异（P〈0．05）;药物性肝病患者SDS和SAS评分均较治疗前显著降低（P〈0．05）。而慢性乙型肝硬化、酒精性肝硬化、自身免疫性肝病、肝癌、胆管癌患者SDS和SAS评分与治疗前相比均无统计学差异（P〉0．05）。结论：S-腺苷蛋氨酸可改善药物性胆汁淤积性肝病并轻、中度抑郁／焦虑患者的肝功能,并有效减轻其抑郁／焦虑情绪。     

S-腺苷蛋氨酸治疗胆汁淤积性肝病伴抑郁/焦虑的临床效果研究

目的:研究S-腺苷蛋氨酸治疗胆汁淤积性肝病伴抑郁/焦虑患者的临床效果。方法:选择2011年3月~2013年3月我院收治的51例不同病因的胆汁淤积性肝病(药物性肝损害13例、慢性乙型肝硬化14例、酒精性肝硬化11例、自身免疫性肝病6例、肝癌5例、胆管癌2例)并抑郁/焦虑的患者,予S-腺苷蛋氨酸1.0 g治疗2周,应用SDS/SAS量表分别评估和比较治疗前后各组患者抑郁/焦虑程度的评分情况。结果:S-腺苷蛋氨酸治疗后,所有组别胆汁淤积性肝病肝病改善的临床总有效率94.12%,其中药物性肝损害、慢性乙型肝硬化、酒精性肝硬化、自身免疫性肝硬化总有效率均为100.00%,肝癌的有效率为60.00%,胆管癌的有效率为50.00%,药物性肝损害患者临床疗效与其他各组有差异(P0.05);药物性肝病患者SDS和SAS评分均较治疗前显著降低(P0.05)。而慢性乙型肝硬化、酒精性肝硬化、自身免疫性肝病、肝癌、胆管癌患者SDS和SAS评分与治疗前相比均无统计学差异(P0.05)。结论:S-腺苷蛋氨酸可改善药物性胆汁淤积性肝病并轻、中度抑郁/焦虑患者的肝功能,并有效减轻其抑郁/焦虑情绪。     

Chronic HBV-related liver disease

Thirty years after its discovery, the hepatitis B virus (HBV) still remains a major global public health problem. Worldwide, two billion subjects have been infected, 300 million have a chronic infection and more than 600,000 die annually of HBV-related liver disease or hepatocellular carcinoma; new infections occur because of the presence of a large reservoir of chronic carriers of the virus. The knowledge of the HBV organization and replication cycle and the availability of sensitive HBV-DNA assays have led to remarkable progress in our understanding of the natural history of chronic hepatitis B infections. Crucial to the prevention of new infections, to the management and the monitoring of HBV carriers and to the choice of best treatment strategy, is the understanding of the natural dynamism of HBV infection and of the virus-host interactions that induce liver damage.     

病毒性肝病抗病毒治疗期间新发肝癌7例临床分析

目的:探讨病毒性肝炎肝硬化患者经抗病毒治疗仍发生原发性肝癌的原因。方法:回顾性分析兰州大学第一医院东岗院区肝病中心在2012年10月-2013年6月收治的7例病毒性肝炎肝硬化患者在规范抗病毒治疗期间新发原发性肝癌的临床资料、抗病毒治疗情况。结果:7例患者中有HBV感染6例,HCV感染1例;慢性肝炎2例,肝硬化5例;HBeAg阴性5例;3例合并糖尿病;经抗病毒治疗后病毒载量均处于低度复制或不可测状态。结论:病毒性肝炎肝硬化患者经抗病毒治疗不能完全消除原发性肝癌发生的风险,病毒载量、HBeAg阴性、糖尿病、肝硬化等可能是肝癌发生的危险因素。     

Survival in Liver Transplant Recipients with Hepatitis B- or Hepatitis C-Associated Hepatocellular Carcinoma: The Chinese Experience from 1999 to 2010

Background

Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and hepatitis C virus (HCV)-HCC are the main indications for liver transplantation. We compared differences in survival outcomes between these two conditions.

Methods and Findings

The China Liver Transplant Registry (CLTR) contains data collated from all transplants performed in 86 liver transplantation centers across China. We analyzed CLTR data from January 1999 to December 2010. In all, 7,658 patients (7,162 with HBV-HCC and 496 with HCV-HCC) were included in this study. Clinical characteristics were compared between the HBV-HCC and HCV-HCC groups; Kaplan–Meier analysis was used to calculate the overall, tumor-free and hepatitis-free survival rates. The 1-year, 3-year and 5-year overall survival was significantly higher in HBV-HCC recipients than in HCV-HCC recipients (76.65%, 56.61% and 49.10% vs. 64.59%, 42.78% and 39.20%, respectively; P<0.001). The corresponding tumor-free survival rates (63.55%, 47.37%, 40.99% vs. 56.84%, 38.04%, 35.66%, respectively) and hepatitis-free survival rates (75.49%, 54.84%, 47.34% vs. 63.87%, 42.15%, 39.33%, respectively) were both superior in HBV-HCC recipients (both P<0.001). Multivariate analyses identified hepatitis, preoperative alpha-fetoprotein (AFP) level, size of largest tumor, number of tumor nodules, TNM stage, vascular invasion and preoperative model for end-stage liver disease (MELD) score as independent predictors of overall, tumor-free and hepatitis-free survival.

Conclusions

Survival outcomes after liver transplantation were significantly better in HBV-HCC patients than in HCV-HCC patients. This finding may be used to guide donor liver allocation in transplantation programs.     

Prognosis for the patients with alcoholic and nonalcoholic liver disease

The purpose of this investigation was to determine the role of alcohol in development of progressive liver disease. For this purpose, 41 alcoholic patients were followed up for 5 years. Criteria for alcohol abuse was that the patients were enjoying 20 g alcohol daily in a period of 5 years for females and respectively 60 g daily for males. In the same time a group of 51 nonalcoholic patients with histologically proven chronic liver disease were investigated. In all 92 patients chronic liver disease and progression of the disease was proven by liver biopsy during a 5-years follow-up. In sera of all patients the markers of hepatitis viruses B, D and C were continuously determined and chronic viral hepatitis was excluded. Also, autoimmune chronic hepatitis was excluded. The results of the investigation showed that alcoholics develop cirrhosis hepatitis, in most cases 78.04%. The most progressive chronic liver diseases--cirrhosis and hepatocellular carcinoma--are significantly present among nonalcoholics (p < or = 0.05). In the mentioned investigation a large group of 51 patients with severe chronic hepatitis without a proven etiology of disease was found and it deserves priority in future research.     

Screening for Hepatocellular Carcinoma: Review and Perspective

In patients with hepatocellular carcinoma, early diagnosis offers the only hope for resection and cure. Data from Asia, where it is closely associated with viral hepatitis, indicate that serum α-fetoprotein assay and abdominal ultrasonography are the most effective and feasible screening tests. These data may not be applicable in America, where most patients at risk for hepatocellular carcinoma have underlying alcoholic cirrhosis. Also, it is unclear whether resecting “curable” lesions prolongs survival, particularly in patients with cirrhosis. Screening trials are indicated to answer these questions. Preventing risk factors, however, especially hepatitis B viral disease, is of paramount importance throughout the world.     

Oxidative stress EPR measurement in human liver by radical-probe technique. Correlation with etiology,histology and cell proliferation

The role of reactive oxygen species (ROS) in liver disease is controversial. This mostly reflects the difficulties to quantify ROS in vivo, particularly in humans. We aimed to measure the presence of ROS in diseased human liver and identify possible relations between ROS levels and etiology, histology and hepatocyte proliferation. Liver biopsy specimens from 102 individuals: 18 healthy controls and 84 patients (42 HCV chronic hepatitis (CHC), 19 HBV chronic hepatitis (CHB), 7 PBC, 4 PSC, 4 HCV relapsing hepatitis after liver transplantation, 3 autoimmune hepatitis, 3 hepatocellular carcinoma, 2 alcoholic hepatitis) underwent analysis by radical-probe electron paramagnetic resonance (EPR). ROS in patients (median = 5 x 10(-6) mmol/mg) were higher than in controls (median = 3 x 10(-11) mmol/mg) (p < 0.001). Progressively increasing levels of ROS were recorded passing from control values to CHB (median = 4 x 10(-7) mmol/mg), CHC (median = 3 x 10(-6) mmol/mg) and PBC (median = 2 x 10(-5) mmol/mg), the differences being significant (p < 0.001). ROS in CHC positively correlated with histological disease activity (r = 0.92; p < 0.001). No correlation was found between ROS and hepatocyte proliferation rate, presence/degree of steatosis, serum ferritin levels and aminotransferases. ROS overproduction in liver appears to be a common thread linking different pathologic conditions and seems to be influenced by diseases' etiologies.     

Comprehensive Comparison of Multiple-Detector Computed Tomography and Dynamic Magnetic Resonance Imaging in the Diagnosis of Hepatocellular Carcinoma with Varying Degrees of Fibrosis

Methods841 patients with liver tumor who had liver CT or dynamic MRI examinations followed by surgical resection were included in the study. We defined typical HCC imaging characteristics as early enhancement in the artery phase and early washout in the venous phase. The tumor size was recorded based on pathological examination after surgery. The pathologic fibrosis score was verified by the METAVIR scoring classification.ResultsAmong the 841 patients, 756 underwent liver CT and 204 underwent dynamic liver MRI before surgery. The etiologies of chronic liver disease included hepatitis B virus, hepatitis C virus, hepatitis B and C virus, and non-hepatitis B or C virus. The sensitivity and accuracy of liver CT or MRI for HCC diagnosis was approximately 80%~90%. Liver CT had a diagnostic accuracy for HCC similar to that of dynamic MRI, and liver fibrosis stage did not influence their diagnostic efficacies.ConclusionsThe application of 4-phase dynamic CT and MRI exhibit similar diagnostic accuracy for hepatocellular carcinoma, in tumors of sizes 1 to 2 cm and >2 cm. Liver fibrosis status did not affect the diagnostic accuracy of liver CT or MRI for HCC. The AASLD and EASL restrictions of dynamic imaging studies for HCC diagnosis to cirrhotic patients alone are unnecessary.     

Immunology of hepatitis B virus and hepatitis C virus infection

More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.     

Importance of markers of hepatitis B virus in alcoholic liver disease.

To determine the importance of the presence of serological markers of hepatitis B virus infection in patients with alcohol related liver disease we compared cumulative alcohol intake and clinical and histological features in patients with markers of hepatitis B virus infection and in those without. Hepatitis B surface antigen (HBsAg) was detected in five (2%) out of 285 patients studied and antibody to HBsAg (anti-HBs) in 41 (14%); one patient had antibody to hepatitis B core antigen alone. The combined prevalence of markers of hepatitis B virus infection was similar in patients with alcoholic cirrhosis (18%) and precirrhotic liver disease (13%). Two patients positive for HBsAg had histological features of both alcoholic liver disease and chronic active hepatitis, with stainable HBsAg. Patients with anti-HBs were, however, histologically indistinguishable from patients without markers, and the mean cumulative alcohol intake of patients with anti-HBs was similar to or even higher than that of patients with liver disease of comparable severity who had no evidence of previous infection. The presence of markers of hepatitis B virus infection was related to former residence in countries with a high prevalence of the infection and to previous parenteral treatment and blood transfusions. Infection with hepatitis B virus does not enhance the development of chronic liver disease in heavy drinkers, except in the small number who remain positive for HBsAg.     

Intracellular hepatitis B virus increases hepatic cholesterol deposition in alcoholic fatty liver via hepatitis B core protein

Hepatitis B virus (HBV) infection is a prevalent infectious disease with serious outcomes like chronic and acute hepatitis, cirrhosis, and hepatocellular carcinoma. However, the metabolic alteration by HBV is rarely taken into consideration. With the high prevalence of alcohol consumption and chronic HBV infection, their overlap is assumed to be an increasing latent hazard; although the extent has not been calculated. Moreover, the impact of chronic alcohol consumption combined with HBV on cholesterol metabolism is unknown. Six-week-old male FVB/Ncrl mice were hydrodynamically injected with a pGEM-4Z-1.3HBV vector and then fed an ethanol diet for 6 weeks. Serum biomarkers and liver histology, liver cholesterol levels, and cholesterol metabolism-related molecules were measured. In vitro assays with HBx, hepatitis B surface (HBs), or hepatitis B core (HBc) protein expression in HepG2 cells costimulated with ethanol were conducted to assess the cholesterol metabolism. HBV expression synergistically increased cholesterol deposition in the setting of alcoholic fatty liver. The increase of intrahepatic cholesterol was due to metabolic alteration in cholesterol metabolism, including increased cholesterol synthesis, decreased cholesterol degradation, and impaired cholesterol uptake. Overexpression of HBV component HBc, but not HBs or HBx, selectively promoted the hepatocellular cholesterol level.     

Small rodent models of hepatitis B and C virus replication and pathogenesis

The narrow host range of infection supporting the long-term propagation of hepatitis B and C viruses is a major limitation that has prevented a more thorough understanding of persistent infection and t...     

Recurrence of hepatitis C virus infection after orthotopic liver transplantation: role of genotypes

In this study, we evaluated the correlation between alanine aminotrasferase levels and hepatitis C virus genotypes in liver transplant patients. We studied 18 patients who had undergone orthotopic liver transplantation because of end-stage cirrhosis (n = 9) or hepatocellular carcinoma (n = 9) hepatitis C virus related. Serum HCV-RNA testing was performed monthly on all the 18 series of serum samples from the first week after liver transplant until the end of the follow up, this period ranging from 1 to 39 months. After liver transplantation, serum HCV-RNA was detected in 14 patients (78%). Of the 8 patients infected with subtype 1b. 1 remained asymptomatic, 2 developed acute liver failure and 5 developed chronic hepatitis. In patients infected with types 1a (Choo et al., 1989), 2a (Choo et al., 1989), with a mixed infection 1b/3 (Kuo et al., 1989) or with an undetermined genotype, significant laboratory abnormalities were not observed. Recurrence of hepatitis C virus infection after liver transplantation is common, and recurrent hepatitis occurs in 50% of cases. Genotype 1b appears to be associated with a higher rate of recurrent hepatitis, compared to other genotypes.     

Mechanisms of human hepatocarcinogenesis

The major risk factors and etiological agents responsible for development of hepatocellular carcinoma in humans have been identified and characterized. Among these are chronic infection with hepatitis B virus or hepatitis C virus, exposure to aflatoxin B1, and cirrhosis of any etiology (including alcoholic cirrhosis and cirrhosis associated with genetic liver diseases). Both chronic hepatitis and cirrhosis represent major preneoplastic conditions of the liver as the majority of hepatocellular carcinomas arise in these pathological settings. Hepatocarcinogenesis represents a linear and progressive process in which successively more aberrant monoclonal populations of hepatocytes evolve. Regenerative hepatocytes in focal lesions in the inflamed liver (chronic hepatitis or cirrhosis) give rise to hyperplastic hepatocyte nodules, and these progress to dysplastic nodules, which are thought to be the direct precursor of hepatocellular carcinoma. In most cases, the neoplastic transformation of hepatocytes results from accumulation of genetic damage during the repetitive cellular proliferation that occurs in the injured liver in response to paracrine growth factor and cytokine stimulation. Hepatocellular carcinomas exhibit numerous genetic abnormalities (including chromosomal deletions, rearrangements, aneuploidy, gene amplifications, and mutations), as well as epigenetic alterations (including modulation of DNA methylation). These genetic and epigenetic alterations combine to activate positive mediators of cellular proliferation (including cellular proto-oncogenes and their mitogenic signaling pathways) and inactivate negative mediators of cellular proliferation (including tumor suppressor genes), resulting in cells with autonomous growth potential. However, hepatocellular carcinomas exhibit a high degree of genetic heterogeneity, suggesting that multiple molecular pathways may be involved in the genesis of subsets of hepatocellular neoplasms. Continued investigation of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in liver, enabling the development of effective strategies for prevention and/or more effective treatment of hepatocellular carcinoma.     

肝动脉栓塞化疗术对原发性肝癌伴 有不同类型肝炎后肝硬化患者预后的影响

目的:探讨肝动脉栓塞化疗(TACE)对原发性肝癌伴有不同肝炎后肝硬化类型患者术后肝功能、凝血功能及其对远期预后的影响。方法:2007年8月至2009年8月,131例曾行TACE的伴有不同肝炎后肝硬化原发性肝癌患者,以肝炎后肝硬化类别(乙肝、丙肝)分类,乙肝后肝硬化组为组1,丙肝后肝硬化组为组2,随访观察术后一年肝功能、凝血功能、血小板等的变化以及预后。两组研究因素采用SPSS17.0进行卡方检验,随访预后采用Kaplan-Meier方法计算生存率,Log-rank法检验生存差异。以P<0.05为差异有统计学意义。结果:随访统计结果显示术后半年和一年AST、ALT、ALP、GGT、PT、PLT在两组间均无统计学差异,(P>0.05);组一半年、一年远处转移率同组二差异间无统计学意义;组一半年、一年生存率分别为70.1%,48.1%;组二半年、一年生存率分别为68.5%,58.9%,两组间同期生存率差异无统计学意义。(X2=0.039,P=0.884;X2=0.183,P=0.669)。结论:TACE治疗PHC安全可靠,对于伴有乙肝或丙肝后肝硬化患者术后肝功能、凝血功能、疗效及预后效果相当。     

Oxidative Stress EPR Measurement in Human Liver by Radical-probe Technique. Correlation with Etiology,Histology and Cell Proliferation

The role of reactive oxygen species (ROS) in liver disease is controversial. This mostly reflects the difficulties to quantify ROS in vivo, particularly in humans. We aimed to measure the presence of ROS in diseased human liver and identify possible relations between ROS levels and etiology, histology and hepatocyte proliferation. Liver biopsy specimens from 102 individuals: 18 healthy controls and 84 patients (42 HCV chronic hepatitis (CHC), 19 HBV chronic hepatitis (CHB), 7 PBC, 4 PSC, 4 HCV relapsing hepatitis after liver transplantation, 3 autoimmune hepatitis, 3 hepatocellular carcinoma, 2 alcoholic hepatitis) underwent analysis by radical-probe electron paramagnetic resonance (EPR). ROS in patients (median=5 &#50 10 &#109 6 mmol/mg) were higher than in controls (median=3 &#50 10 &#109 11 mmol/mg) ( p <0.001). Progressively increasing levels of ROS were recorded passing from control values to CHB (median=4 &#50 10 &#109 7 mmol/mg), CHC (median=3 &#50 10 &#109 6 mmol/mg) and PBC (median=2 &#50 10 &#109 5 mmol/mg), the differences being significant ( p <0.001). ROS in CHC positively correlated with histological disease activity ( r =0.92; p <0.001). No correlation was found between ROS and hepatocyte proliferation rate, presence/degree of steatosis, serum ferritin levels and aminotransferases. ROS overproduction in liver appears to be a common thread linking different pathologic conditions and seems to be influenced by diseases' etiologies.