Impact of chronic hepatitis B and hepatitis C on adverse hepatic fibrosis in hepatocellular carcinoma related to betel quid chewing.

The pathogenesis of hepatocellular carcinoma (HCC) related to habitual betel quid (BQ) chewing is unclear. Risk of HCCis increased with adverse hepatic fibrosis. This study aimed to assess the impact of chronic viral hepatitis on adverse hepatic fibrosis in HCC related to BQ chewing. This hospital-based case-control study enrolled 200 pairs of age- and gender-matched patients with HCC and unrelated healthy controls. Serologic hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV), α-fetoprotein (AFP), and surrogate markers for significant hepatic fibrosis were measured. Information on substance-use habits was obtained with a questionnaire. By analysis of surrogate markers for hepatic fibrosis, the prevalence of significant hepatic fibrosis in patients chewing BQ was between 45.8% and 91.7%, whereas that for patients without BQ chewing was between 18.4% and 57.9%. The difference was significant (P <0.05 for each surrogate marker). Multivariate analysis indicated that cirrhosis with Child-Pugh C (odds ratio (OR) = 3.28; 95% confidence interval (CI), 1.29- 8.37), thrombocytopenia (OR = 3.92, 95% CI, 1.77-8.68), AFP >400 mg/L (OR = 2.21, 95% CI, 1.05-4.66) and male gender (OR = 4.06, 95% CI, 1.29-12.77) were independent factors associated with habitual BQ chewing. In conclusion, adverse hepatic fibrosis and severe liver damage play important roles in the pathogenesis of BQ- related HCC, which could be aggravated by chronic hepatitis B and hepatitis C. BQ-cessation programs and prevention of chronic HBV/HCV infection are needed to prevent HCC related to BQ chewing.

Independent and additive interaction between tumor necrosis factor ß +252 polymorphisms and chronic hepatitis B and C virus infection on risk and prognosis of hepatocellular carcinoma: a case-control study.

To assess the contribution of tumor necrosis factor (TNF)ß +252 polymorphisms to risk and prognosis of hepatocellular carcinoma (HCC), we enrolled 150 pairs of sex- and age-matched patients with HCC, patients with cirrhosis alone, and unrelated healthy controls. TNFß +252 genotypes were determined by polymerase chain reaction with restriction fragment length polymorphism. Multivariate analysis indicated that TNFß G/G genotype [odds ratio (OR), 3.64; 95%CI, 1.49-8.91], hepatitis B surface antigen (OR, 16.38; 95%CI, 8.30-32.33), and antibodies to hepatitis C virus (HCV) (OR, 39.11; 95%CI, 14.83-103.14) were independent risk factors for HCC. There was an additive interaction between TNFß G/G genotype and chronic hepatitis B virus (HBV)/HCV infection (synergy index=1.15). Multivariate analysis indicated that factors associated with TNFß G/G genotype included cirrhosis with Child-Pugh C (OR, 4.06; 95%CI, 1.34-12.29), thrombocytopenia (OR, 6.55; 95%CI, 1.46-29.43), and higher serum α-fetoprotein concentration (OR, 2.53; 95%CI, 1.14-5.62). Patients with TNFß G/G genotype had poor cumulative survival (p=0.005). Cox proportional hazard model indicated that TNFß G/G genotype was a biomarker for poor HCC survival (hazard ratio, 1.70; 95%CI, 1.07-2.69). In conclusion, there are independent and additive effects between TNFß G/G genotype and chronic HBV/HCV infection on risk for HCC. It is a biomarker for poor HCC survival. Carriage of this genotype correlates with disease severity and advanced hepatic fibrosis, which may contribute to a higher risk and poor survival of HCC. Chronic HBV/HCV infected subjects with this genotype should receive more intensive surveillance for early detection of HCC.

Urinary transforming growth factor α and serum α-fetoprotein as tumor markers of hepatocellular carcinoma.

This case-control study aimed to evaluate the diagnostic application of urinary transforming growth factor (TGF) α and serum α-fetoprotein (AFP) in hepatocellular carcinoma (HCC). TGFα and AFP were determined in 90 pairs of age- and gender-matched patients with cirrhotic HCC and patients with cirrhosis alone and 60 healthy controls. The results indicated that TGFα and AFP levels in patients with HCC were higher than in those with cirrhosis alone or healthy controls (each P = 0.0001). Multivariate analysis indicated that TGFα (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.05-1.16) and AFP (OR 1.03, 95% CI 1.01-1.06) were closely associated, in a dose-related fashion, with the development of HCC. The optimal cutoff values, determined with the receiver operating characteristic (ROC) curves, were 29 µg/g creatinine for TGFα and 100 ng/ml for AFP, respectively. The areas under ROC curve (AUC) were 0.74 for TGFα and 0.78 for AFP, respectively. Both biomarkers showed the same sensitivity (52.2%), high specificity, high positive predictive value, and moderate positive likelihood ratio. Determination of both markers in parallel significantly increased the AUC (0.91) and diagnostic accuracy (92.2%), with a high sensitivity (86.7 %), specificity (97.8%), positive predictive value (PPV; 97.5%), and moderate positive likelihood ratio (PLR; 39.4). Among 31 cirrhotic HCC with AFP ≤ 20 ng/ml, the calculated AUC for TGFα was 0.79, with a sensitivity of 64.5%, specificity of 96.7%, PPV of 87.0%, and PLR of 19.5. In conclusion, urinary TGFα and serum AFP are complementary tumor markers for detection of HCC with low AFP production.

Independent and additive interactive effects among tumor necrosis factor-alpha polymorphisms, substance use habits, and chronic hepatitis B and hepatitis C virus infection on risk for hepatocellular carcinoma.

We conducted a case-control study to assess the roles of tumor necrosis factor (TNF)-alpha polymorphisms, substance use habits, and chronic hepatitis B virus (HBV)/hepatitis C virus (HCV) infection on the risk for hepatocellular carcinoma (HCC). We enrolled 200 pairs of sex- and age-matched patients with HCC and unrelated healthy controls. TNF-alpha polymorphisms were detected with polymerase chain reaction and direct sequencing. Serum hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCV) were detected. We used a structured questionnaire to obtain information about substance use habits.Multivariate analysis indicated that TNF308.2 allele (odds ratio [OR], 3.23; p = 0.011), habitual betel quid chewing (OR, 3.70; p = 0.011), HBsAg (OR, 23.62; p = 0.0001), and anti-HCV (OR, 38.73; p = 0.0001) were independent risk factors for HCC. Having at least 2 substance use habits was associated with risk for HCC. The more substance use habits, the higher the OR for HCC (p(for trend) = 0.0001). There were additive interactions among TNF308.2 allele, substance use habits, and chronic HBV/HCV infection. Multivariate analysis indicated that TNF308.2 allele (p = 0.001), cigarette smoking (p = 0.0001), and alcohol drinking (p = 0.0001) were independent risk factors for habitual betel quid chewing. Moreover, patients harboring the TNF308.2 allele and/or those with habits of substance use had low serum albumin concentration and platelet count (each p = 0.0001). In conclusion, there are independent and additive interactive effects among the TNF308.2 allele, substance use habits, and chronic HBV/HCV infection on the risk for HCC. Substance use habits or carrying the TNF308.2 allele correlates with disease severity and hepatic fibrosis, which may contribute to higher risks for HCC.

Heat shock protein A1B 1267 polymorphism is highly associated with risk and prognosis of hepatocellular carcinoma: a case-control study.

We conducted a case-control study to elucidate the role of heat shock protein A1B (HSPA1B) 1267 single nucleotide polymorphism (SNP) on the risk and prognosis of hepatocellular carcinoma (HCC). Subjects enrolled included 150 pairs of sex- and age-matched HCC patients and unrelated controls. Genomic DNA was typed for HSPA1B1267 SNP using polymerase chain reaction with restriction fragment length polymorphism. The frequencies of the HSPA1B P2/P2 genotype and the HSPA1B P2 allele in HCC patients were higher than in unrelated controls (each p = 0.0001). Multivariate analysis identified the following independent risk factors for HCC: HSPA1B P1/P2 genotype (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.07-5.11), HSPA1B P2/P2 genotype (OR, 12.06; 95% CI, 4.43-32.79), hepatitis B surface antigen (HBsAg) (OR, 25.95; 95% CI, 11.88-56.68), and antibodies to hepatitis C virus (anti-HCV) (OR, 70.43; 95% CI, 21.89-226.64). There was an additive interaction between HSPA1B P2 allele carriers and the presence of either HBsAg (synergy index = 2.48) or anti-HCV (synergy index = 1.52). However, as HSPA1B1267 SNP is a silent mutation, it is a surrogate genetic marker for increasing risk of HCC. Our findings indicate that patients with chronic hepatitis B/hepatitis C virus infection who harbor this SNP represent a high-risk group for HCC. They should receive more intensive surveillance for early detection of HCC. Moreover, patients with the HSPA1B P2 allele had significantly longer survival (p = 0.002).The limitations of this study include the unknown functional significance of the HSPA1B1267 polymorphism, the relatively small sample size, the fact that this was not a prospective study of cases and controls, and the questionable generalizability of the findings given the specific ethnic composition of the population studied.

Tumor necrosis factor-alpha 308.2 polymorphism is associated with advanced hepatic fibrosis and higher risk for hepatocellular carcinoma.

BACKGROUND/AIMS: Host genetic factor and hepatic fibrosis may predispose to risk for hepatocellular carcinoma (HCC). This study aimed to assess the association between tumor necrosis factor (TNF) alpha polymorphism and hepatic fibrosis, and risk for HCC. METHODS: One hundred eight pairs of gender-matched and age-matched patients with HCC and unrelated healthy controls were genotyped for TNF308.2 and TNF238.2 alleles with polymerase chain reaction and direct sequencing. RESULTS: The frequency of TNF308.1/TNF308.2 genotype in cases was higher than that in controls [odds ratio (OR) = 4.37]. Multivariate analysis indicated that TNF308.2 allele (OR = 3.23), hepatitis B surface antigen (OR = 17.17), and antibodies to hepatitis C virus (OR = 45.52) were independent risk factors for HCC. Surrogate markers for significant fibrosis implied that cases with the TNF308.2 allele have more advanced liver fibrosis. Moreover, multivariate analysis indicated that cirrhosis with Child-Pugh grade C, low serum albumin, and low platelet count were independent risk factors for carrying the TNF308.2 allele. CONCLUSIONS: TNF308.2 allele carriage and chronic hepatitis B virus/hepatitis C virus infection are independent risk factors for HCC. Carriage of the TNF308.2 allele correlates with disease severity and hepatic fibrosis, which may contribute to a higher risk for HCC.

Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis.

This case-control study aimed to assess the independent and interactive role of habitual betel quid chewing and known risk factors for hepatocellular carcinoma (HCC). Subjects enrolled included 210 pairs of sex- and age-matched cirrhotic patients with HCC, patients with cirrhosis alone, and healthy controls. Information on risk factors was obtained through serologic examination of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), and a standardized personal interview with a structured questionnaire. Multivariate analysis indicated that betel quid chewing (odds ratio [OR], 5.81; 95% confidence interval [CI], 2.26-14.94); HBsAg (OR, 37.98; 95% CI, 19.65-73.42); and anti-HCV (OR, 47.23; 95% CI, 18.86-118.25) were independent risk factors for HCC when HCC patients were compared with healthy controls. Using patients with cirrhosis alone as a reference group, multivariate analysis indicated that only betel quid chewing (OR, 1.69; 95% CI, 1.04-2.76) and HBsAg (OR, 1.54; 95% CI, l.01-2.37) were independent risk factors for HCC. There was an additive interaction between betel quid chewing and the presence of either HBsAg (synergy index, 5.22) or anti-HCV (synergy index, 1.35). Moreover, a higher risk of HCC was associated with a longer duration of betel quid chewing and a larger amount of betel quid consumed (each p(for trend) < 0.0001). In conclusion, betel quid chewing is an independent risk factor for cirrhotic HCC. There is an additive interaction between betel quid chewing and chronic hepatitis B and/or hepatitis C virus infection.

Habitual betel quid chewing as a risk factor for cirrhosis: a case-control study.

Betel quid chewing, part of traditional Taiwanese culture, is common in 10%-20% of the human population worldwide. In this case-control study we assessed the independent and interactive role of habitual betel quid chewing and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on risk of cirrhosis. Subjects enrolled included 210 pairs of sex- and age-matched cirrhotic patients and healthy controls. Information on risk factors was obtained through serologic examination of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), and a standardized personal interview with a structured questionnaire. Univariate analysis indicated that betel quid chewing, HBsAg+, anti-HCV+, alcohol drinking, and smoking are significant risk factors for cirrhosis. Multivariate analysis indicated that betel quid chewing (odds ratio [OR], 3.56), HBsAg (OR 20.37), and anti-HCV (OR 31.43) are independent risk factors for cirrhosis. Most betel quid chewers habitually drink alcohol. Although our analysis indicates that betel quid chewing acts independently from alcohol as a risk factor for cirrhosis, the confounding effect of alcohol cannot be excluded entirely by our study. There was an additive effect of the interaction between betel quid chewing and the presence of either HBsAg or anti-HCV. Moreover, a higher risk of cirrhosis was associated with longer duration of betel quid chewing and greater amount of betel quid consumed (each p for trend <0.0001). In conclusion, betel quid chewing appears to be an independent risk factor for cirrhosis. There is an additive interaction between betel quid chewing and chronic HBV/HCV infection.