Hepatic stellate cell activation occurs in the absence of hepatitis in alcoholic liver disease and correlates with the severity of steatosis.
OBJECTIVE
There is now overwhelming evidence that hepatic stellate cells are the principal cells involved in hepatic fibrogenesis. In several different forms of liver injury it has been demonstrated that they proliferate and undergo phenotypic transformation (activation) into matrix-producing, myofibroblast-like cells in response to necroinflammation, mediated in part, by Kupffer cell-derived factors. In alcoholic liver disease, however, the observation that fibrosis can occur in the absence of alcoholic hepatitis has cast doubt on necroinflammation being an absolute pre-requisite for alcohol-related hepatic stellate cells proliferation/activation and subsequent fibrogenesis.


METHODS
Evidence for hepatic stellate cells activation has been sought in liver biopsies from 38 well-documented alcoholic patients with no evidence of alcoholic hepatitis or cirrhosis and eight normal controls. Activated hepatic stellate cells were identified immunohistochemically using a specific monoclonal antibody to detect cytoplasmic alpha smooth muscle actin (alpha-SMA), which is not present in quiescent cells. Kupffer cells were detected with the monoclonal antibody KP1 and collagen was stained using Sirius red. Immunoreactive cells and the amount of fibrosis were quantified, using a Kontron Vidas Image Analyser. Steatosis was graded from 0 (none-few hepatocytes containing fat) to 3 (> 2/3 hepatocyte containing fat).


RESULTS
Biopsies from alcoholic patients contained significantly greater numbers of activated hepatic stellate cells (alpha-SMA+ve) than control biopsies (average cell counts: 84 +/- 11/mm2 versus 23 +/- 5/mm2, p < 0.0001). There was no correlation between numbers of activated hepatic stellate cells and either numbers of Kupffer cells or amount of fibrosis. There was, however, a significant correlation between hepatic stellate cells activation and steatosis (grade 0, 15 +/- 7 cells/unit area (n = 4), grade 1, 56 +/- 16 (n = 13), grade 2, 85 +/- 20 (n = 9), grade 3, 137 +/- 19 (n = 12); p = 0.002, ANOVA).


CONCLUSIONS
These results suggest that neither necroinflammation nor an increase in Kupffer cells is an absolute prerequisite for hepatic stellate cells proliferation/activation and subsequent fibrogenesis in alcoholic liver disease. The correlation between alcohol-induced hepatic stellate cells activation and severity of steatosis is likely to reflect that both are attributable in part to the metabolic consequences of ethanol metabolism, namely increased concentrations of acetaldehyde and lipid peroxidation.
Reeves
H L
HL
Department of Medicine, Medical School, University of Newcastle upon Tyne, UK.
Burt
A D
AD
Wood
S
S
Day
C P
CP
D000704:Analysis of Variance; D001706:Biopsy; D002452:Cell Count; D018450:Disease Progression; D005235:Fatty Liver, Alcoholic / Q000473:pathology*; D006505:Hepatitis / Q000473:pathology; D006801:Humans; D007728:Kupffer Cells / Q000473:pathology; D008099:Liver / Q000473:pathology*; D008104:Liver Cirrhosis, Alcoholic / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000473:pathology; D014170:Transformation, Genetic