We read with great interest the articles by Lai et al.1 and Veldt et al.2, which show an association between diabetes mellitus and hepatocellular carcinoma (HCC) for patients with chronic hepatitis C. Both of their results indicate that diabetes mellitus is not significantly associated with the development of HCC (P = 0.37 and P = 0.066, respectively) among patients with chronic hepatitis C. But Veldt et al. further performed a subgroup analysis on patients with Ishak fibrosis score 6 (n = 303), in which diabetes mellitus is significantly associated with the development of HCC (P = 0.0087).
We have two questions concerning the results. First, we know that the metabolic pathway and the carcinogenic effect of hepatitis C virus (HCV) are two potential ways for the progression of HCC among patients with chronic hepatitis C and diabetes mellitus. The prospective study by Lai et al.1 demonstrates that the effect of diabetes on the risk of developing HCC plays a more important role in those who are HCV negative than in those who are HCV positive. Only patients with diabetes who are HCV negative have a risk of developing HCC. It seems the increased risk is not explained by the presence of hepatitis C infection. We wonder whether this result could conclude further that the metabolic pathway is more important than the effect of HCV infection on hepatocarcinogenesis. Perhaps HCV has a carcinogenic effect in part by its role in metabolic abnormality. Second, Veldt et al.2 found that among enrolled patients with chronic hepatitis C and advanced fibrosis or cirrhosis (Ishak score 4 to 6), 11 patients (13%) with diabetes developed HCC. However, these patients all had an Ishak fibrosis score of 6. None of the patients with diabetes who had an Ishak fibrosis score of 4 or 5 developed HCC. We think presence of the same Ishak fibrosis score does not indicate a similar severity of hepatic damage. Levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase significantly express the severity of liver damage. In fact, the prevalence of subjects with abnormal levels of enzymes increases as the liver disease advances. Thus, these parameters also should be evaluated for the analysis. In addition, serum alpha-fetoprotein level at entry is suggested as a risk factor for HCC, whereas this is not confirmed in this study.
At present, it is difficult to sort out possible interactions between diabetes and hepatitis C in causing HCC. The relationship between diabetes mellitus, chronic hepatitis C, and HCC should be evaluated further, with a focus on risk factors such as the levels of elevated liver enzymes and alpha-fetoprotein.