Iron overload diseases: causes, symptoms, diagnosis, treatment

When iron (Fe) is taken in in quantities exceeding the body's needs, it is deposited in tissues as hemosiderin. Iron deposition causes tissue damage (with a total iron content in the body > 5 g) and is called hemochromatosis. Local or generalized iron deposition without tissue damage is called hemosiderosis. Iron overload diseases can be primary (genetically determined) with impaired iron metabolism or secondary, caused by other diseases in which iron intake or release increases. Iron can accumulate in almost all tissues, but most often pathological changes develop with iron deposition in the liver, thyroid gland, pituitary gland, hypothalamus, heart, pancreas and joints. Liver damage leads to increased aminotransferase levels (ALT and AST), fibrosis and cirrhosis.

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Hemosiderosis

Local hemosiderosis may be caused by recurrent hemorrhages into an organ. Iron released from red blood cells may lead to significant deposition of hemosiderin in tissues. The most frequently affected organ is the lung, caused by recurrent pulmonary hemorrhages, both idiopathic (eg, Goodpasture's syndrome) and those due to chronic pulmonary hypertension (eg, primary pulmonary hypertension, pulmonary fibrosis, severe mitral stenosis). Sometimes iron loss leads to the development of iron deficiency anemia, since iron in the tissues cannot be reutilized.

Renal hemosiderosis may result from intense intravascular hemolysis. Free hemoglobin is filtered in the glomeruli, and iron is deposited in the kidneys. The renal parenchyma is not damaged, but severe hemosiderinuria may lead to iron deficiency.

Ferroportin disease

Ferroportin disease occurs primarily in southern Europeans and results from an autosomal dominant mutation of the SLC 40 A1 gene. The disease presents in the first decade of life with elevated serum ferritin levels with low or normal transferrin levels, with progressive increases in transferrin saturation in the 3rd and 4th decades of life. Clinical manifestations are milder than in JPE disease and include moderate liver damage and mild anemia. Major phlebotomies are poorly tolerated, and monitoring of hemoglobin levels and transferrin saturation is necessary.

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Transferrin and ceruloplasmin deficiency

In transferrin deficiency, absorbed iron not bound to transferrin enters the portal system and is deposited in the liver. Its subsequent transport to the site of red blood cell production is reduced due to transferrin deficiency. In ceruloplasmin deficiency, there is a shortage of ferroxidase, leading to a disruption in the conversion of divalent iron to trivalent iron, which is necessary for binding to transferrin, which disrupts the transport of iron from the intracellular pool to the blood plasma, causing iron accumulation in tissues.

Impaired iron transport is suspected in patients with iron overload that develops early in life or when features of iron overload are present but genetic testing is normal. Diagnosis is based on serum transferrin (or iron-binding capacity) and ceruloplasmin. Treatment is experimental.

An autosomal recessive form of hemochromatosis may be caused by a mutation in transferrin receptor 2, a protein that controls transferrin saturation. Symptoms and signs are similar to those of HFE.

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Secondary iron overload

Secondary iron overload may occur in thalassemia or sideroblastic anemia, which are disorders of erythropoiesis. Secondary acquired overload may occur after exogenous iron administration through repeated massive transfusions or through treatment with iron dextran. Each unit of transfused blood provides 250 mg of iron. Significant iron deposition may occur with administration of > 20 g (i.e., about 80 units of blood). Iron overload may occur due to abnormal erythropoiesis in thalassemia, sideroblastic anemia, hemoglobinopathies, and red cell enzyme abnormalities. When erythropoiesis is impaired, iron absorption is increased, possibly due to pepsidin. Impaired erythropoiesis may be evident from the patient's history. Iron overload is determined by increases in serum iron, transferrin saturation, and serum ferritin.

Phlebotomy may not always be indicated because these diseases are often accompanied by anaemia, which limits the ability to exfuse sufficient blood. If anaemia is present, deferoxamine [1–2 g daily over 8–24 h in adults; 20–40 mg/(kg/day) over 8–24 h in children] given as a slow intravenous infusion overnight, 5–7 days/week, is effective in reducing iron stores. Tachyphylaxis may occur with deferoxamine therapy, so the effectiveness of therapy should be monitored (usually by measuring urinary iron). Red urine indicates iron loss of more than 50 mg/day. Goals of treatment and monitoring (with serum iron and transferrin levels) are the same as for primary haemochromatosis.

Unexplained Iron Overload

Parenchymatous liver disease, alcoholic liver disease, nonalcoholic steatohepatitis, and chronic hepatitis C may be associated with elevated iron levels. The mechanism is unknown, although primary hemochromatosis may coexist and should be excluded. In patients without primary hemochromatosis, iron reduction does not improve liver function.