Iron Metabolism and Genetic Disorders in Liver Health

Iron is an essential trace element required for oxygen transport, energy production and DNA synthesis. The liver occupies a central role in systemic iron homoeostasis, acting as a primary storage site, producer of the regulatory hormone hepcidin and as a nexus for iron recycling. Dietary iron is absorbed by enterocytes under the control of ferroportin and transported in complex with transferrin to the liver, where ferritin sequesters excess metal and prevents oxidative damage. Genetic disorders that perturb these pathways give rise to clinically significant liver disease. Mutations in the HFE gene, most notably C282Y and H63D variants, diminish hepcidin expression and promote uncontrolled iron uptake, leading to hereditary haemochromatosis with progressive hepatic fibrosis, cirrhosis and elevated risk of hepatocellular carcinoma. Alterations in non-HFE regulators—such as hemojuvelin, transferrin receptor 2 and matriptase-2—further exemplify the genetic complexity of iron overload syndromes. Conversely, iron insufficiency and dysregulation also influence non-alcoholic fatty liver disease through disrupted mitochondrial function and lipid metabolism. Recent advances in genetic screening, iron chelation strategies and targeted modulation of hepcidin offer new avenues for diagnosis and therapy. A thorough understanding of the interplay between iron homoeostasis and genetic variants is therefore critical for the prevention, early detection and management of iron-related liver pathology worldwide.

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Iron Metabolism and Genetic Disorders in Liver Health publication trend

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Technical terms

Hepcidin: Peptide hormone produced by the liver that regulates systemic iron balance by inhibiting ferroportin-mediated iron export.

Ferroportin: Cellular iron exporter located on enterocytes, macrophages and hepatocytes that controls iron release into the circulation.

HFE gene: Gene encoding a major histocompatibility complex class I–like protein that modulates iron uptake via interaction with transferrin receptor; mutations cause hereditary haemochromatosis.

Transferrin: Plasma glycoprotein that binds ferric iron and delivers it to cells through receptor-mediated endocytosis.

Ferritin: Intracellular protein complex that stores iron in a soluble, non-toxic form and releases it in a controlled manner.

Non-alcoholic fatty liver disease (NAFLD): Spectrum of liver disorders characterised by excessive fat accumulation in hepatocytes in the absence of significant alcohol intake.

Hereditary haemochromatosis: Autosomal recessive disorder of iron overload most commonly caused by HFE mutations, leading to progressive hepatic iron deposition and tissue injury.

References

1. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls. PLOS ONE (2016).
2. Association between hereditary hemochromatosis and hepatocellular carcinoma: a comprehensive review. Hepatoma Research (2020).
3. The Hereditary Hemochromatosis Protein, HFE, Specifically Regulates Transferrin-mediated Iron Uptake in HeLa Cells*. Journal of Biological Chemistry (1999).
4. Dietary and Sentinel Factors Leading to Hemochromatosis. Nutrients (2019).