Editing Iron overload (section)

==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 }}</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 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 }}</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 a hemochromatosis.
*