Diagnosis and Treatment of Hereditary Hemochromatosis

An Update

Pushpjeet Kanwar; Kris V Kowdley


Expert Rev Gastroenterol Hepatol. 2013;7(6):517-530. 

In This Article

Abstract and Introduction


Hereditary hemochromatosis is an inherited iron overload disorder caused by inappropriately low hepcidin secretion leading to increased duodenal absorption of dietary iron, most commonly in C282Y homozygous individuals. This can result in elevated serum ferritin, iron deposition in various organs and ultimately end-organ damage, although there is incomplete biochemical and clinical penetrance and variable phenotypic expression of the HFE mutation in hereditary hemochromatosis. An elevated SF <1000 µg/l is associated with an increased risk of cirrhosis and mortality in C282Y homozygotes. Conversely, a SF <1000 µg/l is associated with a very low likelihood of cirrhosis, making liver biopsy unnecessary among C282Y homozygotes in the absence of concomitant risk factors for liver disease. Phlebotomy remains the mainstay of treatment and new treatments being studied include erythrocytapheresis and 'mini-hepcidins'. Iron overload is being recognized to play a carcinogenic role in hepatocellular carcinoma and other cancers, possibly supporting iron depletion in these patients.


Hereditary hemochromatosis (HH) is an inherited autosomal recessive iron overload disorder resulting in the failure of the normal hepcidin response to body iron stores, leading to increased duodenal absorption of dietary iron.[1–3] The increased iron enters the plasma and may be deposited in various target organs and may lead to clinical signs and symptoms.[4]

Our understanding of this condition has grown significantly since the initial description of advanced HH as 'bronze diabetes' by Trousseau[5] in 1865, to the discovery of the role of iron metabolism in its pathogenesis by Sheldon[6] in 1935, to the identification of the C282Y mutation in HFE as responsible for most cases of HH in 1996[7] and most recently to the recognition of a central role of hepcidin in the regulation of iron absorption and pathogenesis of HH.[2,3,8] The current classification system for HH has categorized this disorder into four types.[301] The most common is type 1 or classical HH which is associated with a homozygous cysteine to tyrosine missense mutation in HFE gene. Since HFE-associated hemochromatosis (type 1) is the most common form of inherited iron overload, we will focus primarily on type 1 but will also review the current status of the understanding of types 2–4 HH.