View source for African iron overload

{{Short description|Iron overload disorder caused by consumption of home-brewed beer}}
{{Infobox medical condition (new)
| name            = African iron overload
| synonyms        =
| image           = Protein TF PDB 1a8e.png
| caption         = [[Transferrin]]
| pronounce       =
| field           = [[Hematology]]
| symptoms        =
| complications   =
| onset           =
| duration        =
| types           =
| causes          =
| risks           =
| diagnosis       =
| differential    =
| prevention      =
| treatment       =
| medication      =
| prognosis       =
| frequency       =
| deaths          =
}}
'''African iron overload''' is an [[iron overload disorder]] first observed among people of [[Africa]]n descent in [[Southern Africa]] and [[Central Africa]].<ref name=MacPhail>{{cite journal|last=MacPhail|first=AP|author2=Mandishona, EM |author3=Bloom, PD |author4=Paterson, AC |author5=Rouault, TA |author6= Gordeuk, VR |title=Measurements of iron status and survival in African iron overload.|journal=Suid-Afrikaanse Tydskrif vir Geneeskunde|date=Sep 1999|volume=89|issue=9|pages=966–72|pmid=10554633}}</ref> It is now recognized to actually be two disorders with different causes, possibly compounding each other:<ref name="pmid1727237"/>

* '''Dietary iron overload''' is one contributor to iron overloads observed in African people. Home-brewed beer contains very high amounts of iron compared to commercial beer and causes overload. This form was prevalent in both the rural and urban Black African population. With the introduction of commercial beer in urban areas, the condition has decreased. However, the condition is still common in rural areas.<ref name=Kew>{{cite journal|last=Kew|first=MC|author2=Asare, GA|title=Dietary iron overload in the African and hepatocellular carcinoma.|journal=Liver International|date=Aug 2007|volume=27|issue=6|pages=735–41|pmid=17617115|doi=10.1111/j.1478-3231.2007.01515.x|s2cid=37237869}}</ref>
* '''Bantu [[siderosis]]''', is the genetic side of the disorder. Some African people carry a unique [[ferroportin]] mutation that predisposes them to iron overload, making it a kind of [[Hemochromatosis type 4|ferroportin disease]].<ref name=pmid17490902 /><ref name=Fleming /> African-Americans, who have no exposure to iron-rich beer, can also exhibit this issue.<ref name="pmid1727237"/><ref>{{cite journal |last1=Gordeuk |first1=Victor R |last2=Caleffi |first2=Angela |last3=Corradini |first3=Elena |last4=Ferrara |first4=Francesca |last5=Jones |first5=Russell A |last6=Castro |first6=Oswaldo |last7=Onyekwere |first7=Onyinye |last8=Kittles |first8=Rick |last9=Pignatti |first9=Elisa |last10=Montosi |first10=Giuliana |last11=Garuti |first11=Cinzia |last12=Gangaidzo |first12=Innocent T |last13=Gomo |first13=Z.A.R |last14=Moyo |first14=Victor M |last15=Rouault |first15=Tracey A |last16=MacPhail |first16=Patrick |last17=Pietrangelo |first17=Antonello |title=Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene☆ |journal=Blood Cells, Molecules and Diseases |date=November 2003 |volume=31 |issue=3 |pages=299–304 |doi=10.1016/S1079-9796(03)00164-5|pmid=14636642 |hdl=11380/611688 |hdl-access=free }}</ref>

This disorder can be treated with [[phlebotomy]] therapy or [[Chelation therapy|iron chelation]] therapy.

==Signs and symptoms==
Symptoms can vary from one person to another. It depends on the extent of accumulation and on the body location of the accumulation. African iron overload can be considered in patient with some of these conditions.<ref name=MacPhail /><ref name="Bookmark overload">{{cite web|title=African Iron Overload|url=https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1272/printFullReport|work=National Organization of Rare Disorder|access-date=9 April 2014}}</ref>
{{columns-list|colwidth=30em|
* [[hepatomegaly]]
* mild to moderate [[liver dysfunction]]
* [[fibrosis]]
* [[portal hypertension]]
* [[ascites]]
* liver [[cirrhosis]]
* [[diabetes]] due to iron accumulation in pancreas
* [[osteoporosis]]
* [[cardiac]] abnormalities
* [[hepatocellular carcinoma]]
}}

==Mechanism==
Originally, this was blamed on [[galvanisation|ungalvanised]] barrels used to store [[Homebrewing|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 an iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer (e.g., [[African Americans]]).<ref name="pmid1727237">{{cite journal |author=Gordeuk V |title=Iron overload in Africa. Interaction between a gene and dietary iron content |journal=[[N. Engl. J. Med.]] |volume=326 |issue=2 |pages=95–100 |date=January 1992 |pmid=1727237 |doi= 10.1056/NEJM199201093260204|name-list-style=vanc |author2=Mukiibi J |author3=Hasstedt SJ |display-authors=3 |last4=Samowitz |first4=Wade |last5=Edwards |first5=Corwin Q |last6=West |first6=George |last7=Ndambire |first7=Solomon |last8=Emmanual |first8=Jean |last9=Nkanza |first9=Neal|doi-access=free }}</ref>

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="pmid14636642">{{cite journal |author=Gordeuk VR |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|name-list-style=vanc |author2=Caleffi A |author3=Corradini E |display-authors=3 |last4=Ferrara |first4=Francesca |last5=Jones |first5=Russell A |last6=Castro |first6=Oswaldo |last7=Onyekwere |first7=Onyinye |last8=Kittles |first8=Rick |last9=Pignatti |first9=Elisa|hdl=11380/611688 |hdl-access=free }}</ref>

=== Diet ===
Preparing beer in iron pots or drums results in high iron content. The iron content in home-brewed beer is around 46–82&nbsp;mg/L, compared to 0.5&nbsp;mg/L in commercial beer.<ref name=Kew />

===Genetics===
The [[SLC40A1]] gene encodes for [[ferroportin]]. Ferroportin/SLC40A1 Q248H mutation in [[exon]] 6 occurs as a polymorphism in individuals of sub-Saharan African descent,<ref name=pmid14636642 /><ref name=Beutler /><ref name="Barton 2003">{{cite journal|last=Barton|first=JC|author2=Acton, RT|author3=Rivers, CA|author4=Bertoli, LF|author5=Gelbart, T|author6=West, C|author7= Beutler, E|title=Genotypic and phenotypic heterogeneity of African Americans with primary iron overload.|journal=Blood Cells, Molecules & Diseases|date=Nov–Dec 2003|volume=31|issue=3|pages=310–9|pmid=14636644|doi=10.1016/s1079-9796(03)00166-9}}</ref>  but it was not identified in western [[White people|Caucasians]].<ref name=pmid14636642 />

Q248H has not yet been conclusively found to be responsible for iron overload. It is found in a minority of African American and Native African with primary iron overload<ref name=pmid14636642 /><ref name=Beutler>{{cite journal|last=Beutler|first=E|author2=Barton, JC|author3=Felitti, VJ|author4=Gelbart, T|author5=West, C|author6=Lee, PL|author7=Waalen, J|author8= Vulpe, C|title=Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans.|journal=Blood Cells, Molecules & Diseases|date=Nov–Dec 2003|volume=31|issue=3|pages=305–9|pmid=14636643|doi=10.1016/s1079-9796(03)00165-7}}</ref> but was not found more regularly in Native southern Africans with dietary iron overload.<ref name=McNamara>{{cite journal|last=McNamara|first=L|author2=Gordeuk, VR|author3=MacPhail, AP|title=Ferroportin (Q248H) mutations in African families with dietary iron overload.|journal=Journal of Gastroenterology and Hepatology|date=Dec 2005|volume=20|issue=12|pages=1855–8|pmid=16336444|doi=10.1111/j.1440-1746.2005.03930.x|s2cid=41825542}}</ref> It is also not associated with a statistically significant increase of risk in African Americans and Native Americans.<ref name="pmid17490902">{{cite journal |vauthors=Barton JC, Acton RT, Lee PL, West C |title=SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent |journal=Blood Cells Mol. Dis. |volume=39 |issue=2 |pages=206–11 |year=2007 |pmid=17490902 |doi=10.1016/j.bcmd.2007.03.008 |pmc=1986732}}</ref> In fact, studies have shown that SLC40A1 Q248H aggregate [[allele frequency]] is higher in Native Africans than the aggregate allele frequency in African Americans.<ref name=pmid17490902 />

On the other hand, evidence suggests that Q248H may have an effect on iron supply. Ferroportin Q248H mutation in African families with dietary iron overload showed lower [[mean cell volume]] and higher [[ferritin]] concentration.<ref name=McNamara /> Mice homozygous for the Q248H mutation show similar symptoms. They display only slight iron loading on a normal diet, but accumulates iron when fed a high-iron diet.<ref>{{cite journal |last1=Alhakami |first1=Fatemah |last2=Ahmad |first2=Asrar |last3=Jerebtsova |first3=Marina |last4=Nekhai |first4=Sergei |title=Ferroportin Q248H Mutation Leads to a Moderate Iron Load in Mutant Slc 40a1Q248H/Q248H Mice |journal=Blood |date=15 November 2022 |volume=140 |issue=Supplement 1 |pages=5343–5344 |doi=10.1182/blood-2022-170019|s2cid=254217566 |doi-access=free }}</ref>

The probable cause of African iron overload is the combination of excess iron intake and functional changes in ferroportin.<ref name=pmid17490902 /><ref name=Fleming />  [[Penetrance]] of Q248H as a cause of iron overload is most likely low.<ref name=pmid17490902 /><ref name=McNamara />

===Hepatocellular carcinoma===
Excess hepatic iron in dietary iron overload is typically associated with serum [[ferritin]] saturation of greater than 700pg/L and [[transferrin]] saturation of greater than 55%.<ref name=Moyo>{{cite journal|last=Moyo|first=VM|author2=Gangaidzo, IT|author3=Gomo, ZA|author4=Khumalo, H|author5=Saungweme, T|author6=Kiire, CF|author7=Rouault, T|author8= Gordeuk, VR|title=Traditional beer consumption and the iron status of spouse pairs from a rural community in Zimbabwe.|journal=Blood|date=Mar 15, 1997|volume=89|issue=6|pages=2159–66|doi=10.1182/blood.V89.6.2159|pmid=9058740|doi-access=free}}</ref>

Increased [[hepatic]] iron generates chronic [[oxidative stress]] by disrupting the [[redox]] balance of the cell, which damages DNA, protein, [[hepatocytes]] and [[lipids]].<ref name=Hagen>{{cite journal|last=Hagen|first=TM|author2=Huang, S|author3=Curnutte, J|author4=Fowler, P|author5=Martinez, V|author6=Wehr, CM|author7=Ames, BN|author8= Chisari, FV|title=Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Dec 20, 1994|volume=91|issue=26|pages=12808–12|pmid=7809125|pmc=45529|doi=10.1073/pnas.91.26.12808|bibcode=1994PNAS...9112808H|doi-access=free}}</ref><ref name=Jungst>{{cite journal|last=Jüngst|first=C|author2=Cheng, B|author3=Gehrke, R|author4=Schmitz, V|author5=Nischalke, HD|author6=Ramakers, J|author7=Schramel, P|author8=Schirmacher, P|author9=Sauerbruch, T|author10= Caselmann, WH|title=Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma.|journal=Hepatology|date=Jun 2004|volume=39|issue=6|pages=1663–72|pmid=15185308|doi=10.1002/hep.20241|doi-access=free}}</ref><ref name=Asare>{{cite journal|last=Asare|first=GA|author2=Mossanda, KS |author3=Kew, MC |author4=Paterson, AC |author5=Kahler-Venter, CP |author6= Siziba, K |title=Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity.|journal=Toxicology|date=Feb 15, 2006|volume=219|issue=1–3|pages=41–52|pmid=16337327 |doi=10.1016/j.tox.2005.11.006}}</ref>  Increased [[lipid]] [[peroxidation]] is thought to be a vital contributor to [[hepatocellular carcinoma]] in iron overload.<ref name=Thirunavukkarasu>{{cite journal|last=Thirunavukkarasu|first=C|author2=Sakthisekaran, D|title=Effect of selenium on N-nitrosodiethylamine-induced multistage hepatocarcinogenesis with reference to lipid peroxidation and enzymic antioxidants.|journal=Cell Biochemistry and Function|date=Mar 2001|volume=19|issue=1|pages=27–35|pmid=11223868|doi=10.1002/cbf.895|s2cid=46673802}}</ref>   Oxidative stress leads to lipid [[peroxidation]] of [[unsaturated fatty acids]] in organelles and cell membrane.<ref name=Kew />

==Diagnosis==
Elevation in [[ferritin]] concentration without elevation in [[transferrin]] saturation does not rule out an iron overload disorder. This combination can be observed in loss-of-function [[ferroportin]] mutation and in [[aceruloplasminemia]].<ref name=Fleming>{{cite journal|last=Fleming|first=RE|author2=Ponka, P|title=Iron overload in human disease.|journal=The New England Journal of Medicine|date=Jan 26, 2012|volume=366|issue=4|pages=348–59|pmid=22276824|doi=10.1056/NEJMra1004967}}</ref> Elevated level of ferritin concentration can be observed in acute or chronic inflammatory process without pathologic iron overload.<ref name=Knovich>{{cite journal|last=Knovich|first=MA|author2=Storey, JA |author3=Coffman, LG |author4=Torti, SV |author5= Torti, FM |title=Ferritin for the clinician.|journal=Blood Reviews|date=May 2009|volume=23|issue=3|pages=95–104|pmid=18835072 |doi=10.1016/j.blre.2008.08.001 |pmc=2717717}}</ref>

{| class="wikitable" style="float:left"
|+ Measurement of iron status
|-
! Characteristic !! Normal range !! Unit
|-
| [[Ferritin]]-male || 12–300<ref name=Ferritin-range>{{cite web|title=Ferritin|url=https://www.nlm.nih.gov/medlineplus/ency/article/003490.htm|work=MedlinePlus|access-date=9 April 2014}}</ref>   || ng/mL
|-
| [[Ferritin]]-female || 12–150<ref name=Ferritin-range />  || ng/mL
|-
| [[Transferrin saturation]]-male || 10–50<ref name="transferrin saturation">{{cite web|title=Iron (Fe)|url=http://www.webmd.com/a-to-z-guides/iron-fe?page=2|work=Web MD|access-date=9 April 2014}}</ref>  || %
|-
| [[Transferrin saturation]]-female || 15–50<ref name="transferrin saturation" />  || %
|}
{{clear}}
Ferritin level above 200&nbsp;ng/mL (449 pmol/L) in women or 300&nbsp;ng/mL (674 pmol/L) in men who have no signs of inflammatory disease need additional testing. Transferrin saturation above normal range in male and female also need additional testing.<ref name=McLaren>{{cite journal|last=McLaren|first=CE|author2=Barton, JC |author3=Adams, PC |author4=Harris, EL |author5=Acton, RT |author6=Press, N |author7=Reboussin, DM |author8=McLaren, GD |author9=Sholinsky, P |author10=Walker, AP |author11=Gordeuk, VR |author12=Leiendecker-Foster, C |author13=Dawkins, FW |author14=Eckfeldt, JH |author15=Mellen, BG |author16=Speechley, M |author17=Thomson, E |author18=Hemochromatosis |others=Iron Overload Study Research, Investigators|s2cid=20665357|title=Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.|journal=The American Journal of the Medical Sciences|date=Feb 2003|volume=325|issue=2|pages=53–62|pmid=12589228|doi=10.1097/00000441-200302000-00001}}</ref>

Chemical evidence of tissue [[vitamin C deficiency]] and mild to moderate liver dysfunction are likely to be seen in individuals with African iron overload.<ref name=MacPhail /> Elevation in [[gamma-glutamyl transpeptidase]] can be used as a marker for abnormalities in liver function.<ref name="t576">{{cite web | title=Gamma-glutamyl Transferase (GGT) Test: MedlinePlus Medical Test | website=MedlinePlus | date=2021-11-16 | url=https://medlineplus.gov/lab-tests/gamma-glutamyl-transferase-ggt-test/ | access-date=2024-06-18}}</ref>

{| class="wikitable" style="float:left"
|+ Measurement of iron-related features
|-
! Characteristic !! Normal range !! Unit
|-
| [[Vitamin C]] || 0.2–2<ref name=Vit-C>{{cite web|title=Vitamin-C|url=http://www.globalrph.com/labs_v.htm|work=GlobalRPH|access-date=9 April 2014}}</ref>  <br> 11–114<ref name=Vit-C />  || mg/dL<br> μmol/L
|-
| [[Gamma-glutamyl transpeptidase]] in male || < 55.2<ref name=GGT>{{cite web|title=Gamma-glutamyl transpeptidase |url=http://www.mdi-labor.de/l_leistungsverzeichnis_detail.php?u_id=663&init=letter |work=Medizinsch-Diagnostische Institute |access-date=9 April 2014 |url-status=dead |archive-url=https://web.archive.org/web/20120425233448/http://www.mdi-labor.de/l_leistungsverzeichnis_detail.php?u_id=663&init=letter |archive-date=25 April 2012 }}</ref>  <br> 0.92<ref name=GGT />  || U/L <br> μkat/L
|-
| [[Gamma-glutamyl transpeptidase]] in female || < 37.8<ref name=GGT />  <br> 0.63<ref name=GGT />  || U/L <br> μkat/L
|}
{{clear}}

The severity of iron overload can be determined and monitored using a combination of tests. Measurement of serum ferritin indicates for total body iron overload.<ref name=Knovich />  [[Liver biopsy]] measures the iron concentration of liver. It provides the microscopic examination of the liver.<ref name=Fleming /> Measurement of serum [[hepcidin]] levels may be useful in diagnostic for iron overload.<ref name=Fleming /> [[MRI]] can detect the degree of magnetic disruption due to iron accumulation. MRI can measure iron accumulation within the heart, liver, and pituitary.<ref name=Knovich /> Accumulation of iron in a single organ does not provide proper representation of the total body iron overload.<ref name=Knovich />

==Treatment==
A person's [[hemoglobin]] is important in the physician's consideration of iron reduction therapy. A physician can provide therapeutic [[phlebotomy]] if the patient's hemoglobin level is sufficient to sustain blood removal. The physician can also recommend the patient to routinely donate blood. When a patient's hemoglobin is not sufficient for phlebotomy. Iron reduction will likely require the removal of iron using specific drugs (iron-[[chelation]]). The physician may use a combination of these therapies in some situations.<ref name="Bookmark ovrload 3">{{cite web|title=African Hemochromatosis|url=http://www.irondisorders.org/african-hemochromatosis|work=Iron Disorders Institute|access-date=17 April 2014}}</ref>

==Prognosis==
Individuals of sub-Saharan African descent with [[ferroportin]] Q248H are more likely to be diagnosed with African iron overload than individual without ferroportin mutation because individuals with ferroportin Q248H have elevated level of serum [[ferritin]] concentration.<ref name=McNamara />

==Recent research==
Distinctive [[phenotypes]] of individuals with SLC40A1 Q248H are minor, if any. Serum ferritin concentration is likely to be high in persons with Q248H (mostly heterozygotes) than in wild-type SLC40A1.<ref name="Barton 2003" /> In ''xenopus oocytes'' and [[HEK 293]] cells, the expression of wild type ferroportin was similar to the expression of ferroportin Q248H at the plasma membrane.<ref name="McGregor 2005">{{cite journal|last=McGregor|first=JA|author2=Shayeghi, M|author3=Vulpe, CD|author4=Anderson, GJ|author5=Pietrangelo, A|author6=Simpson, RJ|author7= McKie, AT|s2cid=28927952|title=Impaired iron transport activity of ferroportin 1 in hereditary iron overload.|journal=The Journal of Membrane Biology|date=Jul 2005|volume=206|issue=1|pages=3–7|pmid=16440176|doi=10.1007/s00232-005-0768-1|hdl=11380/303406|hdl-access=free}}</ref> In HEK 293 cells, Q248H was as predisposed to the activities of [[hepcidin]]-25 as wild type ferroportin.<ref name="Drakesmith 2005">{{cite journal|last=Drakesmith|first=H|author2=Schimanski, LM |author3=Ormerod, E |author4=Merryweather-Clarke, AT |author5=Viprakasit, V |author6=Edwards, JP |author7=Sweetland, E |author8=Bastin, JM |author9=Cowley, D |author10=Chinthammitr, Y |author11=Robson, KJ |author12=Townsend, AR|title=Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin.|journal=Blood|date=Aug 1, 2005|volume=106|issue=3|pages=1092–7|pmid=15831700|doi=10.1182/blood-2005-02-0561|doi-access=free}}</ref> Ferroportin Q248H also unregulated the expression of transferrin receptor-1 in the same way as wild type. This indicates the ferroportin Q248H is associated with mild clinical phenotype or causes iron disorder in the presence of other factors.<ref name="Drakesmith 2005" /><ref name="Schimanski 2005">{{cite journal|last=Schimanski|first=LM|author2=Drakesmith, H |author3=Merryweather-Clarke, AT |author4=Viprakasit, V |author5=Edwards, JP |author6=Sweetland, E |author7=Bastin, JM |author8=Cowley, D |author9=Chinthammitr, Y |author10=Robson, KJ |author11=Townsend, AR |title=In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.|journal=Blood|date=May 15, 2005|volume=105|issue=10|pages=4096–102|pmid=15692071|doi=10.1182/blood-2004-11-4502|doi-access=free}}</ref>

==References==
{{Reflist}}

==External links==
* {{RareDiseases|8495|Bantu siderosis}}
{{Medical resources
 | DiseasesDB      = 35029
 | ICD10           =
 | ICD9            =
 | ICDO            =
 | OMIM            = 601195
 | MedlinePlus     =
 | eMedicineSubj   =
 | eMedicineTopic  =
 | MeshID          = C537904
}}
{{Inborn errors of metal metabolism}}
{{Solute carrier disorders}}

[[Category:Inborn errors of metal metabolism]]
[[Category:Iron metabolism]]
[[Category:Red blood cell disorders]]
[[Category:Membrane transport protein disorders]]