Pathogenesis of liver cirrhosis in alcoholic patients: histological evidence for hepatitis C virus responsibility

ABSTRACT— Hepatitis C virus (HCV) has been proposed to be a cofactor in the pathogenesis of cirrhosis in patients with chronic alcoholism. The demonstration of a different liver histological pattern in anti-HCV positive patients might provide additional evidence. We studied 164 patients with chronic alcoholism, and histologically proven cirrhosis. For all of them, serum samples were collected at the time of a liver biopsy and stored at –80°C. Testing for anti-HCV antibodies was done using the Ortho Diagnostic Systems Anti-HCV ELISA test. Only reproducible results were considered positive. A semi-quantitative assessment of seven histological parameters was made independently on liver biopsy samples. In the study group, 29 patients (18%) had anti-HCV antibodies. When compared with anti-HCV negative patients, both groups had similar ALT and AST seric activities. Anti-HCV positive patients had a greater score of mononuclear cells infiltrate (0.71±0.57 vs 0.41 ±0.52; p<0.05) and a lesser score of alcoholic hepatitis (0.19 ±0.57 vs 0.74 ±0.74; p<0.005). The scores for steatosis, perisinusoidal and perinodular fibrosis, and hepatocellular necrosis were similar in the two groups. In anti-HCV positive patients, with a clearly positive recombinant immunobinding assay (RIBA, Chiron-Ortho Diagnostic Systems), a greater score for hepatic necrosis and a lesser one for fibrosis were demonstrated. Among the seven patients with active cirrhosis, six were anti-HCV positive. Therefore, HCV is likely to play a role in the pathogenesis of liver damage in a few patients with alcoholic cirrhosis, especially, those with active cirrhosis.     

Comparison of outcomes between patients with alcoholic cirrhosis and those with hepatitis C virus-related cirrhosis

Background and Aim:  The natural history of alcoholic cirrhosis, especially in Asian countries, has not been completely understood thus far.
Methods:  We retrospectively compared the outcomes of compensated cirrhosis between Japanese alcoholic and hepatitis C virus (HCV)-infected patients.
Results:  A total of 227 patients (75 alcoholic and 152 HCV-infected patients) with compensated cirrhosis were enrolled. The median follow-up period was 4.9 years. The cumulative rates of hepatocellular carcinoma (HCC) development were significantly lower in the alcoholic patients than in the HCV-infected patients (6.8% vs 50.3% at 10 years, P  = 0.0003), while the cumulative rates of hepatic decompensation (37.4% vs 51.7% at 10 years) and survival (53.8% vs 47.4% at 10 years) did not significantly differ between the two groups (Kaplan-Meir analysis). The main causes of death were hepatic failure and non-hepatic diseases in the alcoholic patients and HCC and hepatic failure in the HCV-infected patients. Multivariate analyses using the Cox proportional hazard model revealed that the risk of HCC was lower in alcoholic cirrhosis than in HCV-related cirrhosis (hazard ratio (HR), 0.46), while the risk of hepatic decompensation and mortality was the same. Predictors of decreased survival were non-abstinence (HR, 2.53) in the alcoholic patients and low serum albumin level (1.58) in the HCV-infected patients.
Conclusions:  Survival of patients with alcoholic cirrhosis was similar to that of patients with HCV-related cirrhosis. The risk of HCC development was lower in alcoholic cirrhosis than in HCV-related cirrhosis. Abstinence from alcohol was important for improving the survival of patients with alcoholic cirrhosis.     

Prevalence of hepatitis B or C virus infections in patients with non-Hodgkin's lymphoma

BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) are not only hepatotropic, but also lymphotropic viruses. Recently, some reports suggested that these viruses may participate in the development of malignant lymphoproliferative disorders. METHODS: We investigated the prevalence of HCV or HBV infection in 348 patients with non-Hodgkin's lymphoma (NHL). We also compared these prevalences with those in blood donors as a control group representing the general population in our area (n= 1,513,358). Next, we evaluated the clinical and pathologic characteristics of HCV- or HBV-infected NHL cases. Non-Hodgkin's lymphoma was classified according to the Working Formulation classification. RESULTS: Thirty-seven cases (14.9%) were found to be infected with HCV or HBV; of these, 20 (8.1%) were infected with HCV, and 17 (6.9%) with HBV. In male NHL patients, the rate of HCV infection was significantly higher than in an age- and sex-matched population in the same area (P < 0.001, Mantel-Haenszel test). The rate of HBV infection also tended to be higher in the population (P = 0.0551). In contrast, in female NHL patients, the rate of HCV or HBV infection was not higher than in the general population. In HCV-infected cases, 15 cases (75%) had B-cell NHL and 16 cases (80%) were classified as being in the intermediate grade; B-cell NHL comprised 83% of all NHL cases. In HBV-infected NHL cases, 11 (65%) were of B-cell type and 10 (58%) were classified as being in the intermediate grade. CONCLUSIONS: The high prevalence of HCV or HBV infections in our study population provides epidemiologic evidence suggesting that HCV and HBV infections may be involved in the development of a subgroup of NHL in males. Our investigation also revealed that both HCV- and HBV-infected NHL patients showed certain similarities in clinical and pathologic manifestations.     

Prevalence and clinical significance of GB virus type C/hepatitis G virus coinfection in patients with chronic hepatitis C undergoing antiviral therapy

Summary. Coinfection with GBV‐C/HGV in patients with chronic hepatitis C (CHC) may influence clinical course and response rates of antiviral therapy. Aim of the study was to investigate the prevalence of GBV‐C/HGV/HCV coinfection and its influence on outcome of interferon/ribavirin combination therapy. Three hundred and four patients with CHC [m/f = 211/93, age: 42 (18–65)] were investigated. HGV RNA detection was performed by polymerase chain reaction prior to and 6 months after the end of antiviral therapy. HGV/HCV coinfection could be identified in 37/304 (12.2%) patients with intravenous drug abuse as the most common source of infection (N = 21, (56.8%)). The predominant HCV genotype in coinfected individuals was HCV‐3a (HCV‐3a: 51.4%, HCV‐1: 37.8%, HCV‐4: 10.8%). HGV coinfection was more prevalent in patients infected with HCV‐3 compared to HCV‐1 or HCV‐4 [19/45 (42.2%) vs 14/185 (7.6%) vs 4/52 (7.7%), P < 0.01]. Patients with HGV/HCV coinfection were younger [35 (18–56) vs 43 (19–65), years; P < 0.01], and advanced fibrosis (F3‐F4) was less frequent (22.2%vs 42.9%, P < 0.05). A sustained virological response was achieved more frequently in HGV/HCV coinfected patients [26/37 (70.3%)] than in monoinfected patients [120/267 (44.9%), P < 0.01]. HGV RNA was undetectable in 65.7% of the coinfected patients at the end of follow‐up. Intravenous drug abuse seems to be a major risk factor for HGV coinfection in patients with chronic hepatitis C. Coinfection with HGV does not worsen the clinical course of chronic hepatitis C or diminish response of HCV to antiviral therapy. Interferon/ribavirin combination therapy also clears HGV infection in a high proportion of cases.     

Treatment of chronic hepatitis C virus infection in patients with cirrhosis

Chronic hepatitis C virus (HCV) infection eventually leads to cirrhosis in 20–30% of patients and to hepatocellular carcinoma (HCC) in 1–5% of patients. Rates of sustained virological response with standard interferon-α (IFN-α) are low in patients without cirrhosis (generally < 20%) and are even lower in those with cirrhosis. Combination therapy with IFN and ribavirin improves response rates in patients with chronic hepatitis C without cirrhosis, and the results from subgroups of HCV-infected patients with advanced fibrosis or cirrhosis are encouraging. Importantly, treatment with IFN slows progression of liver fibrosis, regardless of HCV genotype or early response to therapy, and reduces the risk of HCC by two- to fivefold. The risk of development of HCC is also lower in patients who show at least a partial response to IFN therapy compared with those who show no response. There is a clear need for more definitive studies of treatment in patients with chronic hepatitis C and cirrhosis, ideally using therapies with greater efficacy. Nonetheless, based on the potential to slow the progression of liver fibrosis (regardless of treatment response) and to reduce the risk of HCC, a greater number of HCV-infected patients with cirrhosis should be considered as candidates for IFN treatment. Preliminary data indicate that pegylated IFNs have improved virological response rates and may have additional clinical benefits in the prevention or reduction of fibrosis and retardation of progression of cirrhosis and HCC in these patients.     

酒精性肝硬化与乙型肝炎肝硬化、丙型肝炎肝硬化及自身免疫性肝硬化临床特点对比分析

目的探讨酒精性肝硬化的临床特点及其与乙型肝炎（乙肝）肝硬化、丙型肝炎（丙肝）肝硬化和自身免疫性肝硬化临床特点的异同。方法总结和分析2002--2012年住我院的部分酒精性肝硬化患者（373例）的临床特点,并与同期住院的部分乙肝肝硬化患者（205例）、丙肝肝硬化患者（104例）和自身免疫性肝硬化患者（121例）的临床特点进行对比分析。结果酒精性肝硬化患者好发年龄段为40。59岁（68．36％）,尤其以40。49岁发病率最高,达到43．43％。与其他3种病因所致的肝硬化患者相比,酒精性肝硬化患者男性占绝大多数（98．66％）,差异有统计学意义（P〈O．01）。酒精性肝硬化患者的WBC、中性粒细胞绝对值、中性粒细胞绝对值／淋巴细胞绝对值比值和平均红细胞容积均明显高于其他3种病因所致的肝硬化患者,差异有统计学意义（P均〈O．01）。酒精性肝硬化患者的AST／ALT比值、TBIL和GGT／ALP比值均明显高于其他3种病因所致的肝硬化患者,差异有统计学意义（P均〈0．01）。结论酒精性肝硬化在我国的发病率不断升高,且与乙肝肝硬化、丙肝肝硬化和自身免疫性肝硬化相比有其独特的临床特点。应对酒精性肝硬化给予更多关注。     

酒精性肝硬化与乙型肝炎肝硬化并发糖代谢异常男性患者的临床特征对比分析

目的探讨并发糖代谢异常的男性酒精性肝硬化(ALC)与乙型肝炎肝硬化(HBC)患者的临床特征。方法收集2008年1月-2013年9月于广州市番禺区中心医院住院的肝硬化患者287例,包含ALC患者74例,均为男性,其中并发糖代谢异常者54例;HBC患者213例,其中并发糖代谢异常者97例(男69例、女28例)。对并发糖代谢异常的ALC和HBC患者的临床资料进行分组对照研究,探讨患者临床表现和实验室检查指标、胰岛素抵抗指数、糖代谢异常发生率及其与Child-Pugh分级的关系。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验,采用Spearman进行等级相关分析。结果 ALC男性患者糖代谢异常发生率(73.0%vs 32.4%)、肝源性糖尿病发生率(35.1%vs 14.6%)、空腹低血糖发生率(27.0%vs 10.3%)和糖耐量异常发生率(31.1%vs 14.1%)均高于HBC患者(χ2值分别为4.371、3.274、4.784、1.633,P值均0.05);Spearman相关性分析显示,ALC和HBC男性患者糖代谢异常发生率与Child-Pugh分级呈正相关(rs=0.41,P0.05);并发糖代谢异常的ALC患者,Child-Pugh A级所占比例高于并发糖代谢异常的HBC患者;Child-Pugh C级所占比例低于并发糖代谢异常的HBC患者,差异均有统计学意义(χ2值分别为7.520、6.542,P值分别为0.001、0.003);并发糖代谢异常的ALC和HBC男性患者的面色晦暗、面部毛细血管扩张、蜘蛛痣、肝大、肝肾综合征、营养不良、腹水、黄疸、肝性脑病、自发性细菌性腹膜炎和上消化道出血的发生率比较差异均有统计学意义(χ2值分别为3.785、2.651、1.974、3.316、3.771、5.843、7.251、5.214、4.726、2.966、6.312,P值均0.05);与并发糖代谢异常的男性HBC患者相比,并发糖代谢异常的男性ALC患者的AST、TBil、平均红细胞体积、GGT较高,白蛋白较低,差异均有统计学意义(t值分别为2.378、2.587、2.633、2.681、2.210,P值均0.05);并发糖代谢异常的ALC和HBC男性患者的空腹血糖水平、餐后2 h胰岛素水平和胰岛素抵抗指数比较差异均有统计学意义(t值分别为2.378、1.976、1.991,P值均0.05)。结论男性ALC和HBC患者糖代谢异常发生率随肝功能恶化逐步升高,但二者均多以其各自病因肝硬化特征为主要表现,糖代谢异常表现不明显。对这两种不同病因肝硬化男性患者应及时进行相关检查,以明确是否存在糖代谢异常。     

Hepatitis C virus RNA quantitation in hepatic veins and peripheral blood in patients with liver cirrhosis: evidence for low level intrahepatic hepatitis C virus replication in advanced liver disease

BACKGROUND: Very few data exist concerning the level of hepatitis C virus replication within the cirrhotic liver and its relationship to disease severity and progression. AIMS: To quantitate hepatitis C virus RNA in hepatic vein blood and peripheral blood in patients with cirrhosis, to evaluate the correlation of hepatitis C virus levels in paired blood samples, and to compare the results with clinical features. PATIENTS: A series of 25 patients with hepatitis C virus-related liver cirrhosis undergoing hepatic vein catheterization were studied: 11 belonged to Child Pugh class A, 8 to class B and 6 to class C. RESULTS: Hepatitis C virus RNA levels did not differ between hepatic vein blood and peripheral blood (p = 0.26), despite a trend towards higher peripheral hepatitis C virus RNA levels. Hepatitis C virus RNA levels did not differ between patients with genotype 1b and non-1b either in hepatic veins or peripheral blood. Hepatitis C virus loads varied according to the severity of cirrhosis. The patients with more severe liver disease had significantly lower RNA titres than those with less advanced cirrhosis, both in hepatic veins (p = 0.002) and peripheral blood (p = 0.004). No differences in hepatitis C virus load were observed between patients in Child Pugh classes B and C. CONCLUSIONS: The present data show that in patients with cirrhosis hepatitis C virus RNA concentrations do not differ between hepatic blood and peripheral blood and, furthermore, confirm that hepatitis C virus replication is reduced in patients with advanced cirrhosis, compared with patients with less severe liver disease. These findings might indicate that patients with liver cirrhosis maintain an efficient intrahepatic hepatitis C virus replication even in end-stage disease, although hepatitis C virus viraemia decreases according to the severity of liver disease.     

Effect of drinking on the outcome of cirrhosis in patients with hepatitis B or C

Survival rates were calculated for 251 patients with cirrhosis of the liver but without hepatocellular carcinoma, primary biliary cirrhosis, or autoimmune cirrhosis who underwent laparoscopy during the past 21 years at the authors' hospital. The survival rates were calculated by the Kaplan-Meier method. Stored serum was assayed for hepatitis B surface antigen (HBsAg) and antibodies to the hepatitis C virus (HCV). Patients with alcoholic cirrhosis had significantly better survival rates than patients with HBsAg, HCV, or both. Differences in survival rates between patients with hepatitis B and C were insignificant. In both groups, habitual drinkers had a significantly lower survival rate. The results suggested that alcohol accelerates liver damage in subjects with viral hepatitis.     

Low prevalence of hepatitis C virus infection in patients with auto-immune hepatitis type 1

Hepatitis C virus (HCV) antibodies were measured in 28 patients with auto-immune hepatitis type 1 using six different assay kits, three for C100–3 antibody and three for second generation HCV antibody, and two confirmatory tests to determine the prevalence of HCV infection in auto-immune hepatitis. These patients were confirmed to have human leucocyte antigen DR 4 or 2 which is susceptible to auto-immune hepatitis in Japanese. Of the 28 patients, four (14.3%) were positive for HCV antibody in all assays and reacted positively in at least one of the two confirmatory tests, indicating a true positive finding. Eight were positive for HCV antibody only by the Ortho ELISA kit and were negative in both confirmatory tests. The cut-off level for these results was low and became negative soon after the patients received corticosteroid treatment. Thus, these eight patients are presumed to be false-positive reactors. Hepatitis C virus RNA was detected in the serum of two of the four patients with HCV antibody and in none of 24 patients without HCV antibody. No significant difference was observed between the patients with and without HCV antibody in terms of clinical background, liver function tests and auto-antibodies. Our results showed that the prevalence of a past or present HCV infection in patients with auto-immune hepatitis in Japan is low; thus, auto-immune hepatitis is thought to be distinct from hepatitis type C. However, it is also suggested that HCV infection can potentially trigger auto-immune hepatitis.     

Previous hepatitis E virus infection,cirrhosis and insulin resistance in patients with chronic hepatitis C

Background

Hepatitis E virus (HEV) infection in patients with pre-existing liver disease has shown high morbidity and lethality. The consequences of HEV superinfection in patients with chronic hepatitis C virus (HCV) infection are not fully understood. This study aimed to evaluate the association between the presence of anti-HEV antibodies, liver cirrhosis, and insulin resistance.

Hepatitis B virus markers and antibodies to hepatitis C virus in Japanese patients with hepatocellular carcinoma

Sera from Japanese patients with chronic liver disease were tested for hepatitis B virus (HBV) markers and antibodies to hepatitis C virus (anti-HCV), and the results were correlated to the presence of hepatocellular carcinoma. In chronic non-A, non-B liver disease, anti-HCV prevalence was high both in patients with hepatocellular carcinoma (78/89, 88%) and without it (66/84, 79%), while previous HBV infection was more common in patients with hepatocellular carcinoma (65/89, 73%) than in those without it (46/84, 55%) (P<0.05). Coexistence of anti-HCV and antibodies to HBV was observed frequently in patients with hepatocellular carcinoma (56/89, 63%) compared with patients without it (39/84, 46%) (P<0.05). In chronic HBV carriers, anti-HCV was more common in patients with hepatocellular carcinoma (12/38, 32%) than in those without it (3/62, 5%) (P<0.01). These results suggest that infection with the two viruses may be a risk factor for more serious liver disease.This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan.     

Distribution of different hepatitis C virus genotypes in patients with hepatitis C virus infection

AIM:To investigate the presence of mixed infection and discrepancy between hepatitis C virus(HCV) genotypes in plasma,peripheral blood mononuclear cells(PBMCs),and liver biopsy specimens.METHODS:From September 2008 up to April 2009,133 patients with chronic hepatitis C referred to Firouzgar Hospital for initiation of an antiviral therapy were recruited in the study.Five milliliters of peripheral blood was collected from each patient and liver biopsy was performed in those who gave consent or had indications...     

Interferon treatment of cirrhotic patients with chronic hepatitis C

SUMMARY. Hepatitis C virus (HCV) infection is one of the more important infectious diseases yet to be conquered. An estimated 3.5 million people in the USA have chronic HCV. Each year, 8000 to 10000 of these chronically infected patients die of a liver-related complication of their infection. The introduction of effective blood screening assays has resulted in a remarkable decrease in the incidence of post-transfusion HCV infection. Nonetheless it is essential to have a treatment programme for chronic HCV disease that prevents the development and the progression of compensated cirrhosis to either decompensated cirrhosis or hepatocellular carcinoma, as many individuals present to the health care system with chronic active hepatitis or cirrhosis. A completely safe and effective treatment strategy for chronic HCV, with or without cirrhosis, remains to be developed. Of the various treatment alternatives currently available, only interferon (IFN) has been evaluated extensively. IFN therapy has been shown to induce remissions of the hepatic inflammatory process and also to eliminate the viral infection in some treated cases. As a result, the selection of patients for treatment and the dose and the duration of therapy with IFN are still controversial issues. It is widely held that cirrhotic individuals do not respond to IFN therapy and that treatment of decompensated cirrhotic individuals with HCV infection is dangerous. Here we review data regarding the available experience with IFN treatment of HCV-positive individuals with cirrhosis and compare the response rates of cirrhotics to those reported for individuals with chronic active HCV.     

输血后丙型肝炎病毒感染的血清病毒定量研究

目的 研究血清丙型肝炎病毒（ＨＣＶ）含量与ＨＣＶ致病的关系及ＨＣＶ含量与抗－ＨＣＶ和丙氨酸转氨酶（ＡＬＴ）的相关性。方法 以逆转录－聚合酶链反应（ＲＴ－ＰＣＲ）法对ＨＣＶ感染的受血及相关供血系列血清进行ＨＣＶ ＲＮＡ定量分析,同时检测ＡＬＴ与抗－ＨＣＶ。结果 致输血后ＨＣＶ感染的供血中,ＨＣＶ ＲＮＡ平均含量为１０＾８．６拷贝／Ｌ,抗－ＨＣＶ及ＡＬＴ的异常检出率随ＨＣＶ ＲＮＡ滴度升高而增加。结论     

慢性丙型肝炎患者HCV基因型分析

目的研究慢性丙型肝炎患者HCV基因型概况。方法采用基因芯片法检测HCV基因分型;采用PCR法测定HCV RNA定量。结果在570例患者中,HCV RNA阳性552例（95%）,其中1b型400例（72.4%）,2a型63例（11.4%）,3a型20例（3.6%）,3b型20例（3.6%）,1b＋2a型12例（2.1%）,1a型2例（0.4%）,6型7例（1.26%）,1b＋3a型1例（0.18%）,2a＋1b型3例（0.5%）,未定型24例（4.3%）;不同HCV基因型感染者血清HCVRNA水平无统计学差异（P〉0.05）。结论本组患者HCV基因型以1b型为主,2a型次之,多种混合型的出现提示HCV基因型呈现多样化趋势。     

Prevalence of hepatitis C virus and hepatitis G virus in patients with non‐Hodgkin's lymphoma

Hepatitis C virus (HCV) and hepatitis G virus (HGV) belong to the same family of flaviviridea. A causative role of HCV infection in the pathogenesis of non‐Hodgkin's lymphoma (NHL) has been discussed widely. Little is known about the possible association between NHL and HGV discovered recently. In this study, anti‐HCV and HGV‐RNA prevalence were investigated in a group of 70 patients with NHL. The results were compared to a control group of 70 age‐ and sex‐matched healthy subjects. One patient in each group (1.4%) was found to be anti‐HCV‐positive; the difference was not statistically significant (P > 0.05). Five subjects in the patient group (7.1%) were positive for HGV‐RNA, while a single subject was positive in the control group (1.4%); the difference was not statistically significant (P > 0.05). Odds ratios for anti‐HCV and HGV‐RNA were 1 and 5.30, respectively. Our findings suggest that neither HCV nor HGV are causative or contributing factors in the aetiopathogenesis of NHL.