Insulin resistance, adipocytokines, and hepatitis C virus infection: A missing link?
Authors: Ching-Sheng Hsu, Jia-Horng Kao
Journal: Hepatology (2008)

We read with great interest the article by Cua et al.1 Although leptin and adiponectin have been reported to contribute to insulin resistance (IR), the authors found that none of the adipocytokines accounted for elevated IR in hepatitis C virus–infected subjects. In addition, adipocytokines were not associated with histological features of chronic HCV infection except for tumor necrosis factor-α (TNF-α) which correlated with portal/periportal inflammation. They thus concluded that HCV-associated IR is most likely an adipocytokine-independent effect of the virus to modulate insulin sensitivity. However, some of their findings are unexpected and deserve further discussion. First, the comparisons between 154 patients infected with HCV patients and 75 matched healthy volunteers showed that patients with HCV had significantly higher levels of HOMA-IR, TNF-α, and interleukin-6 than controls; however, comparable leptin and adiponectin concentrations were found between the 2 groups. Further inspection indicated that patients with HCV had higher adiponectin levels than controls, although the difference was not statistically significant.1 On the contrary, earlier studies have clearly demonstrated a close association between HCV infection and adipocytokines. For example, leptin and adiponectin levels were associated to steatosis in chronic hepatitis C infection (CHC),2, 3 their serum concentrations were changed under antiviral therapy,4 and were even related to the response of antiviral therapy.5 Our recent study also showed a correlation between serum adiponectin level and hepatitis C viral factors at both serum and liver tissue levels.6 How can these discrepant results be explained? Several studies have shown that both adiponectin and leptin are influenced by gender, and expression of adiponectin is inhibited by testosterone.7 Thus, the lack of difference in leptin and adiponectin levels between patients with HCV and controls in this study might be due to the inhibition effect of testosterone in males. This possibility of gender effect could explain why the results of Cua et al. were different from earlier studies. In addition, it will be more informative if the authors could exclude HCV patients with elevated adipocytokines and reanalyze their data to see whether IR is still associated with HCV infection. Second, multiple ordinal regression analysis revealed that only TNF-α levels were correlated with the extent of histological injury.1 Several studies already showed that IR could serve as a predictor of fibrosis progression. Considering a close link between adipocytokines and IR,8 it is thus reasonable to speculate that adipocytokines could also contribute, at least in part, to fibrosis progression. Although the association between leptin and steatosis in CHC remains controversial,3, 9 prior studies showed that hypoadiponectinemia was associated with steatosis in CHC.2 Because the progression from steatosis to fibrosis may take time,10 the negative association between adipocytokines and the extent of histological injury observed in the present study may be attributed to the time effect. Taken together, a cross-sectional study at a given time point cannot convincingly prove the negative association between adipocytokines and histological injuries, but further prospective studies with a reasonable follow-up duration may provide the missing link. Ching-Sheng Hsu*, Jia-Horng Kao , * Department of Hepatogastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan, Graduate Institute of Clinical Medicine, Department of Internal Medicine, Hepatitis Research Center, and Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.