Hepatitis C Virus Risk Factors in the Turkish Community

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the worldwide. This infection is often insidious and one-half of infected patients are asymptomatic. Determination of risk factors for HCV transmission is very important. The aim of this study was to assess the risk factors, transmission to spouses and children for HCV infection in Turkish population. One hundred and fifty-one patients with chronic hepatitis C and 151 control cases were investigated for the probable risk factors of HCV infection. Complete blood count, ALT, AST, albumin, prothrombin time, upper abdomen ultrasonography assessment and percutaneous liver biopsy (not for cirrhotics) were performed in all patients with chronic hepatitis C. Anti-HCV testing was done by using second-generation ELISA in 302 cases. Minor surgical operation (p< 0.001), major surgical operation (p= 0.001), blood transfusion (p< 0.001), multi-partner sex (p< 0.05), frequent dental therapy (p< 0.05), and dental extraction (p< 0.001) in patients with a chronic HCV infection were found to be higher than the control group. No significant difference was found in other risk factors. The rate of hepatitis C virus in index cases was found to be 1.8% in their spouses and 1.2% in their children. Our study showed that surgical operation, frequent dental therapy, dental extraction, multi-partner sex, and blood transmission are the main risk factors for HCV infection in Turkish community.     

Lower Hepatitis G Virus Infection Prevalence Compared to Hepatitis B and C Virus Infection Prevalences

To more accurately determine the seroprevalence of hepatitis G virus (HGV) infection, we surveyed antibody to HGV (anti-E2) by enzyme-linked immunosorbent assay (ELISA) and HGV RNA by nested polymerase chain reaction (PCR) in 298 residents of a hepatitis C virus (HCV)-endemic area of Japan and in 225 hemodialysis patients. We then compared these findings with known HCV and hepatitis B virus (HBV) infection prevalences. Anti-E2 and HGV RNA prevalences were 32 (10.7%) and 5 (1.7%) in the residents and 24 (10.7%) and 10 (4.4%) in the hemodialysis patients, respectively. Anti-E2 and HGV RNA concurrence was found in two of the hemodialysis patients. Total HGV marker (anti-E2 and/or HGV RNA) prevalences [37 (12.4%) in residents and 32 (14.2%) in hemodialysis patients], were significantly lower than the prevalences of antibody to HCV (anti-HCV) by ELISA [59 (19.8%) and 96 (42.7%)], and antibody to hepatitis B core antigen (anti-HBc) by radioimmunoassay (RIA) [87 (29.2%) and 101 (44.9%)] (P < 0.05). The anti-HCV prevalence in subjects with total HGV marker was significantly higher than in those without total HGV marker. There was no significant difference in anti-HBc prevalence between those with and without total HGV marker. The viremic rate was highest in HCV infection (HCV RNA by PCR/anti-HCV) (83.2%), with HGV infection (HGV RNA/total HGV marker) (21.7%) intermediate, and HBV infection (hepatitis B surface antigen by RIA/anti-HBc) (5.3%) lowest (P < 0.05). These findings indicate that HGV infection was less endemic than HCV and HBV. HGV was eliminated naturally more frequently than HCV infection and less frequently than HBV infection.     

Targeting microRNA-122 to Treat Hepatitis C Virus Infection

An important host factor for hepatitis C virus (HCV) is microRNA-122 (miR-122). miR-122 is a liver-specific member of a family of small, non-coding RNA molecules known as microRNAs that play major roles in the regulation of gene expression by direct interaction with RNA targets. miR-122 binds directly to two sites in the 5' untranslated region (UTR) of HCV RNA and positively regulates the viral life cycle. The mechanism by which this regulation occurs is still not fully understood. There has been a great deal of interest in potential therapeutics based on small RNAs, and targeting miR-122 to combat HCV is one of the furthest advanced. Chemical inhibitors of miR-122 can be introduced into mammals intravenously and result in potent and specific knockdown of the microRNA, with no detectable adverse effects on liver physiology. This strategy was recently applied to chimpanzees chronically infected with HCV and resulted in a sustained reduction in viral load in the animals. Inhibition of miR-122 therefore presents a very attractive novel approach to treating HCV, a virus for which improved therapeutics are urgently needed.     

Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy

A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.     

Hepatitis C Virus Infection in Institutionalized Psychiatric Patients

The objective of this study was to determine if HCV can be transmitted from patient to patient in psychiatric institutions and to determine possible routes of infection. We did a cross-sectional survey of 196 Japanese psychiatric patients tested for HCV and HBV markers and 400 age- and sex-matched controls. Anti-HCV was detected in 10.2% and antibody to hepatitis B core antigen was detected in 44.4% of the patients, a significantly higher prevalence than found among matched controls. A multiple regression logistic analysis was used to identify risk factors that could indicate the route of infection by HCV. Duration of hospitalization, age, razor sharing, and history of surgery proved to be statistically significant independent risk factors associated with positive anti-HCV results [odds ratio (OR), 4.00; 95% confidence interval (CI), CI, 1.74–9.19; OR, 2.19; 95% CI, 1.27–1.3.77; OR, 4.90; 95% CI, 1.29–18.86; OR, 3.35; 95% CI, 0.997–11.3, respectively]. These observations suggest that razor sharing played an important role in the spread of the HCV infection in the institutionalized psychiatric patients we studied.     

Significance of Prior Hepatitis B Virus Infection in the Development of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

To clarify the clinical significance of prior hepatitis B virus (HBV) infection in the development of C-viral hepatocellular carcinoma (HCC), we conducted two studies: (1) Two hundred thirty-four patients with C-viral HCC and 320 patients with C-viral chronic liver disease without HCC admitted to our hospital between 1990 and 1994 were analyzed for the association of hepatitis B core antibody (HBcAb) positivity with HCC by multivariate logistic regression analysis, and this revealed HBcAb positivity as an independent risk factor for development of HCC adjusted for age and sex. (2) Four hundred fifty-nine patients with biopsy-proven hepatitis C virus-related chronic liver disease between 1986 and 1998 were enrolled in the cohort study and followed for the development of HCC. During an average follow-up of 6.6 ± 3.3 years, HCC developed in 63 patients, 37 of 160 patients positive for HBcAb and 26 of 299 patients negative for HBcAb. Multivariate Cox proportional regression analysis showed that the incidence of HCC increased by age, advanced stage of liver fibrosis, mean alanine aminotransferase value of more than 80 IU/liter, and positivity of HBcAb. Sustained virological responders after interferon therapy revealed a reduced risk for HCC development. In conclusion, prior HBV infection was shown to be one of the independent risk factors for development of HCC in C-viral chronic liver disease.     

丙型肝炎病毒慢性感染相关的系统性自身免疫病分析

目的描述和分析丙型肝炎病毒(HCV)慢性感染相关系统性自身免疫病(SAD)患者的临床表现、实验室检查特征、治疗及预后。方法对1989年至2009年北京协和医院收治的12例HCV慢性感染相关SAD患者的临床表现、实验室检查特征及治疗情况进行统计和分析。结果 12例患者在发现慢性HCV感染后发生SAD,其中5例系统性红斑狼疮(SLE)、2例冷球蛋白血症、1例显微镜下多血管炎(MPA)、1例结节性多动脉炎(PAN)、1例系统性硬化(SSc)、1例类风湿关节炎(RA)合并多发性肌炎(PM)、1例皮肌炎(DM)。男女比例为1:11,发现慢性HCV感染时平均年龄为39.8岁(18～62岁),SAD平均发病年龄为41.5岁(23～62岁)。所有患者都符合相应SAD的分类标准,最常见临床表现为血液系统受累(83.3%)和皮肤受累(66.7%),最常见实验室检查特征为抗核抗体(ANA)阳性(83.3%),红细胞沉降率增快(83.3%)和低补体血症(75.0%)。对5例SLE患者进行亚组分析显示,其临床表现和实验室检查结果与一般SLE患者差异无显著性。此外,12例伴发SAD的慢性HCV感染者中,11例(91.7%)丙氨酸转氨酶(ALT)水平正常,ALT正常率显著高于慢性HCV感染患者的平均水平(P<0.01)。SAD的治疗,除1例患者拒绝治疗自行出院外,其余11例患者采用糖皮质激素联合免疫抑制剂治疗均可有效控制SAD。慢性HCV感染的治疗,1例治疗前ALT水平升高患者拒绝干扰素联合利巴韦林抗病毒治疗,剩余11例ALT水平正常患者中3例接受治疗,其中1例由于干扰素使用后白细胞数下降而停用,余2例均获得了持续病毒学应答(SVR)。接受抗病毒治疗的3例患者中,有2例因SAD活动再次入院治疗;未接受抗病毒治疗的9例患者有3例因SAD活动再次入院(P>0.05)。结论 HCV慢性感染相关的SAD在临床表现及实验室检查特征上与未合并HCV慢性感染时相比无差异,使用糖皮质激素联合免疫抑制剂治疗仍安全有效。出现SAD的HCV慢性感染患者的肝炎表现较轻微,ALT大多处于正常范围,是否使用抗病毒治疗需根据个体情况确定。     

Hepatitis C transmission between spouses

To examine inter-spouse transmission as one of the potential routes of infection for hepatitis C virus (HCV), 121 patients with HCV-related chronic liver disease who tested positive for antibodies to HCV (anti-HCV) and their spouses were studied. Of these, 21 (17.4%) patients had spouses with anti-HCV. In 12 couples, the HCV genotype matched (type II: 10 couples, type III: two couples). The genotype differed in six couples. One patient was positive for anti-HCV, but negative for HCV-RNA, while the spouse was positive for both. The remaining two couples were only positive for anti-HCV. Genetic heterogeneity in the hypervariable region 1 of HCV was analysed in 11 couples with matched genotypes. In two couples, no mutation was recognized in the putative E2/NS1 genes using the heteroduplex method. The present study provides evidence to verify household transmission of HCV between patients and their spouses. These results suggest that inter-spouse transmission may be a potential route of transmission of HCV infection. However, other environmental factors (e.g. the duration of the marriage) cannot be ignored.     

Hepatitis C Virus Infection among Patients with Chronic Liver Disease in an Area Hyperendemic for Hepatitis B

Tsai J-F, Jeng J-E, Chang W-Y, Lin Z-Y, Tsai J-H. Hepatitis C virus infection among patients with chronic liver disease in an area hyperendemic for hepatitis B. Scand J Gastroenterol 1994;29:550-552.

Background: The prevalence of hepatitis C virus (HCV) infection was assessed in patients with nonalcoholic chronic liver disease (CLD).

Methods: Antibody levels to HCV (anti-HCV) were assessed in 100 pairs of CLD patients and healthy controls.

Results: The prevalence of anti-HCV was higher in patients (26.0%) than in controls (2.0% p = 0.0001). The patient group with anti-HCV was older (p equals; 0.0001) and had more smokers (p equals; 0.034), fewer hepatitis B surface antigen carriers (p equals; 0.0001), and more patients with active liver disease (p equals; 0.023) and a history of blood transfusion (p equals; 0.026). Multivariate analysis showed that anti-HCV (odds ratio, 8.1; 95% confidence intervals, 3.7-17.6) was strongly associated with CLD.

Conclusions: HCV infection is a risk factor of non-alcoholic CLD, and HCV causes more severe hepatocellular damage than HBV.     

Celiac Disease and Non-organ-specific Autoantibodies in Patients with Chronic Hepatitis C Virus Infection

OBJECTIVE: Considering that celiac disease (CD) is an autoimmune-based entity and the hepatitis C virus is suspected of being able to trigging autoimmune reactions, it has been hypothesized that hepatitis C virus infection might predispose to CD. The aim of this study was to investigate CD-related antibodies in a large series of hepatitis C virus-infected subjects that were also tested for non-organ-specific autoantibodies (NOSA) as indirect marker of autoimmune disorders. METHODS: Two hundred and forty-four patients with chronic hepatitis C virus infection (HCV-patients) and 121 patients with HCV-negative liver disease (non-HCV-patients) underwent NOSA determination and celiac serology (firstly, anti-tissue transglutaminase antibodies, then the cases which tested positive were subsequently evaluated for the presence of antiendomysial antibodies). Serum samples from 42 of the HCV-patients who underwent interferon-alpha therapy after enrollment were tested for celiac antibodies and NOSA even after stopping treatment. Additionally, sera from 1,230 blood donors were assayed for celiac serology as healthy control population. RESULTS: Positive anti-endomysial antibodies (AEA) were found in 5/244 (2%) HCV-patients, 1/121 (0.8%) non-HCV-patients and 2/1,230 (0.16%) blood donors, with a significant difference between HCV-patients and blood donors (P = 0.02; Odds ratio 12.8; 95% Confidence Interval 2.4-66). NOSA were found in 51 HCV-patients but only one of them had positive AEA. Eight out of 42 HCV-patients treated with interferon-alpha developed NOSA under therapy and none of them had CD antibodies. CONCLUSIONS: AEA occur in 2% of HCV-patients and their presence is independent of other patterns of autoimmunity.     

Previous or Occult Hepatitis B Virus Infection in Hepatitis C Virus-Associated Hepatocellular Carcinoma Without Hepatic Fibrosis

We investigated the role of hepatitis B virus infection in development of hepatocellular carcinoma in hepatitis C virus-infected patients without hepatic fibrosis. Of 253 patients, 8 lacked hepatic fibrosis (group 1); group 2 included the remaining 245 patients. Clinicopathologic findings were compared between the groups. Hepatitis B x gene was sought in cancers and adjoining noncancerous liver. Group 1 showed better liver function parameters and milder active hepatitis than group 2. The proportion of patients with anti-hepatitis B virus antibody tended to be higher in group 1 than in group 2. The proportion of patients with hepatitis B x RNA in cancers was significantly higher in group 1 than in group 2. All group 1 patients had previous or occult hepatitis B virus infection. Previous or occult hepatitis B virus infection may be critical in development of hepatocellular carcinomas in hepatitis C virus-infected patients without hepatic fibrosis.     

Hepatitis B Virus Vaccine for Patients with Hepatitis C Virus Infection

Summary Hepatitis C is a disease with varying rates of progression. The role of hepatitis B virus (HBV) as a cofactor in the development of hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC) has been suggested and the use of HBV vaccine in all HCV-infected patients has been advocated. This review presents the implications of HBV and HCV coinfection and addresses the issues of HBV vaccine immunogenicity and safety in patients with chronic HCV infection. Received: December, 1999 · Revision accepted: July 1, 2000     

难治性慢性肝炎与丙型及乙型肝炎病毒感染的关系

选择肝功能异常的慢性肝炎患者143例,采用常用药物治疗6个月,以肝功能不能复常为难治性慢性肝炎,其中慢迁肝26/56例(46.4%),慢活肝25/49例(51.0%),肝硬化29/38例(76.3%).经丙型及乙型肝炎病毒标志检测分析,26例慢迁肝中抗 HCV 阳性率46.2%,明显高于恢复组的16.7%(P<0.025);25例慢活肝中 HBV 复制标志阳性率68.0%,明显高于恢复组的29.2%(P<0.01);29例肝硬化中,HBV 复制标志阳性率58.6%,也明显高于恢复组的11.1%(P<0.05)。提示 HCV 感染可能是慢迁肝难治的重要因素,HBV 复制是慢活肝、肝硬化难治的重要因素。     

Hepatitis C virus genotypes in chronic hepatitis C of children

SUMMARY. Several hepatitis C virus (HCV) genotypes have been recently identified and genotype 1b has been correlated with severe liver disease and a poor response to interferon therapy. HCV infection in children is an interesting model for evaluation of the relationship between HCV genotypes and liver disease, because of its relatively short duration and the infrequent association with confounding cofactors. We have investigated HCV genotypes, using a dot-blot hybridization assay with genotype-specific probes, in 36 Italian children with chronic hepatitis C who were otherwise well and had no other underlying disease. Only four patients were symptomatic; liver histology, obtained in 3 3 patients, showed minimal hepatitis in 17 and mild chronic hepatitis in 16. Infection with HCV genotype Ib was found in 55.5% of patients, with a peak prevalence of 83% in children from southern Italy (P < 0.05 vs other regions). The remaining children were infected with HCV genotype la (16.6%), genotype 2 (11.1%). and mixed (10.9%) or undetermined (2.7%) genotypes. In one patient, HCV viraemia was never detected. There was no statistically significant correlation between genotype and age, sex, source of infection, alanine aminotransferase pattern and histological activity index. These results indicate that genotype 1b is widespread among Italian children with chronic hepatitis C, although with significant geographical variations. It is not associated with a more severe liver disease, therefore suggesting that the greater severity of liver disease recently reported in adults could reflect the cumulative effects of disease duration and of interfering cofactors.     

CASE REPORT: Sarcoidosis-Associated Hepatitis C Virus Infection

Although several reports of sarcoidosis have been reported in hepatitis C virus (HCV)-infected patients treated with interferon-alpha, this association has never been described in nontreated HCV patients. We report two cases of sarcoidosis associated with chronic hepatitis C infection. The patients developed multivisceral sarcoidosis (cutaneous, lungs, nodes) at two and at least six years after the presumed date of infection. One patient obtained remission of sarcoidosis with corticosteroid treatment but the other remained corticodependent. The levels of hepatic enzymes were not significantly modified throughout the course of corticosteroid therapy. In conclusion, these case reports suggest that HCV itself could induce a granulomatous reaction in chronic HCV-infected patients through the stimulation of the cellular immune system. It could be of interest to test for HCV infection all patients diagnosed with sarcoidosis and to watch over every treated or nontreated hepatitis C infected patient for the development of granulomatous lesions.     

Correlation of Genotypes and Route of Transmission with Histologic Activity and Disease Stage in Chronic Hepatitis C

Our objective was to evaluate the histopathological features of chronic hepatitis C of 64 liver biopsies and to correlate this with the route of transmission of hepatitis C virus, the genotype of HCV, and the patient's age. Moderate chronic hepatitis was the most frequently observed (62.5%). Cirrhosis was observed in 14 patients (21.9%) and was more frequently found among patients over 40 years of age (34.3% vs 6.9%, P = 0.025). The mean histopathological activity index (HAI) was significantly higher in the sporadic (10 ± 3.1) than the posttransfusional (7.5 ± 3.7) and the intravenous drug use (IVDU) groups (6.3 ± 2.8) (P < 0.02). Moreover the sporadic group showed more fibrosis (P < 0.04) than the posttransfusional group. No liver cirrhosis was found in the IVDU group. The overall prevalence of HCV variants was: 54.7% type 1b, 4.6% type 1a, 37.5% type 2c, 1.6% type 2b, 1.6% type 2. The genotype distribution showed no relation to the HAI, hepatitis activity (grade), and fibrosis (stage) of the liver disease. In conclusion, the sporadic route of transmission of HCV was related to a more severe chronic hepatic disease, a finding that could influence future antiviral therapies. The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our data suggests that the ultimate consequence of HCV chronic infection depends on patient age rather than on HCV genotype.     

Anti-ENA Antibodies in Patients with Chronic Hepatitis C Virus Infection

The aim of the study was to assess the prevalence of anti-extractable nuclear antigen (ENA) antibodies in patients with chronic HCV infection. We studied 69 consecutive patients with chronic hepatitis C, 59 control subjects with non-HCV liver diseases, and 22 control subjects with extrahepatic, non-immune-mediated, chronic diseases. Thirty-two (46.3%) of 69 patients with HCV infection had anti-ENA antibodies: 16 (23.1%) showed anti-SSA antibodies and 14 (20.2%) had anti-SSB antibodies. Four of the patients with HCV infection suffered from sicca syndrome and three of them had also anti ENA antibodies. The prevalence of anti-ENA antibodies was significantly higher in the anti-HCV subjects compared with both control groups. Twenty-six of 44 HCV-antibodies-positive females had anti-ENA antibodies, compared with 6 of 25 males, showing a sex related difference. In conclusion, our results outline a specific role of HCV infection in the induction of anti-ENA antibodies. Female sex seems a predisposing condition.     

Hepatitis C and liver transplantation

Hepatitis C virus (HCV) is important to the liver transplant recipient for several reasons. First, chronic HCV infection is a frequent cause of end-stage liver disease in North America and Europe, where the majority of liver transplants are performed. Second, recurrence of HCV after liver transplantation is almost universal so that many liver transplant recipients with and without overt hepatitis are viraemic. Third, HCV infection in the organ donor and/or in the blood transfused in the peri-transplant period make acquisition of HCV possible. Finally, liver transplantation for chronic HCV infection represents a major financial burden to the health-care system in the USA and worldwide. Histological hepatitis not due to HBV or cytomegalovirus (CMV) is present in 14–35% of allografts from patients undergoing liver transplantation, and the majority of this is due to HCV infection. HCV infection recurs post-transplant in almost all patients with pre-transplant infection. Proof that HCV does recur has been provided by the sequencing of the hypervariable domain of the E2/NS1 region. The magnitude of HCV infection is underestimated by using serological assays in this immunosuppressed population. Using the b-DNA assay, HCV-RNA levels have been shown to increase in patients with recurrent infection. The long-term consequences remain to be defined but post-transplantation HCV infection is generally much less devastating than post-transplantation HBV infection, and many patients have clinically silent disease. It is likely that a carrier state exists in immunosuppressed transplant recipients since high HCV-RNA levels occur in the absence of liver damage. In one study, 1, 2 and 3 year patient survival rates were shown to be comparable in patients with chronic active HCV infection and with cryptogenic cirrhosis (94, 89 and 87%, and 84, 84 and 73%, respectively). A more recent study from the University of Pittsburgh which compared the outcome of a larger number of HCV-infected patients (n= 237) with a large number of control patients with non-viral disease (n= 801), showed that indeed HCV infection does impact negatively on both patient and graft survival (1, 2 and 3 year patient survival in the study and control groups of 78, 68 and 66% and 84, 82 and 78%, respectively, P= 0.001). Undoubtedly with time, the full impact of recurrent HCV infection will become apparent, although short-term survival is sufficiently good to warrant continued transplantation of this group of patients. While the disease course in many patients is benign, aggressive post-transplant HCV infection leading to liver failure is well documented. Factors which determine why some patients are more susceptible to liver damage than others are currently under study. It is likely that many interrelated variables are involved, including the level of pre-transplant viraemia, genotype of the virus, amount of post-transplantation immunosuppression, and ability of the host immune system to recognize HCV and mount an immune response.