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.

Hepcidin secretion was not directly proportional to intracellular iron-loading in recombinant-TfR1 HepG2 cells: short communication

“…Under physiological conditions, increased hepatic hepcidin secretion in response to elevation in systemic iron levels is a well-established phenomenon [4]. Since hepcidin/iron dysregulation is observed in several hereditary and nonhereditary chronic liver conditions, and hepcidin is recognised as a useful biomarker for liver fibrosis and cirrhosis [8,24], investigation on iron-induced hepcidin response is of immense clinical value. Several studies have investigated on the role of iron on HAMP expression.…”

“…Thus, there is scarcity of information on the regulation of 25-mer hepcidin at post-translational and secretion stages and the role of intracellular iron in these processes. Some reasons for comparatively fewer studies on this topic may include focus on other aspects of hepcidin in the early years following its discovery such as tackling the challenges in the detection and quantification of hepcidin in plasma and urine, difficulties in obtaining hepcidin antibodies due to its small size and limited availability of antigen [31], establishment of standardised protocols for hepcidin assays, identification and analysis of hepcidin in species apart from mammals/human [32], examination of hepcidininducing signalling pathways [27], clinical characterisation of differences in hepcidin levels in the different types of hereditary hemochromatosis [33], analysis of hepcidin levels and hepcidin:ferritin ratios for disease diagnosis [8,25,34] and usage of synthetic hepcidin in therapeutics [35].…”

“…Moreover, hepcidin suppression together with ineffective erythropoiesis contributes to iron-loading anaemias like β-thalassemia [6], whereas excessive hepcidin induction is observed in iron-refractory iron deficiency anaemia [4] and in chronic inflammatory state such as in cancers [7]. Dysregulation of iron and hepcidin is also observed in other chronic liver conditions such as alcoholic liver disease, NAFLD-NASH, viral hepatitis and diabetes [8]. In chronic liver disease whether iron and hepcidin dysregulation is the cause, consequence or mediator of the pathology is not fully known, although hepcidin response to iron alterations appear to be functional [9].…”

Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis—A Novel Form of Non-Apoptotic Cell Death?

“…Regardless of the cause of iron overload, uncontrolled free iron exerts significant oxidative damage in the liver, contributing to the progression of disease and the development of complications such as HCC [106]. Indeed, there is growing evidence supporting the role of iron as a mediator of liver injury and disease beyond well recognized iron-overload disorders such as hemochromatosis and β-thalassemia [16,17].…”

“…Current studies suggests a possible association between ferroptosis and different types of chronic liver disease including hemochromatosis, ALD, HCV, NASH, and HCC, as well as DILI. An imbalance in iron metabolism as well as reactive oxygen species (ROS)-induced lipid peroxidation has been recognized as a mechanism of liver injury in these diseases [16][17][18].…”