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Steatosis occurs to some degree in about half of all patients with chronic HCV infection. In a meta-analysis of data from >3000 patients, steatosis was independently associated with the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, overweight (body mass index >25), age =45 years, and genotype 3 infection. Among 101 HCV-infected patients with no factors predisposing to fatty liver, steatosis was found in 41% of patients, irrespective of sex, age, or infection route.

Two main mechanisms underlie the pathogenesis of steatosis in HCV-infected patients who abstain from alcohol, a direct viral effect and a metabolic mechanism. Viral steatosis is associated with genotype 3 HCV infection, where the severity of steatosis correlates with serum and intrahepatic viral load. This type of steatosis often resolves after viral eradication. It is believed that HCV genotype 3 has a direct effect on hepatocyte lipid metabolism, resulting in fat accumulation. Interactions involving the HCV genotype 3 core protein, such as enhanced fatty acid synthase promoter activation and increased lipid affinity, are being investigated in vitro.

Metabolic steatosis is seen primarily in patients infected with genotype non-3 HCV and is largely due to insulin resistance, characterized by hyperinsulinemia and free fatty acid overflow to organs and non-adipose tissues. These alterations give rise to triglyceride accumulation in hepatocytes, resulting in steatosis.

Steatosis might reduce the likelihood of achieving SVR with HCV treatment, even when other steatosis-inducing factors are accounted for. In one study, SVR rates were 18%–32% lower in people with steatosis versus those without steatosis after adjusting for other potentially confounding cofactors such as genotype, fibrosis score, and viral load.

About 85% of HCV-positive persons in the United States general population can be identified on the basis of 3 characteristics: IDU history, blood transfusion before 1992, or abnormal serum alanine transaminase levels. In selected populations, other characteristics might also be useful for screening. A retrospective study of 5400 US veterans found that the following factors predicted HCV infection: IDU, blood transfusion before 1992, service during the Vietnam war, tattoo, and a history of abnormal liver test results. However, HCV risk factor histories are rarely documented in clinical practice. Infected patients can thus remain undiagnosed until they present with hepatic complications.

The impact of HCV infection on the burden of liver disease is becoming evident as individuals unknowingly infected decades ago age and develop severe sequelae of advanced liver fibrosis. Up to 1 million Americans are predicted to develop HCV-related hepatic complications during the next 2 decades. Persons born between the 1940s and 1960s account for most infections, with the highest risk among those with a history of IDU or blood transfusions before 1992. Once chronic infection is established, disease progression is variable and dependent on several factors. Cirrhosis, liver failure, and HCC might occur at a faster rate and in more patients than previously believed.