Secondary Iron Overload

Haemochromatosis associated with insulin resistance Secondary iron overload, with increased iron absorption... 

Another genetic defect results in failure of hepatic synthesis of ceruloplasmin (aceruloplasminemia), which is a neurodegenerative disease. Retinal damage, secondary iron overload, and insulin-dependent diabetes present in the fourth to fifth decade of life. ... 

Secondary hemochromatosis is the consequence of the uicreased administration and absorption of iron. The administration of iron includes that given with the transfusions that are required in certain anemic patients and the ill-advised and unfortunate administration of iron to anemic patients who are not actually iron deficient. The most common causes of secondary hemochromatosis are thalassemia major and acquired myelodysplastic states, but there are many other circumstances in which secondary iron overload occurs, including pyruvate kinase deficiency and congenital dyserythropoietic anemias. 

S. S. Bottomley Secondary iron overload disorders. Seminars in Hematology 35,77(1998). 

A second form of storage iron is haemosiderin (Weir et al., 1984). This is deposited in humans as a response to the condition of iron overload. Haemosiderin forms as insoluble granules with electron dense cores surrounded by a protein shell. It exists in two forms primary haemosiderin is the result of iron overload due to excessive adsorption of iron in the gut, whereas the secondary form is caused by the numerous blood transfusions which are used to treat thallassaemia (a form of anaemia). Electron diffraction indicated that the iron core in primary haemosiderin is a 3-line ferrihydrite with magnetic hyperfine splitting only below 4 K and, in the secondary form, consists of poorly ordered goethite. As goethite is less soluble in ammonium oxalate buffer solution (pH 3) it has a lower intrinsic toxicity (Mann et al., 1988). 

There are several inherited diseases which are associated with the gradual excess accumulation of iron via the gut. Hereditary haemochromatosis is a relatively rare condition in which iron absorption is increased through an unidentified mechanism. This condition usually presents in the fourth or fifth decade of life with the secondary effects of iron overload such as heart failure, liver cirrhosis or sugar diabetes. As the production of red cells is unaffected, the excess iron can be removed slowly by venesecting a unit of blood every week for up to two years. However, in the acute situation, iron chelation may be used to remove toxic low-molecular-weight iron until sufficient negative iron balance has been obtained by venesection. 

When used in patients without iron overload, deferoxamine can cause iron deficiency (12). In 20 patients, there were falls in ferritin concentrations in six, requiring withdrawal of deferoxamine and parenteral administration of iron dextran (12). Monitoring ferritin concentrations is therefore recommended in patients receiving deferoxamine for aluminium overload. On the other hand, the administration of deferoxamine (500mg/day by subcutaneous infusion) improves chronic anemia in patients with rheumatoid arthritis (77). This effect is thought to be achieved through increased erythropoietin responsiveness, secondary to iron chelation. Iron chelation with deferoxamine also improves hemopoiesis in patients with myelodysplastic syndromes and can reduce transfusion dependency (78). Exactly how deferoxamine works in these patients remains to be explained. 

Iron-overload disease, or hemochromatosis, may occur as a consequence of an, as yet, undefined genetic defect, or as a secondary effect of another medical disorder, such as thalassemia. In the former condition, primary hemochromatosis, iron accumulates in various tissues because of a lack of control of iron absorption from the gut. In the latter, or secondary hemochromatosis, the accumulation of iron results from the breakdown of red blood cells and the consequent need for frequent blood transfusions, which lead to an increase in the levels of tissue iron. In both cases the predominant store for iron is hemosiderin (147). 

Iron deficiency and iron overload are the major disorders of iron metabolism. There are, in addition, many diseases in which abnormal distribution of iron may play primary or secondary roles. Included are such disorders as hyperfer-ritinemia with cataracts, aceruloplasminemia, GRACILE syndrome, neuroferritinopathy, atransferrinemia, and possibly neurodegenerative disease such as Parkinsonism, Hallervorden-Spatz syndrome, and Alzheimer s disease. These latter disorders will not be discussed further here. 

A number of disease states are caused by excessive accumulation of iron in the body. The term primary identifies diseases owing to a recognizable hereditary defect in proteins directly involved in iron homeostasis, as opposed to conditions in which iron overload is secondary to known factors or diseases. 

Iron overload can also cause glucose intolerance secondary to pancreatic injury. Indeed diabetes is one of the classical features of hemochromatosis (Sheldon, 1935 Root, 1929), although a considerable proportion of individuals with hemochromatosis exhibit an impaired glucose tolerance without clinical diabetes (Dymock et al., 1972 Phelps et al., 1989). There was some initial controversy over whether diabetic complications occurred in diabetes induced by hemochromatosis. 

It appears, however, that hemochromatosis-induced diabetes results in complications that are indistinguishable from diabetes mellitus (Becker and Miller, 1960 Dymock et al., 1972). Indeed several authors have suggested a common denominator that exists in both primary diabetes (e.g., IDDM and NIDDM) and diabetes secondary to pancreatic destruction and hemochromatosis, which eventually leads to the same vascular complications (Sheldon, 1935 Becker and Miller, 1960 Dymock et al., 1972). Conversely, iron mobilization and utilization appear to be delayed in diabetes mellitus. A possible link between iron overload and complications is further suggested by the observation that desferrioxamine treatment decreased hyperglycemia and hyperlipidemia in diabetic patients with high ferritin but without hemochromatosis (Cutler, 1989). 

Iron deficiency is the most prevalent nutritional deficiency in humans [8]. It has been estimated that 750 million people suffer from iron deficiency. Moreover, about 250 million people apparently experience overload diseases, generally secondary to hemolytic anemias. 

---