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
The disease was first described by Armand Trousseau in an
article on diabetes: Glycosurie, diab?e sucr? Clinique m?icale de
l'H?el-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 in H?ochromatose. Tageblatt der Naturforschenden
Versammlung 1889. Heidelberg, 1890:324.
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
Hemochromatosis type 1: "classical"
Hemochromatosis type 2: juvenile hemochromatosis :
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
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Signs and symptoms
Hemochromatosis 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
dysfunction of certain endocrine organs:
adrenal gland (leading to adrenal insufficiency)
parathyroid gland (leading to hypocalcaemia)
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:
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
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
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).