Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease.
Nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV)-related liver disease are common in the general population, but their concurrence is 2- to 3-fold higher than would be expected by chance alone. In patients with chronic HCV infection, steatosis is attributable to a variable combination of the mechanisms considered to play a role in the pathogenesis of NAFLD--insulin resistance in the obese and in the lean subject--along with a direct effect of HCV on hepatic lipid metabolism that leads to triglyceride accumulation through inhibition of export proteins that are required for very low density lipoprotein (VLDL) assembly and secretion. Accumulating evidence suggests that steatosis contributes to the progression of fibrosis in HCV-related disease in a pattern similar to that observed in NAFLD. Potential mechanisms of this effect include the increased sensitivity of steatotic livers to oxidative stress and cytokine-mediated injury. Steatosis-related hepatic insulin resistance may also play a role through the profibrogenic effects of the compensatory hyperinsulinemia and provides a potential explanation for the association between HCV and type 2 diabetes mellitus. Indeed, an appreciation of the importance of fat in HCV has recently led to trials of adjuvant therapy for HCV directed at steatosis-associated disease mechanisms, with encouraging results reported for various modalities, including weight loss and antioxidants. Future therapy should be aimed at exploiting the interactions of HCV with host insulin and lipid metabolism, particularly in nonresponders to standard antiviral schedules.
Lonardo
Amedeo
A
Division of Internal Medicine and Gastroenterology, Modena City Hospital, Italy. a.lonardo@libero.it
Adinolfi
Luigi E
LE
Loria
Paola
P
Carulli
Nicola
N
Ruggiero
Giuseppe
G
Day
Christopher P
CP
D001161:Arteriosclerosis / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D018450:Disease Progression; D005234:Fatty Liver / Q000453:epidemiology / Q000628:therapy / Q000821:virology*; D006526:Hepatitis C / Q000150:complications*; D019698:Hepatitis C, Chronic / Q000503:physiopathology; D006801:Humans; D008103:Liver Cirrhosis / Q000821:virology; D015995:Prevalence