Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment

doi:10.1053/j.gastro.2010.06.013

Gastroenterology

Volume 139, Issue 2, August 2010, Pages 393-408.e2

https://doi.org/10.1053/j.gastro.2010.06.013 Get rights and content

In the late 1800s, hemochromatosis was considered an odd autoptic finding. More than a century later, it was finally recognized as a hereditary, multi-organ disorder associated with a polymorphism that is common among white people: a 845G→A change in HFE that results in C282Y in the gene product. Hemochromatosis is now a well-defined syndrome characterized by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 (Tfr2), and hemojuvelin (Hjv) (which all sense the accumulation of iron that hepcidin corrects) or ferroportin (Fpn) (the cellular iron exporter down-regulated by hepcidin), cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown hemochromatosis. Unlike these rare instances, in white people, homozygotes for C282Y polymorphism in HFE are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, when these individuals abuse alcohol or from other unidentified modifying factors. HFE gene testing can be used to diagnose hemochromatosis, but analyses of liver histology and clinical features are still required to identify patients with rare, non-HFE forms of the disease. The role of hepcidin in the pathogenesis of hemochromatosis reveals its similarities to endocrine diseases such as diabetes and indicates new approaches to diagnosis and management of this common disorder in iron metabolism.

Section snippets

What Is Hemochromatosis?

The term “hemochromatosis” was coined by the German pathologist Friedrich Daniel Von Recklinghausen in a short report published in 1889²⁷ describing the bronze stain of organs that was attributed to blood-borne pigments. The term, he maintained, could be applied to different conditions, including “cases of pigmentary cirrhosis, whose association with diabetes,” he noted, “has led the French authors to ask whether the bronze pigment is ([as suggested by] Hanot and Schuchmann) over-produced in

What Causes Hemochromatosis?

Research in the 1930s showed that iron enters the human body exclusively through the small intestine (Table 1);⁴ once it enters, it has to be used or stored because there are no active physiological means for its removal apart from menstrual blood loss. In the 1950s and 1960s, metabolic studies of patients with hemochromatosis (most, if not all, of whom probably had HFE disease) revealed rates of dietary iron absorption by small intestinal enterocytes that exceeded iron loss by approximately 3

Defects in Iron Metabolism

Iron is an important dietary nutrient that is continuously recycled by the body; its uptake, storage, and utilization must be carefully coordinated at the cellular and systemic levels. Intracellular iron levels are controlled by iron regulatory proteins 1 and 2 (reviewed by Muckenthaler et al⁴⁰), which are not significantly disrupted in patients with hemochromatosis. Less is known about the highly complex regulation of systemic iron traffic. Signals from storage compartments (mainly hepatocytes

The Common Pathogenic Basis for All Forms of Hemochromatosis

If one or more components of the blood iron-sensing machinery fail, adequate levels of hepcidin will not be produced in response to the increased levels of iron, intestinal and macrophage iron release will not be checked, and iron overload and hemochromatosis will result. In mice, loss of Hjv,80, 81Bmp6,32, 33Hfe,⁶⁶TfR2,⁸²Smad4,³¹neogenin,³⁴C/EBP alpha,³⁰ and Hamp itself⁸³ all lead to reduced hepcidin synthesis and systemic iron overload that resembles hemochromatosis. In humans, hepcidin

How Frequently Do Cases of Hemochromatosis Occur?

The C282Y polymorphism in HFE is 10-fold more prevalent than the mutation that causes most cases of cystic fibrosis. HFE-related hemochromatosis would be the most frequently inherited metabolic disorder among white individuals if not for the fact that the phenotype penetrance of the polymorphism is low; C282Y increases the risk of hemochromatosis. Because of its prevalence in certain populations, C282Y is a polymorphic variant rather than a pathogenic mutation. Its mean allelic frequency based

Signs of Hemochromatosis

The clinical presentation of HFE-related hemochromatosis, which usually occurs in middle-aged patients, ranges from simple biochemical abnormalities to severe organ damage and disease.⁶⁵ The variations in symptoms occur because C282Y HFE homozygosity only predisposes an individual to hemochromatosis; additional host or environmental factors are required. The classic presentation of hemochromatosis—unexplained cirrhosis, bronze-colored skin, diabetes (and other endocrine diseases), joint

How Is Hemochromatosis Managed?

Bloodletting (phlebotomy) is the standard treatment for all forms of hemochromatosis. It was first used in 1950 to eliminate excess iron in patients with hemochromatosis¹¹ (Table 1). There are no evidence-based guidelines on the use of therapeutic phlebotomy. Systematic studies have never been conducted to determine when it should be started, how frequently it should be performed, or therapeutic end points. Treatment is conventionally initiated when serum ferritin levels exceed the normal

Perspectives

Hemochromatosis was originally considered to be an odd finding in autopsies that was probably alcohol related. More than a century later, hemochromatosis is recognized as a hereditary disorder associated with one of the most common polymorphisms among white people. We have made major advances in understanding this disease, but there is still much that we do not know, such as the exact role of HFE in iron metabolism. Hemochromatosis models of pathogenesis have been developed based on studies of