乙型肝炎肝硬化患者HBV血清学模式与病毒载量关系的研究

目的通过分析乙型肝炎肝硬化患者HBV血清学模式、HBVDNA、肝功能,探讨乙型肝炎肝硬化患者抗病毒治疗的临床意义。方法回顾性分析168例乙型肝炎肝硬化患者的病史、血清病毒学指标、肝功能,按不同的指标进行分组、比较。结果168例乙型肝炎肝硬化患者中以HBVDNA阳性者占绝大多数（91．0％）,其中HBeAg阴性者占81．0％;分组比较提示HBVDNA阳性组ALT、AST显著高于阴性组,ALT异常组HBVDNA载量明显高于ALT正常组（P〈0．01）;不同Child—Push分级之间HBVDNA载量无显著性差异。结论乙型肝炎肝硬化住院患者以HBVDNA阳性及HBeAg阴性者居多,HBVDNA呈较高水平复制者,肝脏炎症损害亦较重,故应及早予以抗病毒治疗。     

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。     

病毒因素及其防治在慢性乙型肝炎肝硬化中的地位

自然史研究证明慢性乙型肝炎（chronic hepatitis B,CHB）肝硬化的发生和发展与HBV复制密切相关。临床研究已证实核苷类似物特别是拉米夫定抑制CHB失代偿性肝硬化是安全有效的,表现在近期可阻断病毒复制所诱导的炎症反应,远期则可减少疾病发作及失代偿。临床治疗的过程需要3～6个月,这提示应在病程早期开始应用核苷类似物治疗。通过抗病毒治疗会使部分患者疾病好转或恢复,生活质量乃至存活率提高而无须进行原位肝移植。对于必须进行肝移植者,可显著降低移植后HBV再感染率。随着阿德福韦、恩替卡韦、替比夫定、替诺福韦及恩曲他滨等核苷类似物的出现,相关治疗的选择逐渐增多,联合治疗的选择也相应增多,但选用时应充分考虑疾病进展、病毒载量、经济条件及长期用药的可持续性（耐药后的处理）等多种影响因素。     

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.     

Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus

Objective. Although hepatitis B virus (HBV) DNA can be detected in liver or sera of patients without serum hepatitis B surface antigen (HBsAg), its clinical relevance in hepatocarcinogenesis remains controversial. This observational cohort study was conducted to clarify the risk factors, including the presence of serum HBV DNA and hepatitis B core antibody (anti-HBc), for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). Material and methods. The study comprised 123 patients with LC due to HCV, and negative for HBsAg. The risk factors for HCC development were analyzed by univariate and multivariate analysis. Serum samples were assayed for HBV DNA using real-time polymerase chain reaction. Results. Serum HBV DNA was detectable in 14 patients (11.4%) and serum anti-HBc in 96 (78.0%). During the follow-up period (mean 53.3 months), 80 patients (65.0%) developed HCC. The cumulative HCC development rate was significantly higher in the anti-HBc-positive group than in the anti-HBc-negative group (p=0.0039), but did not differ between the serum HBV DNA-positive and -negative groups (p=0.8570). The multivariate analysis indicated that male gender, alpha-fetoprotein (AFP) 20 ng/ml or greater, average serum alanine aminotransferase (ALAT) 80 IU/l or greater and the presence of anti-HBc were independent risk factors for development of HCC (p=0.038, p=0.013, p=0.020 and p=0.001, respectively). Conclusions. Serum anti-HBc, which indicates a previous HBV infection, has clinical significance in hepatocarcinogenesis in patients with HCV-related LC, but serum HBV DNA does not. Therefore, anti-HBc in serum is a significant predictor for HCC.     

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.     

Hepatitis B and C virus infection as risk factors for liver cirrhosis and cirrhotic hepatocellular carcinoma: a case-control study

To investigate whether hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are risk factors for liver cirrhosis and hepatocellular carcinoma (HCC), a case-control study of 102 cirrhotic HCC patients, 102 sex-matched and age-matched patients with liver cirrhosis, and 102 matched patients with non-hepatic disease controls was performed. The prevalences of hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) in HCC (70.5%, 39.2%) and liver cirrhosis (74.5%, 27.4%) were higher than controls (16.6%, 10.5%) (P = 0.0001). In HBsAg-negative patients, the prevalence of anti-HCV in cirrhotic HCC (66.6%) and liver cirrhosis (46.1%) was higher than in controls (10.5%; P = 0.0001). There was no such difference in HBsAg-positive patients. Multivariate analysis revealed that both HBsAg and anti-HCV were important risk factors for HCC (odds ratio, 6.52 and 4.59, respectively) and liver cirrhosis (odds ratio, 4.22 and 2.29, respectively). There was no difference in odds ratio when HCC and liver cirrhosis were compared. Our result implies that both HBV and HCV are independent risk factors for cirrhotic HCC and liver cirrhosis in Taiwan.     

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.     

Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan

In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13–36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2–8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 × 103/mm³ prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted.     

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

Aim:  This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT).
Methods:  We reviewed "blindly" allograft biopsy specimens of women who underwent transplantation for PBC ( n  = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV ) ( n  = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients.
Results:  Granulomatous destructive cholangitis was found in five biopsies from four PBC patients ( P  = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis ( P  = 0.0002), lobular necroinflammatory activity ( P  < 0.0001), steatosis ( P  < 0.0001) and fibrosis ( P  < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis ( n  = 2) or cirrhosis ( n  = 2). No other PBC patient had evidence of cirrhosis after OLT.
Conclusions:  Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients.     

Perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis with hepatocellular carcinoma

Liver cirrhosis is reportedly one of the conditions preceding peripheral-type intrahepatic cholangiocarcinoma but not hilar/perihilar cholangiocarcinoma. Herein, we report a case of perihilar cholangiocarcinoma arising in a hepatitis C virus-related cirrhotic liver. The patient was a 69-year-old man. He was diagnosed with hepatitis C virus-related chronic hepatitis at the age of 56 years, and 9 years later, multiple hepatocellular carcinomas were detected by imaging modalities. Despite treatments, including chemotherapy, he died of hepatic failure at the age of 69 years. At autopsy, in addition to multiple nodules of hepatocellular carcinoma, we found a white mucinous and fibrous tumor spreading from the hepatic hilum to the periphery along the left lateral segmental bile ducts in the advanced cirrhotic liver. This tumor was histologically a cholangiocarcinoma that involved mainly the peribiliary glands and showed variable cystic dilation, suggesting that it might have been derived from these peribiliary glands. Immunohistochemically, the cholangiocarcinoma cells were positive for cytokeratin 7 and mucin core protein 1, and negative for cytokeratin 20 and mucin core protein 2. Hilar/perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis has rarely been reported. This case warrants further studies to clarify the possible involvement of hepatitis C virus in tumorigenesis of hilar/perihilar cholangiocarcinoma.     

Serum immunoglobulins predict the extent of hepatic fibrosis in patients with chronic hepatitis C virus infection

Recently, we documented that immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. The aim of the present study was to determine whether there is any association between serum immunoglobulin levels and hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection. Charts from 116 patients with biochemical, serologic, virologic and histologic evidence of chronic hepatitis C infection and serum immunoglobulin levels (IgA, IgG, IgM and total) were reviewed. The mean (+/-SD) age of the study population was 46 +/- 11 years and 67 (58%) were male. There were significant correlations between serum IgA (r = 0.39, P = 0.00001), IgG (r = 0.49, P = 0.000002) and total (r = 0.51, P = 0.000003) immunoglobulin levels and the stage of hepatic fibrosis. When serum immunoglobulin levels were included into logistic regression analysis with variables known to be associated with advanced disease (male gender, age >40 years at onset of infection, duration of infection beyond 20 years and concurrent alcohol abuse) only IgA, IgG and total immunoglobulin levels (P < 0.05, <0.05 and <0.005, respectively) emerged as independent predictors of hepatic fibrosis. Our data indicate a strong association between serum immunoglobulin levels (IgA, IgG and total) and hepatic fibrosis in patients with HCV infection. This finding supports the need to further investigate whether immunoglobulins independently promote disease progression in patients with chronic HCV infection.     

Management of hepatitis C infection before and after liver transplantation

Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti-HCV therapy for pre- and post-LT remains high.     

Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: a cohort study

Summary.  An impact of serum hepatitis B virus (HBV) DNA on hepatocarcinogenesis has not been investigated in a cohort of patients with non-B, non-C cirrhosis. Eighty-two consecutive Japanese patients with cirrhosis, who showed negative hepatitis B surface antigen and negative anti-hepatitis C virus, were observed for a median of 5.8 years. Hepatitis B virus core (HBc) region and HBx region were assayed with nested polymerase chain reaction. Both of HBc and HBx DNA were positive in 9 patients (11.0%) and both were negative in 73. Carcinogenesis rates in the whole patients were 13.5% at the end of the 5th year and 24.6% at the 10th year. The carcinogenesis rates in the patients with positive DNA group and negative DNA group were 27.0% and 11.8% at the end of the 5th year, and 100% and 17.6% at the 10th year, respectively ( P  =   0.0078). Multivariate analysis showed that men ( P  =   0.04), presence of HBc and HBx DNA (hazard ratio: 8.25, P  =   0.003), less total alcohol intake ( P  =   0.010), older age ( P  =   0.010), and association of diabetes ( P  =   0.005) were independently associated with hepatocellular carcinogenesis. Existence of serum HBV DNA predicted a high hepatocellular carcinogenesis rate in a cohort of patients with non-B, non-C cirrhosis.     

Reduction of virus burden-induced splenectomy in patients with liver cirrhosis related to hepatitis C virus infection

AIM: To examine the hepatitis C virus (HCV) levels and immunological markers in cirrhotic patients after splenectomy. METHODS: HCV RNA titers as well as cellular and humoral immune markers were determined in 20 cirrhotic patients after splenectomy and in 32 cirrhotic controls with an intact spleen. RESULTS: Serum HCV RNA titers were lower in the splenectomized patients than in the controls (186±225×103 copies/ml vs 541±417×103 copies/mL, P<0.01). HCV RNA was judged to have been spontaneously eradicated in 4 splenectomized patients, but in none of the controls. Natural killer cell activity was higher in the splenectomized patients than in the controls (41.2±19.3% vs 24.7±15.3%, P<0.01), and natural killer cell activity was negatively correlated to HCV RNA titers in the splenectomized patients except in those with serotype 2-related infection. The CD4/CD8 ratio was significantly lower in the splenectomized patients than in the controls. CONCLUSION: The findings suggest that splenectomy may diminish virus burden in cirrhotic patients with HCV infection at least in part, through augmentation of natural killer cell activity.