Mitochondrial cytochrome C and ultrastructural changes in hepatic steatosis induced by hepatitis C virus

Hepatic steatosis is an important hallmark of hepatitis C virus [HCV] infection. There is substantial body of evidence to implicate steatosis in the development of hepatic fibrosis. The underlying mechanisms of HCV-related steatosis however are not yet clarified. This study was performed to evaluate ultrastructural mitochondrial changes in patients with HCV-induced hepatic steatosis and correlate these findings with serum cytochrome c and apolipoproteins. Thirty-seven HCV-positive patients admitted to Theodore-Bilharz Research Institute were selected. They did not have other confounding prosteatogenic variables: diabetes, overweight, alcohol consumption and prosteatogenic drugs as amiodarone; corticosteroids. In addition, 10 apparently age- matched subjects were selected as a reference group. All subjects were initially subjected to full history, thorough clinical examination, liver function tests; lipid profile, HCV-IgG antibody and hepatitis-B surface antigen. All patients were subjected to ultrasound-guided liver biopsy. Biopsy specimen was processed for light and electron microscopic histopathological examination. According to histopathological findings, patients were divided into 4 groups according to the stage of fibrosis[I, II, III and IV]into :-Group 1 [n=7]; Group 2 [n=9]; Group:3 [n=9] and Group 4 [n=12]or cirrhotic group respectively. Measurement of apolipoproteins A, B and II and specific estimation of serum cytochrome-C was performed. Interpretation of the results revealed accumulated fat droplets by ultrastructure identification in the hepatocytes together with hypobetalipoproteinemia and hypotriglyceridemia. This was accompanied with mitochondrial ultrastructural alterations in all the studied groups ranging from complete dissolution to loss of outer mitochondria] membrane. In addition, it is noteworthy that ultrastructural changes of the rough endoplasmic reticulum [RER] detected in this study may be a contributing factor to abnormal fat metabolism in HCV. Concomittantly, serum cytochrome c was significantly lowered in all the studied groups as compared to the reference mean value. Depletion of mitochondria] cytochrme c might result in accumulation of reactive oxygen species and further accentuation of steatosis. There was significant correlation between serum cytochrome c, apolipoprotein B and serum triglycerides in the patients' group, ushering that it might have its role in HCV-induced lipid changes. In the cirrhotic group, ultrastructural elucidation of homogenous unlocalized intracytoplasmic fat and evident intracytoplasmic collagen fibrils was reported in this study. This was associated with significantly lowered serum ApoAl, ApoB and triglycerides as compared to all other groups. The afore-mentioned data solidifies the evidence that hepatic steatosis and fibrosis are important sequence of HCV infection and confirm the ability of hepatocyte to synthesize collagen. Moreover, the discerned intracytoplasmic unsaturated fat droplets might mirror the inability of the HCV-dysfunctioning hepatocyte to cope with the excessive dietary intake of fat and hence accentuation of steatosis results. In conclusion, ultrastructural. mitochondrial and RER changes seems to confirm their relation- to the associated intracytoplasmic fatty acids accumulation, the decreased serum cytochrome c and apolipoproteins Al and B Moreover it confirms the cytopathic effect of HCV

Plasma and hepatic tissue endothelin-1 levels in cirrhotic patients with and without bleeding varices

Bleeding from varices is the most lethal event in cirrhotic patients. Bleeding esophageal varices contributed to 51.6% of causes of upper gastrointestinal hemorrhage among Egyptians. The potent vasoconstrictive peptide, endothelin [ET] has been suggested to contribute to the pathogenesis of portal hypertension. So, the present study was designed to determine levels of both circulating ET-1 and hepatic tissue ET-1 in cirrhotic patients with and without bleeding varices. Patients suffering from liver cirrhosis, portal hypertension and upper gastrointestinal bleeding due to esophageal and/or gastric varices were included in the study. Patients who had liver cirrhosis but had never bled before were studied as a comparative group. All patients were classifed according to modified Child's classification. Esophago-gastro-dudenoscopy was done to all patients. Liver biopsy was done whenever possible. Material was divided for both histopathological examinations [using hematoxin and eosin stain] and detection of hepatic tissue ET-1. ELIZA determined plasma and tissue ET-1. Seventy-five subjects were included in this study [fifty bleeders from varices and 15 non-bleeders]. Age of patients ranged between 28 and 67 years with a mean of 45.1 +/- 8.5 years. Fifty-two were males and thirteen were females. Ten healthy controls with a mean age of 41.6 +/- 13.8 years had also been studied. They were 8 males and 2 females. There was a statistically significant increase in the level of plasma ET-1 in bleeder group [12.90 +/- 5.51] when compared to the non-bleeder group [7.50 +/- 2.52] [p< 0.05]. In the same time, there was a statistically significant increase in the level of hepatic tissue ET-1 in bleeder group [77.6 +/-14.03] when compared to the non-bleeder group [52 +/-10.56] [p< 0.05]. Plasma endothelin-1 level showed significant correlation with parameters of hepatic function. In conclusion, results demonstrated that plasma and hepatic tissue ET-1 might play an important role in the genesis of bleeding varices seen in advanced liver cirrhosis and portal hypertension