Book Review

Hemochromatosis: Genetics, pathophysiology, diagnosis and treatment

N Engl J Med 2000; 343:516-517August 17, 2000

Article

Hemochromatosis: Genetics, pathophysiology, diagnosis and treatment
Edited by James C. Barton and Corwin Q. Edwards. 616 pp., illustrated. New York, Cambridge University Press, 2000. $215. ISBN: 0-521-593808

Iron is so critical for cell function and survival that, paradoxically, a heritable abnormality that causes increased iron absorption may actually confer a selective advantage. Although this idea may appear simplistic, it could explain how a genetic defect that originated in ancient times among northwestern European populations not only has spread all over the world but also has been maintained in diverse populations.

Hemochromatosis is the most common hereditary disease of metabolism. In mammals, a critical regulatory checkpoint of iron metabolism is located in the small intestine, where dietary iron is absorbed. In the 1970s, when a general model of the regulation of iron homeostasis at the cellular level was proposed, the mechanism of the molecular control of iron metabolism by the intestine was obscure. In the late 1990s, the discovery of new proteins with fundamental roles in iron metabolism and transport began a phase of tremendous progress in our understanding of the control of iron absorption.

Not surprisingly, at the same time, ideas about clinical disorders associated with abnormalities in iron absorption, iron overload, and tissue damage (i.e., diseases resulting in hemochromatosis) also changed. Simon and coworkers provided compelling evidence in the 1970s that hemochromatosis is heritable and linked to a locus on chromosome 6. In the 1990s, Feder and colleagues identified the gene responsible for the most common form of hemochromatosis, thereby opening a new era in the field of iron metabolism.

Barton and Edwards have assembled experts from around the world to write highly authoritative articles about all aspects of hemochromatosis. Molecular genetics, genetic epidemiology, pathophysiology, clinical management, and screening are the main topics. Ethical and social issues related to hemochromatosis are also considered. Throughout this book, the reader can feel the excitement sparked by the discovery of the hemochromatosis (HFE) gene.

This book is particularly strong in its coverage of clinical genetics. Seven chapters are devoted to important issues in the field. Specialists will find up-to-date information and invaluable bibliographic resources. There are extensive and sophisticated discussions of HLA haplotypes and allelic analysis, epidemiology, and population genetics in European populations, and fascinating theories of the origin of the HFE gene. For nonspecialists, the discussions of some of these issues may seem abstruse and somewhat confusing, because different authors have slightly different interpretations or emphases. Only recently, with the characterization of the function of the HFE protein and the discovery of new iron transporters, has the pathophysiology of hemochromatosis begun to be clarified.

Because these latest findings could not be included in the book, the HFE protein and the complex of HFE and the transferrin receptor are missing from all metabolic schemes (except one, in the animal-model section), and exogenous-iron–intoxication models are discussed instead of the genetically manipulated (HFE knockout and “knock-in”) animal models. Nonetheless, in specific chapters, historical concepts of iron absorption and metabolism are recounted with a generous attempt to meld the bulk of old and established physiologic concepts with the available new data.

The clinical section contains valuable information on the management of hemochromatosis. An entire section deals with the findings in heterozygotes, an issue with important clinical and epidemiologic implications. Yet, the discrepancy between the prevalence of the genotype and the number of cases identified by clinical observation or an examination of death records is not emphasized.

The book contains discussions of important issues related to screening for hemochromatosis and a remarkable chapter on social and ethical issues. This book, written by 93 diverse authors, is nevertheless a tight collection of compelling and informative chapters, each one contributing to the cogency of the overall discussion.

Antonello Pietrangelo, M.D., Ph.D.
University of Modena and Reggio Emilia, 41100 Modena, Italy