We thank Dr. Hsu and colleagues for their interest and their comments on our study. In response, we wish to raise several pertinent issues. First, even apart from the present study, the relationship of adipokines to hepatic steatosis in hepatitis C virus (HCV) infection is controversial. The fact that some studies examined the modulation of adipokines in response to antiviral therapy and have demonstrated a relationship to antiviral response is not germane to our published manuscript. We are aware that androgens decrease plasma adiponectin and that androgen-induced hypoadiponectinemia may be related to the high risk of insulin resistance and atherosclerosis in men. In addition, existing data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Prior studies on the role of adipocytokines to the pathogenesis of insulin resistance in chronic HCV infection did not consider that gender-based differences in the adipocytokines are a potential bias in interpreting the results. Therefore, our study in a large, well-defined, all-male cohort of subjects with chronic HCV infection and controls represents the most rigorous examination of the role of adipokines to insulin resistance in HCV infection. We hypothesized that HCV-infected subjects would have significantly lower levels of adiponectin compared with controls. However, there were no significant differences in adiponectin and leptin levels between the 2 groups. Our study therefore clearly demonstrates that these cytokines do not mediate the increased insulin resistance observed in HCV-infected persons.
Exclusion of HCV-infected patients with elevated adipocytokines as suggested by Hsu and colleagues we believe, will introduce selection bias. Furthermore, a reduction in the number of subjects would have affected the statistical power of any analysis. Finally, it should be noted that there is no universally accepted cut-off point for “normality” in adipokine levels. We have shown that insulin resistance is associated with fibrosis, a finding consistent with previous reports. In the present study, as suggested by Hsu and colleagues, we have also demonstrated that, as expected, adipokine levels are associated with insulin resistance. What we were unable to discern, however, was any virus-specific modulation of adipokine levels. Finally, although longitudinal studies on the surface appear attractive, they will be almost impossible to interpret because both HCV disease activity and the host metabolic milieu (insulin resistance and obesity) will change with time. Any valid study would therefore require large cohorts and multiple liver biopsies, which we believe would be very difficult logistically.