Haemochromatosis, also spelled hemochromatosis, 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.
Signs and symptoms
Haemochromatosis is notoriously protean, i.e., it presents with symptoms that are often initially attributed to other diseases.
Symptoms may include:
- 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:
- A darkish colour to the skin (see pigmentation, hence its name Diabete bronze when it was first described by Armand Trousseau in 1865)
- An increased susceptibility to certain infectious diseases caused by:
Males are usually diagnosed after their forties, and women about a decade later, owing to regular iron loss by menstruation (which ceases in menopause), but cases have been found in young children as well.
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 an increased attenuation at 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.
A first step is the measurement of ferritin, the tissue form of accumulated iron which is shed into the blood. Other markers of iron metabolism are the iron carrying protein transferrin (decreased), transferrin saturation (increased) and serum iron (increased). Genetic testing is performed if the biochemical markers are deranged.
When these investigations point at haemochromatosis, it is debatable whether a liver biopsy still needs to occur to quantify the amount of accumulated iron.
Hemochromatosis is one of 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 haemochromatosis 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, through genetic studies, that the "first" haemochromatosis 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. This gene is closely linked to the HLA-A3 locus. 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 haemochromatosis when other factors contribute, but are otherwise healthy. Even if an individual has both copies of the abnormal gene the risk of actual clinical haemochromatosis is low (between 1-25%) due to incomplete penetrance. The variability in these estimates is probably due to different populations studied and how penetrance was defined.
Other genes that cause haemochromatosis are the autosomal dominant SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). They are much rarer than HFE-haemochromatosis.
Recently, a classification has been developed (with chromosome locations):
- Haemochromatosis type 1 (Template:OMIM): "classical" HFE-haemochromatosis (6p21.3).
- Haemochromatosis type 2 (Template:OMIM): juvenile haemochromatosis :
- Type 2A: tentatively called HFE2A (1q21)
- Type 2B (Template:OMIM): mutation in hepcidin antimicrobial peptide (HAMP) or HFE2B (19q13)
- Haemochromatosis type 3 (Template:OMIM): transferrin receptor-2 (TFR2 or HFE3, 7q22).
- Haemochromatosis type 4 (Template:OMIM): autosomal dominant haemochromatosis (all others are recessive), ferroportin (SLC11A3) gene mutation (2q32).
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.
The sensor pathway inside the enterocyte is disrupted due to the genetic errors. The enterocyte in the crypt must sense the amount of circulating iron. Depending on this information, the cell can regulate the quantity of receptors and channel proteins for iron. If there is little iron, the cell will express many of these proteins. If there is a lot, the cell will turn off the expression of this transporters.
In haemochromatosis, the cell is 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.
These proteins are named DMT-1 (divalent metal transporter), for the luminal side of the cell, and ferroportin, for the basal side of the cell.
Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (venesection) (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 (or blood letting) 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).
- Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, and oxalic and phytic acid. (These must be consumed at the same time as the iron-containing foods in order to be effective.)
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.
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. 
- 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.
The disease was first described by Armand Trousseau in an article on diabetes: Glycosurie, diabète sucré. Clinique médicale de l'Hôtel-Dieu de Paris, 2nd ed, Paris, 1865, 2: 663-698. He did not make the link with iron accumulation. This was done by Daniel von Recklinghausen (Biography) in Hämochromatose. Tageblatt der Naturforschenden Versammlung 1889. Heidelberg, 1890:324.
- American Hemochromatosis Society
- Canadian Hemochromatosis Society
- Haemochromatosis page
- "The Bronze Killer" Mary Warder's book on Hemochromatosis
- Haemochromatosis page
- Causes of Haemochromatosis
- Iron Toxicity, What you don't know
- Review of the disease in the New England Journal of Medicine.
- Online Mendelian Inheritance in Man (main article)
- Haemochromatosis Society, UK
- Haemochromatosis Society Australia Inc
- Hemachromatosis page at the National Center for Biotechnology Information
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