Name = Haemochromatosis
DiseasesDB = 5490
ICD10 = ICD10|E|83|1|e|70
ICD9 = ICD9|275.0
OMIM = 235200
OMIM_mult = OMIM2|602390 OMIM2|606464 OMIM2|604720 OMIM2|604653
eMedicineSubj = med
eMedicineTopic = 975
eMedicine_mult = eMedicine2|derm|878
MeshID = D006432
Haemochromatosis, also spelled hemochromatosis (see spelling differences), also called siderophilia and bronze diabetes, is a
hereditary diseasecharacterized by excessive absorption of dietary iron resulting in a pathological increase in total body iron stores. Humans, like virtually all animals, have no means to excrete excess iron.cite web |url=http://sickle.bwh.harvard.edu/iron_epo.html |title=The interaction of iron and erythropoietin |format= |work= |accessdate=] Excess iron accumulates in tissues and organs disrupting their normal function. The most susceptible organs include the liver, adrenal glands, the heartand the pancreas; patients can present with cirrhosis, adrenal insufficiency, heart failure or diabetes. [ [http://www.cdc.gov/ncbddd/hemochromatosis/ Iron Overload and Hemochromatosis] Centers for Disease Control and Prevention] The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of British or Irish descent. [cite web |title=Celtic Curse |url=http://live.psu.edu/index.php?sec=vs&story=10913&pf=1 ]
Haemochromatosis less often refers to the condition of iron overload as a consequence of multiple transfusions. More preferred terms in the United States include for transfusional iron overload or
hemosiderosisused synonomously. Those with hereditary anemiassuch as beta-thalassemia major, sickle cell anemia, and Diamond-Blackfan anemiawho require regular transfusionsof red blood cells are all at risk for developing life-threatening iron overload. Older patients with various forms of bone marrow failure such as with myelodysplastic syndromewho become transfusion-dependent are also at risk for iron overload.
The disease was first described in 1865 by
Armand Trousseauin a report on diabetes in patients presenting with a bronze pigmentation of their skin.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= ] Trousseau did not associate diabeteswith ironaccumulation; the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausenin 1890. [cite journal | author = von Recklinghausen FD | title = Hämochromatose | journal = Tageblatt der Naturforschenden Versammlung 1889 | year = 1890 | pages = 324 | url= ] [ [http://www.whonamedit.com/doctor.cfm/1174.html Biography of Daniel von Recklinghausen] ] 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 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. [ [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] The more common clinical manifestations include: [ [http://www.cdc.gov/ncbddd/hemochromatosis/ Iron Overload and Hemochromatosis] Centers for Disease Control and Prevention] [ [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] [cite web |url=http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=2 |title=Hemochromatosis: Symptoms |format= |work=Mayo Foundation for Medical Education and Research (MFMER) |accessdate=]
Liver cirrhosis(with an increased risk of hepatocellular carcinomaLiver 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 pancreaticdamage from irondeposition
Erectile dysfunctionand hypogonadism
libidosecondary to the above
heart failure, arrhythmias or pericarditis
Arthritisof the hands (especially the first and second MCP joints), but also the knee and shoulder joints
Adrenal gland(leading to adrenal insufficiency)
Less common findings including:
Deafnesscite 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]
Dyskinesias, including Parkinsoniansymptomscite 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] 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]
* Dysfunction of certain
Parathyroid gland(leading to hypocalcaemia)
* 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 diseases caused by siderophilic microorganisms:
Vibrio vulnificus" infections from eating seafood
Salmonella enterica" (serotype Typhymurium)
** "Escherichia coli"
** "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.
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.cite web |url=http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=5 |title=Hemochromatosis: Tests and diagnosis |format= |work=Mayo Foundation for Medical Education and Research (MFMER) |accessdate=]
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
arthropathyincludes degenerative osteoarthritisand chondrocalcinosis. The distribution of the arthropathyis distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand.Fact|date=March 2007 The arthropathycan therefore be an early clue as to the diagnosis of haemochromatosis. MRIalgorithms 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 radiographicmeasurements of liveriron content were becoming more common. 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=]
Serum transferrinand transferrin saturation Transferrinbinds iron and is responsible for iron transport in the blood. [ [http://sickle.bwh.harvard.edu/iron_transport.html Transferrin and Iron Transport Physiology] ] 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.
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. [MedlinePlus|003490|Ferritin Test Measuring iron in the body] 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
echocardiogramfor heart failure, or blood glucose monitoring for patients with haemochromatosis diabetes.
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 biopsyis still necessary to quantify the amount of accumulated iron.
Screeningspecifically means looking for a diseasein people who have no symptoms. Diagnosis, on the other hand refers to testing people who have symptomsof a disease. Standard diagnostic measures for haemochromatosis, serum transferrin saturationand serum ferritintests, are not a part of routine medical testing. Screeningfor haemochromatosis is recommended if the patient has a parent, child or sibling with the disease, or have any of the following signs and symptoms: [cite journal |author= |title=Summaries for patients. Screening for hereditary hemochromatosis: recommendations from the American College of Physicians |journal=Ann. Intern. Med. |volume=143 |issue=7 |pages=I46 |year=2005 |pmid=16204158 |doi= |url=http://www.annals.org/cgi/content/full/143/7/I-46]
*Elevated liver enzymes
screeningof 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 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.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=] [ [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] 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.
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 Africandescent 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 Africandescent 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 ferroportinwhich predisposes some people of African descent to iron overload.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]
Transfusion hemosiderosisis 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 syndromeis a disorder in the production of red blood cells. This leads to increased iron recycling from the bone marrowand accumulation in the liver.
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
genesregulating iron metabolism, the most common allele being the C282Y allele in the "HFE" gene. The prevalenceof mutations in iron metabolism genesvaries in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygouscarriers of an HFE mutation, 0.5% were homozygousfor an "HFE" mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygousfor HFE mutations will not manifest clinically relevant haemochromatosis (see genetics below).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] 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. At that time when dietary iron may have been scarcer than today, the presence of the mutant allelemay have provided a natural selection reproductive advantageby maintaining higher ironlevels in the blood.
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 6which codes for a protein that participates in the regulation of iron absorption. The HFE genehas two common alleles, C282Y and H63D. [cite web |url=http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=3 |title=Hemochromatosis: Causes |format= |work=Mayo Foundation for Medical Education and Research (MFMER) |accessdate=] Heterozygotes for either allele do not manifest clinical iron overload but may display an increased iron uptake. Mutations of the "HFE" geneaccount for 90% of the cases of non-transfusional iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosityfor the C282Y mutationis the most common genotype responsible for clinical iron accumulation, though heterozygosityfor 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.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] 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):
Since the regulation of
ironmetabolism 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 hepcidinin the liver, a function that is impaired in HFE mutations.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]
People with abnormal iron regulatory genes do not reduce their absorption of
ironin response to increased ironlevels in the body. Thus the ironstores of the body increase. As they increase the iron which is initially stored as ferritinis deposited in organs as haemosiderinand this is toxicto tissue, probably at least partially by inducing oxidative stress.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] . 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".
Intestinal crypt enterocytes and iron overload
The sensor pathway inside the
small bowel enterocytecan be disrupted due to genetic errors in the ironregulatory apparatus. The enterocytein the small bowel cryptmust somehow sense the amount of circulating iron. Depending on this information, the enterocyte cellcan regulate the quantity of ironreceptors 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 phenotypeof iron overload. In this theory, low levels of circulating hepcidinresult in higher levels of ferroportinexpression in intestinal enterocytesand reticuloendothelial macrophages. As a result, this causes iron accumulation. HFE, hemojuvelin, BMP's and TFR2 are implicated in regulating hepcidinexpression. 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 haemochromatosis (JH).
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. [cite web |url=http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=6 |title=Hemochromatosis: Complications |format= |work=Mayo Foundation for Medical Education and Research (MFMER) |accessdate=] For example, similar to
alcoholism, haemochromatosis can cause cirrhosisof 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 oesophagusand 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 pancreaswhich 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 failureand 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. Pigmentchanges: Deposits of iron in skin cells can turn skin a bronze or gray color.
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. [cite web |url=http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=7 |title=Hemochromatosis: Treatments and drugs |format= |work=Mayo Foundation for Medical Education and Research (MFMER) |accessdate=] Treatment is initiated when ferritinlevels reach 300 milligrams per litre (or 200 in nonpregnant premenopausalwomen).
Every bag of blood (450-500 ml) contains 200-250
milligrams of iron. Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritinlevels 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 failurewith diuretics and ACE inhibitortherapy).
* 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 (such as spinachor collard greens, which must be consumed at the same time as the iron-containing foods in order to be effective.)
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