Chronic iron overload and toxicity: Clinical chemistry perspective

Clinical Laboratory Science, Summer 2001 by Kang, Jae O

In 1996, Feder identified the gene on chromosome 6 whose mutation is highly correlated with hereditary hemochromatosis.8 From a group of 178 unrelated patients with hereditary hemochromatosis, it was found that 148 patients (83%) were homozygous for a guanine-to-adenine mutation occurring at nucleotide 845 of the HLA-H, a gene related to the major histocompatibility complex (MHQ. This mutation results in a substitution of tyrosine for cysteine at amino acid position 282 (C282Y). The second mutation was in a change in histidine at position 63 to aspartate (H63D). Eight patients (4%) were compound heterozygotes, with one allele containing the C282Y mutation and the other allele containing the H63D mutation (C282Y/H63D). One patient (0.5%) was homozygous for the H63D mutation. The rest of the patients were C282Y/wild type, H63D/wild type, or lacking mutations in this gene. More recently, a new variant, which is a serine-to-cysteine substitution (S65C), has been reported.98 Whether the S65C mutation contributes to iron overload is controversial. The hereditary hemochromatosis gene is now referred to as HFE.9 HFE encodes a cell transmembrane protein (HFE protein) which may play a role in iron transport across cell membranes by binding to the transferrin receptor.10

Subjects with hereditary hemochromatosis absorb about three to five mg of iron from the average American diet daily in comparison to a normal rate of about one mg.3 This relatively small positive balance can lead to 20 to 40 g iron accumulation during adulthood, compared to a normal value of about four g. Clinical manifestations associated with iron overload usually appear between 40 and 60 years of age. Full expression of the disease in women occurs less frequently and at a later age than men because of iron losses from menstruation and childbirth.6

In heterozygotes, body iron increases gradually. Adams compared the results of iron study from heterozygotes to those of controls.11 Heterozygotes showed moderately increased results: serum transferrin saturation-38% vs 29%; serum ferritin-140 vs 87 (mu)g/L. The differences between the heterozygotes and the controls were significant, p

Other diseases

A number of clinical conditions are associated with secondary iron overload. Increased erythropoiesis accompanies elevated iron absorption. Such a situation is observed in some forms of hemolytic anemia, e.g., thalassemia and sideroblastic anemia, that are associated with ineffective erythropoiesis.14 Repeated intravenous administration of whole blood or erythrocytes can introduce excess iron into the body. Each 500 mL transfusion of whole blood contains approximately 200 mg of hemoglobin iron.15 Also, iron accumulation is observed in a defect in the heme synthesis pathway. For example, porphyria cutanea tarda results from a deficiency of uroporphyrinogen decarboxylase, an enzyme required in the heme synthetic pathway. This condition, characterized by photosensitivity, is associated with moderately elevated body iron.16 In addition, hepatic cirrhosis, alcoholism, and pancreatic insufficiency are often associated with iron overload.14