Metabolic syndrome in liver transplantation: The elephant in the room

Hepatitis C virus (HCV) is the leading indication for liver transplantation among adults in the United States. After transplantation, infection of the allograft by HCV is invariable, and the natural history of HCV is greatly accelerated in the posttransplant setting. HCV-induced allograft hepatitis and fibrosis/cirrhosis occur in 70% to 80% and 10% to 21% of recipients at 5 years, respectively. Once histological cirrhosis develops, progression is rapid, with a high risk of clinical decompensation. Indeed, HCV infection significantly impairs patient and allograft survival after liver transplantation, with a 23% increased rate of death and a 30% increased rate of allograft failure. HCV treatment posttransplant is difficult; although sustained virologic response is possible, antiviral therapy certainly is not optimal, with side effects limiting its use. Studies, therefore, have been performed that look at factors associated with fibrosis progression and poor survival, including the year of transplantation, viral load, genotype, use of steroids or OKT3, cytomegalovirus, and donor age. In this issue of Liver Transplantation, Hanouneh et al. provide another piece of this puzzle. The authors performed a retrospective analysis of 95 liver recipients with recurrent HCV to determine if metabolic syndrome (MS) was associated with fibrosis progression. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria at 1 year post-transplant, and the first biopsy demonstrating histological stage F1 or greater (with the LudwigBatts scoring system) was used for analysis. Overall, 50% of recipients had MS; of these, 80.5% had evidence of progression. On univariable analysis, the 4-month HCV viral load, cytomegalovirus infection, use of antiviral therapy, diabetes mellitus (DM), and presence of MS were associated with fibrosis progression. On multivariable analysis, only the 4-month HCV viral load and use of steroids were independent predictors. However, when the authors looked at the interaction (ie, effect modification) between MS and the follow-up time, they found that MS was independently associated with fibrosis progression when the follow-up time exceeded 1 year post-transplant with a hazard ratio of 6.3 (1.428.7, P 0.017). These results are not entirely surprising. In the nontransplant population, hepatitis C infection has been linked to steatosis, DM, and insulin resistance (IR), and each has been associated with fibrosis progression. HCV infection may induce the development of IR via interference with the tyrosine phosphorylation of the insulin receptor substrate, which in turn affects multiple steps in the insulin signaling pathway. Proposed mechanisms for fibrosis include the induction of proinflammatory and profibrotic mediators such as tumor necrosis factor and interleukin-6 and likely share similarities with those involved in nonalcoholic fatty liver disease. Leandro et al. recently performed a meta-analysis of 3068 HCV-positive patients from the United States and Europe and demonstrated that steatosis was associated with fibrosis, even after adjustments for inflammation, gender, body mass index (BMI), diabetes, and genotype (odds ratio 1.66, P 0.001). Furthermore, there is an association between HCV and type 2 DM; in HCV-positive patients, DM is associated with a risk of progression to severe fibrosis both pre-transplant and post-transplant even in the absence of steatosis. In the 1 published study directly looking at IR post-