Chronic hepatitis C and type 2 diabetes mellitus are common conditions. Around 160 million people worldwide are estimated to be chronically infected with hepatitis C virus (HCV). In the USA, HCV has surpassed HIV as the leading viral cause of mortality. Meanwhile, the incidence of diabetes has been increasing steadily. In Asia, 3–10% of the general adult population suffers from type 2 diabetes. It is therefore not surprising to find a large number of individuals suffering from both chronic hepatitis C and diabetes. Subsequent epidemiological studies, however, showed that the coexistence of the two conditions is more than coincidental. In this editorial, we will examine the association between HCV infection and diabetes, the effect of diabetes on the natural history of chronic hepatitis C, and the implications on antiviral treatment.
Association between HCV and diabetes
Hepatitis C virus-infected patients have consistently been shown to have increased prevalence and incidence of diabetes. In a meta-analysis of 34 studies, HCV infection was found to increase the risk of diabetes in both retrospective (adjusted odds ratio 1.68, 95% CI 1.15–2.20) and prospective studies (adjusted hazard ratio 1.67, 95% CI 1.28–2.06). Furthermore, patients with HCV infection have higher risk of diabetes than patients with hepatitis B virus (HBV) infection. Patients co-infected with HCV and HIV also have increased prevalence of diabetes compared to those infected with HIV alone. Other studies further confirmed the relationship by showing a positive correlation between plasma HCV RNA level and insulin resistance. Patients achieving sustained virological response with antiviral therapy also have improved insulin sensitivity.
In the current issue of the Journal, Liu et al. examined the relationship between HCV infection and diabetes further in a large community screening program. This study included 56 338 residents from Tainan County in southern Taiwan. Positive anti-HCV antibody and diabetes were found in 5754 (10.2%) and 5385 (9.6%) subjects, respectively. The crude prevalence of diabetes was 10.5% in subjects with positive anti-HCV and 9.4% in subjects with negative anti-HCV (P = 0.008). The corresponding age- and gender-adjusted prevalence of diabetes in the two groups was 9.2% and 8.3%, respectively (P = 0.024). In contrast, similar to previous studies, subjects with HBV infection had better metabolic profile. Adjusted prevalence of diabetes was 7.6% in HBV-infected subjects and 8.4% in subjects without HBV infection (P = 0.028).
The authors further performed subgroup analysis to dissect the association between HCV infection and diabetes. By multivariate analysis, HCV infection was independently associated with diabetes only in subjects without hyperlipidemia (defined as triglycerides above 150 mg/dL and/or total cholesterol above 200 mg/dL; adjusted odds ratio 1.35, 95% CI 1.17–1.55) but not in those with hyperlipidemia. Among patients with diabetes, anti-HCV was positive in 7.3% of those with hyperlipidemia and 22.4% of those without (P < 0.001). Hypertriglyceridemia occurred in 31.4% of HCV-infected patients and 53.8% of non-infected patients (P < 0.001), and hypercholesterolemia occurred in 34.7% and 60.1%, respectively (P < 0.001).
How may the intriguing findings be explained? HCV infection and replication are closely related to lipoproteins. Attachment of HCV to hepatocyte surface requires binding to low density lipoprotein receptor mediated by apolipoprotein B-100 and apolipoprotein E. In addition, high density lipoprotein is involved in the binding of HCV to scavenger receptor B type 1 on hepatocyte surface. Assembly of HCV lipoviroparticles also requires the formation of triglyceride-rich lipoproteins. Thus, HCV infection leads to impaired lipid export from hepatocytes. This results in hepatic steatosis and low serum levels of triglyceride and cholesterol. This phenomenon is particularly evident in patients with HCV genotype 3 infection.
Therefore, the lack of association between HCV infection and diabetes in subjects with hyperlipidemia in Liu's study may partly be explained by a difference in viral activity. Hyperlipidemia may be a surrogate marker of low HCV RNA. These patients are less likely to have HCV-associated diabetes. Besides, cirrhosis has a profound effect on insulin resistance and lipid metabolism. The current study only examined this effect partially by including platelet count in the multivariate analysis. Further analysis including HCV RNA level, HCV genotype and cirrhosis status will better clarify this issue.
Diabetes and natural history of chronic hepatitis C
Diabetes is associated with cirrhosis and hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. In a community study of 23 820 Taiwan residents, the relative risk of HCC in non-diabetic chronic hepatitis C patients was 15.0 (95% CI 10.0–22.5) compared to subjects without HCV infection, and the relative risk in diabetic patients with chronic hepatitis C further increased to 60.3 (95% CI 23.6–153.6). Similarly, chronic hepatitis C patients with body mass index ≥ 30 kg/m2 were more likely to develop HCC than non-obese subjects without HCV infection (relative risk 34.5; 95% CI 13.5–87.6). In another study of 248 patients with compensated HCV cirrhosis, insulin resistance was independently associated with HCC development. Insulin resistance also increased the risk of liver-related death and the need for liver transplantation.
On the other hand, despite the positive correlation with diabetes, HCV infection does not appear to increase the risk of cardiovascular morbidity and mortality. Similarly, carotid intima-media thickness is not increased in patients with chronic hepatitis C. Atherosclerosis is associated with metabolic risk factors instead of HCV infection. One possible explanation is that the harmful effect of diabetes is partially offset by the more favorable lipid profile in chronic hepatitis C patients.
Diabetes and treatment of chronic hepatitis C
Insulin resistance is a condition associated with decreased response to antiviral therapy in patients with chronic hepatitis C. In one study, 33% of patients with genotype 1 HCV infection and insulin resistance (defined as homeostasis model assessment of insulin resistance [HOMA-IR] > 2) achieved sustained virological response (SVR) after interferon and ribavirin treatment, compared to 61% of those without insulin resistance. In in vitro studies, insulin resistance increases viral replication and the production of lipoviroparticles.
With this background, a few groups have tested the possibility of controlling insulin resistance to enhance the effect of HCV treatment. In one study, 123 patients with genotype 1 HCV infection and HOMA-IR > 2 were randomized to receive metformin 850 mg three times daily or placebo, together with peginterferon and ribavirin for 48 weeks. By intention-to-treat analysis, SVR was achieved in 53% in the metformin arm and 42% in the placebo arm, a non-significant difference. Subgroup analysis showed a possible benefit of metformin in female subjects (58% vs 29%, P = 0.031). Another study in patients with genotype 4 HCV infection showed that the addition of pioglitazone might increase the SVR rate (60% vs 39%; P = 0.04). Though promising, these were small studies with narrow ethnic and genotype background. More studies are required before the use of insulin sensitizers to improve HCV treatment can be recommended.
Closely associated with the issue of diabetes is the effect of lipids on HCV treatment. In a post hoc analysis of the IDEAL trial (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy), elevated baseline low density lipoprotein-cholesterol, reduced high density lipoprotein-cholesterol, and the use of statins were associated with higher SVR rates. Besides, statin when used alone has been shown to reduce HCV RNA by 1–2 log IU/mL.
Once again, community screening studies from Taiwan provided important data on the epidemiology of viral hepatitis. The paper by Liu et al. firmly established the positive association between HCV infection and diabetes in the general population (Fig. 1). Metabolic factors modify the natural history of chronic hepatitis C and may be exploited to improve antiviral therapy. Further studies along this line will increase our understanding of the pathophysiology of HCV infection and identify new targets for treatment.