There is no physiological mechanism for eliminating excess iron from the body, so iron absorption is normally regulated to avoid accumulation.
Iron overload (hemosiderosis) occurs in disorders associated with excessive absorption or in patients with severe refractory anaemias who receive regular blood transfusion.
Excessive iron deposition in tissues may result in serious damage to organs, particularly the heart, liver and endocrine organs.
Hepatic disease (fibrosis, cirrhosis, hepatocellular carcinoma), endocrine disturbances such as diabetes mellitus, hypothyroidism or impotence, melanin skin pigmentation and arthropathy (resulting from pyrophosphate deposition). In some severe cases there is cardiac failure or arrhythmia.

Hereditary Hemochromatosis

Most patients are homozygous for a missense mutation in the *HFE* gene which leads to insertion of a tyrosine residue rather than cysteine in the mature protein (C282Y).
- The allele has a prevalence of approximately 1 in 300 within the white North European population. Only a small proportion of people who are homozygous for the mutation actually present with clinical features of the disease, and these usually show a serum ferritin greater than 1000μg/L.
- A second mutation resulting in a histidine to aspartic acid substitution H63D is found with the C282Y mutation in approximately 5% of patients but homozygotes for the H63D mutation do not have the disease.
HFE is involved in hepcidin synthesis, and other rarer forms are caused by mutations in the genes for hemojuvelin, transferrin receptor 2 and hepcidin, all resulting in low serum hepcidin levels.
Treatment is with regular venesection, initially at 1–2‐week intervals, with each unit of blood removing 200–250mg iron. Venesection is monitored by serum ferritin and the aim is to restore this to normal.

Genetic iron overload in Asian populations is usually due to these mutations rather than mutation of HFE.
Ferroportin gene mutations usually cause reticuloendothelial but not parenchymal cell iron overload but may rarely cause parenchymal overload, depending on the site of the mutation in the ferroportin gene.
Mutations of the ferritin light chain gene cause a raised monoclonal serum ferritin with cataracts resulting from ferritin deposition in the eye but no tissue iron overload.

Thalassemia

Moderately severe forms of thalassemia may lead to increased iron levels even in patients who do not need regular blood transfusions. This is due to increased absorption and may lead to increased levels of iron in the liver.
Iron chelation is indicated if the liver iron concentration is above 5mg/g dry weight, where serum ferritin reaches 800μg/L or when the iron leads to organ damage.
Iron damages the liver and the endocrine organs with failure of growth, delayed or absent puberty, diabetes mellitus, hypothyroidism and hypoparathyroidism.
In the absence of intensive iron chelation, death occurs in the second or third decade in thalassaemia major, usually from congestive heart failure or cardiac arrhythmias.
Serum ferritin and liver iron correlate poorly with cardiac iron.

Skin pigmentation as a result of excess melanin and haemosiderin gives a slate grey appearance even at an early stage of iron overload.

Iron overload is a major problem in patients who require long-term red cell transfusion support for chronic anemias because of bone marrow failure or chronic hemolysis.
Each 500mL of transfused blood contains approximately 250mg iron and iron overload is inevitable unless iron chelation therapy is given. 1ml of pRBC (Hct 80%) contains 1mg of iron.
To make matters worse, iron absorption from food is increased in β‐thalassemia major and many other anemias secondary to ineffective erythropoiesis because of inappropriately low serum hepcidin levels.
This is thought to be due to release of proteins from early erythroblasts that inhibit hepcidin synthesis.
Non‐transferrin bound iron may appear in plasma, because transferrin is 100% saturated, and cause widespread iron deposition in parenchymal tissues.

Chelation is started in thalassemia major after 10–15 units have been transfused.
Chelation is given to keep the serum ferritin level between 1000 and 1500μg/L, when the body iron stores are approximately 5–10 times normal.

In use for over 40 years, but is not active orally.
It is usually given by subcutaneous infusion over 8–12 hours for 5–7 days each week; vitamin C can be given to further increase iron excretion.
Most iron is lost in the urine but up to one‐third is also excreted in the stools.
- Deferoxamine chelates iron released by the RES after the catabolism of senescent RBCs and is excreted in the urine.
- Unbound deferoxamine is absorbed by the hepatic parenchymal cells and chelates iron from the intracellular pool which is excreted in bile.