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| '''For patient information click [[Vitamin B12 deficiency (patient information)|here]]''' | | '''For patient information click [[Vitamin B12 deficiency (patient information)|here]]''' |
| {{Infobox_Disease | | | {{Vitamin B12 deficiency}} |
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| Image = |
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| Caption = |
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| DiseasesDB = 13905 |
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| ICD10 = {{ICD10|E|53|8|e|50}} |
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| ICD9 = {{ICD9|266.2}} |
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| ICDO = |
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| OMIM = |
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| MedlinePlus = 000574 |
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| MeshID = D014806 |
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| {{Search infobox}}
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| {{CMG}} | | {{CMG}} |
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| {{Editor Help}} | | {{SK}} B12 deficiency |
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| ==Overview== | | ==[[Vitamin B12 deficiency overview|Overview]]== |
| '''B12 deficiency''' can potentially cause severe and irreversible damage, especially to the brain and nervous system.
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| The daily cobalamin (vitamin B12) requirement is 1-2 mcg. An intake of 5-20 mcg/day is usual in Western diet. The total body can store 2-5 mg. 60% of vitamin B12 is efficiently absorbed via the ileum when it is bound to intrinsic factor (IF).
| | ==[[Vitamin B12 deficiency historical perspective|Historical Perspective]]== |
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| The first deficiency symptom that was discovered was anemia characterized by enlarged blood corpuscles, so-called [[megaloblastic anemia]].
| | ==[[Vitamin B12 deficiency classification|Classification]]== |
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| The anemia is thought to be due to problems in DNA synthesis, specifically in the synthesis of [[thymine]], which is dependent on products of the [[5-methyltetrahydrofolate-homocysteine methyltransferase#reaction|MTR reaction]]. Other cell lines such as [[white blood cell]]s and [[platelet]]s are often also low. [[Bone marrow]] examination may show megaloblastic [[hemopoiesis]]. The anemia is easy to cure with vitamin B12.
| | ==[[Vitamin B12 deficiency pathophysiology|Pathophysiology]]== |
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| Far more serious is the damage to the nervous system that may occur due to deficiency.
| | ==[[Vitamin B12 deficiency causes|Causes]]== |
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| ==Presentation== | | ==[[Vitamin B12 deficiency differential diagnosis|Differentiating Vitamin B12 deficiency from other Diseases]]== |
| Early and even fairly pronounced deficiency does not always cause distinct or specific symptoms. Common early symptoms are tiredness or a decreased mental work capacity, decreased concentration and decreased memory, irritability and depression.
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| Sleep disturbances may occur, because B12 may be involved in the regulation of the sleep wake cycle by the pineal gland (through melatonin)<ref name="pmid8981490">{{cite journal |author=Hashimoto S, Kohsaka M, Morita N, Fukuda N, Honma S, Honma K |title=Vitamin B12 enhances the phase-response of circadian melatonin rhythm to a single bright light exposure in humans |journal=Neurosci. Lett. |volume=220 |issue=2 |pages=129-32 |year=1996 |pmid=8981490 |doi=}}</ref>.
| | ==[[Vitamin B12 deficiency epidemiology and demographics|Epidemiology and Demographics]]== |
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| Neurological signs of B{{ssub|12}} deficiency, which can occur without anemia, include sensory disturbances due to damage to peripheral nerves caused by [[demyelination]] and irreversible nerve cell death. Symptoms include [[numbness]], tingling of the extremities, disturbed coordination and, if not treated in time, an [[ataxic gait]], a syndrome known as [[subacute combined degeneration of spinal cord]].
| | ==[[Vitamin B12 deficiency risk factors|Risk Factors]]== |
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| B12 deficiency can also cause symptoms of mania and psychosis.<ref name="ijnwvitaminb12">{{cite journal | author=Sethi NK, Robilotti E, Sadan Y | title=Neurological Manifestations Of Vitamin B-12 Deficiency | journal=The Internet Journal of Nutrition and Wellness | volume=2 | issue=1 | year=2005 | doi=}}</ref><ref name="imajvitaminb12">{{cite journal | author=Masalha R, Chudakov B, Muhamad M, Rudoy I, Volkov I, Wirguin I | title=Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency | journal=Israeli Medical Association Journal | volume=3 | year=2001 | pages=701-703 | doi=}}</ref>
| | ==[[Vitamin B12 deficiency screening|Screening]]== |
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| Recent studies have devalued a possible connection between B12 deficiency and Alzheimer's dementia, and such a correlation is unlikely as of June 2007.<ref name="pmid16917153">{{cite journal |author=Morris MC, Evans DA, Schneider JA, Tangney CC, Bienias JL, Aggarwal NT |title=Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease |journal=J. Alzheimers Dis. |volume=9 |issue=4 |pages=435-43 |year=2006 |pmid=16917153 |doi=}}</ref>
| | ==[[Vitamin B12 deficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| Studies showing a relationship between [[clinical depression]] levels and deficient B{{ssub|12}} blood levels in elderly people are documented in the clinical literature.<ref>{{cite journal | author= Brenda W. J. H. Penninx ''et al''| title= Vitamin B{{ssub|12}} Deficiency and Depression in Physically Disabled Older Women: Epidemiologic Evidence From the Women’s Health and Aging Study | journal= Am. J. Psychiatry| year= 2000| volume= 157| pages= 715-721| id= PMID 10784463}}</ref> and 2002 <ref>{{cite journal | author= Henning Tiemeier ''et al''| title= Vitamin B12, Folate, and Homocysteine in Depression: The Rotterdam Study| journal= Am. J. Psychiatry| year= 2002| volume= 159| pages= 2099-2101| id= PMID 12450964}}</ref>
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| [[Bipolar disorder]] appears to genetically co-segregate with the hereditary B12-deficiency disorder [[pernicious anemia]] <ref>{{cite journal | author=Reading CM. | title= X-linked dominant manic-depressive illness: Linkage with Xg blood-group, red-green color-blindness and vitamin-B12 deficiency. | journal= Orthomolecular Psychiatry | year= 1979 | volume= 8 | pages= 68-77| id= }}</ref><ref>{{cite journal | author=Reading CM. | title= Latent pernicious anemia: A preliminary report. | journal= Medical Journal of Australia | year= 1975 | volume= 40 | pages= 91-4 | id= }}</ref>.
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| ==Causes==
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| * Inadequate dietary intake of vitamin B<sub>12</sub>. As the vitamin B<sub>12</sub> occurs naturally only in animal products (eggs, meat, milk) a [[vegan]] diet can produce a deficiency unless one uses supplements or eats enriched food.<ref>[http://www.pernicious-anaemia-society.org/whatispa.html Pernicious Anaemia Society - What is Pernicious Anaemia?], retrieved July 30, 2007.</ref>
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| * Selective impaired absorption of vitamin B<sub>12</sub> due to [[intrinsic factor]] deficiency. This may depend on loss of [[stomach|gastric]] [[parietal cells]] in chronic [[atrophic gastritis]] (in which case, the resulting [[megaloblastic anaemia]] takes the name of "[[pernicious anaemia]]"), or on wide surgical resection of stomach (such as in [[bariatric surgery]]), or on rare hereditary causes of impaired synthesis of intrinsic factor. It takes years to develop deficiency after dietary absorption stops.
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| * Impaired absorption of vitamin B<sub>12</sub> in the setting of a more generalised [[malabsorption]] or maldigestion syndrome. This includes any form of structural damage or wide surgical resection of the terminal [[ileum]] (the principal site of vitamin B<sub>12</sub> absorption), forms of [[achlorhydria]] (including that artificially induced by drugs such as [[proton pump inhibitors]]), as well as [[bacterial overgrowth]] (such as in [[blind loop syndrome]]).
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| * Chronic intestinal infestation by the [[fish tapeworm]] ''[[Diphyllobothrium]]'', that competes for vitamin B<sub>12</sub>, seizing it for its own use and therefore leaving insufficient amount for the host organism. This is mostly confined to Scandinavia and parts of Eastern Europe (for example, in preparers of gefilte fish, who would acquire the tapeworm by sneaking bits of uncooked fish while making the Eastern European delicacy, now eaten by Jews at Pesach).
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| * The [[diabetes]] medication, [[metformin]] may interfere with B12 dietary absorption.<ref>{{cite journal | author = Ting R, Szeto C, Chan M, Ma K, Chow K | title = Risk factors of vitamin B(12) deficiency in patients receiving metformin | journal = Arch Intern Med | volume = 166 | issue = 18 | pages = 1975-9 | year = 2006 | id = PMID 17030830}}</ref>.
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| * Hereditary causes such as severe [[MTHFR]] deficiency, [[homocystinuria]], and [[transcobalamin]] deficiency.
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| ==Incidence/prevalence==
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| Recent research indicates that B12 deficiency is far more widespread than formerly believed. A large study in the US found that 39 percent had low values.<ref>{{cite web |url=http://www.ars.usda.gov/is/pr/2000/000802.htm |title=B12 Deficiency May Be More Widespread Than Thought / August 2, 2000 / News from the USDA Agricultural Research Service |accessdate=2007-07-01 |format= |work=}}</ref> This study at Tufts University used the B12 concentration 258 pmol/l (= 350 pg/liter) as a criterion of "low level". However, recent research has found that B12 deficiency may occur at a much higher B12 concentration (500-600 pg/l). On this basis Mitsuyama and Kogoh <ref>{{cite journal | author=Mitsuyama Y, Kogoh H. | journal=Japanese Journal of Psychiatry and Neurology| year=1988 | title=Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-
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| B12 treatment. | pages=65-71| volume=42 | issue=1 }}</ref>. proposed 550 pg/l, and Tiggelen et al <ref>{{cite journal | author=VanTiggelen CJM, Peperkamp JPC, TerToolen JFW. | journal=Journal of Orthomolecular Psychiatry | year=1983 | title=Vitamin-B12 levels of cerebrospinal fluid in patients with organic mental disorder. | pages=305-11 | volume= | issue=12 }}</ref> proposed 600 pg/l. Against this background, there are reasons to believe that B12 deficiency is present in a far greater proportion of the population than 39% as reported by the Tufts University.
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| In the developing world the deficiency is very widespread, with significant levels of deficiency in Africa, India, and South and Central America. This is due to low intakes of animal products, particular among the poor. Increased intake of animal products or supplements have beens suggested.<ref>{{cite journal | author = Sally P. Stabler and Robert H. Allen(2004)| title = Vitamin B12 Deficiency as a Worldwide Problem. ''Annual Review of Nutrition'' 24: 299-326}}</ref>
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| B12 deficiency is even more common in the elderly <ref>{{cite journal | author = H.W. Baik, R.M. Russell (1999)| title = Vitamin b12 deficiency in the elderly. Annual Review of Nutrition 19: 357-377}}</ref>. This is because B{{ssub|12}} absorption decreases greatly in the presence of atrophic gastritis, which is common in elderly.
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| B12 deficiency is common among vegetarians. In vegans the risk is very high because none of their natural food sources contain B12. One American study found blood levels below normal in 92 % of vegans, 64 % of lactovegetarians, 47 % of lacto-ovovegetarians <ref>{{cite journal | author = Dong A and Scott SC (1982)| title = Ann Nutr Metab 26(4):209-16 }}</ref>. The study applied the old normal values, so in reality a considerably greater proportion may have been deficient.
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| ==Diagnosis== | | ==Diagnosis== |
| Deficiency is defined as serum B{{ssub|12}}levels less than 200 pg/mL (95-100% specific). Borderline B{{ssub|12}} levels are defined between 200 and 400 pg/mL.
| | [[Vitamin B12 deficiency history and symptoms|History and Symptoms]] | [[Vitamin B12 deficiency physical examination|Physical Examination]] | [[Vitamin B12 deficiency laboratory findings|Laboratory Findings]] | [[Vitamin B12 deficiency schilling_test|Schilling Test]] | [[Vitamin B12 deficiency other imaging findings|Other Imaging Findings]] | [[Vitamin B12 deficiency other diagnostic studies|Other Diagnostic Studies]] |
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| Serum B{{ssub|12}} levels are often low in B{{ssub|12}} deficiency, but if other features of B{{ssub|12}} deficiency are present with normal B{{ssub|12}} then the diagnosis must not be discounted. One possible explanation for normal B{{ssub|12}} levels in B{{ssub|12}} deficiency is antibody interference in people with high titres of intrinsic factor antibody.<ref>{{cite journal | author=Hamilton MS, Blackmore S, Lee A. | journal=Brit Med J | year=2006 | title=Possible cause of flase normal B-12 assays (letter) | pages=654–5 | volume=333 | issue=7569 }}</ref>
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| Some researchers propose that the current standard norms of vitamin B12 levels are too low. In Japan, the lowest acceptable level for vitamin B12 in blood has been raised from about 200 picograms/litre (pg/l) = 145 picomol/litre (pm/l) to 550 pg/l = 400 pm/l. <ref>{{cite journal | author=Mitsuyama Y, Kogoh H. | journal=Japanese Journal of Psychiatry and Neurology| year=1988 | title=Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-
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| B12 treatment. | pages=65-71| volume=42 | issue=1 }}</ref>
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| Serum Homocysteine and Methylmalonic acid levels are considered more reliable indicators of B12 deficiency than the concentration of B12 in blood, see for example research at the [[St. Louis University]].<ref name="titleTest used to diagnose B12 deficiency may be inadequate">{{cite web |url=http://www.news-medical.net/?id=5908 |title=Test used to diagnose B12 deficiency may be inadequate |accessdate=2007-12-04 |format= |work=}}</ref> The levels of these substances are high in B{{ssub|12}} deficiency and can be helpful if the diagnosis is unclear. Approximately 10% of patients with vitamin B12 levels between 200-400pg/l will have a vitamin B12 deficiency on the basis of elevated levels of [[homocysteine]] and [[methylmalonic acid]].
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| Routine monitoring of [[methylmalonic acid]] levels in urine is an option for people who may not be getting enough dietary B{{ssub|12}}, as a rise in [[methylmalonic acid]] levels may be an early indication of deficiency.<ref name="donaldson">Donaldson MS. Metabolic vitamin B{{ssub|12}} status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab. 2000;44(5-6):229-34. PMID 11146329.</ref>
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| If nervous system damage is suspected, B12 analysis in cerebrospinal fluid can also be helpful, though such an invasive test would be applicable only after unrevealing blood testing.<ref>{{cite journal | author=Devalia V | title=Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay | journal=Brit J Med | year=2006 | volume=333 | issue=7564 | pages=385-6 | id= PMID 16916826 }}</ref>
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| ==Manifestations==
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| Megaloblastic anemia w/ineffective erythropoiesis (inc bili/LDH); atrophic glossitis; and subacute combined degeneration of spinal cord:
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| *[[Paresthesia]]s, LE weakness, [[spasticity]], [[ataxic gait]]
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| *Loss of vibration and position sense
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| *[[Dementia]], personality change
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| *Dark nails
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| ==Treatment== | | ==Treatment== |
| [[image:6219_thumb.jpg|left|thumb|Moderate filiform taste bud atrophy thought to be due to a vitamin B12, or iron deficiency]] | | [[Vitamin B12 deficiency medical therapy|Medical Therapy]] | [[Vitamin B12 deficiency primary prevention|Primary Prevention]] | [[Vitamin B12 deficiency secondary prevention|Secondary Prevention]] | [[Vitamin B12 deficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Vitamin B12 deficiency future or investigational therapies|Future or Investigational Therapies]] |
| B{{ssub|12}} can be supplemented in healthy subjects by oral pill; [[sublingual]] pill, liquid, or strip; or by injection. B{{ssub|12}} is available singly or in combination with other supplements. B{{ssub|12}} supplements are available in forms including [[cyanocobalamin]], [[hydroxocobalamin]], [[methylcobalamin]], and [[adenosylcobalamin]] (sometimes called "cobamamide" or "dibencozide").
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| Vitamin B{{ssub|12}} can be given as intramuscular injections of [[hydroxycobalamin]], [[methylcobalamin]], or [[cyanocobalamin]]. Body stores (in the liver) are refilled with half a dozen injections in the first couple of weeks and then maintenance with monthly to quarterly injections throughout the life of the [[patient]]. | | ==Case Studies== |
| | [[Vitamin B12 deficiency case study one|Case #1]] |
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| B{{ssub|12}} has traditionally been given [[parenterally]] to ensure absorption in the dosage of 1 mg qd x 1 wk, then qwk x 1month, then monthly. However, oral replacement is now an accepted route, as it has become increasingly appreciated that sufficient quantities of B{{ssub|12}} are absorbed when large doses are given although this is a less efficient path for absorption (1%). This absorption does not rely on the presence of intrinsic factor or an intact ileum. Generally 1 to 2 mg daily is required as a large dose [http://www.bloodjournal.org/cgi/content/full/92/4/1191]. By contrast, the typical Western diet contains 5–7 µg of B{{ssub|12}} ([[Food and Drug Administration]] (FDA) Daily Value <ref>{{cite web| url = http://dietary-supplements.info.nih.gov/factsheets/vitaminb12.asp | title = Dietary Supplement Fact Sheet: Vitamin B12| publisher = National Institutes of Health: Office of Dietary Supplements | accessdate = 2006-06-06 }}</ref>). This method may be more effective than IM Rx, but requires patient compliance.
| | ==Related Chapters== |
| | | *[[Cobalamin deficiency]] |
| [[Hypokalemia]], an excessive low [[potassium]] level in the [[blood]], is anecdotally reported as a complication of vitamin B{{ssub|12}} repletion after deficiency. Excessive quantities of [[potassium]] are used by newly growing and dividing hematopoeitic cells, depleting circulating stores of the [[mineral]]. | | {{WH}} |
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| It has been appreciated since the 1960s that deficiency can sometimes be treated with oral B{{ssub|12}} supplements when given in sufficient doses. When given in oral doses ranging from 0.1–2 mg daily, B{{ssub|12}} can be absorbed in a pathway that does not require an intact ileum or intrinsic factor. However, with the advent of sublingual and intranasal administration, tablet usage is becoming outdated. <ref>{{cite journal | author= Antoinette M. Kuzminski ''et al''| title= Effective Treatment of Cobalamin Deficiency With Oral Cobalamin| journal= Blood| year= 1998| volume= 92| issue= 4| pages= 1191-1198| id= PMID 9694707}}</ref><ref>{{cite journal | journal=Fam Pract | year=2006 | volume=23 | issue=3 | pages=279-85 | title=Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials | author=Butler CC, Vidal-Alaball J, Cannings-John R, ''et al.'' | id=PMID 16585128 }}</ref> Oral absorption is limited so regular intramuscular injections or sublingual/intranasal administration of a cobalamin (preferably methyl- or hydroxycobalamin) is necessary to restore systemic stores to physiological levels. Recent research indicates that sublingual administration eliminates a deficiency as well as injections (reference will be added) with the advantage of evading the allergy risk.
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| ==Laboratory Findings==
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| :''Methylmalonic acid:'' elevated in B12 deficiency (98% sensitive) <br>
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| :''Homocysteine:'' elevated in B12 and folate deficiency <br>
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| :''Anti-IF Antibodies (AB):'' highly specific for PA, but sensitivity only 50-84% <br>
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| :''Anti-parietal cell ABs:'' less sensitive and much less specific <br>
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| ==References==
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| {{Reflist|2}}
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| {{SIB}}
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| {{Nutritional pathology}}
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