Iron Overload Disorders and Genetic Pathogenesis
Summary
Iron overload disorders encompass a spectrum of conditions in which excessive iron accumulation leads to tissue damage and organ dysfunction. Hereditary haemochromatosis, the most prevalent genetic form, arises from pathogenic variants in the HFE gene—particularly the p.Cys282Tyr mutation—that impair hepcidin synthesis and trigger unregulated intestinal iron absorption. Less common subtypes result from mutations in genes encoding ferroportin (SLC40A1), transferrin receptor 2 (TFR2), hemojuvelin (HJV) and hepcidin antimicrobial peptide (HAMP). The consequent elevation in transferrin saturation and serum ferritin facilitates iron deposition in the liver, heart, pancreas, joints and endocrine glands, promoting oxidative stress and fibrosis. Variable penetrance and expressivity reflect interactions between modifier loci, environmental factors such as adiposity and diet, and the central iron‐regulatory network. Early detection through biochemical screening and genetic testing enables timely initiation of phlebotomy or chelation, thereby preventing irreversible organ injury. Advancements in understanding the molecular pathways of iron sensing and hepcidin regulation have informed precision‐medicine approaches and underpin emerging strategies for population screening and targeted therapy.
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Iron Overload Disorders and Genetic Pathogenesis publication trend
The graph below shows the total number of articles in iron overload disorders and genetic pathogenesis across all publications each year (not limited to Nature Index journals).
Technical terms
Haemochromatosis: A genetic disorder of excessive dietary iron absorption leading to systemic iron overload and organ damage.
HFE gene: A gene encoding a protein that interacts with transferrin receptor to regulate hepcidin synthesis and iron uptake.
Hepcidin: A liver-derived peptide hormone that controls iron egress from enterocytes and macrophages by inhibiting the iron exporter ferroportin.
Transferrin saturation: The proportion of iron-binding sites on transferrin occupied by iron, used to assess iron overload.
Ferritin: The intracellular iron‐storage protein whose serum concentration correlates with total body iron stores.
Phlebotomy: A therapeutic procedure involving serial blood removal to deplete excess body iron.
References
- Incidence of liver complications with hemochromatosis-associated HFE p.C282Y homozygosity: The role of central adiposity. Hepatology (2024).
- Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. The BMJ (2019).
- Hyperferritinemia—A Clinical Overview. Journal of Clinical Medicine (2021).
- Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis. International Journal of Molecular Sciences (2012).
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