Pradyumna D. Phatak

Scientific and clinical questions are usually answered partially and in increments. Most of the questions posed by Joseph Sheldon in 1935 and at the First International Conference on Hemochromatosis in 1987 have been answered. Since the discovery of HFE in 1996, there has been an explosion of research interest and reports related to iron biology and diseases of iron homeostasis. Some important “unknowns” presented in the conclusion of a major 2000 text devoted to hemochromatosis have been resolved. This section presents some of the important old and new questions for which answers are needed and changes in medical care delivery are predicted. These topics of interest include the biology and genetics of iron homeostasis and iron overload, hemochromatosis and iron overload screening, advances in diagnosis, complications of iron overload, and improvements in management. Biology and genetics of iron homeostasis and iron overload It is assumed that the common HFE mutations C282Y and H63D conferred some evolutionary advantage, but the mechanism(s) by which such a putative advantage(s) was mediated is not known. C282Y, found predominantly in western European Caucasians, is the most common known mutation that has a profound effect on iron homeostasis and phenotype. Many have inferred that this polymorphism fostered an iron procurement advantage for women during their reproductive years, although this is unproven. Related possibilities include the conjecture that C282Y either increases fertility of women (or men), or promotes greater survival of fetuses in utero or of newborns.

Handbook of Iron Overload Disorders - July 2010

Localized iron overload can sometimes occur in the lungs (pulmonary hemosiderosis) and the kidneys (renal hemosiderosis). Pulmonary hemosiderosis Idiopathic pulmonary hemosiderosis (IPH) (also known as Ceelen–Gellerstedt syndrome) is a rare disorder of unknown etiology characterized by recurrent episodes of diffuse alveolar hemorrhage and accumulation of storage iron in the lung parenchyma. It is most common in children (age 1 to 7 years) but can also occur in adults. Clinical manifestations of IPH include pulmonary symptoms (hemoptysis, dyspnea, cough), parenchymal lesions on chest X-ray, and iron deficiency anemia of unknown cause. Diagnosis depends on exclusion of other disorders, such as inflammatory pulmonary capillaritis, in which diffuse alveolar hemorrhage is a cardinal sign. The clinical course of IPH is variable; in chronic cases, the localized iron overload can result in pulmonary fibrosis, and death can sometimes occur due to pulmonary hemorrhage. Treatment includes supportive therapy and administration of corticosteroids that can be combined with other immunosuppressive agents, such as azathioprine. Successful resolution of some cases of IPH with immunosuppressive drugs suggests that an immunologic mechanism could be involved in the pulmonary capillary damage underlying alveolar bleeding which, in turn, leads to pulmonary iron accumulation. Hematite miners and other workers chronically exposed to iron ore dust may develop iron overload of the lungs and adjacent lymph nodes, but serum iron measures are usually normal. Renal hemosiderosis Marked iron accumulation in the kidneys is rare in hemochromatosis, but when present, storage iron is usually located in cells of the tubules, particularly the convoluted tubules.

Handbook of Iron Overload Disorders - July 2010