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== Epidemiology ==
== Epidemiology ==
Haemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 200. The disease has a variable penetration and about 1 in 10 people of this demographic carry a mutation in one of the [[genes]] regulating [[iron]] [[metabolism]], the most common allele being the C282Y allele in the [[HFE (gene)|''HFE'' gene]]. The [[prevalence]] of mutations in iron metabolism [[genes]] varies in different populations. 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 study population had clinically relevant iron overload. Most patients who are [[homozygous]] for HFE mutations will not manifest clinically relevant haemochromatosis (see Genetics below).<ref name=Olynwk_1999>{{cite journal |author=Olynyk J, Cullen D, Aquilia S, Rossi E, Summerville L, Powell L |title=A population-based study of the clinical expression of the hemochromatosis gene |journal=N Engl J Med |volume=341 |issue=10 |pages=718–24 |year=1999 |pmid=10471457 |doi=10.1056/NEJM199909023411002}}</ref> Other populations have a lower prevalence of both the genetic mutation and the clinical disease.
Haemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 200. The disease has a variable penetration and about 1 in 10 people of this demographic carry a mutation in one of the [[genes]] regulating [[iron]] [[metabolism]], the most common allele being the C282Y allele in the [[HFE (gene)|''HFE'' gene]].<ref name="pmid18762941">{{cite journal |author=Mendes AI, Ferro A, Martins R, ''et al.'' |title=Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes |journal=Ann. Hematol. |volume=88 |issue=3 |pages=229–34 |year=2009 |month=March |pmid=18762941 |doi=10.1007/s00277-008-0572-y |url=http://dx.doi.org/10.1007/s00277-008-0572-y}}</ref> The [[prevalence]] of mutations in iron metabolism [[genes]] varies in different populations. 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 study population had clinically relevant iron overload. Most patients who are [[homozygous]] for HFE mutations will not manifest clinically relevant haemochromatosis (see Genetics below).<ref name=Olynwk_1999>{{cite journal |author=Olynyk J, Cullen D, Aquilia S, Rossi E, Summerville L, Powell L |title=A population-based study of the clinical expression of the hemochromatosis gene |journal=N Engl J Med |volume=341 |issue=10 |pages=718–24 |year=1999 |pmid=10471457 |doi=10.1056/NEJM199909023411002}}</ref> Other populations have a lower prevalence of both the genetic mutation and the clinical disease.


[[Genetics|Genetic]] studies suggest the original haemochromatosis mutation arose in a single person, possibly of [[Celt]]ic ethnicity, who lived 60-70 generations ago.<ref>www.scripps.edu/bcmd/pdfarea/issue_20_98/lucotte.pdf </ref> At that time when dietary iron may have been scarcer than today, the presence of the [[mutant allele]] may have provided a [[natural selection]] [[reproductive advantage]] by maintaining higher [[iron]] levels in the blood.
[[Genetics|Genetic]] studies suggest the original haemochromatosis mutation arose in a single person, possibly of [[Celt]]ic ethnicity, who lived 60-70 generations ago.<ref>www.scripps.edu/bcmd/pdfarea/issue_20_98/lucotte.pdf </ref> At that time when dietary iron may have been scarcer than today, the presence of the [[mutant allele]] may have provided a [[natural selection]] [[reproductive advantage]] by maintaining higher [[iron]] levels in the blood.

Revision as of 03:15, 15 May 2009

Hereditary haemochromatosis
SpecialtyEndocrinology, hepatology Edit this on Wikidata
This article is about hemochromatosis caused by the HFE gene. For other causes of hemochromatosis, see iron overload disorder.

Hemochromatosis type 1 is a hereditary disease characterized by excessive absorption of dietary iron resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron.[1] Excess iron accumulates in tissues and organs disrupting their normal function. The most susceptible organs include the liver, adrenal glands, the heart and the pancreas; patients can present with cirrhosis, adrenal insufficiency, heart failure or diabetes. [2] The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of British or Irish descent.[3]

Terminology

The term "hemochromatosis" is used by many different sources in many different ways.

It is often used to imply an association with the HFE gene. For many years, HFE was the only known gene associated with hemochromatosis, and the term "hereditary hemochromatosis" was used to describe hemochromatosis type 1. However, it is now known that there are many different genetic associations with this condition. The older the text, or the more general the audience, the more likely that HFE is implied.

The term "hemochromatosis" has also been in contexts where there had not been a known genetic association for the iron accumulation. However, it should be noted that in some cases, the understanding of a condition that was considered due to behavior can be refined to accommodate new known genetic associations, as in African iron overload.

History

The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin.[4] Trousseau did not associate diabetes with iron accumulation; the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890.[5][6]

Signs and symptoms

Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon and for most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they suffer premature morbidity.[7] The more common clinical manifestations include:[2][8][9]

Less common findings including:

Males are usually diagnosed after their forties and fifties, and women several decades later, owing to regular iron loss through menstruation (which ceases in menopause). The severity of clinical disease in the hereditary form varies considerably. There is evidence suggesting that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease suffer worse liver disease than those with either condition alone. There are also juvenile forms of hereditary haemochromatosis that present in childhood with the same consequences of iron overload.

Diagnosis

The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint. [13]

Blood tests

Serum transferrin and transferrin saturation are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood.[14] Measuring transferrin provides a crude measure of iron stores in the body. Saturation values in excess of 45% are recognized as a threshold for further evaluation of haemochromatosis. [13] Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene.[15]

Serum Ferritin- Ferritin, a protein synthesized by the liver is the primary form of iron storage within cells and tissues. Measuring ferritin provides another crude estimate of whole body iron stores though many conditions notably inflammation can elevate serum ferritin. Normal values for males are 12-300 ng/ml (nanograms per milliliter) and for female, 12-150 ng/ml.[13][16] Serum ferritin in excess of 1000 nanograms per millilitre of blood is almost always attributable to haemochromatosis.

Other blood tests routinely performed: blood count, renal function, liver enzymes, electrolytes, glucose (and/or an oral glucose tolerance test (OGTT)).

Liver biopsy

Iron accumulation demonstrated by Prussian blue staining in a patient with homozygous genetic hemochromatosis (microscopy, 10x magnified). Parts of normal pink tissue are scarcely present.

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 haemochromatosis 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.[13]

Imaging

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 in MRI scans. 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 haemochromatosis. 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. [17]

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 haemochromatosis diabetes.

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.[18]
  • 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.

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.[19] 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 oesophagus 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: Bronze or gray coloration of the skin is caused primarily by increased melanin deposition, with iron deposition playing a lesser role[20].

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.[21] 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, 1-6 donations per year are usually needed to maintain iron balance.

Other parts of the treatment include:

[22]

Screening

Standard diagnostic measures for haemochromatosis, transferrin saturation and ferritin tests, are not a part of routine medical testing. Screening for haemochromatosis is recommended if the patient has a parent, child or sibling with the disease.[23]

Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force (USPSTF), among other groups. The USPSTF recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than 1 in 1,000. Although there is strong evidence that treatment of iron overload can save lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy) provides any clinical benefit.[24] [25] Recently, it has been suggested that patients be screened for iron overload using serum ferritin as a marker: If serum ferritin exceeds 1000 ng/mL, iron overload is very likely the cause.

Epidemiology

Haemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 200. The disease has a variable penetration and about 1 in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism, the most common allele being the C282Y allele in the HFE gene.[26] The prevalence of mutations in iron metabolism genes varies in different populations. 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 study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations will not manifest clinically relevant haemochromatosis (see Genetics below).[27] Other populations have a lower prevalence of both the genetic mutation and the clinical disease.

Genetic studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60-70 generations ago.[28] At that time when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided a natural selection reproductive advantage by maintaining higher iron levels in the blood.

Genetics

The regulation of dietary iron absorption is complex and our understanding is incomplete. One of the better characterized genes responsible for hereditary haemochromatosis is HFE on chromosome 6 which codes for a protein that participates in the regulation of iron absorption. The HFE gene has two common alleles, C282Y and H63D.[29] Heterozygotes for either allele do not manifest clinical iron overload but may display an increased iron uptake. Mutations of the HFE gene account for 90% of the cases of non-transfusional iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, results in clinically evident iron overload. There is considerable debate regarding the penetrance -- the probability of clinical expression of the trait given the genotype -- is for clinical disease in HHC homozygotes. Most, if not all, males homozygous for HFE C282Y will show manifestations of liver dysfunction such as elevated liver-specific enzymes such as serum gamma glutamyltransferase (GGT) by late middle age. Homozygous females can delay the onset of iron accumulation because of iron loss through menstruation. Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the mutation and the presence of other insults to the liver such as alcohol and viral disease. As such the degree to which the liver and other organs is affected, expressivity, is highly variable and is dependent on such these other factors and co-morbidities as well as age at which they are studied for manifestations of disease.[27] Penetrance differs between different populations.

One of the most common cause of hereditary haemochromatosis is a single point mutation at C282Y in which the cystine residue at position 282 is changed into a tyrosine residue.

Pathophysiology

The normal distribution of body iron stores

Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis 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. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.[30]

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.[31]. Iron is a pro-oxidant. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing".

See also

External links

References

  1. ^ "The interaction of iron and erythropoietin".
  2. ^ a b Iron Overload and Hemochromatosis Centers for Disease Control and Prevention
  3. ^ "Celtic Curse".
  4. ^ Trousseau A (1865). "Glycosurie, diabète sucré". Clinique médicale de l'Hôtel-Dieu de Paris. 2: 663–98.
  5. ^ von Recklinghausen FD (1890). "Hämochromatose". Tageblatt der Naturforschenden Versammlung 1889: 324.
  6. ^ Biography of Daniel von Recklinghausen
  7. ^ Hemochromatosis-Diagnosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
  8. ^ Hemochromatosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
  9. ^ "Hemochromatosis: 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. doi:10.1136/jnnp.2003.027441. PMID 15026513.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ a b c d "Hemochromatosis: Tests and diagnosis". Mayo Foundation for Medical Education and Research (MFMER). Retrieved 2009-04-20.
  14. ^ Transferrin and Iron Transport Physiology
  15. ^ Dadone MM, Kushner JP, Edwards CQ, Bishop DT, Skolnick MH (1982). "Hereditary hemochromatosis. Analysis of laboratory expression of the disease by genotype in 18 pedigrees". American Journal of Clinical Pathology. 78 (2): 196–207. PMID 7102818. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ MedlinePlus Encyclopedia: Ferritin Test Measuring iron in the body
  17. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ 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. doi:10.1016/S1079-9796(03)00164-5. PMID 14636642.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ "Hemochromatosis: Complications". Mayo Foundation for Medical Education and Research (MFMER).
  20. ^ Pedrup A, Poulsen H (1964). "Hemochromatosis and Vitiligo". Archives of Dermatology. 90 (1): 34–37. PMID 14149720.
  21. ^ "Hemochromatosis: Treatments and drugs". Mayo Foundation for Medical Education and Research (MFMER).
  22. ^ http://dynaweb.ebscohost.com/Detail.aspx?id=116469&sid=14aa79e5-a881-407c-94e7-339b81c4cd18@sessionmgr3 accessed October 15, 2008.
  23. ^ "Summaries for patients. Screening for hereditary hemochromatosis: recommendations from the American College of Physicians". Ann. Intern. Med. 143 (7): I46. 2005. PMID 16204158.
  24. ^ "Screening for haemochromatosis: recommendation statement". Ann. Intern. Med. 145 (3): 204–8. 2006. PMID 16880462.
  25. ^ Screening for Hemochromatosis U.S. Preventive Services Task Force (2006). Summary of Screening Recommendations and Supporting Documents. Retrieved 18 March, 2007
  26. ^ Mendes AI, Ferro A, Martins R; et al. (2009). "Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes". Ann. Hematol. 88 (3): 229–34. doi:10.1007/s00277-008-0572-y. PMID 18762941. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  27. ^ 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. doi:10.1056/NEJM199909023411002. PMID 10471457.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ www.scripps.edu/bcmd/pdfarea/issue_20_98/lucotte.pdf
  29. ^ "Hemochromatosis: Causes". Mayo Foundation for Medical Education and Research (MFMER).
  30. ^ Vujić Spasić M, Kiss J, Herrmann T; et al. (2008). "Hfe acts in hepatocytes to prevent hemochromatosis". Cell Metab. 7 (2): 173–8. doi:10.1016/j.cmet.2007.11.014. PMID 18249176. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  31. ^ 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. doi:10.1002/ajh.20743. PMID 16955456.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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