Editing Iron overload (section)

==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 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 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 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" />