Haemochromatosis

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Haemochromatosis
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 end 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.

Contents
[hide]

• 1 History
• 2 Signs and symptoms
• 3 Diagnosis
o 3.1 Imaging features
o 3.2 Chemistry
o 3.3 Functional testing
o 3.4 Histopathology
o 3.5 Screening
o 3.6 Differential diagnosis
• 4 Epidemiology
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 • 5 Genetics
• 6 Pathophysiology
o 6.1 Intestinal crypt enterocytes and iron overload
o 6.2 Hepcidin-ferroportin axis and iron overload
• 7 End-organ damage
• 8 Treatment
• 9 References
• 10 See also
• 11 External links

History
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]

• 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)
due to pancreatic damage from iron
precipitation
• Erectile dysfunction and hypogonadism
• Decreased libido
• Congestive heart failure, arrhythmias or
pericarditis
• Arthritis of the hands (especially the MCP and
PIP joints), knee and shoulder joints
• Deafness[10]
• Dyskinesias, including Parkinsonian
symptoms[11][10][12]
• Dysfunction of certain endocrine organs:
o Pancreatic gland, as above, manifesting
as diabetes
o Adrenal gland (leading to adrenal
insufficiency)
o Parathyroid gland (leading to
hypocalcaemia)
o Pituitary gland
o Testes or ovary (leading to
hypogonadism)
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 • 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 siderophilic microoganisms:
o Vibrio vulnificus infections from eating
seafood
o Listeria monocytogenes
o Yersinia enterocolica
o Salmonella enterica (serotype
Typhymurium)
o Klebsiella pneumoniae
o Escherichia coli
o Rhizopus arrhizus
o 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). Cases of
iron overload have been found in young children as well.

Diagnosis
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]

Chemistry

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.
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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.

Histopathology

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

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.
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 • 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.

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 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.

Genetics

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

Haemochromatosis type 4 is inherited in an autosomal dominant fashion.

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).

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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"-

235200 HFE 6p21.3
haemochromatosis

Haemochromatosis type 2A: juvenile hemojuvelin ("HJV",

602390 1q21
haemochromatosis also known as HFE2)

hepcidin antimicrobial
Haemochromatosis type 2B: juvenile
606464 peptide (HAMP) or 19q13
haemochromatosis
HFE2B

transferrin receptor-2
Haemochromatosis type 3 604720 7q22
(TFR2 or HFE3)

Haemochromatosis type 4 autosomal

dominant haemochromatosis (all others are 604653 ferroportin (SLC11A3) 2q32
recessive), gene mutation

Pathophysiology

The normal distribution of body iron stores

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

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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.

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

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.[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.)

References
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)

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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. ^ [http://www.annals.org/cgi/content/full/143/7/I-46
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.

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 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
• Cirrhosis

External links
• American Hemochromatosis Society
• International Bioiron Society
• Canadian Hemochromatosis Society
• Haemochromatosis page
• Causes of Haemochromatosis
• Haemochromatosis Society, UK
• Haemochromatosis Society Australia Inc

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