Hepatitis B Virus Gene in Liver Tissue Promotes Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P < 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.     

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.     

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.     

Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection

Abstract

Objective. To determine the risk factors for the occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) infection. Material and methods. A total of 620 patients who tested positive for hepatitis B surface antigen and were referred to Chiba University Hospital between February 1985 and March 2008 were included in the study and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen, alanine aminotransferase level, HBV DNA level, and number of platelets (PLTs). Results. HCC was detected in 30 cases during the follow-up period (5.4 ± 5.1 years). Multivariate analysis revealed that age >?40 years [compared with patients aged <?40 years; odds ratio (OR) = 4.28; 95% confidence interval (CI) = 1.68–10.9] and PLT level <?206,000/μl (compared with patients with a higher PLT level; OR = 8.50; 95% CI = 1.98–36.2) were predictive factors for HCC occurrence. In patients aged >?40 years, the HBV DNA level (compared with <?5.0 log copies/ml; OR = 4.22, 95% CI = 1.13–15.8) and PLT level (compared with patients with >?196,000/μl PLTs; OR = 15.6, 95% CI = 2.06–118.3) were predictive factors for HCC occurrence. Conclusions. Advanced age and low PLT level were risk factors for HCC occurrence in patients with HBV infection. In patients aged >?40 years, viral load was also a risk factor for HCC.     

HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral

Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4–4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.     

Evaluation of the Hepatocellular Carcinoma Predictive Scores PAGE-B and mPAGE-B among Brazilian Patients with Chronic Hepatitis B Virus Infection

Hepatitis B virus (HBV) is intrinsically oncogenic and related to hepatocellular carcinoma (HCC). Predictive scores of HCC have been developed but have been poorly studied in admixed populations. Therefore, we aimed to evaluate the performance of PAGE-B and mPAGE-B scores for HCC prediction in HBV Brazilian patients and factors related to HCC occurrence. This is a retrospective study that evaluated patients followed at a tertiary university center. A total of 224 patients were included, with a median follow-up period of 9 years. The mean age at HBV diagnosis was 38.71 ± 14.19 years, predominantly males (66.1%). The cumulative incidence of HCC at 3, 5, and 7 years was 0.993%, 2.70%, and 5.25%, respectively, being related in the univariate logistic regression analysis to male sex (p = 0.0461), older age (p = 0.0001), cirrhosis at HBV diagnosis (p < 0.0001), and higher values of PAGE-B and mPAGE-B scores (p = 0.0002 and p < 0.0001, respectively). Older age, male sex, and cirrhosis at HBV diagnosis were independently associated with HCC occurrence. The AUROCs of PAGE-B and mPAGE-B were 0.7906 and 0.7904, respectively, with no differences between them (p = 0.9767). In conclusion, both PAGE-B and mPAGE-B showed a correct prediction of HCC above 70% in this cohort.     

48例原发性肝癌患者血清丙型肝炎抗体检测

为探讨PHC与丙型肝炎的关系,采用ELISA方法检测48例PHC及106例非肝病患者的扰HCV抗体及HBV-M。结果显示PHC组中抗HCV抗体阳性21例(43.8％),对照组14例(13.2％,P<0.01);HBV-M阳性45例(93.8％),对照组50例(47.2％,P<0.01)。HBV-M阳性PHC病人中,HBsAg、HBeAb及HBcAb三项阳性21例(46.7％),HBsAg、HBeAg及HBcAb三项阳性7例(15.6％),HBsAg及HBcAb二项阳性5例(11.1％)。HBV-M阴性PHC患者中,抗HCV抗体阳性2/3例(66.7％),HBV-M阳性PHC病人中,抗HCV抗体阳性19/45例(42.2％,P<0.05);HBsAg阳性PHC病人中,抗HCV抗体阳性14/38例(36.8％);HBsAg阴性病人中,抗HCV抗体阳性7/10例(70.0％,P<0.05)。在抗HCV抗体阳性PHC患者中,3个月前有明确输血史8例(38.1％)。以上结果提示在我国,PHC与丙型肝炎有关,在HBV-M阳性患者中。HBsAg、HBeAb及HBcAb三项阳性患者发生PHC可能性最大。     

Minor Role of Hepatitis B and C Virus Infection in the Etiology of Hepatocellular Carcinoma in a Low-Endemic Area

Background: The etiologic role of hepatitis B (HBV) and C virus (HCV) for hepatocellular carcinoma (HCC) in a low-endemicity area is obscure. Methods: Patients suspected of having primary liver cancer (PLC) in Göteborg, Sweden (n = 113), were tested serologically for HBV surface antigen and antibodies to HBV surface and core antigens. The presence of HBV surface and core antigens in cancer and non-neoplastic liver tissue in HCC cases was investigated immunohistochemically. Antibodies to HCV were tested by third-generation tests. The prevalence of HBV and HCV infection was compared in 73 patients with HCC and 32 patients with a final diagnosis other than PLC. Results: No patient had signs of chronic HBV infection. Seven of 64 (11%) HCC patients were anti-HCV-positive, compared with 1 of 31 (3%) without PLC. All seven patients with HCC and HCV infection had liver cirrhosis, and two were alcoholics. Alcoholism was judged the commonest (42%) cause of cirrhosis. Conclusion: Contrary to areas with a high incidence of HCC, chronic viral hepatitis, particularly HBV, seems to play a minor etiologic role for HCC in Sweden compared with alcohol-related cirrhosis.     

Hepatitis B Virus-Associated Hepatocellular Carcinoma

Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.     

Association Between Helicobacter pylori Infection and Cirrhosis in Patients with Chronic Hepatitis C Virus

We evaluated, employing a logistic regression model, the association between Helicobacter pylori infection and cirrhosis in a cohort of 106 patients (57 males; mean age, 52.9 years; range, 20–78 years) with chronic hepatitis C virus (HCV) from Rosario, Argentina. HCV was confirmed by ELISA and PCR. H. pylori status was determined by ELISA. Of the 106 patients evaluated, 47 (44.3%) had cirrhosis. A total of 70.2% (33/47) of cirrhotic patients and 47.5% (28/59) of noncirrhotic patients were H. pylori-positive. In univariate analyses, cirrhosis was associated with age (P = 0.016) and H. pylori-positive status (P = 0.019) but not with gender (P = 0.28) or length of infection (P = 0.35). In multivariate analysis, H. pylori infection (P = 0.037; OR = 2.42; 95% CI = 1.06–5.53) and age (P = 0.033; OR = 1.04; 95% CI = 1.00–1.07) of patients remained significant and independently associated with cirrhosis. In conclusion, our results demonstrate an association between H. pylori infection and cirrhosis in patients with hepatitis C virus.     

Kidney Transplantation in Patients with Chronic Hepatitis B Virus Infection

The impact of hepatitis B virus (HBV) infection on the long-term outcome of kidney transplant patients is controversial. A total of 34 chronic hepatitis B surface antigen (HBsAg) carriers among 143 renal allograft recipients were identified in this study (mean follow-up period: 5.6 ± 3.3 years; range: 1–13 years). During the follow-up, one HBsAg-positive recipient with preexisting cirrhosis died of liver failure, and seven (21%) others developed serious HBV-related complications (four fulminant hepatitis, two hepatocellular carcinoma, one cirrhosis), and four died. Although HBsAg-positive recipients had a higher rate of liver-related complications and deaths than HBsAg-negative recipients did, there were no significant differences in the long-term graft and patient survival between the two groups. The survival rates, liver-related complications, and deaths in HBsAg-positive allograft recipients and 28 HBsAg-positive uremic patients under dialysis were similar. In conclusion, HBV infection is not a contraindication to kidney transplantation. However, pretransplant candidates should be warned of potentially serious liver-related complications.     

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.     

Thiamine Deficiency in Hepatitis C Virus and Alcohol-Related Liver Diseases

Thiamine deficiency is a common feature in chronic alcoholic patients, and its pathophysiology remains poorly understood. Until now, thiamine deficiency has been considered to be mainly the result of alcoholism irrespective of the underlying liver disease. The aims of the study were to compare the prevalence of thiamine deficiency in alcohol- and hepatitis C virus- (HCV-) related cirrhosis and in patients with chronic hepatitis C without cirrhosis. Forty patients with alcoholic cirrhosis (group A), 48 patients with HCV-related cirrhosis (group B), and 59 patients with chronic hepatitis C without cirrhosis (group C) were included prospectively. Thiamine status was evaluated by concomitant determination of erythrocyte transketolase activity, thiamine diphosphate (TDP) effect, and direct measurement of erythrocyte thiamine and its phosphate esters by HPLC. Thiamine was mainly present in erythrocytes in its diphosphorylated form. Prevalence of thiamine deficiency and levels of TDP in thiamine-deficient patients were similar in patients of group A (alcoholic cirrhosis) and of group B (viral C cirrhosis). None of the patients with chronic hepatitis (group C) was deficient. Thiamine deficiency was not correlated with the severity of the liver disease or disease activity. No impairment of thiamine phosphorylation was found in the three groups. conclusion, alcoholic or HCV-related cirrhotics have the same range of thiamine deficiency, while no patient without cirrhosis has thiamine deficiency, and impaired phosphorylation does not account for the deficiency observed in cirrhotics. We suggest that thiamine should be given to patients with cirrhosis irrespective of its cause.     

Direct-Acting Antiviral Therapy for Hepatitis C Virus in Patients with BCLC Stage B/C Hepatocellular Carcinoma

Background: The benefits of hepatitis C virus (HCV)eradication for hepatocellular carcinoma (HCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B/C remain uncertain. Methods: In this hospital-based cohort study, all HCV-infected patients with BCLC stage B/C HCC during the period January 2017 to March 2021 were retrospectively screened, with 97 patients who had completed direct-acting antiviral (DAA) therapy being enrolled for final analysis. Results: In total, the sustained virological response (SVR) rate was 90.7%. In logistic regression analysis, progressive disease (PD) to prior tumor treatments was significantly associated with SVR failure (odds ratio 5.59, 95% CI 1.30–24.06, p = 0.021). Furthermore, the overall survival (OS) rate was significantly higher in the SVR group than that in the non-SVR group (1-year OS: 87.5% vs. 57.1%, p = 0.001). SVR was found to be an independent factor related to OS (hazard ratio 8.42, 95% CI 2.93–24.19, p = 0.001). However, even upon achieving SVR, the OS rates in BCLC stage C or Child–Pugh stage B patients remained poor. Conclusions: In BCLC stage B/C HCC, DAA could achieve a high SVR rate except in those patients with PD to prior HCC treatments. SVR was related to improvements in OS; therefore, DAA therapy should be encouraged for patients diagnosed without a short life expectancy.     

Risk Factors for Hepatocellular Carcinoma in Patients with Cirrhosis

Recent research suggests an increase in the incidence of hepatocellular carcinoma (HCC) in the United States, which may be related to an upsurge in the sequelae of chronic liver disease from hepatitis C virus. In addition to factors related to the underlying etiology of liver disease, a number of host factors such as age, gender, and ethnic background may be associated with this increased risk. The aim of this study was to evaluate a number of potential risk factors for HCC in patients with cirrhosis. Patients with biopsy proven HCC were identified from our pathology and cancer registry databases. All those without histologic or clinical cirrhosis and non-HCC hepatic malignancies were excluded. Cirrhotic patients without HCC were also selected from the Cleveland Clinic unified transplant database and were designated controls. Extensive clinicodemographic data were obtained from the databases and chart reviews. When available, paraffin-embedded liver biopsy blocks were obtained for HFE gene analysis. Univariate comparisons were made with chi-square and Fisher's exact test and multivariate analysis was carried out with logistic regression. A total of 760 patients were included in this study, 244 documented cases of HCC and 516 cirrhotic controls without HCC. Patients' age (RR = 3.1 [2.6-3.8]; P < 0.0001), male gender (RR = 3.4 [2.3-5.1]; P < 0.0001), African-American ethnicity (RR = 3.1 [1.6-5.8]; P = 0.0005), and other non-Caucasian ethnicity (RR = 6.9 [3.2-14.4]; P < 0.0001) were independently associated with HCC. Restricting the analysis to HCV-related cirrhosis, the same risk factors remained independently associated with HCC: age (decade; RR = 2.3 [1.6-3.4]; P < 0.0001), male gender (RR = 2.9 [1.2-7.0]; P = 0.02), African-American ethnicity (RR = 3.1 [1.3-7.4]; P = 0.009), and other non-Caucasian ethnicity (RR = 15.8 [1.9-134]; P = 0.01). Iron studies did not reveal an increased risk for iron overload or HFE mutation. Male gender, advancing age, and non-Caucasian ethnic background are independently associated with HCC.     

The Impact of Antiviral Therapy for Hepatitis C Virus on the Survival of Patients after Hepatocellular Carcinoma Treatment

Objective Owing to advances in direct-acting antiviral (DAA) therapy, a considerable number of patients with hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) are now able to achieve a sustained viral response (SVR) after curative treatment of HCC. However, the beneficial effect of a DAA-SVR on the survival remains unclear. Methods A total of 205 patients with HCC who were HCV-positive with Child-Pugh A at the onset from 2008 to 2018 were categorized into 2 groups: 140 patients untreated for HCV throughout the entire course after HCC development (untreated group) and 65 patients treated for HCV with DAAs following HCC treatment who achieved an SVR (SVR group). After propensity score matching, 63 patients from each group were selected. Using these patients, the survival and maintenance of Child-Pugh A after HCC treatment were compared between the untreated group and SVR group. Results There was a significant difference in the overall survival (p<0.001) and the rate of maintaining Child-Pugh A (p<0.001) between the groups. The 5-year survival rates were 96% (SVR group) and 60% (untreated group), and the proportions of patients with Child-Pugh A at 5 years after HCC treatment were 96% (SVR group) and 38% (untreated group). Conclusion In patients with HCV-positive HCC, achieving a DAA-SVR after HCC treatment significantly improved the overall survival rate compared with HCV-untreated patients. The contribution of DAA-SVR during the course of HCC treatment to a longer survival is mainly due to the prevention of the progression of Child-Pugh A to B/C. Further research is needed to determine whether aggressive antiviral therapy is also effective for HCC patients with Child-Pugh B/C.     

Hemoperitoneum as a First Manifestation of Hepatocellular Carcinoma in Western Patients with Liver Cirrhosis

Hemoperitoneum is a well-known form of hepatocellular carcinoma presentation and represents a frequent complication in countries with a high incidence of hepatocellular carcinoma, but it is rarely seen in Western countries. Our aim was to report the results and describe the arteriographic and CT-scan characteristics in a series of seven consecutive patients. They were admitted to our hospital because of hemoperitoneum due to ruptured tumor as a first manifestation of hepatocellular carcinoma, and the rupture was effectively controlled by transcatheter arterial embolization. From April 1989 to April 1998, 440 consecutive patients were admitted to our liver unit with the diagnosis of hepatocellular carcinoma and liver cirrhosis. Fourteen patients (3%) presented with acute hemoperitoneum due to tumor rupture as a first manifestation of hepatocellular carcinoma. We here report our experience in the group of patients treated by transcatheter arterial embolization. Mean age was 67.1 ± 5 years (range, 61–73). All patients presented with sudden abdominal pain, abdominal distension, and four patients had symptoms of acute anemia. In all cases the ruptured tumor was subcapsular. The procedure was effective in the control of bleeding in all cases, without significant impairment in liver function or treatment-related deaths. In six of the seven patients, a self-limited postembolization syndrome was observed. Mean survival time was 273 ± 488.7 days (range: 15–1290). Three patients survived more than six months but at the time of evaluation, only one patient was alive. In conclusion, the present results confirm that transcatheter arterial embolization is an effective and well-tolerated treatment in the management of hemoperitoneum due to ruptured hepatocellular carcinoma in patients with liver cirrhosis.     

Hepatitis D Virus and Hepatocellular Carcinoma

Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.     

Risk Factors of Hepatocellular Carcinoma in Chronic Hepatitis C and Cirrhosis: Special Reference to Laparoscopic Findings

Abstract: It remains unclear whether the hepatitis C virus genotype is associated with the severity and outcome of HCV-related liver disease. The aim of this study was to determine whether hepatitis C virus genotype influenced the risk of developing hepatocelMar carcinoma. Two hundred and sixty nine patients who had chronic hepatitis C and cirrhosis without hepatocellular carcinoma were studied. The stage and activity of hepatitis were determined at laparoscopy and patients were followed up until the development of hepatocellular carcinoma or for a maximum of 16 years. Hepatitis C virus genotypes were determined by a genotyping enzyme-linked immunosorbent assay. A cross-sectional study revealed that the prevalence of hepatitis C virus genotype 1 increased and that of genotype 2 decreased with the progression of liver disease (pc 0.01). A follow-up study using the Kaplan-Meier method showed that hepatocellular carcinoma occurred more frequently in patients with hepatitis C virus genotype 1 (p<0.01), patients with a more advanced disease stage (p<0.01), and patients with reddish markings (p<0.05). Cox multivariate proportional hazards analysis confirmed that these three risk factors were independent. Hepatocellular carcinoma developed more frequently in patients with hepatitis C virus genotype 1 and pre-cirrhosis (stage 3 chronic hepatitis with nodules) or liver cirrhosis, in whom hepatitis showed continued activity and progression. (Dig Endosc 1999; 11: 24–31)