Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C.
The interaction between insulin resistance (IR), steatosis and genotype to fibrosis in chronic hepatitis C virus (HCV) infection has not been comprehensively assessed. We hypothesized that IR is a key mediator for the development of both steatosis and fibrosis in 346 untreated, nondiabetic patients solely infected with either genotype 1 or 3. We examined for genotype-specific interactions between IR, steatosis and fibrosis by performing subgroup analyses. Because cirrhosis is known to cause IR, we repeated the analysis in a cohort of 313 noncirrhotic HCV-infected patients. We confirmed the impact of IR on fibrosis by analysis of 153 lean subjects in whom any effect of steatosis would be minimized. In HCV genotype 3 patients, increased steatosis was linked to high viral load (P = 0.001), and was not associated with fibrosis (P = 0.1). In contrast, body mass index (P = 0.04) and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.01) contributed directly to steatosis in HCV genotype 1. HOMA-IR rather than steatosis was independently associated with fibrosis for both HCV genotype 1 (OR, 3.22; P = 0.02) and genotype 3 (OR, 3.17; P = 0.04). Exclusion of cirrhotic subjects did not alter the findings with respect to the greater contribution of IR compared to hepatic steatosis, as a predictor of fibrosis (P = 0.02). Genotype-specific subgroup analyses did not alter this finding. The extent of HOMA-IR remained significantly associated with fibrosis in lean patients, independent of the confounding effect of body mass index on IR (OR, 8.02; P = 0.003).


CONCLUSIONS
IR is a major independent determinant of fibrosis in chronic HCV infection, regardless of the genotype and the severity of liver damage.
Cua
Ian Homer Y
IH
Storr Liver Unit, Westmead Millennium Institute and Department of Gastroenterology and Hepatology, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia.
Hui
Jason M
JM
Kench
James G
JG
George
Jacob
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D015331:Cohort Studies; D005234:Fatty Liver / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D012720:Severity of Illness Index