HEPATIC STELLATE CELL ACTIVATION IN GENETIC HEMOCHROMATOSIS - LOBULARDISTRIBUTION, EFFECT OF INCREASING HEPATIC IRON AND RESPONSE TO PHLEBOTOMY

Background/Aims: Activated hepatic stellate cells produce increased le vels of collagen in animal models of chronic iron overload; however, t heir role in human genetic haemochromatosis is unknown, This study exa mined the relationship between hepatic iron concentration and hepatic stellate cell activation in genetic haemochromatosis. Methods: Liver b iopsies from 75 patients (55 with haemochromatosis, 14 haemochromatosi s patients both pre- and post-phlebotomy and six non iron-loaded disea se control subjects) were stained for iron using Perls' Prussian Blue, Thirty biopsies in which there was no evidence of either steatosis or inflammation were subjected to immunohistochemistry for alpha-smooth muscle actin and desmin and counterstained for iron, Forty-five biopsi es demonstrated either steatosis or inflammation, in addition to exces s iron. Results: Stellate cells were identified by light microscopy as perisinusoidal cells containing numerous intracellular fat droplets, alpha-Smooth muscle actin was detected in biopsies with an hepatic iro n concentration >60 mu mol/g dry weight, Increasing hepatic iron conce ntration and hepatic iron index correlated with an increase in alpha-s mooth muscle actin expression (r = 0.81 and 0.72, respectively), Phleb otomy resulted in a significant decrease in alpha-smooth muscle actin expression, In early disease prior to histological evidence of collage n deposition, whilst activated stellate cells mere located in Zone 1, greater numbers were found in Zones 2 and 3 distal to the region of he aviest iron overload. Conclusions: This study has demonstrated for the first time in humans a correlation between hepatic iron concentration and stellate cell activation in haemochromatosis, which is reversed b y iron removal, Humoral factors from either iron-loaded hepatocytes or activated Kupffer cells may be responsible for early stellate cell ac tivation in areas of the liver remote from heavy iron loading.