Steatosis in Hepatitis C: What Does It Mean?

Introduction The hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide infecting approximately 170 million people. The severity of the disease varies widely, from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma. Liver lesions are thought to be mainly related to immune-mediated mechanisms. Factors influencing the outcome of chronic hepatitis C, including age, gender, and alcohol consumption, are poorly understood. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic pathology, with simple steatosis without any evidence of necrosis or inflammation at one end, and severe inflammation with extensive fibrosis or cirrhosis at the other. Fatty liver alone probably has a good prognosis; in contrast, nonalcoholic steatohepatitis (NASH) can progress to cirrhosis in a significant proportion of cases. It is important to note that all the data available have been retrospectively collected. Hepatic steatosis is a common histologic feature of chronic hepatitis C. This finding is also associated with other risk factors, including obesity, high alcohol consumption, type 2 diabetes, or hyperlipidemia. These factors may contribute to steatosis in patients with chronic hepatitis C. In addition, virologic factors may also play an important role. In this article we focus on the meaning of steatosis in patients with chronic hepatitis C. Steatosis Mechanisms of steatosis Hepatic steatosis develops in the setting of multiple clinical conditions, including obesity, diabetes mellitus, alcohol abuse, protein malnutrition, total parenteral nutrition, acute starvation, drug therapy (eg, corticosteroid, amiodarone, perhexiline, estrogens, methotrexate), and carbohydrate overload [1–4,5••]. In the fed state, dietary triglycerides are processed by the enterocyte into chylomicrons, which are secreted into the lymph. The chylomicrons are hydrolyzed into fatty acids by lipoprotein lipase. These free fatty acids are transported to the liver, stored in adipose tissue, or used as energy sources by muscles. Free fatty acids are also supplied to the liver in the form of chylomicron remnants, which are then hydrolyzed by hepatic triglyceride lipase. During fasting, the fatty acids supplied to the liver are derived from hydrolysis (mediated by a hormone-sensitive lipase) of triglycerides stored in the adipose tissue. In the liver, the free fatty acids from all these sources are oxidized by mitochondria, used for triglyceride synthesis, or used to form phospholipids and cholesterol esters. There are several mechanisms that can lead to hepatic steatosis (Fig. 1). Hepatic triglyceride accumulation occurs when the amount of fatty acid supplied to the liver from the intestine or adipose tissue exceeds the amount needed for mitochondrial oxidation, synthesis of phospholipids, and synthesis of cholesterol esters. This is the presumed mechanisms for steatosis in the setting of obesity, diabetes mellitus, and excessive dietary intake of fats or carbohydrates. Insulin resistance is found in obesity, type 2 diabetes, and cirrhosis. Patients with NAFLD demonstrate markedly increased insulin resistance compared with control subjects. Insulin resistance could contribute to hepatic steatosis by favoring peripheral lipolysis and hepatic uptake of fatty acids. It may also be the reason for increased expression of CYP2E1, thereby contributing to the production of pro-oxidants in a fatty liver. Decreased fatty acid oxidation with subsequent fatty infiltration of the liver may also contribute to the genesis of steatosis, particularly in the setting of hyperinsulinemia. Triglycerides can also accumulate in the liver because of decreased synthesis of lipoprotein and decreased export of lipids from the liver.