Iron overload, inflammation and fibrosis in genetic haemochromatosis

Abstract

Genetic haemochromatosis (GH) is one of the commonest inherited disorders, with a frequency of 0.4–1.0% in people of northern European origin. Affected individuals absorb excessive amounts of iron from the gut, leading to iron deposition (siderosis) in many internal organs. Clinical manifestations mainly relate to hepatic, cardiac and pancreatic disease. Complications of liver disease include progressive fibrosis leading to cirrhosis and hepatocellular carcinoma, and these are the main cause of death in patients with GH. Fibrosis is also a feature of iron overload in the pancreas and heart. Although the association between iron overload in the liver and hepatic fibrosis is well recognised, the pathogenetic mechanisms of hepatic fibrogenesis in this situation have not been fully elucidated. In most other chronic liver diseases associated with fibrosis (e.g. chronic viral hepatitis or alcoholic liver disease) inflammation is also present and is thought to play and important role in the pathogenesis of hepatic fibrosis. Activated lymphocytes produce a number of cytokines and growth factors such as tumour necrosis factor alpha (TNF-a) and beta (TNF-b), interferon gamma (IFN-g), interleukin-1 (IL-1), interleukin-10 (IL-10) and transforming growth factor beta 1 (TGF-b1). These result in the activation of hepatic stellate cells, which are thought to be the major source of excess collagen in liver cirrhosis. Lymphocyte-derived cytokines can also activate Kupffer cells, leading to the further production of cytokines and growth factors involved in stellate cell activation [1]. Although minor degrees of inflammatory cell infiltration are sometimes seen in GH, these are not generally thought to be an important component of liver damage and alternative pathways of hepatic fibrogenesis, independent of inflammation, have therefore been postulated [2]. The study by Bridle et al, which appears in this issue of the Journal [3], further investigates the relationship between iron overload and inflammation in the liver and provides evidence for a ‘sub-morphological inflammatory process’, which may play a role in the development of iron-induced hepatic fibrosis in haemochromatosis.