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Classification & external resources
ICD-10 E83.1
ICD-9 275.0
OMIM 235200 602390 606464 604720 604653
DiseasesDB 5490
eMedicine med/975  derm/878
MeSH D006432

Haemochromatosis, also spelled hemochromatosis, is a hereditary disease characterized by improper dietary iron metabolism (making it an iron overload disorder), which causes the accumulation of iron in a number of body tissues.[1] Iron accumulation can eventually cause organ damage, most importantly in the liver and pancreas, manifesting as liver failure and diabetes mellitus respectively. It is estimated that roughly one in every 300-400 people is affected by the disease, primarily of Northern European and especially people of Irish, Scottish, Welsh and English descent.[2]

"Hemochromatosis" also refers to the concept of hereditary hemochromatosis, in which certain genetic mutations can predispose people to iron accumulation. However, the two are not always related; not all cases of iron overload are associated with genetic causes, and having such hereditary markers does not necessarily cause significant iron overload.



The disease was first described in 1865 by Armand Trousseau in an article on diabetes in patients with changing skin color.[3] Trousseau did not connect the diabetes with iron accumulation; instead this was done by Friedrich Daniel von Recklinghausen in 1890.[4][5]

Signs and symptoms

Haemochromatosis is notoriously protean, i.e., it presents with symptoms that are often initially attributed to other diseases. It is also true that most people with hereditary hemochromatosis genetics never actually show signs or suffer symptoms of clinical iron overload(i.e., is clinically silent).[6] Symptoms may include:[7][8][9]

Males are usually diagnosed after their forties, and women about a decade later, owing to regular iron loss by menstruation (which ceases in menopause). Cases of iron overload have been found in young children as well.


Haemochromatosis can be difficult to diagnose in the early stages. Early signs may mimic other diseases. Stiff joints, diabetes, and fatigue, for example, are common in haemochromatosis and other maladies.[13]

Imaging features

Clinically the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced CT and a decreased signal intensity at MR imaging. Haemochromatosis arthropathy includes degenerative osteoarthritis and chondrocalcinosis. The distribution of the arthropathy is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand.[citation needed] The arthropathy can therefore be an early clue as to the diagnosis of hemochromatosis. MRI algorithms are available at research institutions to quantify the amount of iron present in the liver, therefore reducing the necessity of a liver biopsy (see below) to measure the liver iron content. As of May, 2007, this technology was only available at a few sites in the USA, but documented reports of radiographic measurements of liver iron content were becoming more common. [14]


Serum transferrin saturation- A first step is the measurement of transferrin saturation, the protein which chemically binds to iron and carries it through the blood to the liver, spleen and bone marrow.[15] Measuring transferrin provides a measurement of iron in the blood. Saturation values of 45% are probably a good cutoff to determine whether a patient is a candidate for further testing. [16] The transferrin saturation is usually expressed as a percentage, and is calculated as the total serum iron level divided by the serum iron transferrin level times 100. Serum Ferritin- Ferritin, the protein which chemically binds to iron and stores it in the body. Measuring ferritin provides a measurement of iron in the whole body. Normal values for males are 12-300 ng/ml (nanograms per milliliter) and for female, 12-150 ng/ml. Low values indicate iron deficiency, which may be attributed to a number of causes. Higher than normal also may indicate other causes including haemochromatosis.[17][18] Other blood tests routinely performed: blood count, renal function, liver enzymes, electrolytes, glucose (and/or an oral glucose tolerance test (OGTT)).

Functional testing

Based on the history, the doctor might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with hemochromatosis diabetes.


Liver biopsy - Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, measured microscopically. Formerly, this was the only way to confirm a diagnosis of hemochromatosis but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis, it is debatable whether a liver biopsy is still necessary to quantify the amount of accumulated iron.[19]


Screening specifically means looking for a disease in people who have no symptoms. Diagnosis, on the other hand refers to testing people who have symptoms of a disease. Standard diagnostic measures for haemochromatosis, serum transferrin saturation and serum ferritin tests, are not a part of routine medical testing. Screening for hemochromatosis is recommended if the patient has a parent, child or sibling with the disease, or have any of the following signs and symptoms:[20][21]

  • Joint disease
  • Severe fatigue
  • Heart disease
  • Elevated liver enzymes
  • Impotence
  • Diabetes

Routine screening of the general population for hereditary hemochromatosis, that is, by genetic testing, has been evaluated by the US Preventive Services Task Force (USPSTF), among other groups. The USPSTF recommended against doing genetic testing to screen the general population for hereditary hemochromatosis because the likelihood of diagnosing clinically relevant, iron accumulating hereditary hemochromatosis in a treatable patient population approaches less than 1 in 1000 unselected patients. Also, there is no evidence that doing phlebotomy to treat asymptomatic, non-iron overloaded carriers of HFE mutations has any clinical benefit. Also, genetic carriers of the disease may never manifest the symptoms of the disease, so that the potential harm of the attendant surveillance, privacy issues, unnecessary invasive work-up, and anxiety outweigh the potential benefits. [22] [23]

Differential diagnosis

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

  • African iron overload, formerly known as Bantu siderosis, was first observed among people of African descent in Southern Africa. Originally, this was blamed on ungalvanised barrels used to store home-made beer, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only some people drinking this sort of beer get an iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer (e.g., African Americans). This led investigators to the discovery of a gene polymorphism in the gene for ferroportin which predisposes some people of African descent to iron overload.[24]
  • Transfusion hemosiderosis is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusions (such as those with thalassemia).
  • Dyserythropoeisis, also known as myelodysplastic syndrome 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.


Hemochromatosis is one of the most common inheritable genetic defects, especially in people of northern European extraction, with about 1 in 10 people carrying a mutation in one of the genes regulating iron metabolism. The prevalence of hereditary mutations in iron metabolism genes varies in different populations. In Northern Europeans it is of the order of one in 400 persons. A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the entire population had a clinically relevant iron overload syndrome. This means that most patients who are homozygous for HFE mutations will not manifest clinically relevant hemochromatosis (see genetics below).[25] Other populations probably have a lower prevalence of both the genetic mutation and the clinical disease. It is presumed, through genetic studies, that the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60-70 generations ago. Around that time, when nutrition was less balanced than today, the presence of a mutant allele may have provided a natural selection reproductive advantage in maintaining sufficient iron levels in the blood. With our current balanced diets, this 'extra help' is unnecessary and indeed harmful.


    The regulation of how much iron enters the body from food is complex, and each year brings new discoveries about the numerous factors working in harmony to bring about balance in the metabolism of iron in humans One of the best-characterized genes that regulates the amount of iron absorbed from food is called HFE. The HFE gene has two common mutations, C282Y and H63D.[26] Inheriting just one of the C282Y mutations (heterozygous) makes a person a carrier who can pass this mutation onward. Carriers of one HFE mutation ordinarily do not manifest with clinically relevant iron accumulation at all. In the United States, most people with clinically measureable haemochromatosis (i.e., iron overload with or without end organ damage) have inherited two copies of C282Y — one from each parent — and are therefore homozygous for the trait. Mutations of the HFE gene account for 90% of the cases of clinical iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most prevalent condition resulting in clinical iron accumulation, although heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, is also known to cause clinical iron overload. So, both homozygotes for C282Y and compound heterozygotes for C282Y/H63D are known to have clinical iron overload and hemochromatosis. Most people with two copies of C282Y or one copy each of C282Y/H63D do not manifest clinical hemochromatosis, a phenomenon known as low incomplete penetrance. [25] Penetrance differs between different populations.

Other genes whose mutations have been associated with iron overload include the autosomal dominant SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). These mutations, and the iron overload they cause, are much rarer than HFE-haemochromatosis.

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

Description OMIM Mutation Locus
Haemochromatosis type 1: "classical"-haemochromatosis 235200 HFE 6p21.3
Haemochromatosis type 2A: juvenile haemochromatosis 602390 hemojuvelin ("HJV", also known as HFE2) 1q21
Haemochromatosis type 2B: juvenile haemochromatosis 606464 hepcidin antimicrobial peptide (HAMP) or HFE2B 19q13
Haemochromatosis type 3 604720 transferrin receptor-2 (TFR2 or HFE3) 7q22
Haemochromatosis type 4 autosomal dominant haemochromatosis (all others are recessive), gene mutation 604653 ferroportin (SLC11A3) 2q32



Since the regulation of iron metabolism is still poorly understood, a clear model of how hemochromatosis operates is still not available as of May, 2007. For example, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. In general, people with abnormal iron regulatory 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 is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.[27]. Iron is a pro-oxidant. Thus, hemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricemic syndrome in Dalmatian dogs. The latter also experience "bronzing".

Intestinal crypt enterocytes and iron overload

The sensor pathway inside the small bowel enterocyte can be disrupted due to genetic errors in the iron regulatory apparatus. The enterocyte in the small bowel crypt must somehow sense the amount of circulating iron. Depending on this information, the enterocyte cell can regulate the quantity of iron receptors and channel proteins. If there is little iron, the enterocyte cell will express many of these proteins. If there is a lot, the cell will turn off the expression of iron transporters. In haemochromatosis, the enterocyte is somehow constantly fooled into thinking there is iron depletion. As a consequence, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption. Details of how this process exactly works in health and disease are still being discovered as of May, 2007. These iron transport proteins are named DMT-1 (divalent metal transporter), for the luminal side of the cell, and ferroportin, the only known cellular iron exporter, for the basal side of the cell.

Hepcidin-ferroportin axis and iron overload

Recently, a new unifying theory for the pathogenesis of hereditary hemochromatosis has been proposed that focuses on the hepcidin-ferroportin regulatory axis. Inappropriately low levels of hepcidin, the iron regulatory hormone, can account for the clinical phenotype of iron overload. In this theory, low levels of circulating hepcidin result in higher levels of ferroportin expression in intestinal enterocytes and reticuloendothelial macrophages. As a result, this causes iron accumulation. HFE, hemojuvelin, BMP's and TFR2 are implicated in regulating hepcidin expression.

End-organ damage

Iron is stored in the liver, the pancreas and the heart. Long term effects of haemochromatosis on these organs can be very serious, even fatal when untreated.[28] For example, similar to alcoholism, haemochromatosis can cause Cirrhosis of the liver. The liver is a primary storage area for iron and will naturally accumulate excess iron. Over time the liver is likely to be damaged by iron overload. Cirrhosis itself may lead to additional and more serious complications, including bleeding from dilated veins in the esophagus and stomach (varices) and severe fluid retention in the abdomen (ascites). Toxins may accumulate in the blood and eventually affect mental functioning. This can lead to confusion or even coma (hepatic encephalopathy).

Liver cancer: Cirrhosis and haemochromatosis together will increase the risk of liver cancer. (Nearly one-third of people with haemochromatosis and cirrhosis eventually develop liver cancer.)

Diabetes: The pancreas which also stores iron is very important in the body’s mechanisms for sugar metabolism. Diabetes affects the way the body uses blood sugar (glucose). Diabetes is in turn the leading cause of new blindness in adults and may be involved in kidney failure and cardiovascular disease.

Congestive heart failure: If excess iron in the heart interferes with the its ability to circulate enough blood, a number of problems can occur including death. The condition may be reversible when haemochromatosis is treated and excess iron stores reduced.

Heart arrhythmias: Arrhythmia or abnormal heart rhythms can cause heart palpitations, chest pain and light-headedness and are occasionally life threatening. This condition can often be reversed with treatment for haemochromatosis.

Pigment changes: Deposits of iron in skin cells can turn skin a bronze or gray color.


Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.[29] Treatment is initiated when ferritin levels reach 300 milligrams per litre (or 200 in nonpregnant premenopausal women).

Every bag of blood (450-500 ml) contains 200-250 milligrams of iron. Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritin levels are less than 20 milligrams per litre. 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 intake of alcoholic beverages, vitamin C (increases iron absorption in the gut), red meat (high in iron) and potential causes of food poisoning (shellfish, seafood).
  • Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, and foods containing oxalic and phytic acids (these must be consumed at the same time as the iron-containing foods in order to be effective.)


  1. ^ Iron Overload and Hemochromatosis Centers for Disease Control and Prevention
  2. ^ Celtic Curse.
  3. ^ Trousseau A (1865). "Glycosurie, diabète sucré". Clinique médicale de l'Hôtel-Dieu de Paris 2: 663–98.
  4. ^ von Recklinghausen FD (1890). "Hämochromatose". Tageblatt der Naturforschenden Versammlung 1889: 324.
  5. ^ Biography of Daniel von Recklinghausen
  6. ^ Hemochromatosis-Diagnosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
  7. ^ Iron Overload and Hemochromatosis Centers for Disease Control and Prevention
  8. ^ Hemochromatosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
  9. ^ Hemochromatosis-Signs and Symptoms Mayo Foundation for Medical Education and Research (MFMER)
  10. ^ a b Jones H, Hedley-Whyte E (1983). "Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs". Neurology 33 (11): 1479-83. PMID 6685241.
  11. ^ Costello D, Walsh S, Harrington H, Walsh C (2004). "Concurrent hereditary haemochromatosis and idiopathic Parkinson's disease: a case report series". J Neurol Neurosurg Psychiatry 75 (4): 631-3. PMID 15026513.
  12. ^ Nielsen J, Jensen L, Krabbe K (1995). "Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome". J Neurol Neurosurg Psychiatry 59 (3): 318-21. PMID 7673967.
  13. ^ Screening and Diagnosis
  14. ^ Tanner MA, He T, Westwood MA, Firmin DN, Pennell DJ (2006). "Multi-center validation of the transferability of the magnetic resonance T2* technique for the quantification of tissue iron". Haematologica 91 (10): 1388-91. PMID 17018390.
  15. ^ Transferrin and Iron Transport Physiology
  16. ^ Screening and Diagnosis
  17. ^ Screening and Diagnosis
  18. ^ Ferritin Test Measuring iron in the body
  19. ^ Screening and diagnosis Mayo Foundation for Medical Education and Research (MFMER) Retrieved 18 March, 2007
  20. ^ Screening and Diagnosis Mayo Foundation for Medical Education and Research (MFMER). Retrieved 18 March, 2007
  21. ^ [ Screening for Hereditary Hemochromatosis: Recommendations from the American College of Physicians Annals of Internal Medicine (2005) 4 October, Volume 143 Issue 7. (Page I-46). American College of Physicians. Retrieved 18 March, 2007
  22. ^ (2006) "Screening for hemochromatosis: recommendation statement". Ann. Intern. Med. 145 (3): 204-8. PMID 16880462.
  23. ^ Screening for Hemochromatosis U.S. Preventive Services Task Force (2006). Summary of Screening Recommendations and Supporting Documents. Retrieved 18 March, 2007
  24. ^ Gordeuk V, Caleffi A, Corradini E, Ferrara F, Jones R, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G, Garuti C, Gangaidzo I, Gomo Z, Moyo V, Rouault T, MacPhail P, Pietrangelo A (2003). "Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene". Blood Cells Mol Dis 31 (3): 299-304. PMID 14636642.
  25. ^ a b Olynyk J, Cullen D, Aquilia S, Rossi E, Summerville L, Powell L (1999). "A population-based study of the clinical expression of the hemochromatosis gene". N Engl J Med 341 (10): 718-24. PMID 10471457.
  26. ^ Hemochromatosis-Causes Mayo Foundation for Medical Education and Research (MFMER) Retrieved March 12, 2007
  27. ^ Shizukuda Y, Bolan C, Nguyen T, Botello G, Tripodi D, Yau Y, Waclawiw M, Leitman S, Rosing D (2007). "Oxidative stress in asymptomatic subjects with hereditary hemochromatosis". Am J Hematol 82 (3): 249-50. PMID 16955456.
  28. ^ Haemochromatosis Complications
  29. ^ Hemochromatosis - Treatment

See also

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Haemochromatosis". A list of authors is available in Wikipedia.
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