Hepatic stellate cell activation in genetic haemochromatosis : Lobular distribution, effect of increasing hepatic iron and response to phlebotomy

Background/Aims: Activated hepatic stellate cells produce increased levels of collagen in animal models of chronic iron overload; however, their role in human genetic haemochromatosis is unknown. This study examined the relationship between hepatic iron concentration and hepatic stellate cell activation in genetic haemochromatosis. Methods: Liver biopsies from 75 patients (55 with haemochromatosis, 14 haemochromatosis patients both pre- and post-phlebotomy and six non iron-loaded disease control subjects) were stained for iron using Perlsʹ Prussian Blue. Thirty biopsies in which there was no evidence of either steatosis or inflammation were subjected to immunohistochemistry for α-smooth muscle actin and desmin and counterstained for iron. Forty-five biopsies demonstrated either steatosis or inflammation, in addition to excess iron. Results: Stellate cells were identified by light microscopy as perisinusoidal cells containing numerous intracellular fat droplets. α-Smooth muscle actin was detected in biopsies with an hepatic iron concentration> 60 μmol/g dry weight. Increasing hepatic iron concentration and hepatic iron index correlated with an increase in α-smooth muscle actin expression (r=0.81 and 0.72, respectively). Phlebotomy resulted in a significant decrease in α-smooth muscle actin expression. In early disease prior to histological evidence of collagen deposition, whilst activated stellate cells were located in Zone 1, greater numbers were found in Zones 2 and 3 distal to the region of heaviest 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 by iron removal. Humoral factors from either iron-loaded hepatocytes or activated Kupffer cells may be responsible for early stellate cell activation in areas of the liver remote from heavy iron loading.