Iron and liver fibrosis: Mechanistic and clinical aspects

Abstract

Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.

Keywords: Iron; Liver pathologies; Liver fibrosis; Hepatic stellate cells; Cirrhosis

Core tip: Excess iron is observed in several liver pathologies, where it can accelerate the progression of liver fibrosis to cirrhosis and hepatocellular carcinoma, regardless of disease aetiology. This review narrates the role of excess iron in liver fibrosis. It examines the mechanisms by which iron enhances fibrogenic responses and describes various iron-related clinical pathologies. Furthermore, it evaluates the significance of iron and iron-related proteins in the diagnosis and therapeutics of liver fibrosis. The review is unique in that it includes both, cellular mechanisms and clinical aspects of liver fibrosis pertaining to iron. This makes it distinct from previous published reviews.