Hepatic steatosis and the risk of hepatocellular carcinoma in chronic hepatitis C

BACKGROUND AND AIM: Obesity associated hepatic steatosis has been suggested to have a premalignant potential. We determined whether hepatic steatosis predisposes to liver cancer in persons with chronic hepatitis C virus (HCV) infection. METHODS: We compared the histological severity of steatosis in the index liver biopsies of 25 patients with chronic hepatitis C who subsequently developed hepatocellular carcinoma (HCC) with matched controls who did not. Cases were aged (mean) 54.7 years, 84% males, 76% genotype 1, and 64% fibrosis stage 4; and controls were matched for these characteristics. Those with a sustained virologic response to antiviral therapy were excluded. RESULTS: Duration of HCV infection, concomitant alcohol intake, body mass index and indices of past hepatitis B virus (HBV) infection were comparable between the groups. Controls were followed for a longer period after the index liver biopsy than were cases (113 months vs 55 months, P < 0.001). As determined by percentage area of biopsy core occupied by steatosis on computer assisted morphometric evaluation, and graded by semiquantitative histological assessment, steatosis was comparable among cases and controls. The odds of developing HCC among those with steatosis grades 1 and 2 did not differ significantly from those without steatosis. There was no association between increasing morphometric percentage area occupied by steatosis and the subsequent development of HCC. Neither steatosis grade or percent area of steatosis on biopsy were selected in multivariate regression analysis as independent predictors for the development of HCC. CONCLUSIONS: Hepatic steatosis does not augment the risk of hepatocarcinogenesis in patients with chronic HCV infection.     

Dynamic risk assessment for hepatocellular carcinoma in patients with chronic hepatitis C

Chronic hepatitis C (HCV) is a primary cause of hepatocellular carcinoma (HCC). Although antiviral treatment reduces risk of HCC, few studies quantify the impact of treatment on long-term risk in the era of direct-acting antivirals (DAA). Using data from the Chronic Hepatitis Cohort Study, we evaluated the impact of treatment type (DAA, interferon-based [IFN], or none) and outcome (sustained virological response [SVR] or treatment failure [TF]) on risk of HCC. We then developed and validated a predictive risk model. 17186 HCV patients were followed until HCC, death or last follow-up. We used extended landmark modelling, with time-varying covariates and propensity score justification and generalized estimating equations with a link function for discrete time-to-event data. Death was considered a competing risk. We observed 586 HCC cases across 104,000 interval-years of follow-up. SVR from DAA or IFN-based treatment reduced risk of HCC (aHR 0.13, 95% CI 0.08–0.20; and aHR 0.45, 95% CI 0.31–0.65); DAA SVR reduced risk more than IFN SVR (aHR 0.29, 95% CI 0.17–0.48). Independent of treatment, cirrhosis was the strongest risk factor for HCC (aHR 3.94, 95% CI 3.17–4.89 vs. no cirrhosis). Other risk factors included male sex, White race and genotype 3. Our six-variable predictive model had ‘excellent’ accuracy (AUROC 0.94) in independent validation. Our novel landmark interval-based model identified HCC risk factors across antiviral treatment status and interactions with cirrhosis. This model demonstrated excellent predictive accuracy in a large, racially diverse cohort of patients and could be adapted for ‘real world’ HCC monitoring.     

Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis

OBJECTIVE:  Hepatocellular carcinoma (HCC) is an uncommon but serious occurrence in autoimmune hepatitis. Our objective was to determine predictors for this neoplasm to improve screening strategies.
METHODS:  Two hundred twenty-seven patients underwent hepatic ultrasonography and serum alpha fetoprotein determinations at 6–12-month intervals.
RESULTS:  Nine patients developed HCC (4%), and each had cirrhosis ≥73 months prior to the malignancy (mean, 110 ± 7 months). By univariate Cox analysis, features at accession associated with a higher risk of HCC were: male gender (Hazard Ratio [HR] 7.0, 95% Confidence Interval [CI] 1.87–26.1, P = 0.004), history of blood transfusion (HR 5.6, 95% CI 1.51–21.1, P = 0.01), thrombocytopenia (HR 7.3, 95% CI 1.89–28.3, P = 0.004), ascites (HR 23.8, 95% CI 4.65–121.8, P = 0.0001), esophageal varices (HR 7.9, 95% CI 1.96–31.8, P = 0.004), and any sign of portal hypertension (HR 19.1, 95% CI 3.91–93.3, P = 0.0003). Features after accession associated with a higher risk of malignancy were: treatment for ≥3 yr (HR 7.6, 95% CI 1.25–18.2, P = 0.02), worsening laboratory tests during corticosteroid therapy (HR 7.6, 95% CI 1.81–32.1, P = 0.006), and cirrhosis for ≥10 yr (HR 8.4, 95% CI 1.69–41.9, P = 0.009).
CONCLUSIONS:  Male gender, features of portal hypertension, history of blood transfusions, immunosuppressive treatment for ≥3 yr, treatment failure, and cirrhosis of ≥10 yr duration identify patients at risk for HCC. These risk factors should focus screening in autoimmune hepatitis.     

Higher risk of hepatocellular carcinoma in chronic hepatitis B vs chronic hepatitis C after achievement of virologic response

It is unclear whether the achievement of virologic response modifies the risk of hepatocellular carcinoma (HCC) differently in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Our aim was to compare the risk of HCC between patients with CHB and CHC who achieved virological response. We analysed data from patients with CHB treated with entecavir (n=2000) or CHC treated with peg‐interferon and ribavirin (n=733) at a tertiary hospital from 2004 to 2011. Virological response was defined as serum HBV DNA<15 IU/mL at 1 year of treatment for CHB or the achievement of sustained virologic response for CHC. Virological response was achieved in 1520 patients with CHB (76.0%) and 475 patients with CHC (64.8%). During the median follow‐up period of 6 years, 228 patients with CHB (11.4%) and 59 patients with CHC (8.0%) developed HCC. Among patients with virological response, CHB was independently associated with a significantly higher incidence of HCC (hazard ratio, 2.17; 95% CI, 1.30‐3.63; P=.003) than CHC. Among patients without virological response, there were no differences in HCC incidence between the two cohorts (P=.52). In patients with cirrhosis at baseline, the incidence of HCC did not differ between the two cohorts even after achieving virological response (P>.99). In conclusion, patients with CHB treated with entecavir were associated with a higher risk of HCC compared to patients with CHC treated with peg‐interferon and ribavirin after achieving virological response. However, the risk of HCC did not differ between the two cohorts if the patients had cirrhosis at baseline, even if virological response was achieved.     

Prevention of hepatocellular carcinoma complicating chronic hepatitis C

Chronic hepatitis C virus (HCV) infection accounts for most cases of hepatocellular carcinoma (HCC) in Japan and is the second major cause in many other countries. Development of HCC takes a considerable time after onset of HCV infection, between 20–40 years in most cases, and usually develops after cirrhosis is established. Although only a minority of HCV infections reach this stage, the high prevalence of chronic HCV infection in many countries (1–3%) is such that HCC related to HCV infection poses a significant public health issue 20–50 years after the onset of HCV epidemics. Due to advances in testing, and accessibility of clean, disposable medical apparatus including syringes and needles, and particularly screening of donor blood for anti-HCV and by nucleic acid testing, new cases of HCV infection have decreased in most countries, except for continued transmission by injection drug users (IDU). A key difference between HBV and HCV infection is that HCV can be eradicated by effective antiviral treatment. Sustained eradication of HCV reverses hepatic fibrosis, thereby preventing progression to cirrhosis and risk of HCC. Further, it has been well demonstrated that interferon-based antiviral therapy suppresses development of HCC in high-risk patients, particularly when sustained viral response (SVR) is obtained. In summary, the two key approaches to prevent development of HCV-related HCC are primary prevention of HCV infection (adequate programs to screen donor blood, universal precautions to stop medical transmission of blood-borne viruses, curbing transmission by IDU) and potent antiviral therapy of chronic HCV infection.     

Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C

AIM:To study the potential association between hepatocellular carcinoma(HCC)in patients with chronic hepatitis C(CHC),cirrhosis and latent hepatitis B(LHB)infection,defined as the absence of detectable serum hepatitis B surface antigen(HBsAg)and the presence of hepatitis B core antibody(HBcAb).METHODS:This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody(HCV Ab)(+)and HBsAg(-)at Wayne State University between 1999 and 2008.From these,108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining(77)were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease.Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-)age,race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC.A subgroup of controls included 118matched patients with liver cirrhosis.χ2test and t test were used for data analysis.RESULTS:Seventy-seven percent of patients in all3 groups were African Americans.Patients with HCC had a significantly higher body mass index(P=0.03),a higher rate of co-infection with human immunodeficiency virus(HIV)(P=0.05)and a higher prevalence of alcohol abuse(P=0.03)than the controls.More patients with HCC had LHB than controls(78%vs39%,P=0.01).Sixty three percent of patients with HCC were both hepatitis B surface antigen(HBsAb)(-)and HBcAb(+)compared to 23%of controls(P<0.01).When compared to cirrhotic controls,the frequency of HBcAb(+)remained higher in patients with HCC(78%vs 45%,P=0.02).Patients with HCC were more likely to be both HBsAb(-)and HBcAb(+)than the cirrhotic controls(63%vs 28%,P=0.01).Although not statistically significant,100%of CHC and HIV coinfected patients with HCC(n=11)were HBcAb(+)when compared to controls(44%;n=9).CONCLUSION:These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.     

慢性乙型肝炎肝硬化患者发生肝细胞癌的危险因素分析

目的 探讨乙型肝炎肝硬化患者发生肝细胞癌(HCC)的危险因素. 方法 收集2009年1月至2014年9月在复旦大学附属中山医院就诊的来自上海及周边地区的汉族乙型肝炎肝硬化患者资料,将其分为肝硬化组和HCC组.收集患者病史、血清学、影像学及病理检查资料,比较两组间的一般情况及临床检测数据,用SPSS 19.0统计软件进行包括采用x2检验的单因素分析和logistic多因素回归分析的统计学分析.结果 共收集715例患者资料,其中肝硬化组281例,HCC组434例.单因素分析结果显示男性、年龄≥50岁,有肝癌家族史、饮酒史、脂肪肝、可检出HBV DNA、未得到有效的抗病毒治疗与乙型肝炎肝硬化患者发生HCC显著相关.多因素回归分析结果显示年龄≥50岁(P=0.005,OR=1.766)、饮酒史(P=0.002,OR=2.570)、肝癌家族史(P=0.014,OR=2.268)、脂肪肝(P=0.023,OR=3.390)、未得到有效的抗病毒治疗(P＜ 0.001,OR=5.389)是乙型肝炎肝硬化患者发生HCC的危险因素.达到持续病毒学抑制(SVS)的乙型肝炎肝硬化患者仍可能发生HCC,HBV感染家族史(P=0.014,OR=2.537)、肝癌家族史(P=0.037,OR=3.339)和脂肪肝(P=0.018,OR=11.646)与达到SVS的乙型肝炎肝硬化患者发生HCC显著相关.结论 乙型肝炎肝硬化患者并发HCC的独立危险因素包括年龄≥50岁、饮酒史、肝癌家族史、脂肪肝和未得到有效的抗病毒治疗.HBV感染家族史、肝癌家族史和脂肪肝是达到SVS的乙型肝炎肝硬化患者发生HCC的危险因素.     

Incidence of hepatocellular carcinoma in chronic hepatitis C after interferon therapy

BACKGROUND/AIMS: We investigated the rate of occurrence and the risk factors for hepatocellular carcinoma in chronic hepatitis C patients who received interferon therapy. METHODOLOGY: We followed 413 chronic hepatitis C patients for more than 6 years after interferon therapy and assessed the following patient characteristics: age, sex, platelet count, response to interferon, hepatitis C virus RNA level, hepatitis C virus genotype, liver histology, and changes in serum alanine aminotransferase levels. RESULTS: Hepatocellular carcinoma was found in 21 patients after interferon therapy. The factor most related to the occurrence of hepatocellular carcinoma was changes in serum alanine aminotransferase levels (univariate analysis, P < 0.0001; multivariate analysis, P = 0.0013), followed by age (univariate analysis, P = 0.0003; multivariate analysis, P = 0.0029). A significant difference was observed in the platelet count and response to interferon based on univariate analysis alone (P = 0.0096, P = 0.0241, respectively), however no significant differences were noted in the other factors. The course of serum alanine aminotransferase levels following interferon therapy rather than the eradication of hepatitis C virus was found to be the factor most profoundly involved in liver carcinogenesis. CONCLUSIONS: Even if interferon therapy fails to eradicate the hepatitis C virus, maintaining low serum alanine aminotransferase levels post-interferon therapy would reduce the risk of hepatocellular carcinoma in chronic hepatitis C.     

Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis

To elucidate the risk factors for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-related liver cirrhosis (LC), we examined 204 cirrhotic patients negative for hepatitis B surface antigen and positive for HCV antibodies. The independent influence of various clinical characteristics in these patients was analyzed by multiple logistic regression, and the risk factors for HCC were identified. Multiple logistic regression analysis identified and ranked the following four risk factors: male sex (P<0.001), habitual heavy drinking (P<0.005), hepatitis B virus antibody positivity (anti-HBs and/or anti-HBc,P<0.05), and age greater than 60 years (P<0.05). The odds ratio of HCC was 4.20 (95% confidence interval; CI, 1.80–9.78) in male patients, 3.27 (95% CI, 1.46–7.30) in habitual heavy drinkers, 2.01 (95% CI, 1.01–3.99) in patients positive for hepatitis B virus antibodies, and 2.06 (95% CI, 1.00–4.23) in patients older than 60 years. The cumulative occurrence rates of HCC after blood transfusion were significantly higher in habitual heavy drinkers (4.8%, 49.4%, and 74.7% at 10, 20, and 30 years, respectively) than in non-drinkers (0%, 21.0%, and 23.3% at 10, 20, and 30 years, respectively,P<0.0003). The mean interval for progression to LC after blood transfusion was significantly shorter in the habitual heavy drinkers than in the non-drinkers (22.4±4.4 years vs 28.4±3.9 years;P<0.0003). This multivariate analysis revealed that habitual heavy drinking and hepatitis B virus antibody positivity are significant risk factors for HCC in HCV-related liver cirrhosis. This work was presented in preliminary form at the annual meeting of the American Association for Study of Liver Diseases, New Orleans, May 16, 1994 and published as an abstract inGastroenterology 14: A875, 1994.     

Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis.

BACKGROUND AND AIMS: In the United States, hepatocellular carcinoma (HCC) is more common among Asians and African Americans than Caucasians, with chronic hepatitis C virus (HCV) infection accounting for up to half of the patients. Our study examined ethnicity as a potential risk factor for HCC among patients with chronic hepatitis C. METHODS: We conducted a case-control study of 464 patients with chronic hepatitis C and cirrhosis (207 cancer patients and 257 controls) using medical records and pathology records at 4 medical centers. We estimated odds ratios with 95% confidence intervals by using conditional logistic regression on case-control sets, matched within study centers and study period on sex and age groups (< or =45, 46-55, 56-65, >65 yr). To control for potential confounding caused by severity of cirrhosis and residual confounding caused by age, we also included Child-Turcotte-Pugh (CTP) scores and age (continuous variable) in all regression analyses. RESULTS: Compared with Caucasians, the cancer risk was increased significantly among Asians (adjusted odds ratio, 4.3; 95% confidence interval, 2.1-9.0 for men, and 4.6; 1.2-18.5 for women) and somewhat increased among African-American men (adjusted odds ratio, 2.4; 95% confidence interval, 0.9-6.3). CONCLUSIONS: This study suggests that, among patients with chronic hepatitis C and cirrhosis, liver cancer risk is increased 4-fold in Asians and may be doubled in African-American men, compared with Caucasians. These results need confirmation in larger studies from racially diverse populations, but, if confirmed, these results point to high-risk populations that should be targeted for screening and preventive efforts.     

Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis

AIM To investigate gender-specific liver estrogen receptor(ER) expression in normal subjects and patients with hepatitis C virus(HCV)-related cirrhosis and hepatocellular carcinoma(HCC).METHODS Liver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression ofinflammatory [activated NF-κB and IκB-kinase(IKK)] and oncogenic(cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman's correlation. RESULTS Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females(P 0.05). We observed significantly higher m RNA expression of ERα in HCV-related HCC liver tissues as compared to normals(P 0.05) and ERβ in livers of HCV-related cirrhosis and HCV-related HCC subjects(P 0.05). At the protein level, there was a significantly higher expression of nuclear ERα in livers of HCV-related HCC patients and nuclear ERβ in HCV-related cirrhosis patients as compared to normals(P 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF-κB and cyclin D1 in diseased livers(P 0.05). There was a positive correlation between the expression of nuclear ER subtypes and nuclear cyclin D1 and a negative correlation between cytoplasmic ER subtypes and cytoplasmic phosphorylated IKK in HCV-related HCC livers. These findings suggest that dysregulated expression of ER subtypes following chronic HCVinfection may contribute to the progression of HCVrelated cirrhosis to HCV-related HCC.CONCLUSION Gender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence genderrelated disparity in HCV-related pathogenesis.