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Iron metabolism and its disorders 

Iron metabolism and its disorders

Iron metabolism and its disorders

T.M. Cox

and John B. Porter



Section on treatment updated.

Further reading updated.

Updated on 30 May 2013. The previous version of this content can be found here.
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date: 28 April 2017

Iron is a component of haem proteins and nonhaem enzyme systems required for oxygen transport, mitochondrial respiration, and other key metabolic reactions. The metal exists in two readily interconvertible redox states (divalent ferrous and trivalent ferric iron) that are highly reactive and toxic to tissues. High-affinity iron-binding proteins, which form stable ferric complexes, have evolved to facilitate iron transport and delivery to sites of storage and utilization, including haem biosynthesis.

Iron homeostasis

Iron is an essential constituent of the diet, with the recommended daily allowance being 10 to 20 mg depending on the bioavailability of food iron components: haem iron may be more readily absorbed than inorganic iron; dietary phytates and some medications (e.g. antacids, proton pump inhibitors, H2 antagonists) reduce iron absorption. The requirement for iron is greater in patients with recurrent bleeding, during pregnancy, and during periods of growth in childhood and adolescence.

Iron absorption—this occurs in the duodenum and upper jejunum. The processes are complex, but the following are involved: (1) divalent metal transporter protein (DMT1)—essential for uptake of ferrous ions; (2) ferrireductase—expression in the apical microvillous membrane of the intestinal mucosa appears to be induced in response to nutritional iron deficiency; (3) uptake of haem by enterocytes—probably mediated principally by an as-yet-unknown membrane protein; (4) ferroportin—mediates egress of ferric ions from enterocytes.

Body iron composition—most iron in the body is coordinated in protoporphyrin IX as haem. Small amounts of iron circulate in the plasma, bound in the ferric form to the glycoprotein transferrin. Iron is stored in the mononuclear phagocyte (reticuloendothelial) system principally as intracellular ferritin and its proteolytic degradation product, haemosiderin.

Iron homeostasis—this is maintained by rigorous control of absorption from the diet, which appears to be orchestrated principally by the actions of the peptide hormone, hepcidin, which is synthesized by the liver and regulates the process by inhibiting efflux of iron from enterocytes. The capacity for safe storage of iron in intracellular deposits (mainly in tissue macrophages) is limited, as is the physiological capacity for disposal of iron by excretion from the body.

Iron deficiency

Clinical features—the commonest manifestations are pallor, angular cheilosis, atrophic glossitis, and dystrophy of the nails with longitudinal ridging and koilionychia.

Investigation and diagnosis—iron deficiency results in a microcytic anaemia, usually in association with an unequivocal reduction in serum transferrin saturation (<16%) and a reduced serum ferritin concentration (<12 µg/litre). In many cases the cause will be obvious, e.g. menorrhagia in a young woman, but in other cases diligent investigation will be required, e.g. to diagnose or exclude colonic carcinoma.

Causes—iron-poor diets rarely cause iron-deficiency anaemia, except in growing children, and the following require consideration: (1) loss of iron—common causes include menstruation, pregnancy, from the gastrointestinal tract (hookworms, ulcerating lesions); (2) malabsorption of iron—e.g. coeliac disease.

Treatment—aside from dealing with the underlying cause, this involves iron-replacement therapy, which should normally be administered orally, although parenteral preparations are occasionally necessary.

Iron storage disease

Ferrous and ferric ions are chemically reactive so that excess of iron is toxic; tissues with elevated concentrations of the metal show functional impairment and structural injury leading to ‘iron storage disease’ (haemochromatosis).

Clinical features—these include (1) heart disease—cardiomyopathy leading to cardiac failure and/or (sometimes fatal) arrhythmia, which are a leading cause of death in refractory anaemias such as β‎-thalassaemia; (2) fibrotic liver disease; (3) endocrine failure—e.g. hypogonadotrophic hypogonadism, diabetes mellitus; and (4) skin and joint manifestations.

Investigation and diagnosis—iron storage disease is usually suspected on the basis of (1) raised serum ferritin measurements, and (2) when the saturation of serum transferrin is over 60%. Definitive diagnosis may require tissue biopsy and specific elemental analysis or histochemical staining for iron.

Causes—these are (1) genetic, hereditary, or primary haemochromatosis—see Chapter 12.7.1); or (2) secondary—including (a) diseases characterized by dyserythropoiesis—e.g. thalassaemia, sideroblastic anaemia—which are associated with increased dietary iron absorption by the intestine; (2) repeated blood transfusion.

Treatment—in the early stages, potentially fatal sequelae of iron toxicity can be prevented by prompt institution of measures to deplete iron: (1) where the bone marrow is normal—repeated venesection; (2) with disordered haematopoiesis—iron chelators; daily administration of parenteral desferrioxamine has provided the best standard of care, but this treatment is challenging for lifelong use, and powerful orally active chelators hold promise for improved acceptability in patients with better therapeutic efficacy overall.

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