Chronic iron overload and toxicity: Clinical chemistry perspective

Clinical Laboratory Science, Summer 2001 by Kang, Jae O

The most powerful promoter of iron absorption is ascorbate (vitamin C).31,32 Ascorbate increases the bioavailability of nonheme iron in two ways: 1) chelating iron to render it more soluble in the alkaline environment of the duodenum; and 2) reducing ferric iron (Fe^sup 3 ^) to ferrous iron (Fe^sup 2 ^) which is three times more efficiently absorbed than ferric iron. 33 Because of its reducing power, ascorbate is a very effective antioxidant. At high concentrations, it can inhibit free radical-mediated damages to biomolecules, However, it should be noted that the administration of vitamin C to individuals with high levels of body iron can cause serious medical problems such as heart failure.19,34 The reason, at least in part, is that body iron is stored as ferric iron in two major proteins: ferritin and hemosiderin. In iron overload, the major storage protein is hemosiderin since it can increase about 100-fold while ferritin increases 10-fold.35 Ascorbate can reduce the ferric iron stored in these proteins to ferrous iron that is released from the proteins. The ferrous iron released can engage in a series of free radical reactions.

Iron deficiency has long been a worldwide medical problem. It still affects one-third of the world's population, particularly in developing countries.23 For many years, efforts have focused on ameliorating this condition through programs to supplement and fortify iron. Also, the idea that iron is an invigorating nutrient has encouraged people to take oral iron preparations and iron-supplemented vitamin tablets. Such practices have occurred even in industrialized countries where red meat consumption is high, and a significant portion of the population carry the hemochromatosis gene.23 Krikker estimated that about 30 million people in the United States acquire excess iron for different reasons.36 In normal adults who consume Western-type diets, there is a steady rise in iron storage as a function of aging (Figure 1). Brothwell points out that it could be anticipated that more patients would be presenting to hospitals with fully developed hemochromatosis because of the widespread use of iron fortification that has occurred over the past decades, but hospital statistics do not support this expectation.23 The author suggests that many subclinical cases are still being missed, or that full expression of the disease does not occur in many affected homozygous individuals. In addition, it is possible that patients have sought medical attention with clinical conditions other than hemochromatosis since excess iron leads to secondary pathological conditions. Recent studies show that subjects with only modestly increased iron stores are at a greater risk of developing malignancy, heart disease, infection, etc.4,37-39

PATHOPHYSIOLOGY

Chronic accumulation of excess amounts of body iron leads to an increase in iron deposits in various tissues resulting in tissue damage and functional impairment of the organs involved. The toxicity involves multi-organs, and its clinical expression is versatile. In patients with advanced hemochromatosis, the most predominant features include hepatomegaly, hepatic dysfunction, heart failure, skin pigmentation, testicular atrophy, diabetes mellitus, and arthropathy.6,14,40 The total iron content of the body is usually between 20 g and 40 g. Particularly in the liver and pancreas, the iron concentrations may be 50 to 100 times normal. Iron concentration is elevated from five to 24 times normal in other organs such as the heart, endocrine glands, and skin.14