Editing Hereditary haemochromatosis (section)

== Diagnosis ==
The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of [[Elevated transaminases|elevated serum liver enzymes]] or elevation of the [[transferrin saturation]] or elevated serum ferritin. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.<ref name=Mayo>{{cite web |url=http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=tests-and-diagnosis |title=Hemochromatosis: Tests and diagnosis |work=Mayo Foundation for Medical Education and Research (MFMER) |access-date=20 April 2009 |archive-date=31 May 2013 |archive-url=https://web.archive.org/web/20130531022317/http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=tests-and-diagnosis |url-status=live }}</ref>

===Blood tests===
[[Ferritin|Serum ferritin]] and fasting [[transferrin saturation]] are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood.<ref>{{Cite web |title=Iron Transport and Cellular Uptake: Transferrin/Iron Physiology |url=http://sickle.bwh.harvard.edu/iron_transport.html |website=sickle.bwh.harvard.edu |access-date=17 March 2007 |archive-url=https://web.archive.org/web/20070307113258/http://sickle.bwh.harvard.edu/iron_transport.html |archive-date=7 March 2007}}</ref> Measuring ferritin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45%, and the serum ferritin more than 250&nbsp;ug/L in males and 200&nbsp;ug/L in females are recognized as a threshold for further evaluation of haemochromatosis.<ref>{{Cite web|url=https://www.merckmanuals.com/professional/hematology-and-oncology/iron-overload/hereditary-hemochromatosis?query=hemochromatosis|title=Hereditary Hemochromatosis - Hematology and Oncology|website=Merck Manuals Professional Edition|access-date=31 May 2021|archive-date=2 June 2021|archive-url=https://web.archive.org/web/20210602213534/https://www.merckmanuals.com/professional/hematology-and-oncology/iron-overload/hereditary-hemochromatosis?query=hemochromatosis|url-status=live}}</ref> Other source says that the normal values for males are 12-300&nbsp;ng/mL and for female, 12-150&nbsp;ng/mL.<ref>{{MedlinePlusEncyclopedia|003490|Ferritin Test}}</ref> Fasting transferrin saturation is a better test to detect HH.<ref name="pmid15175440">{{cite journal |author=Pietrangelo A |title=Hereditary hemochromatosis—a new look at an old disease |journal=N. Engl. J. Med. |volume=350 |issue=23 |pages=2383–97 |date=June 2004 |pmid=15175440 |doi=10.1056/NEJMra031573 }}</ref><ref name=pmid15858186>{{cite journal |vauthors=Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P |title=Hemochromatosis and iron-overload screening in a racially diverse population |journal=The New England Journal of Medicine |date=28 April 2005 |volume=352 |issue=17 |pages=1769–1778 |pmid=15858186 |doi=10.1056/nejmoa041534 |doi-access=free |url=https://cloudfront.escholarship.org/dist/prd/content/qt4pt636cn/qt4pt636cn.pdf |access-date=2 February 2024 |archive-date=22 July 2018 |archive-url=https://web.archive.org/web/20180722163517/https://cloudfront.escholarship.org/dist/prd/content/qt4pt636cn/qt4pt636cn.pdf |url-status=live }}</ref> Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the [[HFE gene]].<ref name="pmid7102818">{{cite journal |vauthors=Dadone MM, Kushner JP, Edwards CQ, Bishop DT, Skolnick MH|title=Hereditary hemochromatosis. Analysis of laboratory expression of the disease by genotype in 18 pedigrees |journal=American Journal of Clinical Pathology |volume=78 |issue=2 |pages=196–207 |date=August 1982 |pmid=7102818 |doi= 10.1093/ajcp/78.2.196}}</ref>

Ferritin, a protein synthesized by the liver, is the primary form of iron storage within cells and tissues.  Measuring ferritin provides a crude estimate of whole-body iron stores, though is raised in many conditions, particularly inflammatory conditions. Examples of causes for raised serum ferritin include but are not limited to: infection, chronic alcohol consumption (mainly >20g/day), [[liver disease]], [[cancer]], [[porphyria]], [[Hemophagocytic lymphohistiocytosis]], [[hyperthyroidism]], [[obesity]], [[metabolic syndrome]], [[diabetes]], several blood transfusions, too many iron supplements, [[aceruloplasminemia]], [[atransferrinemia]], hyperferritinemia cataract syndrome and others. Proinflammatory states account for up to 90% of raised ferritin.<ref name=HH>{{Cite web|url=https://mayoclinic.org/test-procedures/ferritin-test/about/pac-20384928|title=Ferritin test - Mayo Clinic|website=[[Mayo Clinic]]|access-date=21 May 2021|archive-date=8 March 2024|archive-url=https://web.archive.org/web/20240308023319/https://www.mayoclinic.org/tests-procedures/ferritin-test/about/pac-20384928|url-status=live}}</ref><ref>https://webmd.com/a-to-z-guides/ferritin-blood-test {{Webarchive|url=https://web.archive.org/web/20210521043405/https://www.webmd.com/a-to-z-guides/ferritin-blood-test |date=21 May 2021 }}. Reviewed 21 May 2021.</ref><ref name="austpre01" /> Serum ferritin in excess of 1000&nbsp;ng/mL of blood is almost always attributable to haemochromatosis.{{citation needed|date=November 2021}}

Other blood tests routinely performed include [[blood count]], [[renal function]], [[liver enzyme]]s, [[electrolyte]]s, and [[glucose]] (and/or an [[oral glucose tolerance test]]).{{citation needed|date=November 2021}}

===Liver biopsy===
[[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, is 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,  whether a liver biopsy is still necessary to quantify the amount of accumulated iron is debatable.<ref name=Mayo/>

===MRI===
MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations.<ref name="pmid15256427">{{cite journal |author=St Pierre |title=Non-invasive measurement and imaging of liver iron concentrations using proton magnetic resonance |journal=Blood |volume=105 |pages=855–61 |year=2005 |pmid=15256427 |doi=10.1182/blood-2004-01-0177 |issue=2 |last2=Clark |first2=PR |last3=Chua-Anusorn |first3=W |last4=Fleming |first4=AJ |last5=Jeffrey |first5=GP |last6=Olynyk |first6=JK |last7=Pootrakul |first7=P |last8=Robins |first8=E |last9=Lindeman |first9=R |doi-access=free }}</ref>

===Other imaging===
Clinically, the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced [[Computed axial tomography|CT]] and a decreased signal intensity in [[Magnetic resonance imaging|MRI scans]]. 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.<ref>{{Cite journal |last1=Hirsch |first1=J. H. |last2=Killien |first2=F. C. |last3=Troupin |first3=R. H. |date=March 1976 |title=The arthropathy of hemochromatosis |journal=Radiology |volume=118 |issue=3 |pages=591–596 |doi=10.1148/118.3.591 |issn=0033-8419 |pmid=175396}}</ref> The arthropathy can, therefore, be an early clue as to the diagnosis of haemochromatosis.{{citation needed|date=November 2021}}

===Functional testing===
Based on the history, a physician might consider specific tests to monitor organ dysfunction, such as an [[echocardiogram]] for [[heart failure]], or blood glucose monitoring for patients with haemochromatosis [[diabetes]].{{citation needed|date=March 2022}}

=== Stages ===
The American Association for the Study of Liver Diseases suggests the following three stages for the condition (identified by the European Association for the Study of Liver Diseases):<ref name=":0" />

# Genetic susceptibility but no iron overload. Individuals who have the genetic disorder only.
# Iron overload but no organ or tissue damage.
# Organ or tissue damage as a result of iron deposition.

Individuals at each stage do not necessarily progress on to the next stage, and end stage disease is more common in males.

===Differential diagnosis===
Other causes of excess iron accumulation exist, which have to be considered before haemochromatosis type 1 is diagnosed.
* [[Juvenile hemochromatosis|Haemochromatosis type 2]].
* [[Haemochromatosis type 3]].
* [[Haemochromatosis type 4]].
* Haemochromatosis type 5.<ref name=J/>
* [[African iron overload]], formerly known as Bantu siderosis, was first observed among people of [[Ethnic groups of Africa|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 iron overload syndrome, and that a similar syndrome occurred in people of [[Ethnic groups of Africa|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 |vauthors=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>
* Secondary haemochromatosis: its main cause is the [[Transfusion hemosiderosis|Transfusional haemosiderosis]]. It is the accumulation of iron, mainly in the liver, in patients who receive frequent [[blood transfusion]]s (such as those with [[thalassemia|thalassaemia]]). Other causes are: chronic [[hemolytic anemia]], chronic liver disease ([[hepatitis B]], [[hepatitis C]], [[cirrhosis]], [[fatty liver disease]]), dysmetabolic [[Ferritin|hyperferritinemia]], overdose of oral iron pills or iron injections, long-time [[kidney dialysis]], and dyserythropoeisis, also known as [[myelodysplastic syndrome]]. It is a disorder in the production of red blood cells that leads to increased iron recycling from the [[bone marrow]] and accumulation in the liver.
* [[Aceruloplasminemia]].
* [[Atransferrinemia]].
* [[Neonatal hemochromatosis]]
* [[GRACILE syndrome]]
* [[Porphyria cutanea tarda]]