Iron Overload Screening and Diagnosis
Iron Overload Screening and Diagnosis
US Oncological Disease 2006 - Issue II
Published: October 2008
Published: October 2008
Humans contain approximately 3–4g of iron, most of which is present as hemoglobin, as iron bound to transferrin in plasma, or as iron-containing proteins such as myoglobin, cytochromes, and catalase.The remainder is in the storage form of ferritin or hemosiderin (about 1g). Mechanisms for dietary absorption and iron elimination are limited. The body efficiently recycles iron and stores the excess in the liver. This homeostasis may be disrupted in a number of acquired and hereditary states, resulting in iron overload. The most common acquired cause for excess iron in the body is frequent red cell transfusions required by patients with thalassemia, sickle cell disease, chronic bone marrow failure states such as aplastic anemia, and syndromes marked by ineffective erythropoiesis like myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD). Among the hereditary causes of iron overload are C282Y mutations in the HFE gene,1 which can lead to increased absorption of iron from the gut. Approximately 1% of homozygous individuals can develop clinical hemochromatosis.2
Deposition of excess iron from multiple transfusions or increased absorption preferentially occurs in the liver, heart, pituitary, thyroid, pancreas, the gonads, and the skin. Saturation of transferrin receptors leaves non-transferrin-bound iron, which generates free radicals that harm membranes, proteins, and nucleic acids, resulting in tissue damage. This damage can be minimized or prevented through chelation; therefore, all patients at risk of iron overload should be screened periodically.Assessment of iron levels can be performed by the following methods.
Frequency of Transfusions
Normal erythropoiesis accounts for approximately twothirds of the iron content of the human body. The scenescent red blood cells (RBC) are taken up by the reticuloendothelial macrophages of the liver and the hemoglobin is efficiently catabolized to release the iron for recycling. Since there is no physiologic mechanism for removal of iron, chronic transfusion-dependent patients have increasing iron stores and develop an iron excess of ~0.4 to 0.5mg/kg/day.3With a single unit of blood containing approximately 200mg of iron, 10–20 transfusions can lead to clinical signs of iron overload.3
Serum Ferrit in Levels
After intake, iron is normally sequestered in protein complexes. Serum transferrin is the iron transport protein in blood and extracellular fluid, while ferritin binds intracellular iron. Ferritin is a protein, found mainly in the liver, that can store approximately 2,250 iron ions. Serum ferritin level has traditionally been used as an indicator of total body iron stores under steady state conditions. However, it may not always be the most reliable test since it is also an acute phase reactant and may be elevated either because of the disease process itself or due to inflammation. This uncertainty, at least for inflammation, can be eliminated by documenting a normal level of C-reactive protein in the presence of high ferritin levels. The advantages of measuring ferritin are that the test is non-invasive and has been well correlated with liver biopsy or surrogate measurements of total body iron.4 Serum ferritin, therefore, remains the most inexpensive and widely available method to document iron overload.When the levels of ferritin rise to >1,000ng/ml, it is important to consider some form of treatment for the iron overload and the efficacy of chelation can be monitored by serum ferritin levels. It should be noted, however, that ferritin levels represent approximations since the effect of chelation on ferritin is not always linear and may differ between various chelating agents.
References:
- Feder JN, Gnirke A,Thomas W, et al.,“A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis”, Nat Genet (1996);13: pp. 399–408.
- Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T, “Penetrance of 845G—> A (C282Y) HFE hereditary haemochromatosis mutation in the USA”, Lancet (2002);359(9302): pp. 211–218.
- Porter JB,“Practical management of iron overload”, Br J Haematol (2001);115(2): pp. 239–252.
- Beutler E, Felitti V, Ho N, Gelbart T,“Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease”, Acta Haematol (Basel) (2002);107: pp. 145–149.
- Ernst O, Sergent G, Bonvarlet P, et al., “Hepatic iron overload: diagnosis and quantification with MR imaging”, AJR Am J Roentgenol (1997);168: p. 1205.
- St Pierre TG, Clark PR, Chua-Anusom W, “Measurement and mapping of liver iron concentrations using magnetic resonance imaging”, Ann N Y Acad Sci (2005);1054: pp. 379–385.
- Anderson LJ, Holden S, Davis B, et al., “Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload”, Eur Heart J (2001);22: pp. 2171–2179.
- Fischer R, Longo F, Nielsen P, Engelhardt R, “Monitoring long-term efficacy of iron chelation therapy by deferiprone and desferrioxamine in patients with beta-thalassaemia major: application of SQUID biomagnetic liver susceptometry”, Br J Haematol (2003);121: p. 938.
