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Clinical manifestations and diagnosis of hereditary hemochromatosis

Stanley L Schrier, MD
Bruce R Bacon, MD
Section Editors
William C Mentzer, MD
Keith D Lindor, MD
Deputy Editor
Jennifer S Tirnauer, MD


Hereditary hemochromatosis (HH), most commonly due to mutations in the HFE gene, is an autosomal recessive disorder in which these mutations cause increased intestinal iron absorption. Less common causes of HH include mutations in the genes for hemojuvelin, hepcidin, and ferroportin (table 1) (see "Genetics of hereditary hemochromatosis", section on 'The HFE protein'). The clinical manifestations of this disorder, and of other forms of iron overload, are related to excessive iron deposition in tissues, especially the liver, heart, pancreas, and pituitary.

The epidemiology, clinical manifestations, and diagnosis of HH will be reviewed here. The pathophysiology and approach to the patient with suspected iron overload, causes of iron overload other than HH, and treatment of HH are discussed separately. (See "Approach to the patient with suspected iron overload" and "Management of patients with hereditary hemochromatosis".)

These topics are also discussed in an official 2011 guideline issued by the American Association for the Study of Liver Diseases (AASLD). The guideline for the diagnosis and management of hemochromatosis [1], as well as other AASLD guidelines, can be accessed through the AASLD website.


General population — Hereditary hemochromatosis (HH) was previously thought to be a rare disorder to be considered only when the patient had an unusual manifestation such as "bronze diabetes." However, once it was appreciated that HH was transmitted as an autosomal recessive trait associated with the HLA-A locus on the short arm of chromosome 6, accurate family analyses could be performed [2]. These studies revealed that a transferrin saturation (serum iron concentration ÷ total iron binding capacity) greater than 60 percent in men and over 50 percent in women identified the presence of an abnormality in iron metabolism with approximately 95 percent accuracy [2,3]. (See "Screening for hereditary hemochromatosis".)

Following this observation, population screening using these cutoff values for transferrin saturation showed that the frequency of heterozygotes is approximately 10 percent in Caucasian populations in the United States and western Europe [2,4,5], with a frequency of approximately 5 per 1000 (0.5 percent) for the homozygous state [2-5]. The prevalence was higher (approximately 1 percent) in a screening study that assumed that 60 percent of patients with an elevated transferrin saturation but normal serum ferritin had early HH [5]. It is now known that the vast majority of patients so diagnosed were homozygous for the C282Y mutation of the HFE protein. (See "Genetics of hereditary hemochromatosis", section on 'The HFE gene'.)

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Literature review current through: Nov 2017. | This topic last updated: Dec 09, 2016.
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