When Jim Barton and Corwin Edwards edited their multi-authored text Hemochromatosis: Genetics, Pathophysiology, Diagnosis, and Treatment published in 2000 by Cambridge University Press, it filled a void in learning resources for iron overload disorders, in particular those related to the then-recently discovered HFE gene and its common deleterious mutations. I commented in my Foreword to that text that “phenotypic expression … was virtually invariable in individuals possessing the abnormal allele on both chromosomes 6.” That statement has proved to be incorrect in the light of subsequent research demonstrating that phenotypic expression of HFE C282Y homozygous mutation is both unpredictable and variable in its manifestations. This reversal of previous dogma in genetic hemochromatosis and other important new data illustrate the need for an update on iron overload disorders in general.

In the 10 years since the publication of that text, much information has been discovered that provides new insights into the regulation of iron metabolism, and the causation and cosmopolitan distribution of diverse iron overload disorders. These discoveries have come about through the combined research efforts of many investigators, including biochemists, molecular biologists, experimental and clinical pathologists, geneticists, epidemiologists, clinical and research hematologists, and hepatologists. New iron-regulatory proteins and their genes have been discovered that provide an emerging awareness of the complexity of the integration and interactions of all genes, proteins, and tissues that participate in iron homeostasis in humans and other vertebrates.