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Hemochromatosis overview

Published: July 16, 2009. Updated: August 09, 2009

Hemochromatosis, also spelled haemochromatosis, is a hereditary disease characterized by improper processing by the body of dietary iron which causes iron to accumulate in a number of body tissues, eventually causing organ dysfunction. It is the main iron overload disorder.


The disease was first described by Armand Trousseau in an article on diabetes. He did not make the link with iron accumulation. This was done by Daniel von Recklinghausen in 1889.

Genetics and Epidemiology

Hemochromatosis is one the most common inheritable genetic defects, especially in people of northern European extraction, with about 1 in 10 people carrying the defective gene. The prevalence of hemochromatosis varies in different populations. In Northern Europeans it is of the order of one in 400 persons. Other populations probably have a lower prevalence of this disease. It is presumed, though genetic studies, that the "first" hemochromatosis patient, possibly of Celtic ethnicity, lived 60-70 generations ago. Around that time, when diet was poor, the presence of a mutant allelle may have provided a heterozygous advantage in maintaining sufficient iron levels in the blood. With our current rich diets, this 'extra help' is unnecessary and indeed harmful.

Mutations of the HFE gene account for 90% of the cases. Homozygosity for the C282Y mutation is the most important one, although the H63D mutation can contribute to disease (substantially less than C282Y). Carriers of a single copy of either gene have a very slight risk of hemochromatosis when other factors contribute, but are otherwise healthy. Even if an individual has both copies of the abnormal gene the risk of actual clinical hemochromatosis is still quite low (? about 20%). This is called incomplete penetrance.

Other genes that cause hemochromatosis are the autosomal dominant SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). They are much rarer than HFE-hemochromatosis.


Recently, a classification has been developed (with chromosome locations):

  • Hemochromatosis type 1: "classical" HFE-hemochromatosis (6p21.3).
  • Hemochromatosis type 2: juvenile hemochromatosis :
    • Type 2A: tentatively called HFE2A (1q21)
    • Type 2B: mutation in hepcidin antimicrobial peptide (HAMP) or HFE2B (19q13)
  • Hemochromatosis type 3: transferrin receptor-2 (TFR2 or HFE3, 7q22).
  • Hemochromatosis type 4: autosomal dominant hemochromatosis (all others are recessive), ferroportin (SLC11A3) gene mutation (2q32).


Healthy people usually absorb about 10 percent of the iron contained in the food they eat to meet the body needs. People with hemochromatosis absorb more than the body needs. The body has no natural way to rid itself of excess iron, so extra iron is stored in body tissues, especially the liver, heart, and pancreas.

People with the abnormal genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus the iron stores of the body increase. As they increase the iron which is initially stored as ferritin starts to get stored as a breakdown product of ferritin called haemosiderin and this is toxic to tissue.

Signs and symptoms

Hemochromatosis is notoriously protean, i.e. it presents with symptoms that are often initially attributed to other diseases.

Symptoms may include:

  • malaise
  • liver cirrhosis (with an increased risk of hepatocellular carcinoma, affecting up to a third of all homozygotes) - this is often preceded by a period of a painfully enlarged liver.
  • insulin resistance (often patients have already been diagnosed with diabetes mellitus type 2) erectile dysfunction and hypogonadism
  • congestive heart failure, arrhythmias or pericarditis
  • arthritis of the hands (MCP and PIP joints), knee and shoulder joints
  • dysfunction of certain endocrine organs:
    • pancreatic gland
    • adrenal gland (leading to adrenal insufficiency)
    • parathyroid gland (leading to hypocalcaemia)
    • pituitary gland
    • testes (leading to hypogonadism)
  • a darkish colour to the skin (see pigmentation, hence its name Diabete bronze when it was first described by Armand Trousseau in 1865)
  • a increased susceptibility to certain infectious diseases caused by:
    • Vibrio vulnificus infections from eating seafood
    • Listeria monocytogenes
    • Yersinia enterocolica
    • Salmonella enteritidis (serotype Typhymurium)
    • Klebsiella pneumoniae
    • Escherichia coli
    • Rhizopus arrhizus
    • Mucor species

Males are usually diagnosed after their forties, and women about a decade later, owing to regular iron loss by menstruation (which ceases in menopause).


According to some, a one-time study of iron levels early in adult life would be sufficient to evaluate an individual. There is, however, a tendency for iron to accumulate over time. It is therefore doubtful whether screening should be undertaken at all, irrespective of timing problems. Only the most severe cases would be detected by a one-time ferritin check.


A first step is the measurement of ferritin, the tissue form of accumulated iron which is shed into the blood and, the measurement of the transferrin saturation (increased) which is the iron carrying protein. If either of these tests shows higher than normal levels of iron in the body, doctors can order a special blood test to detect the HFE mutation, which will help confirm the diagnosis. (If the mutation is not present, hereditary hemochromatosis is not the reason for the iron buildup, and the doctor will look for other causes). Other markers of iron metabolism are transferrin (decreased) and serum iron (increased).

When these investigations point at Hemochromatosis, it is debatable whether a liver biopsy still needs to occur to quantify the amount of accumulated iron.

Other blood tests routinely performed: blood count, renal function, liver enzymes, electrolytes, glucose (and/or an oral glucose tolerance test (OGTT)).

Based on the history, the doctor might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure.

Differential diagnosis

There exist other causes of excess iron accumulation, which have to be considered before Hemochromatosis is diagnosed.

Transfusion haemosiderosis is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusions (such as those with thalassemia).

Dyserythropoeisis is a disorder in the production of red blood cells. This leads to increased iron recycling from the bone marrow and accumulation in the liver.

Bantu haemosiderosis occurs in the Bantu population in Southern Africa. This is due to the fact that beer is kept in ungalvanised barrels, leading to increased oxidation and increased iron levels in the beer.


Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (comparable in volume to blood donations). Treatment is initiated when ferritin levels reach 300 micrograms per litre (or 200 in nonpregnant premenopausal women).

Every bag of blood (450-500 ml) contains 200-250 milligrams of iron. Phlebotomy is usually done at a weekly interval until ferritin levels have returned to normal. After that, 1-4 donations per year are usually needed to maintain iron balance.

Other parts of the treatment include:

Treatment of organ damage (heart failure with diuretics and ACE inhibitor therapy).

Limiting alcohol intake, vitamin C intake (increases iron absorption in the gut), red meat (is high in iron) and potential causes for food poisoning (shellfish, seafood).

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