Correlation between insulin resistance and hepatitis C viral load

To the Editor: I read with interest the timely article by Bugianesi et al. detailing insulin resistance in chronic liver disease.1 As briefly mentioned in this article, chronic hepatitis C (CHC) is associated with insulin resistance (IR) and the co-existence of NAFLD and IR with CHC is associated with decreased sustained virological responses (SVR) to antiviral therapy. Recently, it has been demonstrated in a hepatitis C replicon system (Apath, Clone B (S11791) that hyperinsulinemia increases HCV-RNA replication.2 We have evaluated 64 naïve CHC patients and found that IR correlated with higher viral loads (P = .04). Insulin resistance was determined by the quantitative insulin sensitivity check index (QUICKI). A score of <0.35 (equivalent to HOMA >1.8) was used as an indicator of IR: No differences in viral load were found with respect to ethnicity, gender or BMI. Among the 4 diabetic patients in the cohort, no significant difference in viral load was found when compared with nondiabetics. Etiologies for the association between IR and elevated viral load in CHC are unclear at present. Insulin resistance could precipitate higher viral loads, there could be a direct viral inhibitory effect on insulin sensitivity, or a combination of the two. In support of the first possibility, there appears to be significant homology between human metabolic and immune pathways. Similar kinases are involved in insulin signaling and activation of immune regulatory pathways by specific Toll-like receptors (TLRs).3 In vitro data suggest that insulin blocks interferon mediated increases in protein kinase R and interferon regulatory factor-1 (IRF-1) via a phosphatidyl inositol-3 kinase (PI3K) pathway.2 Additional evidence suggests that in the absence of PI3K, IRF-3 is incompletely phosphorylated as well.4 Furthermore, hepatic innate immunity is also influenced by a milieu of hormonal, cytokine, and neurotransmitter factors. Leptin is one such hormone that has been shown to influence innate immunity. Experimental data suggest that in leptin deficient ob/ob mice there is altered expression of cytokines IL-12 and IL-15 by Kupffer cells, resulting in decreased hepatic NKT cell populations.5 This reduction in NKT cells was shown to also occur in obese, wild-type mice fed a diet high in fat and/or sucrose.6 Data derived from transgenic mice infected with hepatitis C core protein support the possibility that this virus may also induce IR directly, possibly through a TNF-α mediated pathway.7 Therefore, it is possible that higher degrees of viremia may further enhance insulin resistance. Finally, HCV NS3/4A serine protease has been shown to block the phosporylation of IRF-3, inhibiting endogenous interferon-α production,8 thus, possibly allowing for enhanced HCV-RNA replication. This finding is quite intriguing given recent evidence suggesting that rapid lowering of viremia is associated with increased T cell reactivity.9 These recent observations raise an important question. If up to two-thirds of our naïve CHC patients are insulin resistant, and antiviral efficacy is diminished in this setting, could our SVR rates be further enhanced by improving insulin sensitivity before antiviral therapy? Stephen A. Harrison M.D.*, * Brooke Army Medical Center, Department of Gastroenterology, Fort Sam, Houston, TX.