Morbidity and mortality of recurrent hepatitis C infection after orthotopic liver transplantation.

Through molecular virological testing it is now clear that HCV reinfection of the allograft is virtually universal in liver transplant recipients. Although histopathological recurrence of hepatitis C occurs in the majority of patients, it is absent in a substantial minority. To date, no prognostic factors, other than genotype 1b, have been identified that accurately predict these dissimilar outcomes. The natural history of recurrent hepatitis C varies. Historically, it has been regarded as generally benign. However, with increasing numbers of patients transplanted for hepatitis C it is now clear that a subgroup of patients develops severe progressive cholestatic hepatitis associated with allograft failure and death without retransplantation. Within 5 years following OLT, approximately 15-20% of patients progress to chronic active hepatitis and another 15-20% become cirrhotic. A minority of patients develop glomerulopathy or vasculitis, which are often associated with cryoglobulinaemia. The impact of immunosuppressive medications and rejection episodes on histopathological recurrence of progressive hepatitis C remains controversial and requires further studies. Although actuarial survival rates of patients transplanted for hepatitis C differ among transplantation centres, it appears that histopathological recurrence of hepatitis C does have an adverse impact on actuarial survival compared to the survival of patients transplanted for autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and metabolic liver diseases. When allograft failure develops in patients with recurrent hepatitis C, retransplantation is indicated, even though recent reports indicate that mortality may be increased, especially with concurrent renal insufficiency.

Zonal differences in ethanol-induced impairments in fluid-phase endocytosis in rat hepatocytes.

We have previously shown that ethanol administration impairs the processes of fluid-phase endocytosis (FPE) and receptor-mediated endocytosis (RME) in isolated rat hepatocytes after as early as 1 week of ethanol administration. The defects in RME were most prominent in the perivenule (PV) region of the liver lobule, the area wherein alcoholic liver disease has been shown to start and predominate. We undertook the present study to see if changes in FPE were likewise more apparent in the PV versus the periportal (PP) region of the liver. For these studies, we fed male Sprague-Dawley rats with an ethanol-supplemented liquid diet or an isocaloric control diet for 1 or 5 weeks. PV and PP hepatocytes were isolated using a digitonin-collagenase perfusion method. Internalization and efflux of the marker dye, Lucifer Yellow, was then examined in the cell populations. After as early as 1 week of feeding, cells from the PV region in ethanol-fed animals showed dramatic impairments in the net internalization of dye, compared with PV cells from the pair-fed controls, and these changes persisted throughout the 5-week feeding period. In contrast, internalization of Lucifer Yellow in cells from the PP region of the liver were not different between control and ethanol animals. Because net internalization represents the balance between uptake into the cells versus efflux from the cells, we examined these components individually. Early uptake of the dye into the cell was not altered by ethanol treatment. The decreased net internalization seemed to be caused by enhanced efflux of the dye, which was significantly increased in PV cells, compared with the same cell type in control animals. Cells from the PP region of the ethanol-fed animals did not exhibit altered efflux after either 1 or 5 weeks of feeding. These results indicate that ethanol-induced impairments in FPE are more dramatic in the PV region of the liver, and these impairments seem to result from an ethanol-induced enhancement of efflux.

Time course of ethanol-induced impairment in fluid-phase endocytosis in isolated rat hepatocytes.

The time-course effects of long-term ethanol administration on fluid-phase endocytosis were studied in isolated rat hepatocytes. Rats were pair-fed an ethanol-supplemented liquid diet or an isocaloric control diet for 3 days, 1 wk, 2 wk or 5 wk. Hepatocytes were isolated and incubated at 37 degrees C with various concentrations of the fluid-phase marker Lucifer yellow. Net internalization of the marker dye was determined. After as little as 1 wk, ethanol-fed rats demonstrated marked decreases in the net internalization of dye compared with pair-fed controls; these changes persisted throughout 5 wk of feeding. Because net internalization is the balance between uptake into the cells vs. efflux from the cells, these components were examined individually. Early uptake was not significantly decreased by ethanol feeding; however, efflux of preloaded Lucifer yellow from cells from the ethanol-fed animals was markedly faster than efflux from pair-fed controls. This increased efflux was more prominent in the longer preload time (90 min) compared with a shorter preload time (15 min), indicating an alteration in dye distribution among various intracellular pools. These ethanol-induced changes in fluid-phase endocytosis were apparent for 1 wk through 5 wk of feeding and were similar for all Lucifer yellow concentrations examined. These results indicate that the decreased net internalization of Lucifer yellow through fluid-phase endocytosis is mainly a result of an ethanol-induced increase in efflux possibly caused by altered intracellular trafficking rather than by reduction in uptake.

The effects of chronic ethanol administration on the rates of internalization of various ligands during hepatic endocytosis.

The purpose of the present study was to further characterize the ethanol-induced impairments in hepatic endocytosis. Specifically, we examined the effects of ethanol treatment on receptor-ligand internalization via the coated and noncoated pit pathways. Insulin, epidermal growth factor (EGF) and asialoorosomucoid (ASOR) were used as model ligands to study internalization by isolated hepatocytes. ASOR and EGF are thought to be internalized strictly in coated pit regions of the cell membrane, while insulin may be internalized in both coated and uncoated membrane regions. Ethanol administration for 5-7 weeks decreased internalization of ASOR and EGF while internalization of insulin was unchanged during a single round of endocytosis of surface-bound ligand. Similarly, a more quantitative measure of endocytosis, the endocytic rate constant, was decreased for EGF and ASOR but not for insulin in livers of experimental rats. When endocytosis of Lucifer yellow, a fluorescent dye known to be internalized in the cell by fluid-phase endocytosis was examined, the initial rates of dye uptake were not significantly altered by alcohol administration. These results indicate that ethanol may selectively impair internalization occurring by coated pits while it has a minimal effect on initial uptake of molecules which are internalized by noncoated membrane regions.