Hemochromatosis pathophysiology: Difference between revisions

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==Overview==
==Overview==
Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs. The features of hemochromatosis are due to presence of toxic [[iron]] in pro-oxidant form in surroundings of parenchymatous tissue cells of the [[liver]] and other organs, where it can cause oxidative damage and lead to [[cirrhosis]], [[hypogonadism]], [[diabetes]], [[cardiomyopathy]], [[arthropathy]], and skin pigmentation.


==Pathophysiology==
==Pathophysiology==
[[Image:Iron metabolism svg.png|thumb|left|400px|The normal distribution of body iron stores]]
In the normal liver, iron is present at a concentration lower than 20 μmol/g of dry weight. Iron is normally lost in sweat, shed skin cells, and the gastrointestinal tract at a rate of approximately 1 mg/day. Premenopausal adult women lose an additional 0.5 to 1.0 mg/day because of menses. These losses are usually balanced by the absorption of 10 percent of the 10 to 20 mg of iron in the diet in Western societies. 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]]. 


In general, people with abnormal iron regulatory genes do not reduce their absorption of [[iron]] in response to increased [[iron]] levels in the body.  Thus the [[iron]] stores of the body increase.  As they increase the iron which is initially stored as [[ferritin]] is deposited in organs as [[haemosiderin]] and this is [[toxic]] to [[biological tissue|tissue]], probably at least partially by inducing [[oxidative stress]].<ref name="Shizukuda_2007">{{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}}</ref>.  
* Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs. 
* The features of hemochromatosis are due to presence of toxic [[iron]] in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to [[cirrhosis]], [[hypogonadism]], [[diabetes]], [[cardiomyopathy]], [[arthropathy]], and skin pigmentation. 
* Hemochromatosis is a complex [[Genetics|genetic]] disease with strong environmental disease modifiers. 
* In most cases, hemochromatosis is due to partial or total loss of the activity of a small peptide hormone produced by the [[liver]], [[hepcidin]], which normally restrains iron entry into the circulation 
* 
* Normal [[iron]] in [[liver]] is present at a concentration lower than 20 μmol/g of dry weight.<ref name="pmid26164493">{{cite journal |vauthors=Pietrangelo A |title=Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin |journal=Gastroenterology |volume=149 |issue=5 |pages=1240–1251.e4 |date=October 2015 |pmid=26164493 |doi=10.1053/j.gastro.2015.06.045 |url=}}</ref> 
* Iron is normally lost in sweat, shed skin cells, and the [[gastrointestinal tract]] at a rate of approximately 1 mg/day. 
* [[Premenopausal]] adult women lose an additional 0.5 to 1.0 mg/day because of menses. 
* These losses are usually balanced by the absorption of 10 percent of the 10 to 20 mg of iron in the diet in Western societies. 
* 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]].<ref name="pmid205420383">{{cite journal |vauthors=Pietrangelo A |title=Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment |journal=Gastroenterology |volume=139 |issue=2 |pages=393–408, 408.e1–2 |date=August 2010 |pmid=20542038 |doi=10.1053/j.gastro.2010.06.013 |url=}}</ref> 
 
* Generally, people with abnormal [[iron]] regulatory genes do not reduce their absorption of [[iron]] in response to increased [[iron]] levels in the body.   
* Thus the [[iron]] stores of the body increase.  As they increase the iron which is initially stored as [[ferritin]] is deposited in organs as [[haemosiderin]] and this is [[toxic]] to [[biological tissue|tissue]], probably at least partially by inducing [[oxidative stress]].<ref name="Shizukuda_2007">{{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}}</ref>  
 
* Iron is a [[pro-oxidant]]. Thus, hemochromatosis shares common symptomology (e.g., [[cirrhosis]] and dyskinetic symptoms) with other "pro-oxidant" diseases such as [[Wilson's disease]], chronic [[manganese poisoning]], and [[Hyperuricemia|hyperuricemic]] syndrome in Dalmatian dogs. The latter also experience "bronzing".<ref name="pmid20542038">{{cite journal| author=Pietrangelo A| title=Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. | journal=Gastroenterology | year= 2010 | volume= 139 | issue= 2 | pages= 393-408, 408.e1-2 | pmid=20542038 | doi=10.1053/j.gastro.2010.06.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20542038  }}</ref>


Iron is a [[pro-oxidant]]. Thus, hemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as [[Wilson's disease]], chronic [[manganese poisoning]], and hyperuricemic syndrome in Dalmatian dogs. The latter also experience "bronzing".
===Intestinal crypt enterocytes and iron overload===
===Intestinal crypt enterocytes and iron overload===
The sensor pathway inside the [[small bowel]] [[enterocyte]] can be disrupted due to genetic errors in the [[iron]] regulatory apparatus. The [[enterocyte]] in the small bowel crypt must somehow sense the amount of circulating [[iron]]. Depending on this information, the [[enterocyte cell]] can regulate the quantity of [[iron]] [[Receptor (biochemistry)|receptors]] 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.   
* The sensor pathway inside the [[small bowel]] [[enterocyte]] can be disrupted due to genetic errors in the [[iron]] regulatory apparatus.  
* The [[enterocyte]] in the small bowel crypt must somehow sense the amount of circulating [[iron]].  
* Depending on this information, the [[enterocyte cell]] can regulate the quantity of [[iron]] [[Receptor (biochemistry)|receptors]] 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, the [[enterocyte]] is somehow constantly fooled into thinking there is [[iron]] depletion. 
* As a consequence, 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.   


In haemochromatosis, the [[enterocyte]] is somehow constantly fooled into thinking there is [[iron]] depletion.  As a consequence, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption.  Details of how this process exactly works in health and disease are still being discovered as of May, 2007.
===Hepcidin role:===
* In 2000, [[Hepcidin]] was discovered which is produced from [[HAMP]] gene.<ref name="pmid11034317">{{cite journal| author=Krause A, Neitz S, Mägert HJ, Schulz A, Forssmann WG, Schulz-Knappe P et al.| title=LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. | journal=FEBS Lett | year= 2000 | volume= 480 | issue= 2-3 | pages= 147-50 | pmid=11034317 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11034317  }}</ref>
* [[Hepcidin]] is produced in the [[liver]] as a 84 amino acid prepropeptide that is processed in a 25 [[amino acid]] bio-active circulating form.<ref name="pmid111131312">{{cite journal| author=Park CH, Valore EV, Waring AJ, Ganz T| title=Hepcidin, a urinary antimicrobial peptide synthesized in the liver. | journal=J Biol Chem | year= 2001 | volume= 276 | issue= 11 | pages= 7806-10 | pmid=11113131 | doi=10.1074/jbc.M008922200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11113131 }}</ref>
* [[Hepcidin]] is hormone produced by liver that is lost genetically in hereditary hemochromatosis.<ref name="pmid11113131">{{cite journal| author=Park CH, Valore EV, Waring AJ, Ganz T| title=Hepcidin, a urinary antimicrobial peptide synthesized in the liver. | journal=J Biol Chem | year= 2001 | volume= 276 | issue= 11 | pages= 7806-10 | pmid=11113131 | doi=10.1074/jbc.M008922200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11113131  }}</ref>
* Mutations resulting in modifications in protein that assist hepcicdin are also cause of hereditary hemochromatosis
* Proteins can be HEF or non-HEF such as [[transferrin]]-receptor 2, [[hemojuvelin]], receptor [[ferroportin]].
* Due to the central pathogenic role of [[hepcidin]], it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. 
* [[Hepcidin]] is a defensin-like [[cysteine]]-rich antimicrobial peptide that likely evolved in humans as part of the innate immune defense. Innate immunity relies on a variety of effector mechanisms to defend against microbial invasion. Among them are the abundant and widely distributed disulfide-linked cationic antimicrobial peptides found in plants, insects, and mammals.<ref name="pmid11113132">{{cite journal| author=Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P et al.| title=A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. | journal=J Biol Chem | year= 2001 | volume= 276 | issue= 11 | pages= 7811-9 | pmid=11113132 | doi=10.1074/jbc.M008923200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11113132 }}</ref>
* [[Hepcidin]] is inflammatory responsing agent like to interleukin 6 (IL6) which activates hepcidin transcription through the Jak/STAT3 pathway. <ref name="pmid15124018">{{cite journal| author=Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK et al.| title=IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. | journal=J Clin Invest | year= 2004 | volume= 113 | issue= 9 | pages= 1271-6 | pmid=15124018 | doi=10.1172/JCI20945 | pmc=398432 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15124018  }}</ref>
* [[Hepcidin]] is likely also produced in [[Monocyte|monocytes]]/[[Macrophage|macrophages]] during infection through [[Toll-like receptor|Toll-like receptors]].<ref name="pmid21873546">{{cite journal| author=Armitage AE, Eddowes LA, Gileadi U, Cole S, Spottiswoode N, Selvakumar TA et al.| title=Hepcidin regulation by innate immune and infectious stimuli. | journal=Blood | year= 2011 | volume= 118 | issue= 15 | pages= 4129-39 | pmid=21873546 | doi=10.1182/blood-2011-04-351957 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21873546  }}</ref>


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.
===Genetics===
The regulation of how much iron enters the body from food is complex, and each year brings new discoveries about the numerous factors working in harmony to bring about balance in the metabolism of [[iron]] in [[humans]].<ref name="pmid205420382">{{cite journal |vauthors=Pietrangelo A |title=Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment |journal=Gastroenterology |volume=139 |issue=2 |pages=393–408, 408.e1–2 |date=August 2010 |pmid=20542038 |doi=10.1053/j.gastro.2010.06.013 |url=}}</ref>
* One of the best-characterized genes that regulates the amount of [[iron]] absorbed from food is called [[HFE]]. 
* The [[HFE]] gene has two common mutations, C282Y and H63D.
* Inheriting just one of the C282Y mutations ([[heterozygous]]) makes a person a carrier who can pass this mutation onward.
* Carriers of one [[HFE]] mutation ordinarily do not manifest with clinically relevant iron accumulation at all.
* [[Hepcidin]] and its receptor [[ferroportin]] are the central [[proteins]] in hemochromatosis.<ref name="pmid14568251">{{cite journal| author=Lymboussaki A, Pignatti E, Montosi G, Garuti C, Haile DJ, Pietrangelo A| title=The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. | journal=J Hepatol | year= 2003 | volume= 39 | issue= 5 | pages= 710-5 | pmid=14568251 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14568251  }}</ref>
* Loss of [[HAMP]] gene or or mutations that hamper the interaction of [[hepcidin]] with [[ferroportin]] causes hemoochromatosis.<ref name="pmid12547233">{{cite journal| author=Njajou OT, de Jong G, Berghuis B, Vaessen N, Snijders PJ, Goossens JP et al.| title=Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics. | journal=Blood Cells Mol Dis | year= 2002 | volume= 29 | issue= 3 | pages= 439-43 | pmid=12547233 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12547233  }}</ref>


===Hepcidin-ferroportin axis and iron overload===
===== HFE-Hemochromatosis: =====
Recently, a new unifying theory for the pathogenesis of hereditary hemochromatosis 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 [[phenotype]] of iron overload. In this theory, low levels of circulating [[hepcidin]] result in higher levels of [[ferroportin]] expression in [[intestinal]] [[enterocytes]] and reticuloendothelial macrophages.  As a result, this causes iron accumulation. [[HFE]], [[hemojuvelin]], BMP's and TFR2 are implicated in regulating [[hepcidin]] expression.
* Most common form of the disease.
* [[Homozygosity]] for the 845G−A [[polymorphism]] in [[HFE]] that results in Cys282YTyr (C282Y) in the gene product
* Highly prevalent in whites.
* The prevalence of C282Y is higher in certain patient groups, such as those with [[liver]] disease (5- to 10-fold higher than in the general population) and [[hepatocellular carcinoma]]- which is at least twice as frequent among patients with [[HFE]]-hemochromatosis compared with those who have other types of [[liver]] disease—[[Diabetes mellitus type 1|type 1 diabetes]], [[chondrocalcinosis]], or [[porphyria cutanea tarda]].<ref name="pmid15290237">{{cite journal| author=Distante S, Robson KJ, Graham-Campbell J, Arnaiz-Villena A, Brissot P, Worwood M| title=The origin and spread of the HFE-C282Y haemochromatosis mutation. | journal=Hum Genet | year= 2004 | volume= 115 | issue= 4 | pages= 269-79 | pmid=15290237 | doi=10.1007/s00439-004-1152-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15290237 }}</ref>
* Y231del mutation of HEF gene was found in the Huh-7 [[hepatoma]] cell line in Japan population.<ref name="pmid22093335">{{cite journal| author=Takano A, Niimi H, Atarashi Y, Sawasaki T, Terasaki T, Nakabayashi T et al.| title=A novel Y231del mutation of HFE in hereditary haemochromatosis provides in vivo evidence that the Huh-7 is a human haemochromatotic cell line. | journal=Liver Int | year= 2011 | volume= 31 | issue= 10 | pages= 1593-7 | pmid=22093335 | doi=10.1111/j.1478-3231.2011.02620.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22093335  }}</ref>
* In the United States, most people with clinically measureable haemochromatosis (i.e., [[iron]] overload with or without end organ damage) have inherited two copies of C282Y — one from each parent — and are therefore [[homozygous]] for the trait.  [[Mutation]]s of the ''HFE'' [[gene]] account for 90% of the cases of clinical iron overload. This gene is closely [[genetic linkage|linked]] to the [[Human leukocyte antigen|HLA-A3]] [[Locus (genetics)|locus]]. [[Homozygosity]] for the C282Y [[mutation]] is the most prevalent condition resulting in clinical iron accumulation, although [[heterozygosity]] for C282Y/H63D mutations, so-called compound heterozygotes, is also known to cause clinical [[iron]] overload. So, both [[homozygotes]] for C282Y and compound heterozygotes for C282Y/H63D are known to have clinical [[iron]] overload and hemochromatosis.<ref name="pmid11874997">{{cite journal| author=Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK| title=A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. | journal=Gastroenterology | year= 2002 | volume= 122 | issue= 3 | pages= 646-51 | pmid=11874997 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11874997  }}</ref><ref name="pmid25311314">{{cite journal| author=Zaloumis SG, Allen KJ, Bertalli NA, Turkovic L, Delatycki MB, Nicoll AJ et al.| title=Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12-year study. | journal=J Gastroenterol Hepatol | year= 2015 | volume= 30 | issue= 4 | pages= 719-25 | pmid=25311314 | doi=10.1111/jgh.12804 | pmc=4782752 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25311314  }}</ref>


===Genetics===
* Most people with two copies of C282Y or one copy each of C282Y/H63D do not manifest clinical hemochromatosis, a phenomenon known as low [[Penetrance|incomplete penetration]]. <ref name="Olynwk_1999">{{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}}</ref> In this condtion penetration differs between different populations.<ref name="pmid19554541">{{cite journal| author=Gurrin LC, Bertalli NA, Dalton GW, Osborne NJ, Constantine CC, McLaren CE et al.| title=HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. | journal=Hepatology | year= 2009 | volume= 50 | issue= 1 | pages= 94-101 | pmid=19554541 | doi=10.1002/hep.22972 | pmc=3763940 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19554541  }}</ref> 
The regulation of how much iron enters the body from food is complex, and each year brings new discoveries about the numerous factors working in harmony to bring about balance in the metabolism of [[iron]] in [[humans]]


One of the best-characterized genes that regulates the amount of [[iron]] absorbed from food is called [[HFE]].  The [[HFE]] gene has two common mutations, C282Y and H63D.
* Other genes whose mutations have been associated with iron overload include the [[autosomal dominant]] SLC11A3/ferroportin 1 gene and [[Transferrin receptor-2|TfR2]] ([[transferrin receptor 2]]). These mutations, and the iron overload they cause, are much rarer than ''HFE''-haemochromatosis.


Inheriting just one of the C282Y mutations ([[heterozygous]]) makes a person a carrier who can pass this mutation onward.  Carriers of one [[HFE]] mutation ordinarily do not manifest with clinically relevant iron accumulation at all.
===== Non-HFE Hemochromatosis: =====
* The non-HFE−related forms of hemochromatosis are rarer and not restricted to northern European descent.
* '''Adult Onset Forms:'''


<gallery>
* Are due to [[Transferrin receptor-2|TfR2]] mutations
Image:Autorecessive.jpg|Haemochromatosis types 1-3 are inherited in an [[Recessive gene|autosomal recessive]] fashion.
* identified in different ethnicities, including southern Asian populations<ref name="pmid21901660">{{cite journal| author=Pietrangelo A, Caleffi A, Corradini E| title=Non-HFE hepatic iron overload. | journal=Semin Liver Dis | year= 2011 | volume= 31 | issue= 3 | pages= 302-18 | pmid=21901660 | doi=10.1055/s-0031-1286061 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21901660  }}</ref>
Image:Autodominant2.jpg|Haemochromatosis type 4 is inherited in an [[autosomal dominant]] fashion.
* It is an [[autosomal dominant]] hereditary [[iron]] loading disorder associated with heterozygote mutations of the [[Ferroportin|ferroportin-1]] (FPN) gene and is commonest causes of genetic hyperferritinemia.
</gallery>
* FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in [[Enterocyte|enterocytes]], but they do severely affect [[iron]] transfer in [[Macrophage|macrophages]]. This leads to progressive and preferential iron trapping in tissue [[Macrophage|macrophages]], reduced iron release to serum [[transferrin]] (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting.<ref name="pmid29101207">{{cite journal| author=Pietrangelo A| title=Ferroportin disease: pathogenesis, diagnosis and treatment. | journal=Haematologica | year= 2017 | volume= 102 | issue= 12 | pages= 1972-1984 | pmid=29101207 | doi=10.3324/haematol.2017.170720 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29101207  }}</ref>
* '''Juvenile Onset Forms''':
* It is due to loss of HAMP.<ref name="pmid14873186">{{cite journal| author=PLATTNER HC, NUSSBAUMER T, RYWLIN A| title=[Juvenile and familial hemochromatosis with endocrinomyocardiac syndrome]. | journal=Helv Med Acta | year= 1951 | volume= 18 | issue= 4-5 | pages= 499-502 | pmid=14873186 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14873186  }}</ref>
* It is due to pathogenic mutations of HJV, with the G320V mutation found in nearly 50% of juvenile hemochromatosis.<ref name="pmid13022939">{{cite journal| author=NUSSBAUMER T, PLATTNER HC, RYWLIN A| title=[Juvenile hemochromatosis in three sisters and one brother associated with consanguinity of the parents; anatomo-clinical and genetic study of the endocrino-hepato-myocardial syndrome]. | journal=J Genet Hum | year= 1952 | volume= 1 | issue= 2 | pages= 53-82 | pmid=13022939 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13022939  }}</ref>


In the United States, most people with clinically measureable haemochromatosis (i.e., iron overload with or without end organ damage) have inherited two copies of C282Y — one from each parent — and are therefore [[homozygous]] for the trait.  [[Mutation]]s of the ''HFE'' [[gene]] account for 90% of the cases of clinical iron overload.  This gene is closely [[genetic linkage|linked]] to the [[Human leukocyte antigen|HLA-A3]] [[Locus (genetics)|locus]].  [[Homozygosity]] for the C282Y [[mutation]] is the most prevalent condition resulting in clinical iron accumulation, although [[heterozygosity]] for  C282Y/H63D mutations, so-called compound heterozygotes, is also known to cause clinical iron overload.  So, both [[homozygotes]] for C282Y and compound heterozygotes for C282Y/H63D are known to have clinical iron overload and hemochromatosis. 
=== Macroscopic Pathology: ===
The cut surface is seen as golden-brown in color, having a fine, diffuse nodularity, and being extremely firm in consistency


Most people with two copies of C282Y or one copy each of C282Y/H63D do not manifest clinical hemochromatosis, a phenomenon known as low [[Penetrance|incomplete penetration]].  <ref name="Olynwk_1999">{{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}}</ref> Penetration differs between different populations. 
===Microscopic Pathology:===
'''Liver biopsy:'''


Other genes whose mutations have been associated with iron overload include the [[autosomal dominant]] SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). These mutations, and the iron overload they cause, are much rarer than ''HFE''-haemochromatosis.
In liver biopsy following findings of iron load  are seen in microscopic view<ref name="pmid9608256">{{cite journal| author=Pigolkin IuI, Osipenkova TK| title=[The morphological changes in the internal organs in hemochromatosis]. | journal=Sud Med Ekspert | year= 1998 | volume= 41 | issue= 2 | pages= 20-2 | pmid=9608256 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9608256  }}</ref>:
* [[Kupffer cell]] hypertrophy containing iron-rich remnants of [[Phagocytosis|phagocytosed]] [[Hepatocyte|hepatocytes]].
* Transition of fat-storing cells
* Fat-storing cells close to iron-laden hepatocytes contained multiple lipid droplets and adjacent collagen fibril bundles
* [[Immunohistochemistry]] shows sparse [[intercellular adhesion molecule-1]] ([[ICAM-1]]) expression by [[Hepatocyte|hepatocytes]].<ref name="pmid4846623">{{cite journal| author=Lángos J, Bózner A, Vencel P, Tomík F| title=[Histological and electron microscopy findings in liver biopsy specimens in hemochromatosis]. | journal=Cesk Gastroenterol Vyz | year= 1974 | volume= 28 | issue= 4 | pages= 253-6 | pmid=4846623 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4846623  }}</ref>
* Pigmentary [[cirrhosis]] of the [[liver]]                   


===Microscopic Pathology===
*
'''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]], measured microscopically.  Formerly, this was the only way to confirm a diagnosis of hemochromatosis 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 biopsy]] is still necessary to quantify the amount of accumulated iron.
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==References==
==References==
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Latest revision as of 18:14, 17 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs. The features of hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.

Pathophysiology

  • Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs.
  • The features of hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.
  • Hemochromatosis is a complex genetic disease with strong environmental disease modifiers.
  • In most cases, hemochromatosis is due to partial or total loss of the activity of a small peptide hormone produced by the liver, hepcidin, which normally restrains iron entry into the circulation
  • Normal iron in liver is present at a concentration lower than 20 μmol/g of dry weight.[1]
  • Iron is normally lost in sweat, shed skin cells, and the gastrointestinal tract at a rate of approximately 1 mg/day.
  • Premenopausal adult women lose an additional 0.5 to 1.0 mg/day because of menses.
  • These losses are usually balanced by the absorption of 10 percent of the 10 to 20 mg of iron in the diet in Western societies.
  • 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.[2]
  • Generally, people with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body.
  • Thus the iron stores of the body increase. As they increase the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.[3]

Intestinal crypt enterocytes and iron overload

  • The sensor pathway inside the small bowel enterocyte can be disrupted due to genetic errors in the iron regulatory apparatus.
  • The enterocyte in the small bowel crypt must somehow sense the amount of circulating iron.
  • Depending on this information, the enterocyte cell can regulate the quantity of iron receptors 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, the enterocyte is somehow constantly fooled into thinking there is iron depletion.
  • As a consequence, 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 role:

  • In 2000, Hepcidin was discovered which is produced from HAMP gene.[5]
  • Hepcidin is produced in the liver as a 84 amino acid prepropeptide that is processed in a 25 amino acid bio-active circulating form.[6]
  • Hepcidin is hormone produced by liver that is lost genetically in hereditary hemochromatosis.[7]
  • Mutations resulting in modifications in protein that assist hepcicdin are also cause of hereditary hemochromatosis
  • Proteins can be HEF or non-HEF such as transferrin-receptor 2, hemojuvelin, receptor ferroportin.
  • Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. 
  • Hepcidin is a defensin-like cysteine-rich antimicrobial peptide that likely evolved in humans as part of the innate immune defense. Innate immunity relies on a variety of effector mechanisms to defend against microbial invasion. Among them are the abundant and widely distributed disulfide-linked cationic antimicrobial peptides found in plants, insects, and mammals.[8]
  • Hepcidin is inflammatory responsing agent like to interleukin 6 (IL6) which activates hepcidin transcription through the Jak/STAT3 pathway. [9]
  • Hepcidin is likely also produced in monocytes/macrophages during infection through Toll-like receptors.[10]

Genetics

The regulation of how much iron enters the body from food is complex, and each year brings new discoveries about the numerous factors working in harmony to bring about balance in the metabolism of iron in humans.[11]

  • One of the best-characterized genes that regulates the amount of iron absorbed from food is called HFE.
  • The HFE gene has two common mutations, C282Y and H63D.
  • Inheriting just one of the C282Y mutations (heterozygous) makes a person a carrier who can pass this mutation onward.
  • Carriers of one HFE mutation ordinarily do not manifest with clinically relevant iron accumulation at all.
  • Hepcidin and its receptor ferroportin are the central proteins in hemochromatosis.[12]
  • Loss of HAMP gene or or mutations that hamper the interaction of hepcidin with ferroportin causes hemoochromatosis.[13]
HFE-Hemochromatosis:
  • Most common form of the disease.
  • Homozygosity for the 845G−A polymorphism in HFE that results in Cys282YTyr (C282Y) in the gene product
  • Highly prevalent in whites.
  • The prevalence of C282Y is higher in certain patient groups, such as those with liver disease (5- to 10-fold higher than in the general population) and hepatocellular carcinoma- which is at least twice as frequent among patients with HFE-hemochromatosis compared with those who have other types of liver disease—type 1 diabetes, chondrocalcinosis, or porphyria cutanea tarda.[14]
  • Y231del mutation of HEF gene was found in the Huh-7 hepatoma cell line in Japan population.[15]
  • In the United States, most people with clinically measureable haemochromatosis (i.e., iron overload with or without end organ damage) have inherited two copies of C282Y — one from each parent — and are therefore homozygous for the trait. Mutations of the HFE gene account for 90% of the cases of clinical iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most prevalent condition resulting in clinical iron accumulation, although heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, is also known to cause clinical iron overload. So, both homozygotes for C282Y and compound heterozygotes for C282Y/H63D are known to have clinical iron overload and hemochromatosis.[16][17]
  • Most people with two copies of C282Y or one copy each of C282Y/H63D do not manifest clinical hemochromatosis, a phenomenon known as low incomplete penetration. [18] In this condtion penetration differs between different populations.[19]
  • Other genes whose mutations have been associated with iron overload include the autosomal dominant SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). These mutations, and the iron overload they cause, are much rarer than HFE-haemochromatosis.
Non-HFE Hemochromatosis:
  • The non-HFE−related forms of hemochromatosis are rarer and not restricted to northern European descent.
  • Adult Onset Forms:
  • Are due to TfR2 mutations
  • identified in different ethnicities, including southern Asian populations[20]
  • It is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the ferroportin-1 (FPN) gene and is commonest causes of genetic hyperferritinemia.
  • FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in enterocytes, but they do severely affect iron transfer in macrophages. This leads to progressive and preferential iron trapping in tissue macrophages, reduced iron release to serum transferrin (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting.[21]
  • Juvenile Onset Forms:
  • It is due to loss of HAMP.[22]
  • It is due to pathogenic mutations of HJV, with the G320V mutation found in nearly 50% of juvenile hemochromatosis.[23]

Macroscopic Pathology:

The cut surface is seen as golden-brown in color, having a fine, diffuse nodularity, and being extremely firm in consistency

Microscopic Pathology:

Liver biopsy:

In liver biopsy following findings of iron load are seen in microscopic view[24]:

References

  1. ↑ Pietrangelo A (October 2015). "Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin". Gastroenterology. 149 (5): 1240–1251.e4. doi:10.1053/j.gastro.2015.06.045. PMID 26164493.
  2. ↑ Pietrangelo A (August 2010). "Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment". Gastroenterology. 139 (2): 393–408, 408.e1–2. doi:10.1053/j.gastro.2010.06.013. PMID 20542038.
  3. ↑ Shizukuda Y, Bolan C, Nguyen T, Botello G, Tripodi D, Yau Y, Waclawiw M, Leitman S, Rosing D (2007). "Oxidative stress in asymptomatic subjects with hereditary hemochromatosis". Am J Hematol. 82 (3): 249–50. PMID 16955456.
  4. ↑ Pietrangelo A (2010). "Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment". Gastroenterology. 139 (2): 393–408, 408.e1–2. doi:10.1053/j.gastro.2010.06.013. PMID 20542038.
  5. ↑ Krause A, Neitz S, Mägert HJ, Schulz A, Forssmann WG, Schulz-Knappe P; et al. (2000). "LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity". FEBS Lett. 480 (2–3): 147–50. PMID 11034317.
  6. ↑ Park CH, Valore EV, Waring AJ, Ganz T (2001). "Hepcidin, a urinary antimicrobial peptide synthesized in the liver". J Biol Chem. 276 (11): 7806–10. doi:10.1074/jbc.M008922200. PMID 11113131.
  7. ↑ Park CH, Valore EV, Waring AJ, Ganz T (2001). "Hepcidin, a urinary antimicrobial peptide synthesized in the liver". J Biol Chem. 276 (11): 7806–10. doi:10.1074/jbc.M008922200. PMID 11113131.
  8. ↑ Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P; et al. (2001). "A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload". J Biol Chem. 276 (11): 7811–9. doi:10.1074/jbc.M008923200. PMID 11113132.
  9. ↑ Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK; et al. (2004). "IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin". J Clin Invest. 113 (9): 1271–6. doi:10.1172/JCI20945. PMC 398432. PMID 15124018.
  10. ↑ Armitage AE, Eddowes LA, Gileadi U, Cole S, Spottiswoode N, Selvakumar TA; et al. (2011). "Hepcidin regulation by innate immune and infectious stimuli". Blood. 118 (15): 4129–39. doi:10.1182/blood-2011-04-351957. PMID 21873546.
  11. ↑ Pietrangelo A (August 2010). "Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment". Gastroenterology. 139 (2): 393–408, 408.e1–2. doi:10.1053/j.gastro.2010.06.013. PMID 20542038.
  12. ↑ Lymboussaki A, Pignatti E, Montosi G, Garuti C, Haile DJ, Pietrangelo A (2003). "The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression". J Hepatol. 39 (5): 710–5. PMID 14568251.
  13. ↑ Njajou OT, de Jong G, Berghuis B, Vaessen N, Snijders PJ, Goossens JP; et al. (2002). "Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics". Blood Cells Mol Dis. 29 (3): 439–43. PMID 12547233.
  14. ↑ Distante S, Robson KJ, Graham-Campbell J, Arnaiz-Villena A, Brissot P, Worwood M (2004). "The origin and spread of the HFE-C282Y haemochromatosis mutation". Hum Genet. 115 (4): 269–79. doi:10.1007/s00439-004-1152-4. PMID 15290237.
  15. ↑ Takano A, Niimi H, Atarashi Y, Sawasaki T, Terasaki T, Nakabayashi T; et al. (2011). "A novel Y231del mutation of HFE in hereditary haemochromatosis provides in vivo evidence that the Huh-7 is a human haemochromatotic cell line". Liver Int. 31 (10): 1593–7. doi:10.1111/j.1478-3231.2011.02620.x. PMID 22093335.
  16. ↑ Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK (2002). "A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation". Gastroenterology. 122 (3): 646–51. PMID 11874997.
  17. ↑ Zaloumis SG, Allen KJ, Bertalli NA, Turkovic L, Delatycki MB, Nicoll AJ; et al. (2015). "Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12-year study". J Gastroenterol Hepatol. 30 (4): 719–25. doi:10.1111/jgh.12804. PMC 4782752. PMID 25311314.
  18. ↑ Olynyk J, Cullen D, Aquilia S, Rossi E, Summerville L, Powell L (1999). "A population-based study of the clinical expression of the hemochromatosis gene". N Engl J Med. 341 (10): 718–24. PMID 10471457.
  19. ↑ Gurrin LC, Bertalli NA, Dalton GW, Osborne NJ, Constantine CC, McLaren CE; et al. (2009). "HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity". Hepatology. 50 (1): 94–101. doi:10.1002/hep.22972. PMC 3763940. PMID 19554541.
  20. ↑ Pietrangelo A, Caleffi A, Corradini E (2011). "Non-HFE hepatic iron overload". Semin Liver Dis. 31 (3): 302–18. doi:10.1055/s-0031-1286061. PMID 21901660.
  21. ↑ Pietrangelo A (2017). "Ferroportin disease: pathogenesis, diagnosis and treatment". Haematologica. 102 (12): 1972–1984. doi:10.3324/haematol.2017.170720. PMID 29101207.
  22. ↑ PLATTNER HC, NUSSBAUMER T, RYWLIN A (1951). "[Juvenile and familial hemochromatosis with endocrinomyocardiac syndrome]". Helv Med Acta. 18 (4–5): 499–502. PMID 14873186.
  23. ↑ NUSSBAUMER T, PLATTNER HC, RYWLIN A (1952). "[Juvenile hemochromatosis in three sisters and one brother associated with consanguinity of the parents; anatomo-clinical and genetic study of the endocrino-hepato-myocardial syndrome]". J Genet Hum. 1 (2): 53–82. PMID 13022939.
  24. ↑ Pigolkin IuI, Osipenkova TK (1998). "[The morphological changes in the internal organs in hemochromatosis]". Sud Med Ekspert. 41 (2): 20–2. PMID 9608256.
  25. ↑ Lángos J, Bózner A, Vencel P, Tomík F (1974). "[Histological and electron microscopy findings in liver biopsy specimens in hemochromatosis]". Cesk Gastroenterol Vyz. 28 (4): 253–6. PMID 4846623.

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