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

• Published in: Journal of hepatology Vol. 26; no. 3; pp. 584 - 592
• Main Authors: Ramm, Grant A., Crawford, Darrell H.G., Powell, Lawrie W., Walker, Neal I., Fletcher, Linda M., Halliday, June W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 1997; Elsevier
• Subjects: Actins - metabolism; Adipocytes - metabolism; Adipocytes - pathology; Adult; Biological and medical sciences; Biopsy; Collagen - metabolism; Desmin - metabolism; Fat-storing cell; Female; Hemochromatosis; Hemochromatosis - genetics; Hemochromatosis - metabolism; Hemochromatosis - pathology; Hepatic fibrosis; Humans; Immunohistochemistry; Iron; Iron - metabolism; Ito cell; Lipocyte; Liver; Liver - metabolism; Liver - pathology; Liver Cirrhosis - etiology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Male; Medical sciences; Metabolic diseases; Metals (hemochromatosis...); Middle Aged; Other metabolic disorders; Phlebotomy; Hepatic fibrosis; Fat-storing cell; Lipocyte; Hemochromatosis; Liver; Iron; Ito cell; Spider cell; Human; Pathology; Digestive system; Biopsy; Pathogenesis; Pigments; Metabolic diseases; Activation; Enzymopathy
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/S0168-8278(97)80424-2

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 Perls' 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.