Haemochromatosis
68349
225939073
2008-07-16T02:59:09Z
Hgrosser
590283
add link
{{cleanup|date=January 2008}} <!--tagged for cleanup for source purposes, see talk-->
{{Infobox_Disease |
Name = Haemochromatosis |
Image = |
Caption = |
DiseasesDB = 5490 |
ICD10 = {{ICD10|E|83|1|e|70}} |
ICD9 = {{ICD9|275.0}} |
ICDO = |
OMIM = 235200 |
OMIM_mult = {{OMIM2|602390}} {{OMIM2|606464}} {{OMIM2|604720}} {{OMIM2|604653}} |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 975 |
eMedicine_mult = {{eMedicine2|derm|878}} |
MeshID = D006432 |
}}
'''Haemochromatosis''' (American spelling '''hemochromatosis''', also called '''siderophilia'''), is a [[hereditary disease]] characterized by excessive absorption of dietary [[iron]] resulting in a pathologic increase in total body iron stores. Humans, like virtually all animals, have no means to excrete excess iron.<ref name="urlThe interaction of iron and erythropoietin">{{cite web |url=http://sickle.bwh.harvard.edu/iron_epo.html |title=The interaction of iron and erythropoietin |format= |work= |accessdate=}}</ref> 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]]. <ref>[http://www.cdc.gov/ncbddd/hemochromatosis/ Iron Overload and Hemochromatosis] Centers for Disease Control and Prevention</ref> The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of British or Irish descent.<ref>{{cite web |title=Celtic Curse |url=http://live.psu.edu/index.php?sec=vs&story=10913&pf=1 }}</ref>
Haemochromatosis less often refers to the condition of iron overload as a consequence of multiple transfusions. A more preferred term in the United States for transfusional iron overload is [[hemosiderosis]]. Those with hereditary [[anemias]] such as [[Thalassemia#Beta (β) thalassemias|beta-thalassemia major]], [[sickle cell anemia]], and [[Diamond-Blackfan anemia]] who require regular [[transfusions]] of [[red blood cell]]s are all at risk for developing life-threatening iron overload. Older patients with various forms of bone marrow failure such as with [[myelodysplastic syndrome]] who become transfusion-dependent are also at risk for iron overload.
== History ==
The disease was first described in 1865 by [[Armand Trousseau]] in a report on [[diabetes mellitus|diabetes]] in patients presenting with a bronze pigmentation of their skin.<ref name=Trousseau_1865>{{cite journal | author = Trousseau A| title = Glycosurie, diabète sucré | journal = Clinique médicale de l'Hôtel-Dieu de Paris | year = 1865 | volume = 2| pages = 663–98 | url= }}</ref> 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.<ref>{{cite journal | author = von Recklinghausen FD | title = Hämochromatose | journal = Tageblatt der Naturforschenden Versammlung 1889 | year = 1890 | pages = 324 | url= }}</ref><ref>[http://www.whonamedit.com/doctor.cfm/1174.html Biography of Daniel von Recklinghausen]</ref>
In 1978 the Iron Overload Diseases Association (IOD) was formed to act as a support group and information center for people affected by hemochromatosis.
== Signs and symptoms ==
Haemochromatosis is [[wikt:protean|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. <ref>[http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm Hemochromatosis-Diagnosis] National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services</ref>
The more common clinical manifestations include:<ref>[http://www.cdc.gov/ncbddd/hemochromatosis/ Iron Overload and Hemochromatosis] Centers for Disease Control and Prevention</ref><ref>[http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm Hemochromatosis] National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services</ref><ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=2 Hemochromatosis-Signs and Symptoms] Mayo Foundation for Medical Education and Research (MFMER)</ref>
* [[Malaise]]
* [[Liver cirrhosis]] (with an increased risk of [[hepatocellular carcinoma]] Liver disease is always preceded by evidence of liver dysfunction including elevated serum enzymes specific to the liver.
* [[Insulin resistance]] (often patients have already been diagnosed with [[diabetes mellitus type 2]]) due to [[pancreatic]] damage from [[iron]] deposition
* [[Erectile dysfunction]] and [[hypogonadism]]
* Decreased [[libido]] secondary to the above
* Congestive [[heart failure]], [[arrhythmia]]s or [[pericarditis]]
* [[Arthritis]] of the hands (especially the first and second [[MCP joint]]s), but also the [[knee joint|knee]] and [[shoulder joint|shoulder]] [[joint]]s
** [[Adrenal gland]] (leading to [[adrenal insufficiency]])
Less common findings including:
* [[Deafness]]<ref name=Jones_1983>{{cite journal |author=Jones H, Hedley-Whyte E |title=Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs |journal=Neurology |volume=33 |issue=11 |pages=1479–83 |year=1983 |pmid=6685241}}</ref>
*[[Dyskinesia]]s, including [[Parkinsonian]] symptoms<ref name=Costello_2004>{{cite journal |author=Costello D, Walsh S, Harrington H, Walsh C |title=Concurrent hereditary haemochromatosis and idiopathic Parkinson's disease: a case report series |journal=J Neurol Neurosurg Psychiatry |volume=75 |issue=4 |pages=631–3 |year=2004 |pmid=15026513 |doi=10.1136/jnnp.2003.027441}}</ref><ref name=Jones_1983 /><ref name=Nielsen_1995>{{cite journal |author=Nielsen J, Jensen L, Krabbe K |title=Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome |journal=J Neurol Neurosurg Psychiatry |volume=59 |issue=3 |pages=318–21 |year=1995 |pmid=7673967}}</ref>
* Dysfunction of certain [[endocrine organs]]:
** [[Parathyroid gland]] (leading to [[hypocalcaemia]])
** [[Pituitary gland]]
* A darkish colour to the skin (see [[pigmentation]], hence its name '''''Diabetes bronze''''' when it was first described by [[Armand Trousseau]] in [[1865]])
* An increased susceptibility to certain [[infectious disease]]s caused by [[siderophilic bacteria|siderophilic microorganisms]]:
** ''[[Vibrio vulnificus]]'' infections from eating [[seafood]]
** ''[[Listeria monocytogenes]]''
** ''[[Yersinia enterocolica]]''
** ''[[Salmonella enterica]]'' (serotype Typhymurium)
** ''[[Klebsiella pneumoniae]]''
** ''[[E. coli|Escherichia coli]]''
** ''[[Rhizopus arrhizus]]''
** ''Mucor'' species
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 excessive iron binding saturation of transferrin exceeding the normal value of 50%. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint. The evaluation of abnormal transferrin saturation commonly involves determining the level of ferritin, a protein found in serum made by liver that binds iron. Serum ferritin in excess of 1000 nanograms per millilitre of blood is almost always attributable to haemochromatosis.<ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=5 Screening and Diagnosis]</ref>
=== 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 [[Computed axial tomography|CT]] and a decreased signal intensity at [[Magnetic resonance imaging|MR imaging]]. Haemochromatosis [[arthropathy]] includes degenerative [[osteoarthritis]] and [[Pseudogout|chondrocalcinosis]]. The distribution of the [[arthropathy]] is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand.{{Fact|date=March 2007}} 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. <ref name="pmid17018390">{{cite journal |author=Tanner MA, He T, Westwood MA, Firmin DN, Pennell DJ |title=Multi-center validation of the transferability of the magnetic resonance T2* technique for the quantification of tissue iron |journal=Haematologica |volume=91 |issue=10 |pages=1388–91 |year=2006 |pmid=17018390 |doi=}}</ref>
=== Chemistry ===
'''Serum transferrin and transferrin saturation''' [[Transferrin]] binds iron and is responsible for iron transport in the blood.<ref>[http://sickle.bwh.harvard.edu/iron_transport.html Transferrin and Iron Transport Physiology]</ref> Measuring transferrin provides a crude measure of iron stores in the body. Saturation values in excess of 62% are recognized as a threshold for further evaluation of haemochromatosis. <ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=5 Screening and Diagnosis]</ref>
'''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.<ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=5 Screening and Diagnosis]</ref><ref>[http://www.nlm.nih.gov/medlineplus/ency/article/003490.htm Ferritin Test] Measuring iron in the body</ref>
Other blood tests routinely performed: [[blood count]], [[renal function]], [[liver enzyme]]s, [[electrolyte]]s, [[glucose]] (and/or an [[oral glucose tolerance test]] (OGTT)).
===Functional testing===
Based on the history, the [[physician|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]].
=== 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 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.<ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=5 Screening and diagnosis] Mayo Foundation for Medical Education and Research (MFMER) Retrieved 18 March, 2007</ref>
=== 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 haemochromatosis is recommended if the patient has a parent, child or sibling with the disease, or have any of the following signs and symptoms:<ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=5 Screening and Diagnosis] Mayo Foundation for Medical Education and Research (MFMER). Retrieved 18 March, 2007</ref><ref>[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</ref>
*Joint disease
*Severe fatigue
*Heart disease
*Elevated liver enzymes
*Impotence
*Diabetes
Routine [[screening]] of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the US Preventive Services Task Force (USPSTF), among other groups. The USPSTF recommended against genetic screening of the general population for hereditary hemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than 1 in 1000. Although there is strong evidence that treatment of iron overload can saves 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.<ref name="pmid16880462">{{cite journal |author= |title=Screening for haemochromatosis: recommendation statement |journal=Ann. Intern. Med. |volume=145 |issue=3 |pages=204–8 |year=2006 |pmid=16880462 |doi=}}</ref> <ref>[http://www.ahrq.gov/clinic/uspstf/uspshemoch.htm Screening for Hemochromatosis] U.S. Preventive Services Task Force (2006). Summary of Screening Recommendations and Supporting Documents. Retrieved 18 March, 2007</ref> 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.
=== 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 [[galvanisation|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 (biology)|polymorphism]] in the gene for [[ferroportin]] which predisposes some people of African descent to iron overload.<ref name=Gordeuk_2003>{{cite journal |author=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 |title=Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene |journal=Blood Cells Mol Dis |volume=31 |issue=3 |pages=299–304 |year=2003 |pmid=14636642 |doi=10.1016/S1079-9796(03)00164-5}}</ref>
* '''[[Transfusion hemosiderosis]]''' is the accumulation of iron, mainly in the [[liver]], in patients who receive frequent [[blood transfusion]]s (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 ==
Haemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 150. Thus, about 1 in 12 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. 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|Celtic]] ethnicity, who lived 60-70 generations ago. 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==
[[Image:Autorecessive.jpg|thumb|right|Haemochromatosis types 1-3 are inherited in an [[Recessive gene|autosomal recessive]] fashion.]]
[[Image:Autodominant.jpg|thumb|right|Haemochromatosis type 4 is inherited in an [[autosomal dominant]] fashion.]]
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 gene|HFE]] which codes for a protein that participates in the regulation of iron absorption. The [[HFE gene]] has two common alleles, C282Y and H63D.<ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=3 Hemochromatosis-Causes] Mayo Foundation for Medical Education and Research (MFMER) Retrieved March 12, 2007</ref>
Heterozygotes for either allele do not manifest clinical iron overload but may display an increased iron uptake. [[Mutation]]s of the ''HFE'' [[gene]] account for 90% of the cases of non-transfusional iron overload. This gene is closely [[genetic linkage|linked]] to the [[Human leukocyte antigen|HLA-A3]] [[Locus (genetics)|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 are delay the onset of iron accummulation because of iron loss through menstruation. Each patient with the susceptible genotype accummulates 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.<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> 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.
Recently, a classification has been developed (with chromosome locations):
{| class="wikitable"
| '''Description''' || '''[[OMIM]]''' || '''Mutation''' || '''[[Locus (genetics)|Locus]]'''
|-
| Haemochromatosis type 1: "classical"-haemochromatosis || {{OMIM2|235200}} || [[HFE (gene)|HFE]] || 6p21.3
|-
| Haemochromatosis type 2A: juvenile haemochromatosis || {{OMIM2|602390}} || [[hemojuvelin]] ("HJV", also known as HFE2) || 1q21
|-
| Haemochromatosis type 2B: juvenile haemochromatosis || {{OMIM2|606464}} || hepcidin antimicrobial peptide (''[[HAMP]]'') or HFE2B || 19q13
|-
| Haemochromatosis type 3 || {{OMIM2|604720}} || [[transferrin receptor-2]] (TFR2 or HFE3) || 7q22
|-
| Haemochromatosis type 4 [[autosomal dominant]] haemochromatosis (all others are [[Recessive gene|recessive]]), gene mutation || {{OMIM2|604653}} || [[ferroportin]] (SLC11A3) || 2q32
|}
== Pathophysiology ==
[[Image:Iron metabolism.svg|thumb|400px|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 gene|HFE]] is only part of the story, since many patients with mutated [[HFE gene|HFE]] do not manifest clinical iron overload, and some patients with iron overload have a normal [[HFE gene|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.<ref name="pmid18249176">{{cite journal |author=Vujić Spasić M, Kiss J, Herrmann T, ''et al'' |title=Hfe acts in hepatocytes to prevent hemochromatosis |journal=Cell Metab. |volume=7 |issue=2 |pages=173–8 |year=2008 |pmid=18249176 |doi=10.1016/j.cmet.2007.11.014}}</ref>
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 [[biological tissue|tissue]], probably at least partially by inducing [[oxidative stress]].<ref name=Shizukuda_2007>{{cite journal |author=Shizukuda Y, Bolan C, Nguyen T, Botello G, Tripodi D, Yau Y, Waclawiw M, Leitman S, Rosing D |title=Oxidative stress in asymptomatic subjects with hereditary hemochromatosis |journal=Am J Hematol |volume=82 |issue=3 |pages=249–50 |year=2007 |pmid=16955456 |doi=10.1002/ajh.20743}}</ref>. 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 [[Dalmatians|Dalmatian dogs]]. The latter also experience "bronzing".
=== Intestinal crypt enterocytes and iron overload===
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]] [[Receptor (biochemistry)|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, a mutation in the HFE gene leads to a lack of the basolateral transporter that endocytoses iron from the plasma into the epithelial cell. As a consequence of being unable to detect serum iron concentrations, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption.
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 haemochromatosis 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 gene|HFE]], [[hemojuvelin]], BMP's and TFR2 are implicated in regulating [[hepcidin]] expression. In particular, mutations in hemojuvelin (HJV), also called RGMc (Repulsive Guidance Molecule c), result in a severe form of iron overload that has a juvenile onset (by the second decade of life) called juvenile hemochromatosis (JH).
==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.<ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=6 Haemochromatosis Complications]</ref> 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.
'''[[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 [[Venipuncture|phlebotomies]] (by venesection) comparable in volume to [[blood donation]]s.<ref>[http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=7 Hemochromatosis - Treatment]</ref> Treatment is initiated when [[ferritin]] levels reach 300 [[Kilogram#SI multiples|milligrams]] per litre (or 200 in nonpregnant [[premenopausal]] women).
Every bag of blood (450-500 [[millilitre|ml]]) contains 200-250 [[milligram]]s 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 [[diuretic]]s and [[ACE inhibitor]] therapy).
* Limiting intake of [[alcoholic beverage]]s, [[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 acid|oxalic]] and [[phytic acid]]s (such as [[spinach]] or [[collard greens]], which must be consumed at the same time as the iron-containing foods in order to be effective.)
==References==
<!-- ---------------------------------------------------------------
See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for a
discussion of different citation methods and how to generate
footnotes using the <ref> & </ref> tags and the {{Reflist}} template
-------------------------------------------------------------------- -->
{{Reflist|2}}
== See also ==
* [[Cirrhosis]]
== External links ==
* {{DMOZ|Health/Conditions_and_Diseases/Genetic_Disorders/Hemochromatosis}}
{{Hematology}}
{{Mineral metabolic pathology}}
[[Category:Arthritis]]
[[Category:Gastroenterology]]
[[Category:Genetic disorders]]
[[Category:Hematology]]
[[Category:Hepatology]]
[[Category:Iron]]
[[bn:লৌহ সঞ্চয় ব্যাধি]]
[[de:Hämochromatose]]
[[es:Hemocromatosis]]
[[fi:Hemokromatoosi]]
[[fr:Hémochromatose génétique]]
[[he:המוכרומטוזיס]]
[[it:Emocromatosi ereditaria]]
[[nl:Hemochromatose]]
[[no:Hemokromatose]]
[[pl:Hemochromatoza]]
[[pt:Hemocromatose]]
[[sv:Hemokromatos]]