Juei-Hsiung Tsai

Effect of hepatitis C and B virus infection on risk of hepatocellular carcinoma : a prospective study

To assess whether there is an additive effect between chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on the development of hepatocellular carcinoma (HCC), 400 consecutive cirrhotic patients were followed prospectively with periodic abdominal ultrasound examination and measurement of serum alpha-fetoprotein (AFP) level every 4 months. During a follow-up of 1185 person-years, 80 (20%) patients developed HCC, with an annual incidence of 6.8%. The annual incidence was 2.0% in patients negative for hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCV), 6.6% in patients with HBsAg alone, 7.0% in patients with anti-HCV alone and 13.3% in patients co-infected with HBV and HCV. There was a positive linear trend in the annual incidence of HCC among patients without either marker, patients with single viral infection and patients with dual viral infection (P[for trend] < 0.0001). Coxs proportional hazard model indicated that HCV/HBV co-infection [hazard ratio (HR), 6.41; 95% confidence interval (CI), 1.80-22.80], anti-HCV alone (HR, 3.74; 95% CI, 1.07-13.07) and HBsAg alone (HR, 4.06; 95% CI, 1.23-13.34) were independently risk factors of HCC. In conclusion, there is an additive and independent effect modification of HCV and HBV infection on HCC development.

Elevated urinary transforming growth factor-beta1 level as a tumour marker and predictor of poor survival in cirrhotic hepatocellular carcinoma.

To assess the clinical relevance of transforming growth factor-beta1 (TGF-beta1) in hepatocellular carcinoma (HCC), urinary TGF-beta1 and serum alpha-fetoprotein (AFP) were determined in 94 patients with cirrhotic HCC, 94 age- and sex-matched patients with cirrhosis alone and 50 healthy adults. TGF-beta1 level in HCC was higher than in cirrhosis alone or in healthy controls (each P = 0.0001). There is an inverse correlation between TGF-beta1 and AFP levels (r = -0.292, P = 0.004). Significantly higher TGF-beta1 level was found in HCC patients with worsening Child-Pugh stages, diffuse HCC, tumour size > 3 cm, multilobular tumour and AFP < or = 20 ng ml(-1). TGF-beta1 level decreased after complete treatment with transcatheter arterial chemoembolization (P = 0.0001). The median survival in HCC patients with raised TGF-beta1 was shorter than those with normal TGF-beta1 (P = 0.018). Multivariate analysis indicated that TGF-beta1 and AFP were significantly correlated with the presence of HCC. In addition, TGF-beta1 could be used as a diagnostic marker for HCC, particularly in tumours with low AFP production. In conclusion, elevated urinary TGF-beta1 level is a tumour marker and predictor of poor survival for cirrhotic HCC.

Independent and additive effect modification of hepatitis C and B viruses infection on the development of chronic hepatitis

BACKGROUND/AIMSnThis study aimed to assess the effects and interaction between hepatitis B virus and hepatitis C virus infection on the development of chronic hepatitis.nnnMETHODSnAnti-HCV and HBsAg were detected in 125 histology-proven chronic hepatitis and 250 sex-matched and age-matched healthy controls.nnnRESULTSnThe prevalences of anti-HCV (24.8%) and HBsAg (68.0%) in patients were higher than in controls (2.4% and 18.0%, respectively; each p < 0.0001). Univariate analysis showed that anti-HCV and HBsAg were strongly associated with the development of chronic hepatitis. Calculation of synergy index and Mantel extension test for trend indicated that there was additive effect modification between HCV and HBV. Multivariate analysis indicated that anti-HCV (odds ratio, 46.1; 95% confidence interval, 9.1-233.2) and HBsAg (odds ratio, 25.8; 95% confidence interval (9.3-67.2) were independent risk factors of chronic hepatitis. The population-attributable risk was estimated as 15.6% for anti-HCV alone, 52.4% for HBsAg alone and 6.8% for both anti-HCV and HBsAg. The frequency of chronic active hepatitis in patients with anti-HCV alone (100%) was higher than in patients with HBsAg alone (75%, p < 0.001).nnnCONCLUSIONSnHCV and HBV infections are risk factors of chronic hepatitis. They act independently and probably with additive effect modification.

Additive effect modification of hepatitis B surface antigen and e antigen on the development of hepatocellular carcinoma

To assess the role of hepatitis B e antigen (HBeAg) and its interaction with hepatitis B surface antigen (HBsAg) on the development of hepatocellular carcinoma (HCC), this case-control study included 361 age- and sex-matched pairs of patients with histologically proven HCC and healthy control subjects. HBsAg, HBeAg and antibody to HBeAg (anti-HBe) were detected by radioimmunoassay. Antibodies to hepatitis C virus (anti-HCV) were detected by second-generation enzyme immunoassay. The prevalences of HBeAg (20.2%), HBsAg (80.3%) and anti-HCV (29.5%) in cases were higher than in controls (1.9%, 20.7%, and 2.7% respectively; each P < 0.0001). Using patients negative for HBsAg, HBeAg and anti-HBe as a referent group, univariate analysis indicated that HBsAg alone or HBsAg and HBeAg were risk factors for HCC (P for trend < 0.0001). Calculation of incremental odds ratio indicated that there was additive interaction between HBsAg and HBeAg. Multivariate analysis indicated that HCC development was strongly associated with the presence of HBeAg (odds ratio, 8.1; 95% confidence interval, 2.4-27.1), HBsAg (odds ratio, 68.4; 95% confidence interval, 20.5-227.8) and anti-HCV (odds ratio, 59.3; 95% confidence interval, 13.6-258.4). In conclusion, HBsAg, HBeAg and anti-HCV are independent risk factors for HCC. There is additive and independent effect modification between HBsAg and HBeAg on the development of HCC.

Frequency of raised alpha-fetoprotein level among Chinese patients with hepatocellular carcinoma related to hepatitis B and C.

Antibody to hepatitis C virus (anti-HCV) was found to be an independent risk factor for hepatocellular carcinoma and raised serum alpha-fetoprotein (AFP) level. In addition, the frequency of raised AFP in patients with anti-HCV was higher than in those without (91.5% vs 65.2%, P = 0.0001).

Clinical relevance of transforming growth factor-beta 1 in the urine of patients with hepatocellular carcinoma.

To assess the clinical relevance of transforming growth factor-beta 1 (TGF-beta 1) in the urine of patients with hepatocellular carcinoma (HCC), TGF-beta 1 was measured, by radioimmunoassay, in 140 patients with HCC, 50 cirrhotic patients, 30 patients with chronic active hepatitis, and 50 healthy controls. The results indicate that there were significantly increased urinary TGF-beta 1 levels in patients with HCC. Raised TGF-beta 1 levels were associated, in a dose-related fashion, with increased risk for development of HCC (odds ratio, 1.05, 95% confidence interval, 1.03-1.07). HCC patients with raised TGF-beta 1 levels had shorter survival than those with normal TGF-beta 1 levels (p = 0.038). TGF-beta 1 levels decreased after successful anticancer therapy (p < 0.0001). There was an inverse correlation between TGF-beta 1 and serum alpha-fetoprotein (AFP) (r = -0.199, p < 0.04). Receiver operating characteristics (ROC) curve analysis indicated that parallel determination of TGF-beta 1 and AFP significantly increased the sensitivity and diagnostic accuracy, with a high specificity. In conclusion, raised urinary TGF-beta 1 was associated with HCC development. It is a predictor of poor prognosis, and a tumor marker for diagnosis and therapeutic follow-up of HCC.

Clinical evaluation of serum alpha-fetoprotein and circulating immune complexes as tumour markers of hepatocellular carcinoma.

To evaluate the diagnostic application of serum alpha-fetoprotein (AFP) and circulating immune complexes (CICs), AFP, 3% polyethylene glycol (PEG)-CICs, 4% PEG-CICs, and C1q-CICs were determined in 101 patients with cirrhosis alone, 101 sex-matched and age-matched cirrhotic patients with hepatocellular carcinoma (HCC) and 54 healthy controls. Multivariate analysis indicated that AFP (odds ratio 1.014; 95% confidence interval 1.004-1.024) and 3% PEG-CICs (odds ratio 1.011; 95% confidence interval 1.005-1.017) are associated, in a dose-related fashion, with an increased risk for HCC. A receiver operative characteristic (ROC) curve was used to determine the optimal cut-off values of AFP (120 ng ml-1) and 3% PEG-CICs (310 micrograms aggregated IgG equivalent ml-1). The area under ROC curve was 0.875 for AFP and 0.812 for 3% PEG-CIC. Both AFP and 3% PEG-CICs show a high specificity (100%) and positive likelihood ratio. The sensitivity was 65.3% for 3% PEG-CICs and 67.3% for AFP. Determination of both markers in parallel significantly increase the diagnostic accuracy (92.1%) and sensitivity (84%), with a high specificity (100%) and positive likelihood ratio (> 84). In conclusion, both 3% PEG-CICs and AFP are independent risk factors of HCC, and may be used as complementary tumour markers to discriminate HCC from cirrhosis. Determination of 3% PEG-CICs should be performed in cirrhotics negative for AFP to improve detection of HCC.

Increased IgM-containing circulating immune complexes in patients co-infected with hepatitis C and hepatitis B.

To assess the role of circulating immune complexes (CIC) in chronic hepatitis C virus (HCV) infection, the relative frequency of CIC was determined in 60 patients with chronic hepatitis C alone, 19 patients co-infected with hepatitis B and C, 15 asymptomatic HCV carriers, and 54 healthy controls. Levels of CIC were determined with immunoglobulin-specific C1q-binding and conglutinin (K)-binding immune complex assays. Although there was no statistical difference in the levels of each type of CIC between asymptomatic HCV carriers and healthy controls, elevated levels of CIC containing IgM and IgG were common in patients with chronic HCV infection. Compared to patients with hepatitis C alone, patients co-infected with hepatitis B and C have a higher frequency of abnormal IgM-containing CIC and significantly higher levels of IgM-containing CIC. CIC levels in patients with chronic active hepatitis were significantly higher than those in patients with chronic lobular hepatitis or chronic persistent hepatitis. In conclusion, although CIC containing IgM and IgG were common in patients with chronic hepatitis C, abnormal IgM-containing CIC are the major types of CIC in patients co-infected with hepatitis B and C. An immune-mediated mechanism may play a role in the pathogenesis of chronic hepatitis C.

Sex differences in relation to serum hepatitis B e antigen and alanine aminotransferase levels among asymptomatic hepatitis B surface antigen carriers

Abstract: This study aimed to investigate sex differences in relation to hepatitis B e antigen (HBeAg) and serum alanine aminotransferase (ALT) levels in chronic asymptomatic hepatitis B virus (HBV) infection. HBeAg and ALT level were determined in 636 asymptomatic hepatitis B surface antigen carriers. There was no significant sex differences in the age-adjusted prevalence of HBeAg. Abnormal ALT level (>45 IU/l) was more frequent in carriers with HBeAg (17.5% vs 7.6%; P = 0.001). Multivariate analysis indicated that male sex (odds ratio, 2.0; 95% confidence interval, 1.1–3.6) and HBeAg (odds ratio, 2.6; 95% confidence interval, 1.6–4.3) were independent risk factors for abnormal ALT levels. Male sex and HBeAg-positivity are independent risk factors for abnormal ALT activity in chronic HBV infection. This observation may be related to sex differences in chronic HBV infection.

Elevation of Circulating Immune Complexes and Its Relationship to Alpha-Fetoprotein Levels in Patients with Hepatitis B Surface Antigen-Positive Hepatocellular Carcinoma

In an attempt to evaluate the relationship between circulating immune complexes (CIC) and alpha-fetoprotein (AFP), CIC and AFP were detected in 93 hepatitis B surface antigen-positive (HBsAg+) patients with hepatocellular carcinoma (HCC) and 54 healthy controls. The median level of 3% PEG (polyethylene glycol)-CIC and Clq-CIC were higher in patients than in controls (p less than 0.001). In patients with HCC, the prevalence of elevated 3% PEG-CIC, Clq-CIC, and AFT was 27.9%, 55.9%, and 77.4%, respectively. There was association between AFP and 3% PEG-CIC positivity (p less than 0.01). The median level of 3% PEG-CIC and Clq-CIC increased as AFP levels elevated (p less than 0.05), but decreased as AFP exceeded 1599 ng/ml (p less than 0.05). For adjusting the effect of impaired liver function on the level of CIC, multivariate analysis with stepwise logistic regression revealed that 3% PEG-CIC was associated, in a dose-related fashion, with an increased risk for developing HCC (odds ratio = 1.003, p less than 0.001). These results imply that elevation of 3% PEG-CIC may be related to tumor mass. Additionally, 3% PEG-CIC is a useful marker to monitor therapy with transcatheter arterial embolization in patients with HBsAg+ HCC.