Abstract
Context.—Alcoholic liver disease in humans frequently leads to cirrhosis. Experimental models of hepatic fibrogenesis are available, but extrapolation of those findings to human ethanol-induced liver injury is difficult. Hepatic ethanol-induced fibrosis in humans has often been studied in relatively small patient populations. During the past decade, several animal models and human studies have attributed fibrogenesis in the liver to the role played by hepatocytes, Kupffer cells, endothelial cells, and especially stellate cells.
Objective.—To determine the contribution of the main liver cell types to ethanol-induced fibrogenesis. For that purpose, we studied the expression of the following immunologic parameters: smooth muscle–specific α actin (SMSA), CD68, CD34, transforming growth factor β1, intercellular adhesion molecule 1, and collagen types 1 and 3. The Dako LSAB+ kit (peroxidase method) was used.
Design.—We recently studied a large cohort of patients with alcoholic liver disease in France. In this cohort, we found 87 cases in which liver biopsies revealed only pericentral injury with nonpathologic portal areas. We compared cases in which the portal areas were nonpathologic with 324 patients in whom staging ranged from F0 to F3. Patients with cirrhosis (F4) were excluded from evaluation. To stage fibrosis, we used the METAVIR system. Furthermore, we selected 40 cases in which the biopsies measured at least 25 mm in length for further histochemical evaluation. Ten additional normal cases from our archives were used as controls. We divided this patient population into the following 5 groups of 10 patients each: group 1A, F0 with steatosis; group 1B, F0 without steatosis; group 2, F0 to F1, central injury; group 3, F3, fibrosis with multiple septa; and group 4, nonpathologic livers (controls).
Results.—Smooth muscle–specific α actin was expressed by stellate cells, pericentrally, with increasing severity and intensity in the advanced stage of fibrosis of group 3, less intense expression was noted in group 2, and expression was practically absent in group 1 and in nonpathologic controls. CD68 was the best marker for Kupffer cells and was expressed diffusely within the lobules in all groups. Its expression correlated directly with the degree of disease severity, progressing from stage I through stage III, but was absent in nonpathologic livers. CD34 was consistently expressed by endothelial cells in the periportal areas in all groups. The expression of collagen type 1 was intense in the bands of fibrosis or bridging, while type 3 expression was poor. Transforming growth factor β1 and intercellular adhesion molecule 1 were not expressed in any group.
Conclusions.—In this study, stellate cell activation (SMSA) was most intense pericentrally in the early stages and diffusely with progression to fibrosis and maximum intensity in stage III. Kupffer cell activation, as determined by CD68 expression, was intense and diffuse, while endothelial cells expressed CD34 periportally in a similar manner in all stages. Fibrogenesis in human ethanol injury is due to the activity of stellate cells, Kupffer cells, and to a lesser extent, to endothelial cells.
Glucagon receptors in endothelial and Kupffer cells of mouse liver.
