In the past seven years numerous genes that influence
iron homeostasis have been discovered. Dr. Beutler provides a brief overview of these genes, genes that encode HFE, DMT-1,
ferroportin,
transferrin receptor 2, hephaestin, and
hepcidin to lay the groundwork for a discussion of the various clinical forms of
iron storage disease and how they differ from one another. In Section I, Dr. Beutler also discusses the types of
hemochromatosis that exist as acquired and as hereditary forms. Acquired
hemochromatosis occurs in patients with marrow failure, particularly when there is active ineffective erythropoiesis. Hereditary
hemochromatosis is most commonly due to mutations in the HLA-linked HFE gene, and
hemochromatosis clinically indistinguishable from HFE
hemochromatosis is the consequence of mutations in three
transferrin receptor-2 gene. A more severe, juvenile form of
iron storage disease results from mutations of the gene encoding
hepcidin or of a not-yet-identified gene on chromosome 1q. Autosomal dominant
iron storage disease is a consequence of
ferroportin mutations, and a polymorphism in the
ferroportin gene appears to be involved in the
African iron overload syndrome. Evidence regarding the biochemical and clinical penetrance of
hemochromatosis due to mutations of the HFE gene is rapidly accumulating. These studies, emanating from several centers in Europe and the United States, all agree that the penetrance of
hemochromatosis is much lower than had previously been thought. Probably only 1% of homozygotes develop clinical findings. The implications of these new findings for the management of
hemochromatosis will be discussed. In Section II, Dr. Victor Hoffbrand discusses the management of
iron storage disease by
chelation therapy, treatment that is usually reserved for patients with secondary
hemochromatosis such as occurs in the
thalassemias and in patients with transfusion requirements due to myelodysplasia and other marrow failure states. Tissue
iron can be estimated by determining serum
ferritin levels, measuring liver
iron, and by measuring cardiac
iron using the MRI-T2* technique. The standard form of
chelation therapy is the slow intravenous or
subcutaneous infusion of desferoxamine. An orally active bidentate
iron chelator,
deferiprone, is now licensed in 25 countries for treatment of patients with
thalassemia major. Possibly because of the ability of this compound to cross membranes, it appears to have superior cardioprotective properties.
Agranulocytosis is the most serious complication of
deferiprone therapy and occurs in about 1% of treated patients.
Deferiprone and desferoxamine can be given together or on alternating schedules. A new orally active
chelating agent ICL 670 seems promising in early clinical studies. In Section III, Dr. James Cook discusses the most common disorder of
iron homeostasis,
iron deficiency. He will compare some of the standard methods for identifying
iron deficiency, the
hemoglobin level,
transferrin saturation, and mean corpuscular hemoglobin and compare these with some of the newer methods that have been introduced, specifically the percentage of hypochromic erythrocytes and reticulocyte
hemoglobin content. The measurement of storage
iron is achieved by measuring serum
ferritin levels. The soluble
transferrin receptor is a truncated form of the cellular
transferrin receptor and the possible value of this measurement in the diagnosis of
iron deficiency will be discussed. Until recently
iron dextran was the only parental
iron preparation available in the US.
Sodium ferric gluconate, which has been used extensively in Europe for many years, is now available in the United States. It seems to have a distinct advantage over
iron dextran in that
anaphylactic reactions are much less common with the latter preparation.