Intrinsic factor: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Robot: Automated text replacement (-{{SIB}} + & -{{EH}} + & -{{EJ}} + & -{{Editor Help}} + & -{{Editor Join}} +))
 
imported>Ylok
m (added wiklink for intrinsic factor deficiency)
 
(One intermediate revision by one other user not shown)
Line 1: Line 1:
{{CMG}}
{{Infobox_gene}}


'''Intrinsic factor''' ('''IF'''), also known as '''gastric intrinsic factor''' ('''GIF'''), is a [[glycoprotein]] produced by the [[parietal cell]]s of the [[stomach]]. It is necessary for the absorption of [[vitamin B12]] later on in the ileum of the small intestine.<ref name = "Pocock_2006">{{cite book | vauthors = Pocock G, Richards C | title = Human Physiology: The Basis of Medicine | date = 2006 | publisher = Oxford University Press | isbn = 978-019-856878-0 | page = 230 | edition = 3rd }}</ref> In humans, the gastric intrinsic factor [[protein]] is encoded by the ''GIF'' [[gene]].<ref name = "Alpers_2013"/>{{rp|989}}


[[Haptocorrin]] (also known as HC, R protein, and transcobalamin I, TCN1) is another glycoprotein secreted by the [[salivary gland]]s which binds to  vitamin B<sub>12</sub>. Vitamin B<sub>12</sub> is acid sensitive and in binding to transcobalamin I it can safely pass through the acidic stomach to the duodenum.<ref name="Fedosov_2012"/> In the less acidic environment of the small intestine, pancreatic enzymes digest the glycoprotein carrier and vitamin B<sub>12</sub> can then bind to intrinsic factor.<ref name="Fedosov_2012"/> This new complex is then absorbed by the epithelial cells ([[enterocyte]]s) of the ileum.<ref name="Fedosov_2012">{{cite journal | vauthors = Fedosov SN | title = Physiological and molecular aspects of cobalamin transport | journal = Sub-Cellular Biochemistry | volume = 56 | issue = | pages = 347–67 | year = 2012 | pmid = 22116708 | doi = 10.1007/978-94-007-2199-9_18 | department = (review) }}</ref> Inside the cells, B<sub>12</sub> dissociates once again and binds to another protein, [[transcobalamin|transcobalamin II]] (TCN2); the new complex can then exit the epithelial cells to be carried to the liver.<ref name = "Alpers_2013">{{cite journal | vauthors = Alpers DH, Russell-Jones G | title = Gastric intrinsic factor: the gastric and small intestinal stages of cobalamin absorption. a personal journey | journal = Biochimie | volume = 95 | issue = 5 | pages = 989–94 | date = May 2013 | pmid = 23274574 | doi = 10.1016/j.biochi.2012.12.006 | department = (review) }}</ref>


==Overview==
== Site of secretion ==
{{protein
The intrinsic factor is secreted by the stomach, and so is present in the gastric juice as well as in the gastric mucous membrane.<ref name = "Sharma_2016">{{cite book | last = Sharma | first = K.N. | editor-last1 = Talwar | editor-first1 = G.P. | editor-last2 = Hasnain | editor-first2 = Seyed E. | editor-last3 = Sarin | editor-first3 = Shiv Kumar | name-list-format = vanc | title = Textbook Of Biochemistry, Biotechnology, Allied And Molecular Medicine | date = 2016 | publisher = PHI Learning Private Limited | isbn = 978-81-203-5125-7 | page = 632 | edition = 4th | chapter = Gastrointestinal System | chapter-url = https://books.google.com/books?id=mVuNCwAAQBAJ&pg=PA632&dq=gastric+intrinsic+factor+secreted++parietal+cells&hl=en&sa=X&redir_esc=y#v=onepage&q=gastric%20intrinsic%20factor%20secreted%20%20parietal%20cells&f=false | department = (secondary) }}</ref> The optimum pH for its action is approximately 7.<ref name = "Shum_1971">{{cite journal | vauthors = Shum HY, O'Neill BJ, Streeter AM | title = Effect of pH changes on the binding of vitamin B12 by intrinsic factor | journal = Journal of Clinical Pathology | volume = 24 | issue = 3 | pages = 239–43 | year = 1971 | pmid = 5103294 | pmc = 476962 | doi = 10.1136/jcp.24.3.239 }}</ref> Its concentration does not correlate with the amount of [[hydrochloric acid|HCl]] or [[pepsin]] in the gastric juice, e.g., intrinsic factor may be present even when pepsin is largely absent.<ref name="pmid13512593">{{cite journal | vauthors = Poliner IJ, Spiro HM, Pask BA, Trocchio N | title = The independent secretion of acid, pepsin, and intrinsic factor by the human stomach | journal = Gastroenterology | volume = 34 | issue = 2 | pages = 196–209 | year = 1958 | pmid = 13512593 | doi = 10.1016/S0016-5085(58)80102-X | department = (primary) }}</ref> The site of formation of the intrinsic factor varies in different species. In pigs it is obtained from the pylorus and beginning of the [[duodenum]];<ref name="pmid13193076">{{cite journal | vauthors = Heatley NG, Florey H, Turnbull A, Jennings MA, Watson GM, Wakisaka G, Witts LJ | title = Intrinsic factor in the pyloric and duodenal secretions of the pig | journal = Lancet | volume = 267 | issue = 6838 | pages = 578–80 | year = 1954 | pmid = 13193076 | doi = 10.1016/S0140-6736(54)90355-4 | department = (primary) }}</ref>  in human beings it is present in the [[Fundus (stomach)|fundus]] and body of the [[stomach]].<ref name="pmid8886952">{{cite journal | vauthors = Howard TA, Misra DN, Grove M, Becich MJ, Shao JS, Gordon M, Alpers DH | title = Human gastric intrinsic factor expression is not restricted to parietal cells | journal = Journal of Anatomy | volume = 189 | issue = Pt 2 | pages = 303–13 | year = 1996 | pmid = 8886952 | pmc = 1167747 | doi = | url = | department = (primary) }}</ref>
| Name = gastric intrinsic factor
| caption =  
| image =  
| width =  
| HGNCid = 4268
| Symbol = GIF
| AltSymbols =  
| EntrezGene = 2694
| OMIM = 609342
| RefSeq = NM_005142
| UniProt = P27352
| PDB =  
| ECnumber =  
| Chromosome = 11
| Arm = q
| Band = 13
| LocusSupplementaryData =  
}}
{{SI}}
'''Intrinsic factor''' is a [[glycoprotein]] produced by the [[parietal cell]]s of the [[stomach]]. It is necessary for the absorption of [[vitamin B12|vitamin B{{ssub|12}}]] later on in the terminal ileum.


Upon entry into the stomach, vitamin B{{ssub|12}} becomes bound to one of two B{{ssub|12}} binding proteins present in [[gastric juice]]. In the less acidic environment of the small intestine, these proteins dissociate from the vitamin, enabling it to bind to intrinsic factor and enter the [[Portal venous system|portal circulation]] through a receptor in the [[ileum|ileal]] [[mucosa]] specific for the B{{ssub|12}}-intrinsic factor complex.
The limited amount of normal human gastric intrinsic factor limits normal efficient absorption of B<sub>12</sub> to about 2&nbsp;μg per meal, a nominally adequate intake of B<sub>12</sub>.<ref>{{cite journal | vauthors = Watanabe F | title = Vitamin B12 sources and bioavailability | journal = Experimental Biology and Medicine | volume = 232 | issue = 10 | pages = 1266–74 | date = Nov 2007 | pmid = 17959839 | doi = 10.3181/0703-MR-67 | url = http://ebm.sagepub.com/content/232/10/1266 | department = (review) }}</ref>


==Clinical significance==
== Insufficiency ==
In [[pernicious anemia]], an [[autoimmune disease]], [[autoantibody|autoantibodies]] directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, [[malabsorption]] of vitamin B{{ssub|12}}, and subsequent [[megaloblastic anemia]]. [[Atrophic gastritis]] can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall. [[Exocrine pancreatic insufficiency|Pancreatic exocrine insufficiency]] can interfere with normal dissociation of vitamin B{{ssub|12}} from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.
In [[pernicious anemia]], which is usually an [[autoimmune disease]], [[autoantibody|autoantibodies]] directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, [[malabsorption]] of vitamin B<sub>12</sub>, and subsequent [[megaloblastic anemia]].<ref name="pmid25936607">{{cite journal | vauthors = Osborne D, Sobczyńska-Malefora A | title = Autoimmune mechanisms in pernicious anaemia & thyroid disease | journal = Autoimmunity Reviews | volume = 14 | issue = 9 | pages = 763–8 | year = 2015 | pmid = 25936607 | doi = 10.1016/j.autrev.2015.04.011 | department = (review) }}</ref> [[Atrophic gastritis]] can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall.<ref name="pmid23774773">{{cite journal | vauthors = Neumann WL, Coss E, Rugge M, Genta RM | title = Autoimmune atrophic gastritis--pathogenesis, pathology and management | journal = Nature Reviews. Gastroenterology & Hepatology | volume = 10 | issue = 9 | pages = 529–41 | year = 2013 | pmid = 23774773 | doi = 10.1038/nrgastro.2013.101 | department = (review) }}</ref> [[Exocrine pancreatic insufficiency|Pancreatic exocrine insufficiency]] can interfere with normal dissociation of vitamin B<sub>12</sub> from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.<ref name="pmid2235967">{{cite journal | vauthors = Guéant JL, Champigneulle B, Gaucher P, Nicolas JP | title = Malabsorption of vitamin B12 in pancreatic insufficiency of the adult and of the child | journal = Pancreas | volume = 5 | issue = 5 | pages = 559–67 | year = 1990 | pmid = 2235967 | doi = 10.1097/00006676-199009000-00011| url = http://journals.lww.com/pancreasjournal/pages/articleviewer.aspx?year=1990&issue=09000&article=00011&type=abstract | department = (review) }}</ref> Other risk factors contributing to pernicious anemia are anything that damages or removes a portion of the stomach's parietal cells, including [[bariatric surgery]], gastric tumors, gastric ulcers, and excessive consumption of alcohol.


[[Bariatric surgery]] is a known risk factor in the development of pernicious anemia. Other risk factors contributing to this condition are stomach tumors, gastric ulcers, and excessive consumption of alcohol.
Mutations in the GIF gene are responsible for a rare inheritable disease called [[intrinsic factor deficiency]] which results in malabsorption of vitamin B<sub>12</sub>.<ref name="pmid23178706">{{cite journal | vauthors = Kozyraki R, Cases O | title = Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders | journal = Biochimie | volume = 95 | issue = 5 | pages = 1002–7 | year = 2013 | pmid = 23178706 | doi = 10.1016/j.biochi.2012.11.004 | department = (review) }}</ref>


==Note==
== Treatment ==
Patients experiencing an insufficiency in their intrinsic factor levels cannot benefit from a low dose oral vitamin B-12 supplement, because it will not absorb through the wall of the small intestine. Historically, the disease was thought untreatable before the discovery that it could be managed with regular injections of vitamin B-12, thus bypassing the digestive tract. More recently, Swedish researchers discovered that sufficiently large doses of B-12 can also be absorbed [[sublingual]]ly, so injections are necessary only for those unable to take pills by sublingual administration.


==External links==
In most countries, [[intramuscular injection]]s of vitamin B<sub>12</sub> are used to treat  pernicious anemia.<ref name="Shipton_2015"/> Orally administered vitamin B<sub>12</sub> is absorbed without intrinsic factor, but at levels of less than one percent than if intrinsic factor is present.<ref>{{cite journal | vauthors = Alpers DH | title = What is new in vitamin B(12)? | journal = Current Opinion in Gastroenterology | volume = 21 | issue = 2 | pages = 183–6 | date = Mar 2005 | pmid = 15711210 | doi =  10.1097/01.mog.0000148331.96932.44| url = http://journals.lww.com/co-gastroenterology/Citation/2005/03000/What_is_new_in_vitamin_B12_.9.aspx | department = (review) }}</ref>  Despite the low amounts absorbed, oral vitamin B<sub>12</sub> therapy is effective at reducing symptoms of pernicious anemia.<ref name="pmid20088746">{{cite journal | vauthors = Andrès E, Fothergill H, Mecili M | title = Efficacy of oral cobalamin (vitamin B12) therapy | journal = Expert Opinion on Pharmacotherapy | volume = 11 | issue = 2 | pages = 249–56 | year = 2010 | pmid = 20088746 | doi = 10.1517/14656560903456053 | department = (review) }}</ref> Vitamin B<sub>12</sub> can also be given [[sublingual administration|sublingually]], but there is no evidence that this route of administration is superior to the oral route.<ref name="pmid14616423">{{cite journal | vauthors = Sharabi A, Cohen E, Sulkes J, Garty M | title = Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route | journal = British Journal of Clinical Pharmacology | volume = 56 | issue = 6 | pages = 635–8 | year = 2003 | pmid = 14616423 | pmc = 1884303 | doi = 10.1046/j.1365-2125.2003.01907.x | department = (primary) }}</ref> Despite evidence of efficacy of oral vitamin B<sub>12</sub> treatment, only Canada and Sweden routinely prescribe this route of administration.<ref name="Shipton_2015">{{cite journal | vauthors = Shipton MJ, Thachil J | title = Vitamin B12 deficiency - A 21st century perspective | journal = Clinical Medicine | volume = 15 | issue = 2 | pages = 145–50 | year = 2015 | pmid = 25824066 | doi = 10.7861/clinmedicine.15-2-145 | department = (review) }}</ref>
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Devalia V, Hamilton MS, Molloy AM | title = Guidelines for the diagnosis and treatment of cobalamin and folate disorders | journal = British Journal of Haematology | volume = 166 | issue = 4 | pages = 496–513 | date = Aug 2014 | pmid = 24942828 | doi = 10.1111/bjh.12959 | department = (review) }}
* {{cite journal | vauthors = Coati I, Fassan M, Farinati F, Graham DY, Genta RM, Rugge M | title = Autoimmune gastritis: Pathologist's viewpoint | journal = World Journal of Gastroenterology | volume = 21 | issue = 42 | pages = 12179–89 | date = Nov 2015 | pmid = 26576102 | doi = 10.3748/wjg.v21.i42.12179  | department = (review) | pmc=4641135}}
* {{cite journal | vauthors = Quadros EV | title = Advances in the understanding of cobalamin assimilation and metabolism | journal = British Journal of Haematology | volume = 148 | issue = 2 | pages = 195–204 | date = Jan 2010 | pmid = 19832808 | doi = 10.1111/j.1365-2141.2009.07937.x | department = (review) | pmc=2809139}}
* {{cite journal | vauthors = Christensen EI, Nielsen R, Birn H | title = From bowel to kidneys: the role of cubilin in physiology and disease | journal = Nephrology, Dialysis, Transplantation | volume = 28 | issue = 2 | pages = 274–81 | date = Feb 2013 | pmid = 23291372 | doi = 10.1093/ndt/gfs565 | department = (review) }}
 
{{refend}}
 
== External links ==
* {{MeshName|Intrinsic+factor}}
* {{MeshName|Intrinsic+factor}}
* {{MedlinePlus|002381}}
* {{MedlinePlusEncyclopedia|002381}}
* [http://www.vivo.colostate.edu/hbooks/pathphys/digestion/stomach/intrinsic_factor.html Overview at colostate.edu]
* [http://www.vivo.colostate.edu/hbooks/pathphys/digestion/stomach/intrinsic_factor.html Overview at colostate.edu]


{{Gastrointestinal physiology}}
{{Gastrointestinal physiology}}
{{Mucoproteins}}
{{Mucoproteins}}


[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
 
[[Category:Genes mutated in mice]]
[[de:Intrinsic-Faktor]]
[[Category:Stomach]]
[[he:פקטור פנימי]]
[[nl:Intrinsic factor]]
[[pl:Czynnik wewnętrzny]]
[[fi:Sisäinen tekijä]]
{{WH}}
{{WikiDoc Sources}}

Latest revision as of 20:39, 7 September 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Intrinsic factor (IF), also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the ileum of the small intestine.[1] In humans, the gastric intrinsic factor protein is encoded by the GIF gene.[2]:989

Haptocorrin (also known as HC, R protein, and transcobalamin I, TCN1) is another glycoprotein secreted by the salivary glands which binds to vitamin B12. Vitamin B12 is acid sensitive and in binding to transcobalamin I it can safely pass through the acidic stomach to the duodenum.[3] In the less acidic environment of the small intestine, pancreatic enzymes digest the glycoprotein carrier and vitamin B12 can then bind to intrinsic factor.[3] This new complex is then absorbed by the epithelial cells (enterocytes) of the ileum.[3] Inside the cells, B12 dissociates once again and binds to another protein, transcobalamin II (TCN2); the new complex can then exit the epithelial cells to be carried to the liver.[2]

Site of secretion

The intrinsic factor is secreted by the stomach, and so is present in the gastric juice as well as in the gastric mucous membrane.[4] The optimum pH for its action is approximately 7.[5] Its concentration does not correlate with the amount of HCl or pepsin in the gastric juice, e.g., intrinsic factor may be present even when pepsin is largely absent.[6] The site of formation of the intrinsic factor varies in different species. In pigs it is obtained from the pylorus and beginning of the duodenum;[7] in human beings it is present in the fundus and body of the stomach.[8]

The limited amount of normal human gastric intrinsic factor limits normal efficient absorption of B12 to about 2 μg per meal, a nominally adequate intake of B12.[9]

Insufficiency

In pernicious anemia, which is usually an autoimmune disease, autoantibodies directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, malabsorption of vitamin B12, and subsequent megaloblastic anemia.[10] Atrophic gastritis can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall.[11] Pancreatic exocrine insufficiency can interfere with normal dissociation of vitamin B12 from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.[12] Other risk factors contributing to pernicious anemia are anything that damages or removes a portion of the stomach's parietal cells, including bariatric surgery, gastric tumors, gastric ulcers, and excessive consumption of alcohol.

Mutations in the GIF gene are responsible for a rare inheritable disease called intrinsic factor deficiency which results in malabsorption of vitamin B12.[13]

Treatment

In most countries, intramuscular injections of vitamin B12 are used to treat pernicious anemia.[14] Orally administered vitamin B12 is absorbed without intrinsic factor, but at levels of less than one percent than if intrinsic factor is present.[15] Despite the low amounts absorbed, oral vitamin B12 therapy is effective at reducing symptoms of pernicious anemia.[16] Vitamin B12 can also be given sublingually, but there is no evidence that this route of administration is superior to the oral route.[17] Despite evidence of efficacy of oral vitamin B12 treatment, only Canada and Sweden routinely prescribe this route of administration.[14]

References

  1. ↑ Pocock G, Richards C (2006). Human Physiology: The Basis of Medicine (3rd ed.). Oxford University Press. p. 230. ISBN 978-019-856878-0.
  2. ↑ 2.0 2.1 Alpers DH, Russell-Jones G (May 2013). "Gastric intrinsic factor: the gastric and small intestinal stages of cobalamin absorption. a personal journey". (review). Biochimie. 95 (5): 989–94. doi:10.1016/j.biochi.2012.12.006. PMID 23274574.
  3. ↑ 3.0 3.1 3.2 Fedosov SN (2012). "Physiological and molecular aspects of cobalamin transport". (review). Sub-Cellular Biochemistry. 56: 347–67. doi:10.1007/978-94-007-2199-9_18. PMID 22116708.
  4. ↑ Sharma K (2016). "Gastrointestinal System". In Talwar G, Hasnain SE, Sarin SK. Textbook Of Biochemistry, Biotechnology, Allied And Molecular Medicine. (secondary) (4th ed.). PHI Learning Private Limited. p. 632. ISBN 978-81-203-5125-7.
  5. ↑ Shum HY, O'Neill BJ, Streeter AM (1971). "Effect of pH changes on the binding of vitamin B12 by intrinsic factor". Journal of Clinical Pathology. 24 (3): 239–43. doi:10.1136/jcp.24.3.239. PMC 476962. PMID 5103294.
  6. ↑ Poliner IJ, Spiro HM, Pask BA, Trocchio N (1958). "The independent secretion of acid, pepsin, and intrinsic factor by the human stomach". (primary). Gastroenterology. 34 (2): 196–209. doi:10.1016/S0016-5085(58)80102-X. PMID 13512593.
  7. ↑ Heatley NG, Florey H, Turnbull A, Jennings MA, Watson GM, Wakisaka G, Witts LJ (1954). "Intrinsic factor in the pyloric and duodenal secretions of the pig". (primary). Lancet. 267 (6838): 578–80. doi:10.1016/S0140-6736(54)90355-4. PMID 13193076.
  8. ↑ Howard TA, Misra DN, Grove M, Becich MJ, Shao JS, Gordon M, Alpers DH (1996). "Human gastric intrinsic factor expression is not restricted to parietal cells". (primary). Journal of Anatomy. 189 (Pt 2): 303–13. PMC 1167747. PMID 8886952.
  9. ↑ Watanabe F (Nov 2007). "Vitamin B12 sources and bioavailability". (review). Experimental Biology and Medicine. 232 (10): 1266–74. doi:10.3181/0703-MR-67. PMID 17959839.
  10. ↑ Osborne D, Sobczyńska-Malefora A (2015). "Autoimmune mechanisms in pernicious anaemia & thyroid disease". (review). Autoimmunity Reviews. 14 (9): 763–8. doi:10.1016/j.autrev.2015.04.011. PMID 25936607.
  11. ↑ Neumann WL, Coss E, Rugge M, Genta RM (2013). "Autoimmune atrophic gastritis--pathogenesis, pathology and management". (review). Nature Reviews. Gastroenterology & Hepatology. 10 (9): 529–41. doi:10.1038/nrgastro.2013.101. PMID 23774773.
  12. ↑ Guéant JL, Champigneulle B, Gaucher P, Nicolas JP (1990). "Malabsorption of vitamin B12 in pancreatic insufficiency of the adult and of the child". (review). Pancreas. 5 (5): 559–67. doi:10.1097/00006676-199009000-00011. PMID 2235967.
  13. ↑ Kozyraki R, Cases O (2013). "Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders". (review). Biochimie. 95 (5): 1002–7. doi:10.1016/j.biochi.2012.11.004. PMID 23178706.
  14. ↑ 14.0 14.1 Shipton MJ, Thachil J (2015). "Vitamin B12 deficiency - A 21st century perspective". (review). Clinical Medicine. 15 (2): 145–50. doi:10.7861/clinmedicine.15-2-145. PMID 25824066.
  15. ↑ Alpers DH (Mar 2005). "What is new in vitamin B(12)?". (review). Current Opinion in Gastroenterology. 21 (2): 183–6. doi:10.1097/01.mog.0000148331.96932.44. PMID 15711210.
  16. ↑ Andrès E, Fothergill H, Mecili M (2010). "Efficacy of oral cobalamin (vitamin B12) therapy". (review). Expert Opinion on Pharmacotherapy. 11 (2): 249–56. doi:10.1517/14656560903456053. PMID 20088746.
  17. ↑ Sharabi A, Cohen E, Sulkes J, Garty M (2003). "Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route". (primary). British Journal of Clinical Pharmacology. 56 (6): 635–8. doi:10.1046/j.1365-2125.2003.01907.x. PMC 1884303. PMID 14616423.

Further reading

External links

Retrieved from "https://www.wikidoc.org/index.php?title=Intrinsic_factor&oldid=1527694"