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.