Haemochromatosis

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Haemochromatosis
Classifications and external resources
ICD-10 E83.1
ICD-9 275.0
OMIM 235200 602390 606464 604720 604653

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.

Contents

[edit] History

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 Friedrich Daniel von Recklinghausen in Hämochromatose. Tageblatt der Naturforschenden Versammlung 1889. Heidelberg, 1890:324.[1]

[edit] Signs and symptoms

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

Symptoms may include:

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.

[edit] Diagnosis

[edit] 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 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.

[edit] Chemistry

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.

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.

[edit] Histopathology

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

[edit] Epidemiology

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. A study of 3,011 unrelated white Australians found that 14% were carriers and 0.5% had the genetic condition.[6] 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.

[edit] Genetics

Haemochromatosis types 1-3 are inherited in an autosomal recessive fashion.
Enlarge
Haemochromatosis types 1-3 are inherited in an autosomal recessive fashion.

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 heterozygosity C282Y/H63D mutations are also associated to disease (both conditions are sufficient to reach the diagnosis). 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 4 is inherited in an autosomal dominant fashion.
Enlarge
Haemochromatosis type 4 is inherited in an autosomal dominant fashion.

[edit] Pathophysiology

The normal distribution of body iron stores
The normal distribution of body iron stores

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, probably at least partially by inducing Oxidative stress.[7]

[edit] Crypt cell hypothesis

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, the only known cellular iron exporter, for the basal side of the cell.

[edit] Hepcidin-ferroportin axis

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 hereditary hemochromatosis. In this view, low levels of circulating hepcidin result in higher levels of ferroportin expression in intestinal epithelial cells and reticuloendothelial macrophages. As a result, this causes increased levels of serum iron, first biochemically detected as increasing transferrin saturation. HFE, hemojuvelin, and TFR2 are implicated in regulating hepcidin expression. Higher serum iron levels lead to progressive iron loading in tissues.

[edit] Treatment

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. 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 bloodletting) is usually done at a weekly interval until ferritin levels are less than 50 nanograms per litre. After that, 1-4 donations per year are usually needed to maintain iron balance.

Other parts of the treatment include:

[edit] Screening

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.

[edit] 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.[8]
  • 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.

[edit] References

  1. ^ Biography of Daniel von Recklinghausen
  2. ^ PMID 6685241
  3. ^ PMID 15026513
  4. ^ PMID 6685241
  5. ^ PMID 7673967
  6. ^ Olynyk JK et al. PMID 10471457 "A population-based study of the clinical expression of the hemochromatosis gene." N Engl J Med. 1999 Sep 2;341(10):755-7.
  7. ^ PMID 16955456
  8. ^ PMID 14636642

[edit] See also

[edit] External links

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