Hepatitis C virus and insulin resistance/diabetes mellitus.

The significance of insulin resistance with or without type II diabetes mellitus (DM) in the setting of hepatitis C virus infection is clear. Insulin resistance is associated with the progression of liver disease as well as a decreased responsiveness to therapy with pegylated interferon and ribavirin.1–5 A recent multivariate analysis showed DM to be associated with progression of fibrosis.6 The question of whether insulin resistance or DM is an extraintestinal manifestation of hepatitis C virus infection is less clear and does not fit into a simple cause-and-effect scenario. This complex relationship is further complicated by high baseline prevalence of obesity, metabolic syndrome, and DM in the general population, all of which are factors that can lead to chronic liver disease in the form of nonalcoholic steatohepatitis independent of hepatitis C virus infection. Khokhar and Fischer describe a patient with preexisting DM who was found to have increasing insulin resistance with 10 hospital admissions for diabetic ketoacidosis over a 1-year period.7 The patient was unable to tolerate long-acting insulin secondary to hypoglycemia, though his short-acting insulin requirement topped 1,500 units daily. During the course of these hospital admissions, the patient was diagnosed with chronic hepatitis C (CHC) infection and eventually cirrhosis via ultrasound. His clinical course was notably complicated by alcohol and cocaine abuse, which made treatment for his CHC prohibitive. Interestingly, he was given a trial of plasmapheresis in an effort to improve his glycemic control, which the authors speculated was secondary to his hepatitis C virus infection. The description of a “modest and transient improvement” in blood sugar control was attributed to the results of this entirely experimental procedure, and any efficacy was limited by the patient's inability to tolerate plasmapheresis secondary to hypotension. Although this case report describes severe insulin resistance in the setting of DM and CHC infection without interferon therapy, it is not the first report to do so. Oliveira and coworkers recently compared 15 type II diabetic patients with CHC to 15 type II diabetic patients without CHC and demonstrated that insulin resistance is much higher in those patients with CHC, independent of age, body mass index (BMI), or gender.8 Collectively, these studies highlight the known complex relationship between hepatitis C virus and host metabolism, a relationship that extends beyond a simple cause-and-effect paradigm with distinct differences between genotypes 1 and 4 versus genotypes 2 and 3. Genotypes 1 and 4 comprise the majority of patients with CHC and have shown the greatest association with insulin resistance. Animal models using genotype 1 constructs have shown that hepatitis C virus infection without weight gain causes insulin resistance.9 This finding was supported by a recent prospective study of 500 CHC patients compared to chronic hepatitis B patients, which demonstrated, on multivariate analysis, a significant correlation between genotype 1 or 4 infection and insulin resistance, both in the presence and absence of DM.5 Interestingly, patients with genotype 2 or 3 hepatitis C virus infection showed only a 22% rate of insulin resistance versus the 40.1% seen in genotype 1 or 4 infected patients, despite similar BMIs, supporting other previous studies that showed low rates of insulin resistance in genotype 2 or 3 infected patients.1 The correlation of genotype 1 hepatitis C virus infection and insulin resistance (as well as hepatic steatosis) was also demonstrated by Vidali and colleagues.10 This study highlighted the known differences between nongenotype 3 and genotype 3 infection, as the association of insulin resistance with CHC infection was seen only in nongenotype 3 patients on multivariate analysis. This difference is thought to be secondary to the direct metabolic effects of genotype 1 infection that result in hepatic steatosis/insulin resistance versus the more viral cytopathic effects of genotype 3 infection. Unraveling the intricate web of pathways involved in the development of insulin resistance is difficult. Increased circulating tumor necrosis factor-α and viralmediated induction of suppressor of cytokine signaling (SOCS) 3 with subsequent downregulation of insulin receptor substrates 1 and 2 are potential mechanisms by which hepatitis C virus infection is thought to promote insulin resistance. Although far from straightforward, the association of insulin resistance with genotype 1 infection may partially explain the lower rates of sustained virologic response when compared to genotype 3 CHC, though certainly more evidence is required before this can be concluded. The presence of advanced fibrosis or cirrhosis such as that seen in the patient treated by Khokhar and Fischer also has host metabolic effects that must be taken into account when assessing the effect of hepatitis C virus on insulin resistance. Cirrhosis, independent of hepatitis C virus, has been shown to adversely affect glucose homeostasis, and there is a clear association of cirrhosis with diabetes.11 In fact, some studies show that upwards of 96% of patients with cirrhosis have insulin resistance with or without DM.12 However, certain causes of cirrhosis are more often associated with insulin resistance, as shown by a study conducted by Zein and associates in which diabetes rates were 25% in patients with hepatitis C virus cirrhosis, 19% in patients with alcoholic liver disease, but only 1.3% in patients with cholestatic liver disease.13 These findings would suggest that mechanisms leading to cirrhosis, and not the cirrhosis itself, are the cause of insulin resistance. Both preexisting, insulin-requiring diabetes and cirrhosis existed in the patient treated by Khokhar and Fischer, though a stable insulin requirement of less than 100 units daily was noted prior to the diagnosis of hepatitis C virus infection. As the patient appeared to have recurring risk factors for hepatitis C virus infection, it is impossible to date his onset of infection. He certainly could have had long-term CHC that progressed to cirrhosis and led to increased insulin resistance/worsening of his diabetes, or a newer onset of infection could have tipped the scales, so to speak, into diabetic ketoacidosis requiring large volumes of insulin. Regardless of the cause, this patient's overall prognosis remains poor. In summary, the number of patients infected with hepatitis C virus worldwide is increasing, as is the prevalence of obesity and metabolic syndrome. Hepatitis C virus infection, particularly of genotypes 1 and 4, may cause insulin resistance or may exacerbate preexisting insulin resistance. In turn, this may lead to more advanced liver disease and decreased responsiveness to therapy with pegylated interferon and ribavirin. The mechanisms leading to insulin resistance in the setting of hepatitis C virus infection are currently under study and may lead to the development of new and improved therapies for CHC.