In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy
Introduction
Chronic infection with the hepatitis C virus (HCV) results in progressive hepatic fibrosis and cirrhosis in up to 20% of cases. Factors implicated in the cause of liver injury and progressive disease include viral factors, the host immune response to the virus and cofactors such as excessive alcohol intake and an elevated body mass index (BMI). A number of studies have now demonstrated a significant relationship between steatosis and fibrosis, suggesting that in chronic HCV, steatosis plays a role in disease progression [1], [2]. Clinical studies have shown that there is a higher prevalence of and more severe steatosis in patients infected with HCV genotype 3 compared with other genotypes [3]. The mechanism responsible for this viral genotype 3-specific association with more severe steatosis remains unclear. However, irrespective of viral genotype, host factors, in particular an increased BMI, are important co-factors in the development of steatosis [1], [4].
The mechanisms by which an elevated BMI and steatosis contribute to progressive fibrosis in chronic HCV remain uncertain. In patients with non-alcoholic fatty liver disease (NAFLD), insulin resistance appears to be fundamental to the pathogenesis of this disorder [5] irrespective of BMI [6], [7]. Type 2 diabetes mellitus is a risk factor for more severe NAFLD [8] and a study examining risk factors for steatosis and fibrosis in chronic HCV reported a relationship between diabetes and fibrosis level [4]. Recent studies have suggested that increased circulating insulin levels may have a direct role in the fibrogenic process. Molecules involved in fibrogenesis such as connective tissue growth factor were increased following culture of hepatic stellate cells with insulin [9] and in patients with chronic HCV, insulin receptors have been demonstrated on hepatic stellate cells [10].
In addition to insulin, several recent studies have implicated leptin as a hormone involved in liver fibrogenesis in animal models [11], [12], [13], [14]. Leptin is produced predominantly in adipose tissue and the circulating leptin concentration correlates with fat mass, size and distribution [15]. In addition to regulating food intake and energy expenditure, leptin has other metabolic effects on peripheral tissue, including modulation of insulin action [16] and wound healing [17]. Activated rat hepatic stellate cells express leptin [18] and rat sinusoidal endothelial cells and Kupffer cells express the signalling-competent isoform of the leptin receptor (OB-RL) [13]. Exposure of these cells to leptin results in increased expression of TGF-β which in turn stimulates fibrogenesis in hepatic stellate cells [19].
We hypothesized that in patients with chronic HCV, host metabolic factors associated with an increased BMI such as circulating insulin and leptin may have a role in the progression of hepatic fibrosis. To investigate this, we studied 160 consecutive patients with untreated chronic HCV, to assess the relationship between BMI, circulating insulin and leptin levels and hepatic steatosis and fibrosis. Circulating insulin and leptin levels in HCV-infected patients were also compared with results from an age, gender and BMI-matched control group.
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Patients
Fasting serum was obtained at the time of liver biopsy from 164 consecutive patients with chronic HCV between 1994 and 2002. No patient with HCV had prior antiviral treatment with interferon-alpha. Informed consent was obtained from each patient and the study protocol was approved by the Princess Alexandra Hospital Research Ethics Committee. Inclusion criteria consisted of: (a) chronic HCV with circulating HCV RNA (detected by Amplicor HCV Monitor Assay, Roche, NJ, USA); (b) serum collected at
Demographic, biochemical and metabolic characteristics of HCV-infected patients and control subjects
The demographic, biochemical and metabolic characteristics of 160 patients with chronic HCV and 45 control subjects are detailed in Table 1. As is consistent with the general distribution of the Australian HCV population, study patients were predominantly male (110M/50F), and all were HCV RNA positive with either viral genotype 1 (n=85) or 3 (n=75). BMI ranged from 16.5 to 40.7 kg/m2 with the mean BMI considered overweight at 25.6±0.35 kg/m2 (healthy BMI range 18.5–24.9 kg/m2) [24].The age of
Discussion
This study demonstrates that patients with chronic HCV and hepatic steatosis have increased fibrosis compared with patients without steatosis irrespective of viral genotype. Although steatosis was more severe in patients with viral genotype 3, overweight patients with either viral genotypes 1 or 3 had significantly more steatosis than lean subjects. Overweight patients had increased circulating insulin and leptin levels compared with lean patients and demonstrated a significant relationship
Acknowledgments
Funding for this study was provided by the National Health and Medical Research Council, Australia (IH and EP), Gastroenterology Foundation/Pharmacia & Upjohn Research Fellowship (JJ) and the Princess Alexandra Hospital Research and Development Foundation.
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