View source for Iron overload

{{Short description|Human disease}}
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{{Infobox medical condition (new)
| name            = Iron overload
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| image           = Hemosiderosis_high_mag.jpg
| caption         = [[Micrograph]]
of liver [[biopsy]] showing iron deposits due to haemosiderosis. [[Perls' Prussian blue|Iron stain]].
| field           = [[Hematology]], [[gastroenterology]]/[[hepatology]]
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'''Iron overload''' is the abnormal and increased accumulation of total [[iron]] in the body, leading to organ damage.<ref name="pmid35699322">{{cite journal |vauthors=Hsu CC, Senussi NH, Fertrin KY, Kowdley KV |title=Iron overload disorders |journal=Hepatol Commun|date=June 2022 |volume=6 |issue=8 |pages=1842–54 |pmid=35699322 |doi=10.1002/hep4.2012|pmc=9315134 |doi-access=free }}</ref> The primary mechanism of organ damage is [[oxidative stress]], as elevated intracellular iron levels increase [[free radical]] formation via the [[Fenton reaction]]. Iron overload is often ''primary'' (i.e, [[hereditary haemochromatosis]], [[aceruloplasminemia]]) but may also be ''secondary'' to other causes (i.e., [[transfusion hemosiderosis|transfusional iron overload]]).<ref>{{cite book |first1=Robert C. |last1=Hider |first2=Xiaole |last2=Kong |chapter=Iron: Effect of Overload and Deficiency |editor=Astrid Sigel, Helmut Sigel and Roland K. O. Sigel |title=Interrelations between Essential Metal Ions and Human Diseases |series=Metal Ions in Life Sciences |volume=13 |year=2013 |publisher=Springer|pages=229–94 |doi=10.1007/978-94-007-7500-8_8 |pmid=24470094 |isbn=978-94-007-7499-5 }}</ref> Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints. People with iron overload classically present with the triad of [[liver cirrhosis]], secondary [[diabetes mellitus]], and bronze skin.<ref name=":1">{{Cite journal |last1=Daniłowicz-Szymanowicz |first1=Ludmiła |last2=Świątczak |first2=Michał |last3=Sikorska |first3=Katarzyna |last4=Starzyński |first4=Rafał R. |last5=Raczak |first5=Alicja |last6=Lipiński |first6=Paweł |date=2021-07-16 |title=Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis-The Cardiological Point of View |journal=Diagnostics (Basel, Switzerland) |volume=11 |issue=7 |pages=1279 |doi=10.3390/diagnostics11071279 |doi-access=free |issn=2075-4418 |pmc=8304945 |pmid=34359361}}</ref> However, due to earlier detection nowadays, symptoms are often limited to general chronic [[malaise]], [[arthralgia]], and [[hepatomegaly]].<ref name=":1" />

==Signs and symptoms==

Organs most commonly affected by hemochromatosis include the [[liver]], [[heart]], and [[endocrine gland]]s.<ref>{{cite journal |last1=Andrews |first1=Nancy C. |title=Disorders of Iron Metabolism |journal=New England Journal of Medicine |volume=341 |issue=26 |pages=1986–95 |year=1999 |pmid=10607817 |doi=10.1056/NEJM199912233412607}}</ref>

Hemochromatosis may present with the following clinical syndromes:
* liver: [[chronic liver disease]] and [[cirrhosis]] of the liver.<ref name="Murtagh, 2007">{{cite book|title=General Practice|author=John Murtagh|publisher=McGraw Hill Australia|year=2007|isbn=978-0-07-470436-3}}{{page needed|date=December 2010}}</ref>
* heart: [[heart failure]], [[cardiac arrhythmia]].<ref name="Murtagh, 2007" />
* hormones: diabetes (see below) and [[hypogonadism]] (insufficiency of the sex hormone producing glands) which leads to low sex drive and/or loss of fertility in men and loss of fertility and menstrual cycle in women.<ref name="Murtagh, 2007" />
* metabolism: [[diabetes]] in people with iron overload occurs as a result of selective iron deposition in islet [[beta cells]] in the [[pancreas]] leading to functional failure and cell death.<ref name="Selective iron deposition in pancre">{{cite journal |last1=Lu|first1=JP |title=Selective iron deposition in pancreatic islet B cells of transfusional iron-overloaded autopsy cases |journal=Pathol Int |volume=44 |pages= 194–99 |year=1994 |issue=3 |pmid=802561  |doi= 10.1111/j.1440-1827.1994.tb02592.x|s2cid=25357672 }}</ref>
* skeletal: [[arthritis]], from iron deposition in joints leading to joint pains. The most commonly affected joints are those of the hands, particularly the [[knuckle]]s or [[metacarpophalangeal joints]], wrists or [[radiocarpal joint]]s, elbow, hip, knee, and ankle joints.<ref name="NEJM Olynyk" /><ref name="Bacon and Schrier, UpToDate">{{cite web|url=http://www.uptodate.com/contents/hemochromatosis-hereditary-iron-overload-beyond-the-basics|title=Patient information: Hemochromatosis (hereditary iron overload) (Beyond the Basics)|author=Bruce R Bacon, Stanley L Schrier|website=[[UpToDate]]|access-date=2016-07-14}} Literature review current through: Jun 2016. | This topic last updated: Apr 14, 2015.</ref> Risk factors for the development of arthritis in those with hemochromatosis include elevated iron levels ([[ferritin]] greater than 1000 or [[transferrin]] saturation greater than 50%) for an extended period, increasing age, and concurrent advanced liver fibrosis.<ref name="NEJM Olynyk" />
* skin: melanoderma (darkening or 'bronzing' of the skin).<ref name="Bacon and Schrier, UpToDate" /><ref name="Brissot et al., Nat Rev Dis Prim 2018">{{cite journal |last1=Brissot |first1=P |last2=Pietrangelo |first2=A |last3=Adams |first3=PC |last4=de Graaff |first4=B |last5=McLaren |first5=CE |last6=Loréal |first6=O |title=Haemochromatosis. |journal=Nature Reviews. Disease Primers |date=5 April 2018 |volume=4 |pages=18016 |doi=10.1038/nrdp.2018.16 |pmid=29620054|pmc=7775623 }}</ref>
Hemochromatosis leading to secondary diabetes (through iron deposition in the insulin secreting beta cells of the pancreas), when combined with a bronzing or darkening of the skin, is sometimes known as "bronze diabetes".<ref name="Diabetes.org.uk">{{cite web |title=Haemochromatosis and diabetes |url=https://www.diabetes.org.uk/diabetes-the-basics/related-conditions/haemochromatosis-diabetes |website=Diabetes UK |language=en}}</ref>

==Causes==
The term ''hemochromatosis'' was initially used to refer to what is now more specifically called [[haemochromatosis type 1|hemochromatosis type 1]] ([[HFE (gene)|HFE]]-related hereditary hemochromatosis or classical hereditary hemochromatosis). Currently, hemochromatosis (without further specification) is mostly defined as iron overload with a hereditary or primary cause,<ref>[http://medical-dictionary.thefreedictionary.com/hemochromatosis thefreedictionary.com > hemochromatosis], citing:
* ''The American Heritage Medical Dictionary'', 2004 by Houghton Mifflin Company
* ''McGraw-Hill Concise Dictionary of Modern Medicine''. 2002
</ref><ref>[http://www.merriam-webster.com/medical/hemochromatosis Merriam-Webster's Medical Dictionary > hemochromatosis] Retrieved on December 11, 2009</ref> or originating from a metabolic disorder.<ref>[http://medical-dictionary.thefreedictionary.com/hemochromatosis thefreedictionary.com], citing:
* ''Dorland's Medical Dictionary for Health Consumers'', 2007
* ''Mosby's Medical Dictionary'', 8th edition. 2009
* Jonas: ''Mosby's Dictionary of Complementary and Alternative Medicine''. 2005.
</ref> 

=== Primary hemochromatosis and hemosiderosis ===
==== Hereditary hemochromatosis ====
Hereditary hemochromatoses (HH or HHC) are genetic disorders. Hereditary hemochromatosis type 1 (HH type 1) is caused by mutations of [[HFE gene]], mainly C282Y/C282Y mutation. This mutation is present in 1:200-300 of the Caucasian population in the [[United States]] and [[Northern Europe]] with lower incidence in other ethnic groups, but only 10-33% (clinical penetrance) of them will develop iron overload.<ref>{{cite web | title = Hemochromatosis | url = http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm | access-date = 2012-10-05 | archive-url = https://web.archive.org/web/20070318063028/http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm | archive-date = 2007-03-18 | url-status = dead }}</ref> Mutations of the HFE gene (homeostatic iron regulator) located on chromosome 6 (responsible for iron regulatory protein [[hepcidin]] regulation) are responsible for most cases of hereditary hemochromatosis; 80-90% of cases of hereditary hemochromatosis involve a mutation of this HFE gene; 90-95% in [[Northern Europe]].<ref name="pmid35699322"/><ref name="NEJM Olynyk" /> Non-HFE hereditary hemochromatosis involves mutations in genes coding for the iron regulatory proteins [[hemojuvelin]], [[transferrin receptor-2]], [[ferroportin]], and HAMP.<ref name="NEJM Olynyk" />

Hereditary hemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues. This typically begins to be expressed in the third to fifth decades of life, but may occur in children. The clinical presentation of hepatic [[cirrhosis]], [[hypogonadism]], [[cardiomyopathy]], [[diabetes]], [[arthritis]], or [[hyperpigmentation]] is uncommon in current patients. Because of the severe [[sequela]]e of this disorder if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important.<ref name="pmid20542038">{{cite journal |last1=Pietrangelo |first1=Antonello |title=Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment |journal=Gastroenterology |volume=139 |issue=2 |pages=393–408 |year=2010 |pmid=20542038 |doi=10.1053/j.gastro.2010.06.013|doi-access=free |hdl=11380/643921 |hdl-access=free }}</ref><ref name="pmid10488796">{{cite journal |last1=Brandhagen |first1=D J |last2=Fairbanks |first2=V F |last3=Batts |first3=K P |last4=Thibodeau |first4=S N |title=Update on hereditary hemochromatosis and the HFE gene |journal=Mayo Clinic Proceedings |volume=74 |issue=9 |pages=917–21 |year=1999 |pmid=10488796 |doi=10.4065/74.9.917|doi-access=free }}</ref>

==== Hemosiderosis ====
In general, the term ''[[haemosiderosis|hemosiderosis]]'' is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of the iron-storage complex [[haemosiderin|hemosiderin]].<ref>[http://www.merriam-webster.com/medical/hemosideroses Merriam-Webster's Medical Dictionary > hemosideroses] Retrieved on December 11, 2009</ref><ref>[http://medical-dictionary.thefreedictionary.com/hemosiderosis thefreedictionary.com > hemosiderosis], citing:
* ''The American Heritage Medical Dictionary'', 2004 by Houghton Mifflin Company
* ''Mosby's Medical Dictionary'', 8th edition.</ref> Sometimes, the simpler term [[siderosis]] is used instead.

Other definitions distinguishing hemochromatosis or hemosiderosis that are occasionally used include:
* Hemosiderosis is hemochromatosis caused by excessive blood transfusions; that is, hemosiderosis is a form of secondary hemochromatosis.<ref>[http://emedicine.medscape.com/article/369012-overview eMedicine Specialties > Radiology > Gastrointestinal > Hemochromatosis] Author: Sandor Joffe, MD. Updated: May 8, 2009</ref><ref>[http://medical-dictionary.thefreedictionary.com/hemosiderosis thefreedictionary.com > hemosiderosis], citing:
* ''Gale Encyclopedia of Medicine. Copyright 2008''</ref>
* Hemosiderosis is hemosiderin deposition within cells, while hemochromatosis is hemosiderin within cells and the interstitium.<ref>[http://chorus.rad.mcw.edu/to-go/00184.html Notecards on radiology gamuts, diseases, anatomy] {{Webarchive|url=https://web.archive.org/web/20100721200303/http://chorus.rad.mcw.edu/to-go/00184.html |date=2010-07-21 }} 2002, Charles E. Kahn, Jr., MD. Medical College of Wisconsin</ref>
* Hemosiderosis is iron overload that does not cause tissue damage,<ref>[http://medical-dictionary.thefreedictionary.com/hemosiderosis thefreedictionary.com > hemosiderosis], citing:
* ''Dorland's Medical Dictionary for Health Consumers'', 2007
* ''Mosby's Dental Dictionary'', 2nd ed.
* ''Saunders Comprehensive Veterinary Dictionary'', 3rd ed. 2007</ref> while hemochromatosis does.<ref>[http://www.healthscout.com/ency/68/743/main.html The HealthScout Network > Health Encyclopedia > Diseases and Conditions > Hemochromatosis] {{Webarchive|url=https://web.archive.org/web/20100209060309/http://www.healthscout.com/ency/68/743/main.html |date=2010-02-09 }} Retrieved on December 11, 2009</ref>
* Hemosiderosis is arbitrarily differentiated from hemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.<ref>[http://medical-dictionary.thefreedictionary.com/hemosiderosis thefreedictionary.com > hemosiderosis], citing:
* ''McGraw-Hill Concise Dictionary of Modern Medicine''. 2002</ref>
The causes of hemochromatosis broken down into two subcategories: ''primary cases'' (hereditary or genetically determined) and less frequent ''secondary cases'' (acquired during life).<ref name="pmid12651879">{{cite journal |last1=Pietrangelo |first1=A |title=Haemochromatosis |journal=Gut |volume=52 |pages=ii23–30 |year=2003 |pmid=12651879 |pmc=1867747 |doi=10.1136/gut.52.suppl_2.ii23 |issue=90002}}</ref> 

People of Northern European descent, including [[Celts|Celtic]] (Irish, Scottish, Welsh, Cornish, Breton etc.), [[English people|English]], and [[Scandinavia]]n origin<ref>[https://www.theatlantic.com/health/archive/2013/01/the-iron-in-our-blood-that-keeps-and-kills-us/266936/?single_page=true The Atlantic: "The Iron in Our Blood That Keeps and Kills Us" by Bradley Wertheim] January 10, 2013</ref> have a particularly high incidence of hemochromatosis type 1, with about 1:8 people being carriers of the principal genetic variant, the C282Y mutation on the [[HFE (gene)|HFE]] gene, and 0.5% of the population having the condition.<ref>{{cite web|title=Hemachromatosis|url=https://www.britannica.com/science/hemochromatosis|website=Encyclopædia Britannica.com|access-date= 17 April 2017}}</ref>

==== Non-classical hereditary hemochromatosis ====

The overwhelming majority of hereditary hemochromatoses are caused by mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary hemochromatosis",<ref name="pmid18762941">{{cite journal |last1=Mendes |first1=Ana Isabel |last2=Ferro |first2=Ana |last3=Martins |first3=Rute |last4=Picanço |first4=Isabel |last5=Gomes |first5=Susana |last6=Cerqueira |first6=Rute |last7=Correia |first7=Manuel |last8=Nunes |first8=António Robalo |last9=Esteves |first9=Jorge |title=Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes |journal=Annals of Hematology |volume=88 |issue=3 |pages=229–34 |year=2008 |pmid=18762941 |doi=10.1007/s00277-008-0572-y |last10=Fleming |first10=Rita |last11=Faustino |first11=Paula|s2cid=23206256 |url=https://hal.archives-ouvertes.fr/hal-00477968/file/PEER_stage2_10.1007%252Fs00277-008-0572-y.pdf }}</ref> "non-HFE related hereditary hemochromatosis",<ref name="isbn0-7817-6040-2">{{cite book |author1=Maddrey, Willis C. |author2=Schiff, Eugene R. |author3=Sorrell, Michael F. |title=Schiff's diseases of the liver |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2007 |pages=1048  |isbn=978-0-7817-6040-9 }}</ref> or "non-HFE hemochromatosis".<ref name="pmid16315138">{{cite journal |last1=Pietrangelo |first1=Antonello |title=Non-HFE Hemochromatosis |journal=Seminars in Liver Disease |volume=25 |issue=4 |pages=450–60 |year=2005 |pmid=16315138 |doi=10.1055/s-2005-923316|s2cid=260320984 |hdl=11380/307365 |hdl-access=free }}</ref> They are hemochromatosis [[Juvenile hemochromatosis|type 2]] (2A and 2B), [[Haemochromatosis type 3|type 3]], [[Hemochromatosis type 4|type 4]], type 5<ref>https://rarediseases.info.nih.gov/diseases/13472/hemochromatosis-type-5.</ref>

=== Other causes of primary iron overload (non-hemochromatosis) ===

* [[Aceruloplasminemia]]
* Congenital [[Atransferrinemia]]
* [[GRACILE syndrome]]

{| class="wikitable"
! Description !! [[OMIM]] !! Mutation
 |-
 | [[Haemochromatosis type 1|Hemochromatosis type 1]]: "classical" hemochromatosis  || {{OMIM|235200||none}} || [[HFE (gene)|HFE]]
 |-
 | [[Juvenile haemochromatosis|Hemochromatosis type 2A]]: juvenile hemochromatosis || {{OMIM|602390||none}} || [[Hemojuvelin|Haemojuvelin]] (HJV, also known as RGMc and HFE2)
 |-
 | [[Juvenile haemochromatosis|Hemochromatosis type 2B]]: juvenile hemochromatosis || {{OMIM|606464||none}} || hepcidin antimicrobial peptide (''[[HAMP]]'') or HFE2B
 |-
 | [[Haemochromatosis type 3|Hemochromatosis type 3]] || {{OMIM|604250||none}} || [[transferrin receptor-2]] (TFR2 or HFE3)
 |-
 | [[Haemochromatosis type 4|Hemochromatosis type 4]] || {{OMIM|604653||none}} || [[ferroportin]] (SLC11A3/SLC40A1)
 |-
 |  [[Neonatal haemochromatosis|Neonatal hemochromatosis]] || {{OMIM|231100||none}} || (unknown)
 |-
 | [[Aceruloplasminemia|Acaeruloplasminaemia]] (very rare) || {{OMIM|604290||none}} || [[caeruloplasmin]]
 |-
 | Congenital [[atransferrinaemia]] (very rare) || {{OMIM|209300||none}} || [[transferrin]]
 |-
 | [[GRACILE syndrome]] (very rare) || {{OMIM|603358||none}} || [[BCS1L]]
|}

Most types of hereditary hemochromatosis have [[autosomal recessive]] inheritance, while type 4 has [[autosomal dominant]] inheritance.<ref name="pmid16493621">{{cite journal |last1=Franchini |first1=Massimo |title=Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment |journal=American Journal of Hematology |volume=81 |issue=3 |pages=202–09 |year=2006 |pmid=16493621 |doi=10.1002/ajh.20493|doi-access=free }}</ref>

===Secondary hemochromatosis===
* Severe chronic [[haemolysis|hemolysis]] of any cause, including intravascular hemolysis and [[ineffective erythropoiesis]] (hemolysis within the [[bone marrow]])
* Multiple frequent [[blood transfusion]]s (either whole blood or just [[red blood cell]]s), which are usually needed either by individuals with hereditary [[anaemia]]s (such as [[Thalassemia#Beta (?) thalassemias|beta-thalassaemia major]], [[sickle cell anaemia]], [[Diamond–Blackfan anaemia]]), or by older patients with severe acquired anaemias such as in [[myelodysplastic syndrome]]s.<ref name="Selective iron deposition in pancre"/>
* Excess parenteral (non-ingested) iron supplements, such as what can acutely happen in [[iron poisoning]]
* Excess dietary iron (i.e. [[African iron overload]])
* Some disorders do not normally cause hemochromatosis on their own, but may do so in the presence of other predisposing factors. These include [[cirrhosis]] (especially related to [[alcohol use disorder]]), alcoholic [[steatohepatitis]], prolonged [[haemodialysis|hemodialysis]], and post-[[portacaval shunt]]ing

=== Other causes of iron overload ===

* [[Neonatal hemochromatosis|GALD-NH]] (Gestacional alloimmune liver disease)  
* Dysmetabolic Iron Overload Syndrome (DIOS) 
It is a condition characterized by a mild to moderate accumulation of iron in the liver associated with metabolic disorders, particularly [[Metabolic dysfunction-associated steatotic liver disease]] (MASLD) and [[metabolic syndrome]]. Transferrin saturation is generally 20-45%; if this is above 60%, it is highly unlikely to be due to DIOS. It is not hemochromatosis.
*

==Pathophysiology==
Defects in iron metabolism, specifically involving the iron regulatory protein [[hepcidin]] are thought to play an integral role in the pathogenesis of hereditary hemochromatosis.<ref name="NEJM Olynyk">{{cite journal |last1=Olynyk |first1=John K. |last2=Ramm |first2=Grant A. |title=Hemochromatosis |journal=New England Journal of Medicine |date=8 December 2022 |volume=387 |issue=23 |pages=2159–70 |doi=10.1056/NEJMra2119758|pmid=36477033 |s2cid=254432917 }}</ref>

Normally, hepcidin acts to reduce iron levels in the body by inhibiting intestinal iron absorption and inhibiting iron mobilization from stores in the [[bone marrow]] and [[liver]].<ref name="NEJM Olynyk" /> Iron is absorbed from the intestines (mostly in the [[duodenum]]) and transported across intestinal [[enterocyte]]s or mobilized out of storage in liver [[hepatocyte]]s or from [[macrophage]]s in the bone marrow by the transmembrane [[ferroportin]] transporter.<ref name="NEJM Olynyk" /> In response to elevated plasma iron levels, hepcidin inhibits the ferroportin transporter, leading to decreased iron mobilization from stores and decreased intestinal iron absorption, thus functioning as a negative iron regulatory protein.<ref name="NEJM Olynyk" />

In hereditary hemochromatosis, mutations in the proteins involved in hepcidin production including [[HFE (gene)|HFE (homeostatic iron regulator)]], [[hemojuvelin]] and [[transferrin receptor 2]] lead to a loss or decrease in hepcidin production, which subsequently leads to the loss of the inhibitory signal regulating iron absorption and mobilization and thus leads to iron overload.<ref name="NEJM Olynyk" /> In very rare instances, mutations in ferroportin result in ferroportin resistance to hepcidin's negative regulatory effects, and continued intestinal iron absorption and mobilization despite inhibitory signaling from hepcidin.<ref name="NEJM Olynyk" /> 

The resulting iron overload causes iron to deposit in various sites throughout the body, especially the liver and joints, which, coupled with [[oxidative stress]], leads to organ damage or joint damage and the pathological findings seen in hemochromatosis.<ref name="NEJM Olynyk" />

==Diagnosis==

[[File:Left column showing selective iron deposition (blue) in pancreatic islet beta cells(red) from transfusional hemochromatosis autopsy cases versus that of controls (right lower one).jpg|thumb|upright=1.4|Selective iron deposition (blue) in pancreatic islet beta cells (red)]]
There are several methods available for diagnosing and monitoring iron overload. Current guidelines recommend quantitative liver MRI combined with HFE genotyping as a diagnostic approach; liver biopsy and calculation of the hepatic iron index are reserved for equivocal cases or for staging hepatic fibrosis. 

===Blood test===

Blood tests are usually the initial test if there is a clinical suspicion of iron overload. Serum [[ferritin]] testing is a low-cost, readily available, and minimally invasive method for assessing body iron stores. However, ferritin levels may be elevated due to a variety of other causes, including [[obesity]], infection, inflammation (as an [[acute phase protein]]), chronic alcohol intake, liver disease, kidney disease, and cancer.<ref name="NEJM Olynyk" /><ref name="Blood 2007">{{cite journal |last1=Waalen |first1=Jill |last2=Felitti |first2=Vincent J. |last3=Gelbart |first3=Terri |last4=Beutler |first4=Ernest |title=Screening for hemochromatosis by measuring ferritin levels: a more effective approach |journal=Blood |date=1 April 2008 |volume=111 |issue=7 |pages=3373–76 |doi=10.1182/blood-2007-07-102673|pmid=18025154 |pmc=2275006 }}</ref><ref name="BMJ 2015">{{cite journal |last1=Koperdanova |first1=Marianna |last2=Cullis |first2=Jonathan O. |title=Interpreting raised serum ferritin levels |journal=BMJ |date=3 August 2015 |volume=351 |pages=h3692 |doi=10.1136/bmj.h3692|pmid=26239322 |s2cid=44923011 }}</ref> In males and [[postmenopausal]] females, normal range of serum ferritin is between 12 and 300&nbsp;ng/mL (670 pmol/L) .<ref name="medline">[https://www.nlm.nih.gov/medlineplus/ency/article/003490.htm Ferritin] by: Mark Levin, MD, Hematologist and Oncologist, Newark, NJ. Review provided by VeriMed Healthcare Network</ref><ref name="medscape-ferritin">{{cite web|url=http://emedicine.medscape.com/article/177216-workup#c8|title=Hemochromatosis Workup|author=Andrea Duchini|website=[[Medscape]]|access-date=2016-07-14}} Updated: Jan 02, 2016</ref><ref name="molar">[[Molar concentration]] is derived from mass value using molar mass of 450,000 g•mol−1 for ferritin</ref> In premenopausal females, normal range of serum ferritin is between 12 and 150<ref name="medline" /> or 200<ref name="medscape-ferritin" /> ng/mL (330 or 440&nbsp;pmol/L).<ref name="molar" /> In those with hemochromatosis, the serum ferritin level correlates with the degree of iron overload.<ref name="NEJM Olynyk" /> Ferritin levels are usually monitored serially in those with hemochromatosis to assess response to treatment.<ref name="NEJM Olynyk" />

Elevations in serum levels of the iron transporter protein [[transferrin]] saturation as well as increased red blood cell [[mean corpuscular volume]] and [[mean corpuscular hemoglobin concentration]] usually precede ferritin elevations in hemochromatosis.<ref name="NEJM Olynyk" /> Transferrin saturation of greater than 45% combined with an elevated ferritin level is highly sensitive in diagnosing HFE hemochromatosis.<ref name="NEJM Olynyk" /> [[Total iron binding capacity]] may be low in hemochromatosis, but can also be normal.<ref>[http://www.labtestsonline.org/understanding/analytes/tibc/test.html labtestsonline.org TIBC & UIBC, Transferrin] Last reviewed on October 28, 2009.</ref> There are cases of iron overload with normal transferrin saturation.

===Genetics===

General screening for hemochromatosis is not recommended, however [[first-degree relatives]] of those affected should be screened.<ref name="NEJM Olynyk" /><ref name="AFP2013">{{cite journal|last=Crownover|first=BK|author2=Covey, CJ|date=Feb 1, 2013|title=Hereditary hemochromatosis.|journal=American Family Physician|volume=87|issue=3|pages=183–90|pmid=23418762}}</ref><ref name="AASLD guidelines" /><ref name="ACG guidelines" />

Once iron overload has been established, [[HFE gene|''HFE'' gene]] mutation [[genetic testing]] for hereditary causes of iron overload is indicated.<ref name="AASLD guidelines" /><ref name="pmid20542038" /> The presence of ''HFE'' gene mutations in addition to iron overload confirms the clinical diagnosis of hereditary hemochromatosis type 1.<ref name="AASLD guidelines" /> The alleles evaluated by ''HFE'' gene analysis are mutated (C282Y/C282Y; C282Y/H63D; C282Y/S65C; H63D/H63D) in 80-90% of patients with hereditary hemochromatosis; a negative report for these mutations of HFE gene does not rule out hemochromatosis.{{citation needed|date=June 2023}}

=== Biopsy ===
[[File:Kupffer cell with hemosiderin and hepatocyte with lipofuscin.jpg|thumb|[[Histopathology]] of the liver, showing [[Kupffer cell]]s with significant [[hemosiderin]] deposition (shown next to a hepatocyte with [[lipofuscin]] pigment, which is a common normal finding). H&E stain.]]
[[File:Kupffer cell with hemosiderin and hepatocyte with lipofuscin, iron stain.jpg|thumb|[[Prussian blue]] iron staining, highlighting the hemosiderin pigment as blue. This finding indicates mesenchymal iron overload (within Kupffer cells and/or portal macrophages) rather than parenchymal iron overload (within hepatocytes).<ref>Image by Mikael Häggström, MD. Source for mesenchymal versus parenchymal iron overload {{cite journal| author=Deugnier Y, Turlin B| title=Pathology of hepatic iron overload. | journal=World J Gastroenterol | year= 2007 | volume= 13 | issue= 35 | pages= 4755–60 | pmid=17729397 | doi=10.3748/wjg.v13.i35.4755 | pmc=4611197 | doi-access=free }}</ref>]]
The gold standard for confirming iron overload is the liver biopsy. [[Liver biopsy]] is the removal of a small sample in order to be studied and can determine the cause of inflammation or cirrhosis. In someone with negative ''HFE'' gene testing, elevated iron status for no other obvious reason, and a family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of hemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy.{{citation needed|date=November 2021}}

===Imaging===
[[Magnetic resonance imaging]] (MRI) is used as a noninvasive method to estimate iron deposition levels in the liver and heart, which may aid in determining a response to treatment or prognosis.<ref name="NEJM Olynyk" /> A T2*-weighted gradient-echo MRI sequence (often called T2* relaxometry) is used for the quantification of liver iron, but it does not detect some cases of mild iron overload. [[Elastography|Liver elastography]] has limited utility in detecting mild liver fibrosis.<ref name="NEJM Olynyk" />

==Treatment==

=== Phlebotomy ===

[[Phlebotomy]], [[bloodletting]] or [[venesection]] is the mainstay of treatment in iron overload, consisting of regularly scheduled blood draws to remove red blood cells (and iron) from the body.<ref name="NEJM Olynyk" /> Upon initial diagnosis of iron overload, the phlebotomies may be performed weekly or twice weekly, until iron levels are normalized. Once the serum ferritin and transferrin saturation are within the normal range, maintenance phlebotomies may be needed in some (depending upon the rate of reabsorption of iron), scheduled at varying frequencies to keep iron stores within the normal range.<ref name="AASLD guidelines" /> A phlebotomy session typically draws between 450 and 500 mL of blood.<ref>{{cite journal|last1=Barton|first1=James C.|title=Management of Hemochromatosis|journal=Annals of Internal Medicine|date=1 December 1998|volume=129|issue=11_Part_2|pages=932–39|doi=10.7326/0003-4819-129-11_Part_2-199812011-00003|pmid=9867745|s2cid=53087679}}</ref> Routine phlebotomy may reverse liver fibrosis and alleviate some symptoms of hemochromatosis, but chronic arthritis is usually not responsive to treatment.<ref name="NEJM Olynyk" /> In those with hemochromatosis; the blood drawn during phlebotomy is safe to be [[blood donation|donated]].<ref>{{cite web|author=NIH blood bank|title=Hemochromatosis Donor Program|url=https://clinicalcenter.nih.gov/blooddonor/donationtypes/hemochromatosis.html}}</ref><ref name="AASLD guidelines" />

Phlebotomy is associated with improved survival if it is initiated before the onset of cirrhosis or diabetes.<ref name="AASLD guidelines" />

=== Diet ===

The human diet contains iron in two forms: [[heme]] iron and [[Non-heme iron protein|non-heme iron]]. Heme iron is usually found in red meat, whereas non-heme iron is found in plant-based sources. Heme iron is the most easily absorbed form of iron. In those with hemochromatosis undergoing phlebotomy for treatment, restriction of dietary iron is not required.<ref name="AASLD guidelines">{{cite journal |last1=Bacon |first1=Bruce R. |last2=Adams |first2=Paul C. |last3=Kowdley |first3=Kris V. |last4=Powell |first4=Lawrie W. |last5=Tavill |first5=Anthony S. |title=Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases |journal=Hepatology |date=July 2011 |volume=54 |issue=1 |pages=328–43 |doi=10.1002/hep.24330|pmid=21452290 |s2cid=9311604 |pmc=3149125 }}</ref><ref name="ACG guidelines">{{cite journal |last1=Kowdley |first1=Kris V. |last2=Brown |first2=Kyle E. |last3=Ahn |first3=Joseph |last4=Sundaram |first4=Vinay |title=ACG Clinical Guideline: Hereditary Hemochromatosis |journal=American Journal of Gastroenterology |date=August 2019 |volume=114 |issue=8 |pages=1202–18 |doi=10.14309/ajg.0000000000000315|pmid=31335359 |s2cid=198192589 |doi-access=free }}</ref><ref name="NEJM Olynyk" /> However, those who do restrict dietary iron usually require less phlebotomy (about 0.5–1.5 liters of blood less per year).<ref name="American Journal of Clinical Nutrition">{{cite journal |journal= The American Journal of Clinical Nutrition|doi=10.3945/ajcn.112.048264 |title=Relevance of dietary iron intake and bioavailability in the management of HFE hemochromatosis: A systematic review |year=2013 |last1=Moretti |first1=Diego |last2=Van Doorn |first2=Gerrigje M. |last3=Swinkels |first3=Dorine W. |last4=Melse-Boonstra |first4=Alida |volume=98 |issue=2 |pages=468–79 |pmid=23803887 |doi-access=free }}</ref> Vitamin C and iron supplementation should be avoided as vitamin C accelerates intestinal absorption of iron and mobilization of body iron stores.<ref name="AASLD guidelines" /><ref name="ACG guidelines" /> Raw seafood should be avoided because of increased risk of infections from iron-loving pathogens (called [[Siderophilic bacteria|siderophilic]]) such as ''[[Vibrio vulnificus]]''.<ref name="NEJM Olynyk" /><ref name="JAMA 1991">{{cite journal |last1=Bullen |first1=John J. |title=Hemochromatosis, Iron, and Septicemia Caused by Vibrio vulnificus |journal=Archives of Internal Medicine |date=1 August 1991 |volume=151 |issue=8 |pages=1606–09 |doi=10.1001/archinte.1991.00400080096018|pmid=1872665 }}</ref> Alcohol consumption should be avoided due to the risk of compounded liver damage with iron overload.<ref name="NEJM Olynyk" />

=== Medication ===

Medications are used for those unable to tolerate routine blood draws, there are [[chelating]] agents available for use.<ref>{{Cite journal| doi = 10.1021/cr00097a011| volume = 89| issue = 7| pages = 1563–79| last = Miller| first = Marvin J.| title = Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogs| journal = Chemical Reviews| date = 1989-11-01}}</ref> The drug [[deferoxamine]] binds with iron in the bloodstream and enhances its elimination in urine and faeces. Typical treatment for chronic iron overload requires subcutaneous injection over a period of 8–12 hours daily.{{citation needed|date=May 2015}} Two newer [[Chelation therapy|iron-chelating drugs]] that are licensed for use in patients receiving regular blood transfusions to treat [[thalassaemia]] (and, thus, who develop iron overload as a result) are [[deferasirox]] and [[deferiprone]].<ref>{{cite journal|vauthors=Choudhry VP, Naithani R |title=Current status of iron overload and chelation with deferasirox |journal=Indian J Pediatr |volume=74 |issue=8 |pages=759–64 |year=2007 |pmid=17785900 |doi=10.1007/s12098-007-0134-7|s2cid=19930076 }}</ref><ref>{{cite journal|last1=Hoffbrand|first1=A. V.|title=Role of deferiprone in chelation therapy for transfusional iron overload|journal=Blood|date=20 March 2003|volume=102|issue=1|pages=17–24|doi=10.1182/blood-2002-06-1867|pmid=12637334|doi-access=free}}</ref>

===Chelating polymers===

A minimally invasive approach to [[hereditary haemochromatosis|hereditary hemochromatosis]] treatment is the [[maintenance therapy]] with [[Ion-exchange resin|polymeric chelators]].<ref name="Polomoscanik2005">{{cite journal|last1=Polomoscanik|first1=Steven C.|last2=Cannon|first2=C. Pat|last3=Neenan|first3=Thomas X.|last4=Holmes-Farley|first4=S. Randall|last5=Mandeville|first5=W. Harry|last6=Dhal|first6=Pradeep K.|title=Hydroxamic Acid-Containing Hydrogels for Nonabsorbed Iron Chelation Therapy: Synthesis, Characterization, and Biological Evaluation|journal=Biomacromolecules|volume=6|issue=6|year=2005|pages=2946–53|issn=1525-7797|doi=10.1021/bm050036p|pmid=16283713}}</ref><ref name="QianSullivan2017">{{cite journal|last1=Qian|first1=Jian|last2=Sullivan|first2=Bradley P.|last3=Peterson|first3=Samuel J.|last4=Berkland|first4=Cory|title=Nonabsorbable Iron Binding Polymers Prevent Dietary Iron Absorption for the Treatment of Iron Overload|journal=ACS Macro Letters|volume=6|issue=4|year=2017|pages=350–53|issn=2161-1653|doi=10.1021/acsmacrolett.6b00945|pmid=35610854 }}</ref><ref name="Groborz2020">{{cite journal|last1=Groborz|first1=Ondřej|last2=Poláková|first2=Lenka|last3=Kolouchová|first3=Kristýna|last4=Švec|first4=Pavel|last5=Loukotová|first5=Lenka|last6=Miriyala|first6=Vijay Madhav|last7=Francová|first7=Pavla|last8=Kučka|first8=Jan|last9=Krijt|first9=Jan|last10=Páral|first10=Petr|last11=Báječný|first11=Martin|last12=Heizer|first12=Tomáš|last13=Pohl|first13=Radek|last14=Dunlop|first14=David|last15=Czernek|first15=Jiří|last16=Šefc|first16=Luděk|last17=Beneš|first17=Jiří|last18=Štěpánek|first18=Petr|last19=Hobza|first19=Pavel|last20=Hrubý|first20=Martin|title=Chelating Polymers for Hereditary Hemochromatosis Treatment|journal=Macromolecular Bioscience|year=2020|volume=20|issue=12|pages=2000254|issn=1616-5187|doi=10.1002/mabi.202000254|pmid=32954629|s2cid=221827050}}</ref> These polymers or particles have a negligible or null systemic [[bioavailability|biological availability]] and they are designed to form stable complexes with Fe<sup>2+</sup> and Fe<sup>3+</sup> in the [[gastrointestinal tract|GIT]] and thus limiting their uptake and long-term accumulation. Although this method has only a limited efficacy, unlike [[chelation therapy|small-molecular chelators]], the approach has virtually no side effects in sub-chronic studies.<ref name="Groborz2020" /> Interestingly, the simultaneous chelation of Fe<sup>2+</sup> and Fe<sup>3+</sup> increases the treatment efficacy.<ref name="Groborz2020" />

==Prognosis==

In general, provided there has been no liver damage, patients should expect a normal life expectancy if adequately treated by venesection. If the serum ferritin is greater than 1,000&nbsp;μg/L at diagnosis, there is a risk of liver damage and cirrhosis, which may eventually shorten their life.<ref>{{cite journal|last1=Allen|first1=KJ|last2=Gurrin|first2=LC|last3=Constantine|first3=CC|last4=Osborne|first4=NJ|last5=Delatycki|first5=MB|last6=Nicoll|first6=AJ|last7=McLaren|first7=CE|last8=Bahlo|first8=M|last9=Nisselle|first9=AE|last10=Vulpe|first10=CD|last11=Anderson|first11=GJ|last12=Southey|first12=MC|last13=Giles|first13=GG|last14=English|first14=DR|last15=Hopper|first15=JL|last16=Olynyk|first16=JK|last17=Powell|first17=LW|last18=Gertig|first18=DM|title=Iron-overload-related disease in HFE hereditary hemochromatosis.|journal=The New England Journal of Medicine|date=17 January 2008|volume=358|issue=3|pages=221–30|doi=10.1056/NEJMoa073286|pmid=18199861|url=http://espace.library.uq.edu.au/view/UQ:183461/UQ183461_OA.pdf}}</ref> The presence of [[cirrhosis]] increases the risk of [[hepatocellular carcinoma]].<ref name=Kow2004>{{cite journal|last1=Kowdley|first1=KV|title=Iron, hemochromatosis, and hepatocellular carcinoma.|journal=Gastroenterology|date=November 2004|volume=127|issue=5 Suppl 1|pages=S79–86|pmid=15508107|doi=10.1016/j.gastro.2004.09.019}}</ref> Other risk factors for liver damage in hemochromatosis include alcohol use, diabetes, liver iron levels greater than 2,000 μmol/gram, and increased [[aspartate transaminase]] levels.<ref name="NEJM Olynyk" />

The risk of death and liver fibrosis is elevated in males with HFE type hemochromatosis but not in females; this is thought to be due to a protective effect of menstruation and pregnancy seen in females, as well as possible hormone-related differences in iron absorption.<ref name="NEJM Olynyk" />

==Epidemiology==

HH type 1 is most common in certain European populations (such as those of Irish or Scandinavian descent) and occurs in 0.6% of that population.<ref name=AFP2013/> Men have a 24-fold increased rate of iron-overload disease compared with women.<ref name=AFP2013/>

===Stone Age===
Diet and the environment are thought to have had a large influence on the mutation of genes related to iron overload. Starting during the [[Mesolithic era]], communities of people lived in an environment that was fairly sunny, warm, and had the dry climates of the Middle East. Most humans who lived at that time were foragers, and their diets consisted largely of wild plants, fish, and game. Archaeologists studying [[dental plaque]] have found evidence of [[tuber]]s, nuts, [[Cooking banana|plantains]], grasses, and other foods rich in iron. Over many generations, the human body became well-adapted to a high level of iron content in the diet.<ref>{{Cite news|url=https://www.nationalgeographic.com/foodfeatures/evolution-of-diet/|title=The Evolution of Diet|work=National Geographic|access-date=2018-04-11}}</ref>

=== Neolithic ===
In the [[Neolithic era]], significant changes are thought to have occurred in both the environment and diet. Some communities of foragers migrated north, leading to changes in lifestyle and environment, with a decrease in temperatures and a change in the landscape that the foragers then needed to adapt to. As people began to develop and advance their tools, they learned new ways of producing food, and [[History of agriculture|farming also slowly developed]]. These changes would have led to serious stress on the body and a decrease in the consumption of iron-rich foods. This transition is a key factor in the mutation of genes, especially those that regulate dietary iron absorption. 70% of the body’s iron is found in the [[red blood cell|red blood cells]], and it is a critical [[micronutrient]] for effective [[thermoregulation]] in the body.<ref>{{Cite journal|last1=Rosenzweig|first1=P. H.|last2=Volpe|first2=S. L.|date=March 1999|title=Iron, thermoregulation, and metabolic rate|journal=Critical Reviews in Food Science and Nutrition|volume=39|issue=2|pages=131–148|doi=10.1080/10408399908500491|issn=1040-8398|pmid=10198751}}</ref> Iron deficiency will lead to a drop in the core temperature. In the chilly and damp environments of Northern Europe, supplementary iron from food was necessary to keep temperatures regulated; however, without sufficient iron intake, the human body would have started to store iron at higher rates than normal. In theory, the pressures caused by migrating north would have selected for a [[gene mutation]] that promoted greater absorption and storage of iron.<ref>
{{Cite journal|last1=Heath|first1=Kathleen M.|last2=Axton|first2=Jacob H.|last3=McCullough|first3=John M.|last4=Harris|first4=Nathan|date=May 2016|title=The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic|journal=American Journal of Physical Anthropology|volume=160|issue=1|pages=86–101|doi=10.1002/ajpa.22937|issn=0002-9483|pmc=5066702|pmid=26799452}}
</ref>

===Viking hypothesis===
Studies and surveys conducted to determine the frequencies of hemochromatosis help explain how the mutation migrated around the globe. In theory, the disease initially evolved from travelers migrating from the north. Surveys show a particular distribution pattern with large clusters and frequencies of gene mutations along the western European coastline.<ref>{{Cite web|url=http://www.hematology.org/Thehematologist/Diffusion/6103.aspx|title=Clinical Penetrance of HFE Hereditary Hemochromatosis, Serum Ferritin Levels, and Screening Implications: Can We Iron This Out?|date=2008-05-01|website=www.hematology.org|access-date=2018-04-11|archive-date=2018-06-15|archive-url=https://web.archive.org/web/20180615135540/http://www.hematology.org/Thehematologist/Diffusion/6103.aspx|url-status=dead}}</ref> This led the development of the "[[Viking]] Hypothesis".<ref>{{Cite journal|last1=Symonette|first1=Caitlin J|last2=Adams|first2=Paul C|date=June 2011|title=Do all hemochromatosis patients have the same origin? A pilot study of mitochondrial DNA and Y-DNA|journal=Canadian Journal of Gastroenterology|volume=25|issue=6|pages=324–326|issn=0835-7900|pmc=3142605|pmid=21766093|doi=10.1155/2011/463810|doi-access=free}}
</ref> Cluster locations and mapped patterns of this mutation correlate closely to the locations of [[Viking expansion|Viking settlements in Europe]] established c.700 AD to c.1100 AD. The Vikings originally came from Norway, Sweden, and Denmark. [[Viking ships]] made their way along the coastline of Europe in search of trade, riches, and land. Genetic studies suggest that the extremely high frequency patterns in some European countries are the result of migrations of Vikings and later [[Normans]], indicating a genetic link between hereditary hemochromatosis and Viking ancestry.<ref name=":2">{{Cite web|url=https://www.toomuchiron.ca/video/|title=Videos: Hereditary Hemochromatosis {{!}} Canadian Hemochromatosis Society|website=www.toomuchiron.ca|access-date=2018-04-11|archive-date=2018-04-11|archive-url=https://web.archive.org/web/20180411174723/https://www.toomuchiron.ca/video/|url-status=dead}}</ref>

===Modern times===
In 1865, [[Armand Trousseau]] (a French internist) was one of the first to describe many of the symptoms of a diabetic patient with cirrhosis of the liver and bronzed skin color. The term hemochromatosis was first used by German pathologist [[Friedrich Daniel von Recklinghausen]] in 1889 when he described an accumulation of iron in body tissues.<ref name=":0">{{Cite journal|last1=Fitzsimons|first1=Edward J.|last2=Cullis|first2=Jonathan O.|last3=Thomas|first3=Derrick W.|last4=Tsochatzis|first4=Emmanouil|last5=Griffiths|first5=William J. H.|last6=the British Society for Haematology|date=May 2018|title=Diagnosis and therapy of genetic haemochromatosis (review and 2017 update)|journal=British Journal of Haematology|language=en|volume=181|issue=3|pages=293–303|doi=10.1111/bjh.15164|pmid=29663319|doi-access=free}}</ref>

== Identification of genetic factors ==
Although it was known most of the 20th century that most cases of hemochromatosis were inherited, they were incorrectly assumed to depend on a single gene.<ref name="isbn1-58829-202-9">{{cite book |author1=Cam Patterson |author2=Marschall S. Runge |title=Principles of molecular medicine |publisher=Humana Press |location=Totowa, NJ |year=2006 |pages=567  |isbn=978-1-58829-202-5 }}</ref>

In 1935, J.H. Sheldon, a British physician, described the link to iron metabolism for the first time, as well as demonstrating its hereditary nature.<ref name=":0" />

In 1996, Feder and colleagues identified the hemochromatosis gene, ''HFE'' gene. Felder found that the ''HFE'' gene has two main mutations, causing amino acid substitutions C282Y and H63D, which were the main cause of hereditary hemochromatosis.<ref name=":0"/><ref>{{Cite journal|last1=Feder|first1=J.N.|last2=Gnirke|first2=A.|last3=Thomas|first3=W.|last4=Tsuchihashi|first4=Z.|last5=Ruddy|first5=D.A.|last6=Basava|first6=A.|last7=Dormishian|first7=F.|last8=Domingo|first8=R.|last9=Ellis|first9=M.C.|date=August 1996|title=A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis|journal=Nature Genetics|language=en|volume=13|issue=4|pages=399–408|doi=10.1038/ng0896-399|pmid=8696333|s2cid=26239768}}</ref> The next year the CDC and the National Human Genome Research Institute sponsored an examination of hemochromatosis following the discovery of the ''HFE'' gene, which helped lead to the population screenings and estimates that are still being used today.<ref>{{Cite journal|last1=Burke|first1=Wylie|last2=Thomson|first2=Elizabeth|last3=Khoury|first3=Muin J.|last4=McDonnell|first4=Sharon M.|last5=Press|first5=Nancy|last6=Adams|first6=Paul C.|last7=Barton|first7=James C.|last8=Beutler|first8=Ernest|last9=Brittenham|first9=Gary|date=1998-07-08|title=Hereditary Hemochromatosis: Gene Discovery and Its Implications for Population-Based Screening|journal=JAMA|language=en|volume=280|issue=2|pages=172–78|doi=10.1001/jama.280.2.172|pmid=9669792|issn=0098-7484}}</ref>

==See also==
* [[Human iron metabolism]]
* [[Iron deficiency]]

== References ==
{{Reflist|30em}}

== External links ==
{{Medical resources
|  ICD10          = {{ICD10|E|83|1|E|83}}
|  ICD9           = {{ICD9|275.03}}
|  ICDO           =
|  OMIM           =
|  DiseasesDB     = 5581
|  MedlinePlus    = 000327
|  eMedicineSubj  =
|  eMedicineTopic =
|  MeshID         = D019190
}}
{{Commons category|Hemochromatosis}}
* [https://www.ncbi.nlm.nih.gov/books/NBK1440/ GeneReview/NCBI/NIH/UW entry on HFE-Associated Hereditary Hemochromatosis]
* [https://www.ncbi.nlm.nih.gov/books/NBK1349/ GeneReview/NCBI/NIH/UW entry on TFR2-Related Hereditary Hemochromatosis]
* [https://www.ncbi.nlm.nih.gov/books/NBK1170/ GeneReview/NCBI/NIH/UW entry on Juvenile Hereditary Hemochromatosis]
* [https://www.ncbi.nlm.nih.gov/books/NBK1493/ GeneReview/NCBI/NIH/UW entry on Aceruloplasminemia]

{{Inborn errors of metal metabolism}}
{{Elements in biology}}
{{Authority control}}

{{DEFAULTSORT:Iron Overload}}
[[Category:Inborn errors of metal metabolism|Overload disorder]]
[[Category:Abnormal clinical and laboratory findings for blood]]
[[Category:Articles containing video clips]]
[[Category:Iron metabolism]]