Hepatitis C virus genotype 3 is cytopathic to hepatocytes: Reversal of hepatic steatosis after sustained therapeutic response

Abstract

On the basis of cross-sectional studies, it has been proposed that hepatic steatosis is a cytopathic effect of hepatitis C virus (HCV) genotype 3 but not genotype 1 infections. We tested this hypothesis by examining whether antiviral treatment altered hepatic steatosis in chronic hepatitis C. In 28 patients with genotype 1 and 34 with genotype 3 HCV, we determined the severity of steatosis in pre-and posttreatment liver biopsies using computerassisted morphometric image analysis as well as conventional semiquantitative scoring. Before treatment, hepatic steatosis was present in 16 (57%) patients infected with HCV genotype 1 and 21 (62%) of those with genotype 3. Sustained viral response (SVR) was achieved in 9 (32%) patients with genotype 1 and 22 (65%) with genotype 3. In neither group were there significant changes in body weight or alcohol consumption between preand posttreatment biopsies. In patients with HCV genotype 1, there was no change in hepatic steatosis after treatment, irrespective of the treatment response. Among those infected with genotype 3, SVR significantly reduced steatosis (P < .001), but there was no change in steatosis among those without a SVR. By logistic regression analysis, SVR was the only variable predictive of improvement in hepatic steatosis (OR ‫؍‬ 36, 95% CI ‫؍‬ 2.7-481, P ‫؍‬ .007). In conclusion, these data provide strong support for a direct causal association between HCV genotype 3 infection and hepatic steatosis. H epatic steatosis is a common feature on liver biopsy specimens from patients with chronic hepatitis C, and its presence is associated with fibrotic progression. 1,2 The pathogenesis is complex; host factors including alcohol consumption, exposure to other hepatotoxins, obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia have been identified as determinants. 3 We and others have recently found that viral factors, particularly hepatitis C virus (HCV) genotype, may be a critical determinant of steatosis in chronic hepatitis C. 2,4,5 Thus, patients with HCV genotype 3 infection and chronic hepatitis C are more likely to have steatosis and more likely to have extensive hepatic steatosis than those infected with HCV genotype 1. Furthermore, hepatic steatosis in genotype 3 chronic hepatitis C correlates directly with serum and intrahepatic titers of HCV RNA and inversely with apolipoprotein B levels. 2,5,6 In contrast, steatosis in HCV genotype 1 infection appears independent of virus levels but correlates with measures of obesity, including body mass index and visceral fat distribution. 2,4 We hypothesized that, if the genotype-specific associations between HCV and hepatic steatosis are real, then a sustained response to antiviral therapy should be accompanied by improvement in steatosis in those infected with genotype 3 but not in those with genotype 1 HCV infection.The effect of viral eradication on hepatic steatosis in relation to HCV genotype has not been evaluated. Published data on steatosis after antiviral treatment of hepatitis C are limited b...

Chronic hepatitis C: pathological anatomy

“…In a series of patients with genotype 3 and steatosis, a sustained virological response led to regression of steatosis in 91% of the cases, a much higher index than the 19% observed for those who did not present sustained virological response [6], making the cytopathic effect a more consistent cause of steatosis. Other authors have reported similar results [22,36].…”

Steatosis: Co-factor in Other Liver Diseases *

“…8 The development of cirrhosis in patients with HCV may be associated with regression of steatosis, 21 as has previously been documented in non-alcoholic steatohepatitis (NASH). 22,23 The mechanisms leading to a reduction in steatosis in the liver with cirrhosis remain Mihm et al 99 Yes Ratziu et al 18 Yes Fartoux et al 19 Yes Czaja et al 9 Yes Yes Yes Hourigan et al 10,11 Yes Yes Yes Adinolfi et al 12 Yes Yes Yes Yes Westin et al 13 Yes Weak Yes Yes Castera et al 14 Yes Yes Monto et al 15 Yes Yes Yes Kumar et al 100 Yes Camps et al 101 Yes (BMI) Kaserer et al 102 Yes Bressler et al 60 Yes (BMI) Rubbia-Brandt et al 28 Yes Yes Poynard et al 16 Yes Yes Yes Yes Yes Patton et al 17 Yes Yes Yes Yes Yes Nair et al 70 No* Marrero et al 103 Yes Ohata et al 74 Yes *Steatosis was a risk for HCC in alcoholic and cryptogenic cirrhosis only. Abbreviation: BMI, body mass index.…”

Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection†

“…14 Moreover, resolution of HCV infection after antiviral therapy is associated with a decrease in hepatic steatosis, particularly in patients with genotype 3. 15 Although hepatic steatosis has been considered a benign finding, recent studies have suggested that both steatosis and the more severe lesion of non-alcoholic steatohepatitis may be associated with progression of fibrosis in patients with hepatitis C. [16][17][18] However, many of the studies were cross-sectional and involved selected populations with unknown duration of steatosis. Furthermore, progression of fibrosis was estimated based on a single liver biopsy together with the clinical history of exposure and assumed that progression of fibrosis was linear over time.…”