It is known that patients with chronic liver disease have a high prevalence of diabetes mellitus and diabetics have an increased prevalence of liver cirrhosis¹⁾. Recent epidemiological data suggested that hepatitis C virus (HCV) infection may contribute to the development of diabetes. It has been reported that patients with chronic HCV infection were more likely to be diabetic compared to those with liver diseases of other etiologies^2,3). In some reports from western countries, the prevalence of HCV infection in diabetics was higher than expected in the general population^4,5). However, others reported negative association between HCV infection and diabetes⁶⁾. HCV infection has been associated with a variety of extrahepatic disorders, in which either immunological or direct cytopathic mechanism is likely to play a role in its pathogenesis. It remains to be determined whether HCV infection predisposes to the development of diabetes. Unlike western countries where HCV infection is a major cause of chronic liver disease, hepatitis B virus (HBV) infection is a leading cause of chronic liver disease in Korea. Additionally, clinical characteristics of Korean diabetics are different from those of western diabetics⁷⁾.

To establish a potential relationship between hepatitis viral infection and diabetes, we performed two studies in Koreans. First, a prospective cross-sectional study was done to determine the prevalence of diabetes in patients with chronic viral hepatitis or liver cirrhosis. Second, a seroprevalence study of anti-HCV and HBV surface antigen (HBsAg) was done to determine the prevalence of HBV and HCV infection in Korean diabetics.

Disorders in carbohydrate metabolism and impaired glucose tolerance were observed in patients with cirrhosis. Hyperinsulinemia and insulin resistance has been observed in cirrhotic patients who developed diabetes. In recent epidemiological studies, the association between diabetes and HCV infection has been suggested. HCV infection is related to a variety of extrahepatic manifestations such as mixed cryoglobulinemia and membranous proliferative glomeruone-phritis. Recently, hyperglycemia is suggested to be one of the extrahepatic manifestations attributed to HCV infection.

The prevalence of HCV infection in the Korean population is known as 1.3–1.6%^8,9) and the etiologic proportion of HCV in chronic liver disease is only 20–30%⁸⁾. Korea is one of the endemic area of HBV infection and HBV is a common cause of chronic liver disease. The prevalence of HBV infection is 5–7% in the general population^10,11). In a study, the prevalence of diabetes and impaired glucose tolerance in the adult Korean population was 7.2% and 8.9%, respectively¹²⁾. The prevalence is less than 1.0% in subjects less than 40 years of age and increases thereafter¹²⁾.

In our study, the prevalence of diabetes in patients with chronic viral hepatitis was 12.9%, which seems to be higher than that in the general population¹²⁾. The prevalence of diabetes in cirrhotics was 19.4%. However, the prevalence of diabetes was not significantly different between chronic hepatitis and cirrhosis groups. Additionally, univariate analysis revealed that cirrhosis was not an independent risk factor for diabetes in our study. Cirrhosis is known to cause glucose intolerance and may have higher postprandial serum glucose concentration even though the fasting level is in the normal range. In our study, diabetes was diagnosed by the fasting serum glucose concentration, so the prevalence of diabetes in cirrhotics might be underestimated.

Diabetes was observed more frequently in HCV infected patients than in HBV infected patients (p<0.05). However, the distribution of age between the two groups was different. HCV infected group had a higher proportion of patients over the age 60. So, we stratified the age into three groups. In our analysis, significant difference of diabetes prevalence between HBV and HCV infected patients was present only in the age of 41–60 years. Under the age of 40, similarity of diabetic prevalence may be partially explained by the relatively low overall prevalence of diabetes in this age and the small number of enrolled patients. Over the age of 61, higher prevalence of diabetes with aging and chronicity of liver disease may confound our analysis. In support of our findings, Mason et al.⁵⁾ also reported the similar prevalence of diabetes between HCV and HBV infected chronic liver disease over the age of 61. Several cohort studies of chronic liver disease also showed that diabetes was observed in 24% to 26% of patients with HCV infection while it was detected in 9% to 13% of patients with HBV infection^3,5,13–15). However, a few reports disproved the association of HCV infection and diabetes^6,16).

In our chronic liver disease group, we excluded healthy HBV carriers, in whom HBV was not considered to affect the development of diabetes. Other variables associated with diabetes were systematically analyzed. Alcohol consumption was a risk factor for diabetes, while the degree of alcohol consumption was similar, irrespective of viral etiology. So, alcohol consumption might not contribute to the high prevalence of diabetes in patients with HCV infection. BMI was not a risk factor for diabetes in our study. That could be explained by the fact that obese patients (BMI over 30) were relatively rare. In Korea, obese people, whose BMI is over 30, is relatively rare, in general, and even in diabetics⁷⁾.

In our diabetes group, the seroprevalence of HBsAg was 4.5%, which is similar to that in the Korean population^10,11). However, the seroprevalence of anti-HCV was 2.1%, which seems to be higher than that in the Korean population (1.3–1.6%)^8,9). Our data rather suggest that the diabetic population is more likely to have HCV infection.

The mechanism by which HCV infection may have predisposed to diabetes was not established yet. Although there is no evidence, HCV may injure pancreatic islet cells directly, like coxsackievirus, cytomegalovirus and adenovirus. El-Zayadi et al.¹⁷⁾ reported that HCV seropositives were more prone to require insulin therapy, reflecting pancreatic beta cell destruction and insulin deficiency. However, in our study, random serum c peptide level was not different between HBsAg and anti-HCV positive diabetic group, which seems to be contradictory to the idea that HCV infection may involve pancreatic beta cells as an extrahepatic target. Cirrhotics with HCV infection and alcoholic cirrhotics have common histological features of increased hepatic fat and iron deposition. It has been suggested that hepatic fat deposition may contribute to the development of insulin resistance¹⁸⁾. Fasting plasma insulin levels from patients with HCV-related cirrhosis and diabetes were elevated, which was consistent with insulin resistance, but acute insulin response to glucose loading was blunted, suggesting the concomitant pancreatic beta cell dysfunction and insulin deficiency¹⁵⁾.

In conclusion, our study demonstrates an association between diabetes and chronic HCV infection. Age and alcohol consumption are additional risk factors for diabetes in patients with chronic liver disease.