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The role of steatosis in the progression of liver damage in chronic hepatitis C (CHC) was studied. Enrolled were 180 consecutive liver biopsy-proven CHC patients and 41 additional subjects with a known duration of infection. We evaluated the histological activity index (HAI), grade of fibrosis and steatosis, body mass index (BMI; kg/m(2)), distribution of body fat, HCV genotype, and levels of HCV RNA. Eighty six (48%) patients showed steatosis, and a higher prevalence was observed in genotype 3a infection (P <.01). A correlation between the grade of steatosis and fibrosis was observed (P <.001). Fibrosis was also associated with age (P <.001). After adjusting for age, the association between steatosis and fibrosis remained significant. The grade of steatosis also correlated with the HAI (P <.007) with a significant increase in periportal necrosis. No relation was found between steatosis and age, gender, iron storage, or levels of HCV RNA. Patients with a high grade of steatosis (>30%) showed higher serum levels of gamma-GT and ALT (P <.001). Overall, steatosis was not significantly associated to BMI. Analysis by single genotype showed a significant association between the grade of steatosis and BMI in type 1 infection r =.689; P <.001) and with levels of HCV RNA in type 3a infection r =.786; P <.001). Visceral fat distribution rather than BMI proved to be associated with steatosis (P <.001). Data obtained from patients with a known date of infection confirmed that steatosis grades 3-4 were associated with a higher annual rate of fibrosis progression, and showed that alcohol and steatosis act together in increasing fibrosis (P <.05). Our data indicate that steatosis is an important cofactor in increasing liver necroinflammatory activity and in accelerating fibrosis in CHC. Visceral obesity and genotype 3a play a role in the development of steatosis.

This study was designed to test the hypothesis that increasing the infusion rate of bile salts could overcome drug-induced cholestasis. Cholestasis was induced by administration of 17.5 mumol/L estradiol-17 beta-D-glucuronide during the infusion of taurocholate, tauroursodeoxycholate or dehydrocholate at 20 nmol/min/gm liver. After 30 min, a bolus of 10 mumol of the bile salts was added to the perfusate, and the infusion rate of each bile salt was increased. Taurocholate at a rate of 62 or 125 nmol/min/gm liver, caused a prompt dose-dependent increase of the depressed bile flow and bile salt excretion. A higher rate of taurocholate infusion (180 nmol/min/gm liver) was less effective than either the 62 or 125 rate in increasing bile flow. Infusion of tauroursodeoxycholate at 250 or 390 nmol/min/gm liver also led to a dose-dependent recovery. Further increase of tauroursodeoxycholate infusion rate of 580 nmol/min/gm liver did not provide any additional recovery in bile flow. Dehydrocholate, at rates of 62 or 125 nmol/min/gm liver, gave only a slight enhancement of bile flow. Both taurocholate and tauroursodeoxycholate caused a marked removal of the estradiol-17 beta-D-glucuronide, which had accumulated in the liver. At lower taurocholate infusion rates, the estradiol-17 beta-D-glucuronide was excreted mainly in the bile. At the highest rate, however, biliary excretion of estradiol-17 beta-D-glucuronide declined significantly, and a marked back-efflux of the estrogen into the perfusate was noted. In contrast, tauroursodeoxycholate led to enhanced biliary estradiol-17 beta-D-glucuronide excretion at all increased tauroursodeoxycholate infusion rates and to only a small increase in back-efflux of estradiol-17 beta-D-glucuronide at the two highest tauroursodeoxycholate infusion rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Estradiol-17 beta-D-glucuronide (E-17G), a metabolite of natural estrogen, is a potent cholestatic agent in vivo. We, therefore, studied the mechanisms of E-17G cholestasis using in vitro perfused rat liver system. Furthermore, since it has been postulated that sodium taurocholate (TC) may interfere with either uptake or biliary excretion of other steroid agents, we tested whether E-17G cholestasis could be modified by TC administration. During a constant infusion of TC at a physiological rate (0.50 mumole per min), a dose-dependent decrease of bile flow was observed after E-17G addition from 1.5 to 5 X 10(-5) M. E-17G decreased bile acid excretory rate but not bile acid concentration in bile. In separate experiments, TC was infused at different rates (0, 0.25, 0.50, and 0.75 mumole per min) into the perfusate over the entire experimental period, and E-17G was added at 1.75 X 10(-5) M. In this setting, E-17G cholestasis was diminished by increasing TC infusion rate and was prevented by TC at 0.75 mumole per min. Infusion of sodium dehydrocholate (0.75 mumole per min), a nonmicelle-forming bile acid, did not prevent E-17G cholestasis. During E-17G cholestasis, an increased biliary permeability to 14C-sucrose was observed. This effect was also prevented by TC, but not by sodium dehydrocholate which was infused at 0.75 mumole per min. The perfusate disappearance curves of 3H-E-17G at the different TC infusion rates showed no changes in the initial uptake phase, but a profound dose-dependent difference in the excretory phase.(ABSTRACT TRUNCATED AT 250 WORDS)