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Hepatitis C virus in chronic liver disease and hepatocellular carcinoma in Taiwan
1Hepatitis Research Center, National Taiwan University Hospital, Department of Internal Medicine, National Taiwan University College of Medicine, Taipel, Taiwan.
Insights
Hepatitis B and C are major causes of liver disease and cancer in Taiwan. Dual infections do not accelerate cancer, but HBV may play a role in non-cirrhotic liver cancer.
Area of Science:
- Hepatology
- Virology
- Oncology
Background:
- Hepatitis B virus (HBV) is the primary cause of chronic liver disease and hepatocellular carcinoma (HCC) in Taiwan, responsible for 80-90% of cases.
- Hepatitis C virus (HCV) is the second most common cause, with high prevalence of antibody to HCV (anti-HCV) and viremia in HBsAg-negative patients.
- Horizontal transmission is the major route for HCV infection in Taiwan, with blood transfusion previously being a significant factor.
Purpose of the Study:
- To investigate the epidemiology and clinical significance of HBV and HCV infections in Taiwan.
- To determine the role of viral genotypes and viremia levels in HCV infection.
- To assess the incidence of HCC in patients with HBV, HCV, or dual infections.
Main Methods:
- Analysis of anti-HCV prevalence and HCV-RNA levels using competitive polymerase chain reaction.
- Sequencing of Taiwanese HCV isolates and comparison with international strains.
- Prospective follow-up of cirrhotic patients (HBV+, anti-HCV+, both, or neither) for HCC development.
Main Results:
- The predominant HCV genotype in Taiwan is type II/lb, associated with higher viremia levels.
- Mixed HCV genotype infections correlate with acute exacerbations of chronic hepatitis C.
- HCC incidence was similar across HBV, HCV, and dual-infected cirrhotic groups; dual infection did not accelerate HCC.
- HBV DNA was detected in 50% of non-cirrhotic HCC patients who were negative for HBsAg and anti-HCV, suggesting a role for HBV.
Conclusions:
- Both HBV and HCV contribute significantly to liver disease and HCC in Taiwan.
- HCV genotype influences viremia levels, and mixed infections can trigger hepatitis flares.
- Cirrhosis, regardless of viral etiology (HBV or HCV), carries a high risk of HCC development; HBV may contribute to HCC in non-cirrhotic patients.
Abstract:
Hepatitis B virus (HBV) has long been known to be the major etiologic factor of chronic liver diseases and hepatocellular carcinoma (HCC), and in Taiwan 80-90% of chronic liver diseases and HCC are caused by HBV. Assays for antibody to hepatitis C virus (HCV) and to detect its viral genome (HCV-RNA) have revealed HCV as the next most common cause of these diseases in Taiwan. The prevalence of antibody to HCV (anti-HCV) in hepatitis B surface antigen (HBsAg)-negative patients is around 70-80%, and most of the patients are viremic. Anti-HCV is found in 0.5-1.0% of healthy adults. The epidemiology of HCV infection in Taiwan is similar to other areas of the world, with horizontal transmission as the major route of infection. Blood transfusion was an important route of transmission, accounting for 30-40% of chronic HCV infection. After screening for anti-HCV in blood donors was instituted, this infection route was effectively controlled. The nucleotide sequences of a Taiwanese isolate of HCV are similar to Japanese isolates (homology of > 90%) and less similar to the prototype U.S. isolate (78% homology). The predominant genotype is type II/lb, being detected in 66-71% of patients with chronic hepatitis C and in 83% of those with cirrhosis or HCC. Analysis of serum HCV cDNA levels by competitive polymerase chain reaction showed that the levels ranged from 10(1) to 10(7) copies/ml and did not correlate with the gender of the patients, past blood transfusion, serum aminotransferase activities, or histologic severity. However, the serum HCV levels were higher in patients with genotype II/lb than those with type III/2a or type IV/2b (p < 0.005), indicating genotype as an important determinant of levels of HCV viremia. Mixed infections of multiple genotypes of HCV may contribute to the acute exacerbations of chronic hepatitis C; among 20 patients with exacerbations, 11 (55%) had evidence indicating the emergence of a different predominant HCV genotype; among 26 without exacerbations, this was found in only 2 (8%) (p < 0.005). The incidence of HCC was studied by prospective follow-up of patients with cirrhosis by regular hepatic ultrasound examinations and serum alpha-fetoprotein surveillance in the following four groups: i) HBsAg-positive, 300 patients; ii) anti-HCV positive, 151 patients; iii) both positive, 144 patients; and iv) both negative, 62 patients. Each year, 3-5% developed HCC, and the difference in incidence between the four groups was not statistically significant. The mean age when HCC was detected was 56 +/- 10, 63 +/- 9, 55 +/- 11 and 60 +/- 14 years in each group, respectively. The results indicate a high incidence of HCC in cirrhotic patients in Taiwan, whether the cirrhosis was related to HBV or HCV; dual infections of both viruses did not accelerate the occurrence of HCC. Although most anti-HCV-positive patients with HCCs had cirrhosis, HCC did occur in some patients without cirrhosis. Studies of these two groups of HBsAg-negative, anti-HCV-positive HCC patients revealed less frequent detection of HCV-RNA in serum and lower titers of HCV RNA in HCC without cirrhosis. In fact, 10/20 (50%) non-cirrhotic HCC patients were actually positive for serum HBV DNA by PCR, indicating the possible role of HBV in the etiology of HCC in these patients.