View source for Medicine:Vitamin B12 deficiency anemia

{{DISPLAYTITLE:Vitamin B<sub>12</sub> deficiency anemia}}
{{short description|Anemia caused by vitamin B12 deficiency}}
{{Infobox medical condition (new)
| name            = Vitamin B<sub>12</sub> deficiency anemia
| image           = Metaplastic atrophic gastritis - body - chromogranin A -- intermed mag.jpg
| caption         = [[Micrograph]] showing nodular enterochromaffin-like cell hyperplasia, as demonstrated with [[Biology:Chromogranin A|chromogranin A]] immunostaining, in the body of the [[Biology:Stomach|stomach]]. [[Biology:Parietal cell|Parietal cell]]s are not readily apparent. These changes are in keeping with autoimmune metaplastic atrophic gastritis, a [[Biology:Histology|histologic correlate]] of Vitamin B<sub>12</sub> deficiency anemia.  
| field           = [[Medicine:Hematology|Hematology]]
| synonyms        = Pernicious anemia, Biermer's anemia,<ref name=Andres2012/> Addison's anemia,<ref name=Wol2009/> Addison–Biermer anemia<ref>{{cite book|last1=Forbis|first1=Pat|title=Stedman's medical eponyms|date=2005|publisher=Lippincott Williams & Wilkins|location=Baltimore, Md.|isbn=9780781754439|page=6|edition=2nd|url=https://books.google.com/books?id=isqcnR6ryz0C&pg=PA6}}</ref>
| symptoms        = Feeling tired, shortness of breath, pale skin, numbness in the hands and feet, poor reflexes, confusion<ref name=NIH2011Sign/>
| complications   = 
| onset           = > 60 years old<ref name=Andres2012/>
| duration        = 
| types           = 
| causes          = Not enough [[Biology:Vitamin B12|vitamin B<sub>12</sub>]]<ref name=NIH2011What/>
| risks           = 
| diagnosis       = Blood tests, bone marrow tests<ref name=NIH2011Diag/>
| differential    = 
| prevention      = 
| treatment       = Vitamin B<sub>12</sub> pills or injections<ref name=NIH2011Tx/>
| medication      = 
| prognosis       = With treatment a normal life<ref name=NIH2011What/>
| frequency       = 1 per 1000 people<ref name=Andres2012/>
| deaths          = 
}}
<!-- Definition and symptoms -->
'''Vitamin B<sub>12</sub> deficiency anemia''', of which '''pernicious anemia''' ('''PA''') is a type,<ref>{{cite web|title = ICD-10 Version:2015|url = http://apps.who.int/classifications/icd10/browse/2015/en#/D51.0|website = apps.who.int|access-date = 2015-11-13|url-status = live|archive-url = https://web.archive.org/web/20151102042503/http://apps.who.int/classifications/icd10/browse/2015/en#/D51.0|archive-date = 2015-11-02}}</ref> is a disease in which not enough [[Biology:Red blood cell|red blood cell]]s are produced due to a deficiency of [[Biology:Vitamin B12|vitamin B<sub>12</sub>]].<ref name=NIH2011What>{{cite web|title=What Is Pernicious Anemia?|url=https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia|website=NHLBI|access-date=14 March 2016|date=April 1, 2011|url-status=live|archive-url=https://web.archive.org/web/20160314111724/https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia|archive-date=14 March 2016}}</ref> The most common initial symptom is [[Medicine:Fatigue|feeling tiredness and weakness]].<ref name=NIH2011Sign/> Other symptoms may include shortness of breath, pale skin, feeling like one may pass out (lightheadedness), chest pain, [[Medicine:Palpitations|rapid heartbeat]], numbness in the hands and feet, poor balance, a frequent [[Medicine:Hypotension|fall of blood pressure]], loss of appetite, a smooth red tongue, memory problems, poor reflexes, and in severe cases even depression and confusion.<ref name=NIH2011Sign>{{cite web|title=What Are the Signs and Symptoms of Pernicious Anemia?|url=https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/signs|website=NHLBI|access-date=14 March 2016|date=April 1, 2011|url-status=live|archive-url=https://web.archive.org/web/20160314112837/https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/signs|archive-date=14 March 2016}}</ref> Without treatment some of these problems may become permanent.<ref name=NIH2011What/>

<!-- Cause and diagnosis -->
Pernicious anemia refers to [[Medicine:Anemia|anemia]] that results from lack of vitamin B12.<ref name=NIH2011What/> Lack of intrinsic factor is most commonly due to an autoimmune attack on the cells that create it in the [[Biology:Stomach|stomach]].<ref name=NIH2011Cas/> It can also occur following the surgical removal of part of the stomach or from an inherited disorder.<ref name=NIH2011Cas/> Other causes of low vitamin B<sub>12</sub> include not enough dietary intake (which can be a risk in a vegan diet), celiac disease, or tapeworm infection.<ref name=NIH2011Cas>{{cite web|title=What Causes Pernicious Anemia?|url=https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/causes|website=NHLBI|access-date=14 March 2016|date=April 1, 2011|url-status=live|archive-url=https://web.archive.org/web/20160314115517/https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/causes|archive-date=14 March 2016}}</ref> When suspected, diagnosis is made by blood and, occasionally, bone marrow tests.<ref name=NIH2011Diag/> Blood tests may show fewer but larger red blood cells, low numbers of [[Biology:Reticulocyte|young red blood cells]], low levels of vitamin B<sub>12</sub>, and [[Biology:Antibodies|antibodies]] to intrinsic factor.<ref name=NIH2011Diag>{{cite web|title=How Is Pernicious Anemia Diagnosed?|url=https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/diagnosis|website=NHLBI|access-date=14 March 2016|date=April 1, 2011|url-status=live|archive-url=https://web.archive.org/web/20160314115225/https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/diagnosis|archive-date=14 March 2016}}</ref>

<!-- Prevention and treatment -->
Pernicious anemia can be treated with injections of vitamin B<sub>12</sub>.<ref name=NIH2011Tx/> If the symptoms are severe, injections are typically recommended initially.<ref name=NIH2011Tx/> For those who have trouble swallowing pills, a nasal spray is available.<ref name=NIH2011Tx>{{cite web|title=How Is Pernicious Anemia Treated?|url=https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/treatment|website=NHLBI|access-date=14 March 2016|date=April 1, 2011|url-status=live|archive-url=https://web.archive.org/web/20160314111520/https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/treatment|archive-date=14 March 2016}}</ref> Often, treatment is lifelong.<ref name=NIH2011Prog>{{cite web|title=Living With Pernicious Anemia|url=https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/livingwith|website=NHLBI|access-date=14 March 2016|date=April 1, 2011|url-status=live|archive-url=https://web.archive.org/web/20160314110059/https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia/livingwith|archive-date=14 March 2016}}</ref>

<!-- Epidemiology, prognosis, and history -->
Pernicious anemia due to autoimmune problems occurs in about one per 1000 people.<ref name=Andres2012/> Among those over the age of 60, about 2% have the condition.<ref name=Andres2012>{{cite journal |vauthors=Andres E, Serraj K | title = Optimal management of pernicious anemia. | journal = Journal of Blood Medicine | volume = 3 | pages = 97–103 | year = 2012 | pmid = 23028239 | pmc = 3441227 | doi = 10.2147/JBM.S25620 }}</ref> It more commonly affects people of northern European descent.<ref name=Wol2009>{{cite book|title=Professional guide to diseases.|date=2009|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia|isbn=9780781778992|page=[https://archive.org/details/isbn_9780781778992/page/502 502]|edition=9|url=https://archive.org/details/isbn_9780781778992|url-access=registration}}</ref> Women are more commonly affected than men.<ref>{{cite book|last1=Greer|first1=John P.|title=Wintrobe's clinical hematology.|date=2009|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia|isbn=9780781765077|page=1157|edition=12th|url=https://books.google.com/books?id=68enzUD7BVgC&pg=PA1157|url-status=live|archive-url=https://web.archive.org/web/20160314111810/https://books.google.ca/books?id=68enzUD7BVgC&pg=PA1157|archive-date=2016-03-14}}</ref> With proper treatment, most people live normal lives.<ref name=NIH2011What/> Due to a higher risk of [[Medicine:Stomach cancer|stomach cancer]], those with pernicious anemia should be checked regularly for this.<ref name=NIH2011Prog/> The first clear description was by Thomas Addison in 1849.<ref>{{cite book|last1=Wailoo|first1=Keith|title=Drawing blood technology and disease identity in twentieth-century America|date=1999|publisher=Johns Hopkins University Press|location=Baltimore, Md.|isbn=9780801870293|page=Chapter 4|edition=Johns Hopkins Paperbacks|chapter-url=https://books.google.com/books?id=1vYa5ipzJtoC&pg=PT50|chapter=The Corporate "Conquest" of Pernicious Anemia|url-status=live|archive-url=https://web.archive.org/web/20160314160726/https://books.google.ca/books?id=1vYa5ipzJtoC&pg=PT50|archive-date=2016-03-14}}</ref><ref>{{cite book|title=Dictionary of Medicine|date=2014|publisher=Routledge|isbn=9781135928414|page=404|url=https://books.google.com/books?id=xD3JAwAAQBAJ&pg=PA404|url-status=live|archive-url=https://web.archive.org/web/20160314112849/https://books.google.ca/books?id=xD3JAwAAQBAJ&pg=PA404|archive-date=2016-03-14}}</ref> The term "pernicious" means "deadly", and this term came into use because before the availability of treatment the disease was often fatal.<ref name=NIH2011What/><ref>{{cite book|last1=Tamparo|first1=Carol|title=Diseases of the Human Body|date=2016|publisher=F.A. Davis|isbn=9780803657915|page=295|url=https://books.google.com/books?id=eMOCCwAAQBAJ&q=Diseases%20of%20the%20Human%20Body&pg=PA295|url-status=live|archive-url=https://web.archive.org/web/20160317174529/https://books.google.ca/books?id=eMOCCwAAQBAJ&lpg=PA52&dq=Diseases%20of%20the%20Human%20Body&pg=PA295|archive-date=2016-03-17}}</ref>

==Signs and symptoms==
The progression of pernicious anemia come on slowly. It may be difficult to recognize the symptoms because may become used to not feeling well.<ref name=":0">{{Cite web|date=2020-05-13|title=Pernicious Anemia|url=https://www.healthline.com/health/pernicious-anemia|access-date=2021-10-12|website=Healthline|language=en}}</ref> untreated, it can lead to neurological complications, and in serious cases, death. Many of the signs and symptoms are due to anemia itself, when anemia is present.<ref>In 20% of cases of cobalamin deficiency, anemia is not observed.</ref> Symptoms may include:
[[File:Anemia.JPG|thumb|upright=1.3|A hand of a person with severe anemia (the hand on the image's left, wearing a ring) compared to one without (the hand to the right)]]
* [[Medicine:Fatigue|feeling tired, weak constantly]] (fatigue)<ref name="emedicine1">{{cite web | editor1 = Schick, P. |editor2=Conrad, Marcel E. |editor3=Besa, Emmanuel C. | work = Medscape | date = 2015-08-15 | title = Pernicious Anemia, Clinical Presentation | url = http://emedicine.medscape.com/article/204930-clinical#a0256 | access-date = 21 January 2013 | url-status = live | archive-url = https://web.archive.org/web/20121117034428/http://emedicine.medscape.com/article/204930-clinical#a0256 | archive-date = 17 November 2012 }}</ref><ref name="isbn0781765072">{{cite book|title=Wintrobe's Clinical Hematology|publisher=Wolters Kluwer/Lippincott Williams & Wilkins|year=2009|isbn=978-0781765077|editor1=Greer, J.P.|edition=12th|volume=1|location=Philadelphia, PA, USA|pages=779–809, esp. 782|chapter=Anemia: General Considerations (Chapter 26)|access-date=10 March 2016|editor2=Foerster, J.|editor3=Rodgers, G.M.|editor4=Paraskevas, F.|editor5=Glader, B.|editor6=Arber, D.A.|editor7=Means Jr., R.T.|chapter-url=https://books.google.com/books?isbn=0781765072|authors=Means, Robert T. Jr. & Glader, Bertil}}</ref><ref name="isbn0198569467">{{cite book | last=Ramani | first=James Carton, Richard Daly, Pramila | title=Clinical pathology | year=2007 | publisher=Oxford University Press | location=Oxford, ENG | isbn=978-0198569466 | url-access=registration | url=https://archive.org/details/clinicalpatholog0000cart }}</ref>
* [[Medicine:Dizziness|dizziness]], or feeling faint (lightheadedness)<ref name=WB6>{{Cite web|title=Vitamin B12 Deficiency: Causes, Symptoms, and Treatment|url=https://www.webmd.com/diet/vitamin-b12-deficiency-symptoms-causes|access-date=2021-09-21|website=WebMD|language=en}}</ref><ref name=UN8>{{Cite web|title=Harmful and Sneaky - Vitamin B12 deficiency {{!}} Unjury Protein|url=https://unjury.com/newsletters/harmful-and-sneaky-vitamin-b12-deficiency/|access-date=2021-09-21|website=unjury.com}}</ref>
* cold hands and feet
* upset stmoach and nausea
* a sore red tongue ([[Medicine:Glossitis|glossitis]]), also called ''cherry tongue''<ref name=WB6 />
* [[Medicine:Tachycardia|rapid heartbeat]] (fluttering, or Irregular heartbeat)
* a frequent fall of blood pressure (hypotension)
* a yellowish, pale skin ([[Medicine:Jaundice|jaundice]])<ref name=WB6 />
* breathlessness “the sighs”<ref name=WB6 />
* low-grade [[Medicine:Fever|fever]]s, shakiness and [[Medicine:Cold sensitivity|constantly feeling cold]]
* loss of appetite and weight loss<ref name="emedicine1" />
* [[Medicine:Diarrhea|diarrhea]] or [[Medicine:Constipation|constipation]]<ref name=WB6 />
* [[Medicine:Angular cheilitis|Angular cheilitis]] (inflammatory lesions at the mouth's corners)
* hair loss and weakness, early greying of the hair<ref name="isbn0781765072" />
* chest pain ([[Medicine:Angina|angina]])
In more severe or prolonged cases of pernicious anemia;<ref name=":0" /> it may lead to nerve damage, which may include:
* [[Unsolved:Paresthesia|Abnormal sensations]] including tingling or numbness to the fingers and toes (''pins and needles''), sense loss, difficulty in [[Biology:Proprioception|proprioception]],<ref name="pmid17043022">{{cite journal|vauthors=Hvas AM, Nexo E|date=November 2006|title=Diagnosis and treatment of vitamin B12 deficiency—an update.|journal=Haematologica|volume=91|issue=11|pages=1506–12|pmid=17043022}}</ref> and neuropathic pain (vitamin B<sub>12</sub> deficiency anemia its the only anemia that affects the nervous system and brain)
* decreased mental abilities, including personality changes, [[Medicine:Depression (mood)|depression]],<ref name="WB6" /> Irritability, confusion, stupor, cognitive impairment (including difficulty concentrating and sluggish responses, colloquially referred to as brain fog)
* changes in mobility; including unsteady walking ([[Medicine:Ataxia|ataxia]]),<ref name="isbn0781765072" /> poor balance and loss of sensation in the feet<ref name="pmid17043022" />
* blurred vision (disturbed)<ref name="WB6" />
* memory problems<ref name="WB6" />
* [[Medicine:Muscle weakness|muscle weakness]],<ref name="isbn0198569467" /> severe joint pain ([[Medicine:Arthralgia|arthralgia]])

The most common initial symptom is feeling tiredness and weakness (in general), although; anemia may  presents with a number of further common symptoms,<ref name="isbn0198569467" /><ref name="isbn0781750075">{{cite book|last=Turgeon|first=Mary L.|title=Clinical hematology : theory and procedures|year=2005|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0781750073|edition=4th}}</ref> including mouth ulcers, bleeding gum,<ref name="WB6" /> a look of exhaustion with pale and dehydrated or cracked lips and dark circles around the eyes, as well as brittle nails.<ref name="isbn0781765072" /> Because PA affects the nervous system, which causes neurological complications, symptoms may also include loss and changes in reflexes, mood swings, tinnitus, impaired urination,<ref name="emedicine1" /> unsteady gait,<ref name="isbn0781765072" /> fertility problems,<ref>{{Cite web|date=2017-10-20|title=Vitamin B12 or folate deficiency anaemia - Complications|url=https://www.nhs.uk/conditions/vitamin-b12-or-folate-deficiency-anaemia/complications/|access-date=2021-10-13|website=nhs.uk|language=en}}</ref> anxiety, psychosis and clumsiness. also, decreased taste or smell may occur.<ref name="UN8" /> Anemia may also lead to cardiac murmurs,<ref name="emedicine1" /><ref name="isbn0781765072" /> altered blood pressure (low or high). The deficiency also may present with thyroid disorders.<ref name="isbn0198569467" /> In severe cases, the anemia may cause evidence of congestive heart failure.<ref name="isbn0781750075" /> A complication of severe chronic PA is [[Medicine:Subacute combined degeneration of spinal cord|subacute combined degeneration of spinal cord]], which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response.<ref name="GerstenMedlinePlus">{{cite encyclopedia | authors = Gersten, Todd & VeriMed Healthcare Network | year = 2016 |editor1= Zieve, David |editor2=Ogilvie, Isla |display-editors=etal | url = https://www.nlm.nih.gov/medlineplus/ency/article/000569.htm | title = Pernicious anemia | encyclopedia = MedlinePlus Medical Encyclopedia | location = Washington, DC | publisher = nlm.nih.gov | access-date = 11 March 2016 | url-status = live | archive-url = https://web.archive.org/web/20160311145451/https://www.nlm.nih.gov/medlineplus/ency/article/000569.htm | archive-date = 11 March 2016 }}</ref> Other than anemia, hematological symptoms may include [[Medicine:Cytopenia|cytopenia]]s, intramedullary [[Medicine:Hemolysis|hemolysis]], and pseudothrombotic microangiopathy.<ref name="Andres2012" /> Pernicious anemia can contribute to a delay in physical growth in children, and may also be a cause for delay in puberty for adolescents.

==Causes==
Vitamin B<sub>12</sub> cannot be produced by the human body, and must be obtained from the diet. When foods containing B<sub>12</sub> are eaten, the vitamin is usually bound to protein and is released by proteases released by the pancreas in the small bowel. Following its release, most B<sub>12</sub> is absorbed by the body in the small bowel ([[Biology:Ileum|ileum]]) after binding to a protein known as [[Medicine:Intrinsic factor|intrinsic factor]]. Intrinsic factor is produced by [[Biology:Parietal cell|parietal cell]]s of the [[Biology:Stomach|gastric]] mucosa (stomach lining) and the intrinsic factor-B<sub>12</sub> complex is absorbed by cubilin receptors on the ileum epithelial cells.<ref name="pmid16716475">{{cite journal|last=Wickramasinghe|first=SN|title=Diagnosis of megaloblastic anaemias.|journal=Blood Reviews|date=November 2006|volume=20|issue=6|pages=299–318|pmid=16716475|doi=10.1016/j.blre.2006.02.002}}</ref><ref name="pmid11994745">{{cite journal |vauthors=Christensen EI, Birn H |title=Megalin and cubilin: multifunctional endocytic receptors |journal=Nat. Rev. Mol. Cell Biol. |volume=3 |issue=4 |pages=256–66 |date=April 2002 |pmid=11994745 |doi=10.1038/nrm778 |s2cid=21893726 }}</ref> PA is characterised by B<sub>12</sub> deficiency caused by the absence of intrinsic factor.<ref name="pmid21296191">{{cite journal |vauthors=Banka S, Ryan K, Thomson W, Newman WG | title = Pernicious anemia – genetic insights. | journal = Autoimmunity Reviews | volume = 10 | issue = 8 | pages = 455–9 | date = June 2011 | pmid = 21296191 | doi = 10.1016/j.autrev.2011.01.009 }}</ref>

PA may be considered as an end stage of immune [[Medicine:Gastritis|gastritis]], a disease characterised by stomach atrophy and the presence of [[Biology:Antibodies|antibodies]] to parietal cells and intrinsic factor.<ref name="pmid18029461">{{cite journal |vauthors=De Block CE, De Leeuw IH, Van Gaal LF | title = Autoimmune gastritis in type 1 diabetes: a clinically oriented review. | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 2 | pages = 363–71 | date = February 2008 | pmid = 18029461 | doi = 10.1210/jc.2007-2134 }}</ref> A specific form of chronic gastritis, [[Medicine:Atrophic gastritis|type A gastritis]] or atrophic body gastritis, is highly associated with PA. This autoimmune disorder is localised to the body of the stomach, where parietal cells are located.<ref name="pmid21296191"/> Antibodies to intrinsic factor and parietal cells cause the destruction of the oxyntic gastric mucosa, in which the parietal cells are located, leading to the subsequent loss of intrinsic factor synthesis. Without intrinsic factor, the ileum can no longer absorb the B<sub>12</sub>.<ref name="pmid19891010"/>

Although the exact role of ''Helicobacter pylori'' infection in PA remains controversial, evidence indicates ''H. pylori'' is involved in the pathogenesis of the disease. A long-standing ''H. pylori'' infection may cause gastric autoimmunity by a mechanism known as [[Biology:Molecular mimicry|molecular mimicry]]. Antibodies produced by the immune system can be cross-reactive and may bind to both ''H. pylori'' [[Biology:Antigen|antigen]]s and those found in the [[Biology:Gastric mucosa|gastric mucosa]]. The antibodies are produced by activated [[Biology:B cell|B cell]]s that recognise both pathogen and self-derived peptides. The autoantigens believed to cause the autoreactivity are the alpha and beta subunits of the H<sup>+</sup>/K<sup>+</sup>-ATPase.<ref name="pmid19891010"/><ref>{{cite journal |vauthors=Desai HG, Gupte PA | title = Helicobacter pylori link to pernicious anaemia. | journal = The Journal of the Association of Physicians of India | volume = 55 | pages = 857–9 | date = December 2007 | pmid = 18405134 }}</ref> In a study, B12 deficiency caused by Helicobacter pylori was positively correlated with CagA positivity and gastric inflammatory activity, rather than gastric atrophy.<ref>Ulasoglu C, Temiz HE, Sağlam ZA. The Relation of Cytotoxin-Associated Gene-A Seropositivity with Vitamin B12 Deficiency in Helicobacter pylori-Positive Patients. Biomed Res Int. 2019;2019:[tel:1450536 1450536]. Published 2019 Dec 9. doi:10.1155/2019/1450536</ref>

Less commonly, ''H. pylori'' and Zollinger-Ellison syndrome may also cause a form of nonautoimmune gastritis that can lead to pernicious anemia.<ref>{{cite journal |vauthors=Kaferle J, Strzoda CE | title = Evaluation of macrocytosis. | journal = American Family Physician | volume = 79 | issue = 3 | pages = 203–8 | date = Feb 1, 2009 | pmid = 19202968 }}</ref>

Impaired B<sub>12</sub> absorption can also occur following gastric removal ([[Medicine:Gastrectomy|gastrectomy]]) or gastric bypass surgery. In these surgeries, either the parts of the stomach that produce gastric secretions are removed or they are bypassed. This means intrinsic factor, as well as other factors required for B<sub>12</sub> absorption, are not available. However, B<sub>12</sub> deficiency after gastric surgery does not usually become a clinical issue. This is probably because the body stores many years' worth of B<sub>12</sub> in the liver and gastric surgery patients are adequately supplemented with the vitamin.<ref name="pmid19321896">{{cite journal |vauthors=von Drygalski A, Andris DA | title = Anemia after bariatric surgery: more than just iron deficiency. | journal = Nutrition in Clinical Practice | volume = 24 | issue = 2 | pages = 217–26 | date = Apr–May 2009 | pmid = 19321896 | doi = 10.1177/0884533609332174 | s2cid = 21448167 | url = https://semanticscholar.org/paper/6ecb1caeb13e33f9ab2580021d9b2ba5e9cd98df }}</ref><ref>{{cite journal |vauthors=John S, Hoegerl C | title = Nutritional deficiencies after gastric bypass surgery. | journal = The Journal of the American Osteopathic Association | volume = 109 | issue = 11 | pages = 601–4 | date = November 2009 | pmid = 19948694 | doi=10.7556/jaoa.2009.109.11.601| doi-broken-date = 31 May 2021 |url=https://jaoa.org/article.aspx?articleid=2093757}}
</ref>

Although no specific PA susceptibility genes have been identified, a genetic factor likely is involved in the disease. Pernicious anemia is often found in conjunction with other autoimmune disorders, suggesting common autoimmune susceptibility genes may be a causative factor.<ref name="pmid21296191"/> In spite of that, previous family studies and case reports focusing on PA have suggested that there is a tendency of genetic heritance of PA in particular, and close relatives of the PA patients seem to have higher incidence of PA and associated PA conditions.<ref name="Whittingham, S. 1969">{{cite journal | author1-last=Whittingham | author1-first=S. | author2-last=Ungar | author2-first=B. | author3-last=Mackay | author3-first=I. R. | author4-last=Mathews | author4-first=J. D. | year = 1969 | title = The Genetic Factor in Pernicious Anemia. A Family Study in Patients with Gastritis | pmid = 4180811|doi=10.1016/S0140-6736(69)91856-X| journal = The Lancet | volume = 1 | issue = 7602| pages = 951–954 }}</ref><ref>{{cite journal | author = McIntyre O. R., Sullivan L. W., Jeffries G. H., Silver R. H. | year = 1965 | title = Pernicious Anemia in Childhood | journal = The New England Journal of Medicine | volume = 272 | issue = 19| pages = 981–986 | doi=10.1056/nejm196505132721901| pmid = 14279251 }}</ref><ref name="Wangel, A. G. 1968">{{cite journal | author1-last=Wangel | author1-first=A. G. | author2-last=Callender | author2-first=S. T. | author3-last=Spray | author3-first=G. H. | author4-last=Wright | author4-first=R. | year = 1968 | title = A Family Study of Pernicious Anemia II. Intrinsic Factor Secretion, Vitamin B12 Absorption and Genetic Aspects of Gastric Autoimmunity | journal = British Journal of Haematology | volume = 14 | issue = 2| pages = 183–204 | doi=10.1111/j.1365-2141.1968.tb01486.x| pmid = 5635601 | s2cid = 6994133 }}</ref> Moreover, it was further indicated that the formation of antibodies to gastric cells was autosomal dominant gene determined, and the presence of antibodies to the gastric cells might not be necessarily related to the occurrence of atrophic gastritis related to PA.<ref name="Whittingham, S. 1969"/><ref name="Wangel, A. G. 1968"/>

==Pathophysiology==
Although the healthy body stores three to five years' worth of B<sub>12</sub> in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to B<sub>12</sub> depletion and the resulting anemia; pernicious anemia refers to one of the hematologic manifestations of [[Medicine:Atrophic gastritis|chronic auto-immune gastritis]], in which the immune system targets the parietal cells of the stomach or [[Medicine:Intrinsic factor|intrinsic factor]] itself, leading to decreased absorption of vitamin B<sub>12</sub>. Asymptomatic autoimmune gastritis likely precedes gastric atrophy by 10 to 20 years, followed by the onset of Iron deficiency anemia that occurs as early as 20 years before vitamin B<sub>12</sub> deficiency “''pernicious anemia.''”<ref>{{Cite journal|last=Langan|first=Robert C.|last2=Goodbred|first2=Andrew J.|date=2017-09-15|title=Vitamin B12 Deficiency: Recognition and Management|url=https://www.aafp.org/afp/2017/0915/p384.html|journal=American Family Physician|volume=96|issue=6|pages=384–389|issn=0002-838X}}</ref>

B<sub>12</sub> is required by enzymes for two reactions: the conversion of methylmalonyl CoA to succinyl CoA, and the conversion of [[Chemistry:Homocysteine|homocysteine]] to [[Chemistry:Methionine|methionine]]. In the latter reaction, the [[Chemistry:Methyl group|methyl group]] of 5-methyltetrahydrofolate is transferred to homocysteine to produce tetrahydrofolate and methionine. This reaction is catalyzed by the enzyme [[Biology:Methionine synthase|methionine synthase]] with B<sub>12</sub> as an essential cofactor. During B<sub>12</sub> deficiency, this reaction cannot proceed, which leads to the accumulation of 5-methyltetrahydrofolate. This accumulation depletes the other types of folate required for [[Chemistry:Purine|purine]] and thymidylate synthesis, which are required for the synthesis of DNA. Inhibition of [[Biology:DNA replication|DNA replication]] in maturing red blood cells results in the formation of large, fragile megaloblastic erythrocytes. The neurological aspects of the disease are thought to arise from the accumulation of methylmalonyl CoA due to the requirement of B<sub>12</sub> as a cofactor to the enzyme methylmalonyl CoA mutase.<ref name="pmid16716475" /><ref>{{cite journal |vauthors=Oh R, Brown DL | title = Vitamin B12 deficiency. | journal = American Family Physician | volume = 67 | issue = 5 | pages = 979–86 | date = Mar 1, 2003 | pmid = 12643357 }}</ref><ref>{{cite journal |vauthors=O'Leary F, Samman S | title = Vitamin B12 in health and disease. | journal = Nutrients | volume = 2 | issue = 3 | pages = 299–316 | date = March 2010 | pmid = 22254022 | pmc = 3257642 | doi = 10.3390/nu2030299 | doi-access = free }}</ref><ref>{{cite journal|last=Stover|first=PJ|title=Physiology of folate and vitamin B12 in health and disease.|journal=Nutrition Reviews|date=June 2004|volume=62|issue=6 Pt 2|pages=S3–12; discussion S13|pmid=15298442|doi=10.1111/j.1753-4887.2004.tb00070.x}}</ref>

==Diagnosis==
[[File:GASTRIC PARIETAL CELL ANTIBODIES.jpg|thumb|[[Biology:Immunofluorescence|Immunofluorescence]] staining pattern of gastric parietal cell antibodies on a stomach section]]
Pernicious anemia is thought mainly to be an autoimmune disorder that damages the parietal cells of the stomach - as it leads to decreased production of the [[Medicine:Intrinsic factor|intrinsic factor]] and impaired absorption of B-<sub><small>12</small></sub>; However, pernicious anemia may also have a [[Biology:Genetics|genetic component]] to it as well, potentially running in families.<ref name=":0" /> Pernicious anemia may be suspected when a patient's [[Medicine:Blood smear|blood smear]] shows large, brittle, immature, erythrocytes, known as megaloblasts. a diagnosis of pernicious anemia It requires a blood count test and a blood smear and these tests include:<ref name="NIH2011Diag" /><ref name="pmid16716475" />

* [[Medicine:Complete blood count|'''Complete blood count''']] '''and peripheral blood smear;''' PA first requires demonstration of megaloblastic anemia by conducting a full blood count and blood smear,<ref name=":0" /> which evaluates the [[Medicine:Mean corpuscular volume|mean corpuscular volume]] (MCV), as well the [[Medicine:Mean corpuscular hemoglobin concentration|mean corpuscular hemoglobin concentration]] (MCHC). PA is identified with a high MCV ([[Medicine:Macrocytic anemia|macrocytic anemia]]) and a normal MCHC (normochromic anemia).<ref>{{Cite book|author1=Pagana, Timothy James|url=https://archive.org/details/mosbysmanualofdi00paga_1|title=Mosby's manual of diagnostic and laboratory tests|author2=Pagana, Kathleen Deska|publisher=Mosby Elsevier|year=2006|isbn=978-0-323-03903-1}}{{Page needed|date=September 2010}}</ref> Ovalocytes are also typically seen on the blood smear, and a [[Medicine:Pathognomonic|pathognomonic]] feature of megaloblastic anemias (which include PA and others) is hypersegmented neutrophils.<ref name="isbn0781765072" />

* '''Serum vitamin B<sub>12</sub>'''; serum levels are used to detect its deficiency,<ref name=":0" /> but they do not distinguish its causes. vitamin B<sub>12</sub> levels can be falsely high or low and data for [[Sensitivity and specificity|sensitivity and specificity]] vary widely. Normal serum levels may be found in cases of deficiency where myeloproliferative disorders, liver disease, transcobalamin II deficiency, or [[Medicine:Small intestinal bacterial overgrowth|intestinal bacterial overgrowth]] are present.<ref>{{Cite journal|author=Devalia V|date=August 2006|title=Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay|journal=BMJ|volume=333|issue=7564|pages=385–6|doi=10.1136/bmj.333.7564.385|pmc=1550477|pmid=16916826}}</ref><ref name="pmid10386505">{{cite journal|last=Snow|first=CF|date=Jun 28, 1999|title=Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician|journal=Archives of Internal Medicine|volume=159|issue=12|pages=1289–98|doi=10.1001/archinte.159.12.1289|pmid=10386505}}</ref>
* '''Intrinsic factor and parietal cell antibodies'''; The blood is checked for antibodies against IF and parietal cells in the stomach. The presence of antibodies to gastric parietal cells and IF is common in PA. Parietal cell antibodies are found in other autoimmune disorders and also in up to 10% of healthy individuals. However, around 85% of PA patients have parietal cell antibodies, which means they are a sensitive marker for the disease. Intrinsic factor antibodies are much less sensitive than parietal cell antibodies, but they are much more specific. They are found in about half of PA patients and are very rarely found in other disorders. These antibody tests can distinguish between PA and food-B<sub>12</sub> malabsorption.<ref name="pmid10386505" /><ref name="10.1309/CVHKLE2R4W68K2NQ">{{cite journal|last=Moridani|first=Majid|author2=Shana Ben-Poorat|date=March 2006|title=Laboratory Investigation of Vitamin B12 Deficiency|journal=Laboratory Medicine|volume=37|issue=3|pages=166–74|doi=10.1309/cvhkle2r4w68k2nq}}</ref>

* '''[[Chemistry:Methylmalonic acid|Methylmalonic acid]] and/or [[Chemistry:Homocysteine|homocysteine]];'''  vitamin B<sub>12</sub> plays an important role in metabolic processes and cellular functions. Therefore, its deficiency leads to the accumulation of some metabolic products. Methylmalonic acid and/or homocysteine is one of the metabolic products that can be measured in the blood. as the increase in the levels of both helps differentiate between vitamin B<sub>12</sub> deficiency and folic acid deficiency, because homocysteine alone increases in the latter.<ref name="pmid10386505" /><ref name="10.1309/CVHKLE2R4W68K2NQ" />

Elevated [[Biology:Gastrin|gastrin]] levels can be found in around 80-90% of PA cases, but they may also be found in other forms of gastritis. Decreased pepsinogen I levels or a decreased pepsinogen I to pepsinogen II ratio may also be found, although these findings are less specific to PA and can be found in food-B<sub>12</sub> malabsorption and other forms of gastritis.<ref name="10.1309/CVHKLE2R4W68K2NQ" />

The diagnosis of atrophic gastritis type A should be confirmed by gastroscopy and stepwise biopsy.<ref>Miederer, S.E. (1977). ''The Histotopography of the Gastric Mucosa.'' Thieme, {{ISBN|3-13-508601-1}}</ref> About 90% of individuals with PA have antibodies for parietal cells; however, only 50% of all individuals in the general population with these antibodies have pernicious anemia.<ref name="pmid16585128">{{Cite journal|author=Butler CC |title=Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials |journal=Family Practice |volume=23 |issue=3 |pages=279–85 |date=June 2006 |pmid=16585128 |doi=10.1093/fampra/cml008|name-list-style=vanc|author2=Vidal-Alaball J|author3=Cannings-John R|display-authors=3|last4=McCaddon|first4=A|last5=Hood|first5=K|last6=Papaioannou|first6=A|last7=McDowell|first7=I|last8=Goringe|first8=A}}</ref>

Forms of vitamin B<sub>12</sub> deficiency other than PA must be considered in the [[Medicine:Differential diagnosis|differential diagnosis]] of megaloblastic anemia. For example, a B<sub>12</sub>-deficient state which causes megaloblastic anemia and which may be mistaken for classical PA may be caused by infection with the tapeworm ''Diphyllobothrium latum'', possibly due to the parasite's competition with host for vitamin B<sub>12</sub>.<ref>{{cite book|editor-last=Ramakrishnan|editor-first=Usha|title=Nutritional anemias|year=2000|publisher=CRC Press|location=Boca Raton|isbn=978-0849385698}}</ref>

The classic test for PA, the [[Chemistry:Schilling test|Schilling test]], is no longer widely used, as more efficient methods are available. This historic test consisted, in its first step, of taking an oral dose of radiolabelled vitamin B<sub>12</sub>, followed by quantitation of the vitamin in the patient's urine over a 24-hour period via measurement of the radioactivity. A second step of the test repeats the regimen and procedure of the first step, with the addition of oral intrinsic factor. A patient with PA presents lower than normal amounts of intrinsic factor; hence, addition of intrinsic factor in the second step results in an increase in vitamin B<sub>12</sub> absorption (over the baseline established in the first). The Schilling test distinguished PA from other forms of B<sub>12</sub> deficiency,<ref name="pmid16716475"/> specifically, from Imerslund-Grasbeck Syndrome (IGS), a vitamin B12-deficiency caused by mutations in cubilin the cobalamin receptor.<ref>{{cite journal | author = Andres E., Serra K. | year = 2012 | title = Optimal management of pernicious anemia | journal = Journal of Blood Medicine | volume = 3 | pages = 97–103 | doi = 10.2147/JBM.S25620 | pmid = 23028239 | pmc = 3441227 }}</ref>

==Treatment==
[[File:Hydroxocobalamin Injection.jpg|thumb|Hydroxocobalamin injection usp(1000 mcg/ml) is a clear red liquid solution of hydroxocobalamin which is available in a 30-ml brown glass multidose vial packaged in a paper box. Shown is 500 mcg B-12 (as 1/2 cc) drawn up in a 0.5-cc U-100 27 gauge x 1/2" insulin syringe, as prepared for subcutaneous injection.]]
The treatment of PA varies by country and area. Opinions vary over the efficacy of administration (parenteral/oral), the amount and time interval of the doses, or the forms of vitamin B<sub>12</sub> (e.g. cyanocobalamin/hydroxocobalamin). More comprehensive studies are still needed in order to validate the feasibility of a particular therapeutic method for PA in clinical practices. A permanent cure for PA is lacking, although repletion of B<sub>12</sub> should be expected to result in cessation of anemia-related symptoms, a halt in neurological deterioration, and in cases where neurological problems are not advanced, neurological recovery and a complete and permanent remission of all symptoms, so long as B<sub
>12</sub> is supplemented. Repletion of B<sub>12</sub> can be accomplished in a variety of ways.

===Intramuscular injections===
The standard treatment for PA has been intramuscular injections of cobalamin in the form of [[Biology:Cyanocobalamin|cyanocobalamin]] (CN-Cbl), [[Chemistry:Hydroxocobalamin|hydroxocobalamin]] (OH-Cbl) or [[Chemistry:Methylcobalamin|methylcobalamin]].<ref name=reference0>{{cite journal | last1 = Andrès | first1 = E. | last2 = Fothergill | first2 = H. | last3 = Mecili | first3 = M. | title = Efficacy of oral cobalamin (vitamin B12) therapy | journal = Expert Opinion on Pharmacotherapy | volume = 11 | issue = 2 | pages = 249–256 | year = 2010 | pmid = 20088746 | doi = 10.1517/14656560903456053 | s2cid = 37088496 }}</ref>

===Oral doses===
Treatment with high-dose vitamin B<sub>12</sub> 1000 mcg (1 mg) oral form also appears as effective as and cheaper than the parenteral form.<ref name=reference0/><ref name=reference1>{{cite journal | last1 = Andrès | first1 = E. | last2 = Dali-Youcef | first2 = N. | last3 = Vogel | first3 = T. | last4 = Serraj | first4 = K. | last5 = Zimmer | first5 = J. | title = Oral cobalamin (vitamin B12) treatment. An update | journal = International Journal of Laboratory Hematology | volume = 31 | issue = 1 | pages = 1–8 | year = 2009 | pmid =  19032377| doi = 10.1111/j.1751-553X.2008.01115.x | s2cid = 40586000 }}</ref><ref>{{cite journal|last1=Carmel|first1=R.|title=How I treat cobalamin (vitamin B12) deficiency|journal=Blood|date=7 July 2008|volume=112|issue=6|pages=2214–2221|doi=10.1182/blood-2008-03-040253|pmid=18606874|pmc=2532799}}</ref><ref>Vidal-Alaball, J et al. “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.” The Cochrane database of systematic reviews ,3 CD004655. 20 Jul. 2005, doi:10.1002/14651858.CD004655.pub2</ref>

==Prognosis==
A person with well-treated PA can live a healthy life. Failure to diagnose and treat in time, however, may result in permanent neurological damage, excessive fatigue, depression, memory loss, and other complications. In severe cases, the neurological complications of pernicious anemia can lead to death - hence the name, "pernicious", meaning deadly.
 
An association has been observed between pernicious anemia and certain types of gastric cancer, but a causal link has not been established.<ref name="pmid19891010">{{Cite journal |vauthors=Lahner E, Annibale B |title=Pernicious anemia: New insights from a gastroenterological point of view |journal=World J. Gastroenterol. |volume=15 |issue=41 |pages=5121–8 |date=November 2009 |pmid=19891010 |pmc=2773890 |doi=10.3748/wjg.15.5121 }}</ref>

== Epidemiology ==
PA is estimated to affect 0.1% of the general population and 1.9% of those over 60, accounting for 20–50% of B<sub>12</sub> deficiency in adults.<ref name=Andres2012/> A review of literature shows that the prevalence of PA is higher in Northern Europe, especially in Scandinavian countries, and among people of African descent, and that increased awareness of the disease and better diagnostic tools might play a role in apparently higher rates of incidence.<ref>{{cite journal | author = Stabler S. P., Allen R. H. | year = 2004 | title = Vitamin B12 deficiency as a worldwide problem | journal = Annual Review of Nutrition | volume = 24 | issue = 1| pages = 299–326 | doi=10.1146/annurev.nutr.24.012003.132440 | pmid=15189123}}</ref>

==History==
The symptoms are first described in 1822 by Dr James Scarth Combe in the ''Transactions of the Medico-Chirurgical Society of Edinburgh'', under the title of ''History of a Case of Anaemia''.<ref>{{cite web|url=http://www.leithhistory.co.uk/2006/05/12/james-scarth-combe/|title=History of Leith, Edinburgh|work=leithhistory.co.uk|access-date=11 March 2016}}</ref>

However, this was not investigated in more depth until 1849, by British physician Thomas Addison, from which it acquired the common name of Addison's anemia. In 1871, German physician Michael Anton Biermer (1827–1892) noticed the particular characteristic of the anemia in one of his patients; he later coined the term "progressive pernicious anemia".<ref>{{cite web | author = Enersen, Ole Daniel | year = 2016 | url = http://www.whonamedit.com/doctor.cfm/81.html | title = Whonamedit Dictionary of Medical Eponyms | work = whonamedit.com | access-date = 11 March 2016 | url-status = live | archive-url = https://web.archive.org/web/20160303193457/http://www.whonamedit.com/doctor.cfm/81.html | archive-date = 3 March 2016 }}{{better source|date=March 2016}}</ref>{{better source|date=March 2016}} In 1907, Richard Clarke Cabot reported on a series of 1200 patients with PA; their average survival was between one and three years.<ref>{{Cite journal|last=Bunn|first=H. Franklin|date=2014-02-20|editor-last=Longo|editor-first=Dan L.|title=Vitamin B 12 and Pernicious Anemia — The Dawn of Molecular Medicine|url=http://www.nejm.org/doi/10.1056/NEJMcibr1315544|journal=New England Journal of Medicine|language=en|volume=370|issue=8|pages=773–776|doi=10.1056/NEJMcibr1315544|pmid=24552327|issn=0028-4793}}</ref> William Bosworth Castle performed an experiment whereby he ingested raw hamburger meat and regurgitated it after an hour, and subsequently fed it to a group of 10 patients.<ref>William B. Castle 1897–1990 A Biographical Memoir by James H. Jandl Copyright 1995 National Academies Press Washington D.C.{{full citation needed|date=March 2016}}</ref>{{full citation needed|date=March 2016}} Untreated raw hamburger meat was fed to the control group. The former group showed a disease response, whereas the latter group did not. This was not a sustainable practice, but it demonstrated the existence of an 'intrinsic factor' from gastric juice.

Pernicious anemia was a fatal disease before about the year 1920, when [[Biography:George Whipple|George Whipple]] suggested raw [[Biology:Liver|liver]] as a treatment.{{citation needed|date=March 2016}} The first workable treatment for pernicious anemia began when Whipple made a discovery in the course of experiments in which he bled dogs to make them anemic, then fed them various foods to see which would make them recover most rapidly (he was looking for treatments for anemia from bleeding, not pernicious anemia). Whipple discovered ingesting large amounts of liver seemed to cure anemia from blood loss, and tried liver ingestion as a treatment for pernicious anemia, reporting improvement there, also, in a paper in 1920.{{citation needed|date=March 2016}} George Minot and [[Biography:William P. Murphy|William Murphy]] then set about to partly isolate the curative property in liver, and in 1926 showed it was contained in raw liver juice (in the process also showing it was the iron in liver tissue, not the soluble factor in liver juice, which cured the anemia from bleeding in dogs); thus, the discovery of the liver juice factor as a treatment for pernicious anemia had been by coincidence.{{citation needed|date=March 2016}} Frieda Robscheit-Robbins worked closely with Whipple, co-authoring 21 papers from 1925 to 1930.{{citation needed|date=March 2016}} For the discovery of the cure of a previously fatal disease of unknown cause, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Medicine.<ref>{{Cite web|title=The Nobel Prize in Physiology or Medicine 1934|url=https://www.nobelprize.org/prizes/medicine/1934/summary/|url-status=live|access-date=2021-06-09|website=NobelPrize.org|language=en-US}}</ref>

After Minot and Murphy's verification of Whipple's results in 1926, pernicious anemia victims ate or drank at least one-half pound of raw liver, or drank raw liver juice, every day.{{Citation needed|date=December 2012}} This continued for several years, until a concentrate of liver juice became available. In 1928, chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural food (liver).{{Citation needed|date=December 2012}} The extract could even be injected into muscle, which meant patients no longer needed to eat large amounts of liver or juice. This also reduced the cost of treatment considerably.{{Citation needed|date=December 2012}}

The active ingredient in liver remained unknown until 1948, when it was isolated by two chemists, Karl A. Folkers of the United States and [[Biography:Alexander R. Todd|Alexander R. Todd]] of Great Britain.{{Citation needed|date=December 2012}} The substance was a cobalamin, which the discoverers named [[Biology:Vitamin B12|vitamin B<sub>12</sub>]]. The new vitamin in liver juice was eventually completely purified and characterized in the 1950s, and other methods of producing it from bacteria were developed.{{Citation needed|date=December 2012}} It could be injected into muscle with even less irritation, making it possible to treat PA with even more ease.{{Citation needed|date=December 2012}} Pernicious anemia was eventually treated with either injections or large oral doses of B<sub>12</sub>, typically between 1 and 4&nbsp;mg daily.{{Citation needed|date=December 2012}}

One writer has hypothesized that Mary Todd Lincoln, the wife of American President Abraham Lincoln, had pernicious anemia for decades and died from it.<ref>John G. Sotos, ''The Mary Lincoln Mind-Body Sourcebook: Including a Unifying Diagnosis to Explain Her Public Decay, Manifest Insanity, and Slow Death'' (Mt. Vernon, VA: Mt. Vernon Book Systems, 2016) {{ISBN|978-0-9818193-8-9}}</ref><ref>John G. Sotos, ''What an Afflication'' -- Mary Todd Lincoln's Fatal Pernicious Anemia. Perspectives in Biology and Medicine. 2015; 58: 419-443.</ref>

==Research==

===SNAC complex===
Although oral megadoses and intramuscular injections are the most common methods of treatment currently available, several novel methods are being tested, with high promise for future incorporation into mainstream treatment methods. As injections are unfavourable vehicles for drug delivery, current research involves improving the passive diffusion across the ileum upon oral ingestion of cobalamin derivatives. Researchers have recently taken advantage of the novel compound sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), which greatly enhances both bioavailability and metabolic stability.<ref>{{cite journal | last1 = Castelli | first1 = M. C. | last2 = Wong | first2 = D. F. | last3 = Friedman | first3 = K. | last4 = Riley | first4 = M. G. I. | title = Pharmacokinetics of Oral Cyanocobalamin Formulated with Sodium N-\8-(2-hydroxybenzoyl)amino]caprylate (SNAC): An Open-Label, Randomized, Single-Dose, Parallel-Group Study in Healthy Male Subjects | journal = Clinical Therapeutics | volume = 33 | issue = 7 | pages = 934–945 | year = 2011 | pmid = 21722960 | doi = 10.1016/j.clinthera.2011.05.088 }}</ref> SNAC is able to form a noncovalent complex with cobalamin while preserving its chemical integrity.{{citation needed|date=March 2016}} This complex is much more lipophilic than the water-soluble vitamin B<sub>12</sub>, so is able to pass through cellular membranes with greater ease.

===Recombinant intrinsic factor===
Another method for increasing absorption through the ileum is to ingest a Cbl complex to which IF is already bound. The lack of intrinsic factor produced by the patient's body can be supplemented by using synthetic human IF produced from pea plant [[Biology:Recombinant DNA|recombinants]].<ref>{{cite journal | last1 = Fedosov | first1 = S. N. | last2 = Laursen | first2 = N. B. | last3 = Nexo | first3 = E. | last4 = Moestrup | first4 = S. K. | last5 = Petersen | first5 = T. E. | last6 = Jensen | first6 = E. O. | last7 = Berglund | first7 = L. | title = Human intrinsic factor expressed in the plant Arabidopsis thaliana | journal = European Journal of Biochemistry | volume = 270 | issue = 16 | pages = 3362–3367 | year = 2003 | pmid = 12899693 | doi = 10.1046/j.1432-1033.2003.03716.x | url = https://pure.au.dk/ws/files/18925399/2003__IF__plants__EJBioch.pdf }}</ref> However, in cases where IF-[[Biology:Antibody|antibodies]] are the reason for malabsorption across the ileum, this treatment would be ineffective.{{citation needed|date=April 2020}}

===Sublingual delivery===
[[Medicine:Sublingual administration|Sublingual]] treatments have also been postulated to be more effective than oral treatments alone. A 2003 study<ref>{{cite journal | last1 = Sharabi | first1 = A. | last2 = Cohen | first2 = E. | last3 = Sulkes | first3 = J. | last4 = Garty | first4 = 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 = 635–638 | year = 2003 | pmid = 14616423 | pmc = 1884303 | doi = 10.1046/j.1365-2125.2003.01907.x }}</ref> found, while this method is effective, a dose of 500 μg of cyanocobalamin given either orally or sublingually, is equally efficacious in restoring normal physiological concentrations of cobalamin.

==References==
{{reflist|colwidth=32em}}

== External links ==
* {{Curlie|Health/Conditions_and_Diseases/Blood_Disorders/Anemia/Pernicious/}}

{{Medical resources
|   DiseasesDB     = 9870
|   ICD10          = {{ICD10|D|51|0|d|50}}
|   ICD9           = {{ICD9|281.0}}
|   ICDO           =
|   OMIM           =
|   MedlinePlus    = 000569
|   eMedicineSubj  = med
|   eMedicineTopic = 1799
|   MeshID         = D000752
}}

{{Diseases of RBCs}}
{{Hypersensitivity and autoimmune diseases}}

{{DEFAULTSORT:Pernicious Anemia}}
[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Vitamin B12 deficiency anemia|1}}