ROBERT C. LANGAN, MD, FAAFP, and ANDREW J. GOODBRED, MD, St. Luke’s Household Drugs Residency Program, Bethlehem, Pennsylvania
Affected person data: A handout on this subject is obtainable at https://familydoctor.org/vitamin-b-12.
This medical content material conforms to AAFP standards for persevering with medical schooling (CME). See the CME Quiz Questions.
Vitamin B12 (cobalamin) is a water-soluble vitamin obtained by way of the ingestion of fish, meat, and dairy merchandise, in addition to fortified cereals and dietary supplements.1,2 It’s coabsorbed with intrinsic issue, a product of the abdomen’s parietal cells, within the terminal ileum after being extracted by gastric acid1,2 (Determine 13). Vitamin B12 is essential for neurologic operate, purple blood cell manufacturing, and DNA synthesis, and is a cofactor for 3 main reactions: the conversion of methylmalonic acid to succinyl coenzyme A; the conversion of homocysteine to methionine; and the conversion of 5-methyltetrahydrofolate to tetrahydrofolate.1,2
In the US and the UK, the prevalence of vitamin B12 deficiency is roughly 6% in individuals youthful than 60 years, and almost 20% in these older than 60 years.1 Latin American international locations have a medical or subclinical deficiency price of roughly 40%.1 The prevalence is 70% in Kenyan college kids, 80% in East Indian preschool-aged kids, and 70% in East Indian adults.1 Sure threat elements enhance the prevalence of vitamin B12 deficiency (Desk 1).4,5 Dietary insufficiency, pernicious anemia (i.e., an autoimmune course of that reduces obtainable intrinsic issue and subsequent absorption of vitamin B121,2,6,7), and long-term use of metformin or acid-suppressing medicines have been implicated in B12 deficiency.8,9
A multicenter randomized managed trial of 390 sufferers with diabetes mellitus confirmed that these taking 850 mg of metformin thrice per day had an elevated threat of vitamin B12 deficiency (quantity wanted to hurt = 14 per 4.3 years) and low vitamin B12 ranges (quantity wanted to hurt = 9 per 4.3 years) vs. placebo.8 This impact elevated with length of remedy, and sufferers had an unclear prophylactic supplementation response. 8 A case-control examine that in contrast 25,956 sufferers who had vitamin B12 deficiency with 184,199 management sufferers discovered a considerably elevated threat of vitamin B12 deficiency in sufferers who had taken proton pump inhibitors (odds ratio = 1.65) or histamine H2 blockers (odds ratio = 1.25) for at the least two years.9 In gentle of those findings, long-term use of those medicines ought to be periodically reassessed, significantly in sufferers with different threat elements for vitamin B12 deficiency.8,9
Vitamin B12 deficiency is a standard explanation for megaloblastic anemia, varied neuropsychiatric signs, and different medical manifestations. Screening average-risk adults for vitamin B12 deficiency shouldn’t be advisable. Screening could also be warranted in sufferers with a number of threat elements, akin to gastric or small gut resections, inflammatory bowel illness, use of metformin for greater than 4 months, use of proton pump inhibitors or histamine H2 blockers for greater than 12 months, vegans or strict vegetarians, and adults older than 75 years. Preliminary laboratory evaluation ought to embody a whole blood rely and serum vitamin B12 stage. Measurement of serum methylmalonic acid ought to be used to substantiate deficiency in asymptomatic high-risk sufferers with low-normal ranges of vitamin B12. Oral administration of high-dose vitamin B12 (1 to 2 mg every day) is as efficient as intramuscular administration for correcting anemia and neurologic signs. Intramuscular remedy results in extra fast enchancment and ought to be thought of in sufferers with extreme deficiency or extreme neurologic signs. Absorption charges enhance with supplementation; subsequently, sufferers older than 50 years and vegans or strict vegetarians ought to eat meals fortified with vitamin B12 or take vitamin B12 dietary supplements. Sufferers who’ve had bariatric surgical procedure ought to obtain 1 mg of oral vitamin B12 per day indefinitely. Use of vitamin B12 in sufferers with elevated serum homocysteine ranges and heart problems doesn’t cut back the chance of myocardial infarction or stroke, or alter cognitive decline.
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A = constant, good-quality patient-oriented proof; B = inconsistent or limited-quality patient-oriented proof; C = consensus, disease-oriented proof, typical observe, knowledgeable opinion, or case sequence. For details about the SORT proof ranking system, go to https://www.aafp.org/afpsort.
A = constant, good-quality patient-oriented proof; B = inconsistent or limited-quality patient-oriented proof; C = consensus, disease-oriented proof, typical observe, knowledgeable opinion, or case sequence. For details about the SORT proof ranking system, go to https://www.aafp.org/afpsort.
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Reprinted with permission from Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Doctor. 2003;67(5):981.
Reprinted with permission from Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Doctor. 2003;67(5):981.
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Tailored with permission from Langan RC, Zawistoski KJ. Replace on vitamin B12 deficiency. Am Fam Doctor. 2011;83(12):1426, with further data from reference 5.
Tailored with permission from Langan RC, Zawistoski KJ. Replace on vitamin B12 deficiency. Am Fam Doctor. 2011;83(12):1426, with further data from reference 5.
Manifestations
Vitamin B12 deficiency impacts a number of methods, and sequelae fluctuate in severity from delicate fatigue to extreme neurologic impairment 1,2,6,10 (Desk 24,10). The substantial hepatic storage of vitamin B12 can delay medical manifestations for as much as 10 years after the onset of deficiency.11 Bone marrow suppression is widespread and probably impacts all cell traces, with megaloblastic anemia being most typical.1,2,6 The resultant irregular erythropoiesis can set off different notable irregular laboratory findings, akin to decreased haptoglobin ranges, excessive lactate dehydrogenase ranges, and elevated reticulocyte rely.1,2,6 Signs sometimes embody being simply fatigued with exertion, palpitations, and pores and skin pallor.1,2,6 Pores and skin hyperpigmentation, glossitis, and infertility have additionally been reported.1,2,6 Neurologic manifestations are attributable to progressive demyelination and might embody peripheral neuropathy, areflexia, and the lack of proprioception and vibratory sense. Areflexia might be everlasting if neuronal dying happens within the posterior and lateral spinal twine tracts.1,2,6,12 Dementia-like illness, together with episodes of psychosis, is feasible with extra extreme and persistent deficiency.1,12 Medical analysis appears to indicate an inverse relationship between the severity of megaloblastic anemia and the diploma of neurologic impairment.2
Maternal vitamin B12 deficiency throughout being pregnant or whereas breastfeeding might result in neural tube defects, developmental delay, failure to thrive, hypotonia, ataxia, and anemia.4,13–16 Girls at excessive threat or with recognized deficiency ought to complement with vitamin B12 throughout being pregnant or whereas breastfeeding.4,14–16
Screening and Analysis
Screening individuals at common threat of vitamin B12 deficiency shouldn’t be advisable.17 Screening ought to be thought of in sufferers with threat elements, and diagnostic testing ought to be thought of in these with suspected medical manifestations.1,2,6,18
The advisable laboratory analysis for sufferers with suspected vitamin B12 deficiency features a full blood rely and serum vitamin B12 stage.2,19–21 A stage of lower than 150 pg per mL (111 pmol per L) is diagnostic for deficiency.1,2 Serum vitamin B12 ranges could also be artificially elevated in sufferers with alcoholism, liver illness, or most cancers due to decreased hepatic clearance of transport proteins and resultant increased circulating ranges of vitamin B12; physicians ought to use warning when decoding laboratory leads to these sufferers.22,23 In sufferers with a traditional or low-normal serum vitamin B12 stage, full blood rely outcomes demonstrating macrocytosis, or suspected medical manifestations, a serum methylmalonic acid stage is an acceptable subsequent step 1,2,6,18 and is a extra direct measure of vitamin B12’s physiologic exercise.1,2 Though not clinically validated or obtainable for widespread use, measurement of holotranscobalamin, the metabolically energetic type of vitamin B12, is an rising technique of detecting deficiency.1,2,18 Desk 3 lists the relative sensitivities and specificities of varied laboratory checks.24
Pernicious anemia refers to one of many hematologic manifestations of persistent auto-immune gastritis, during which the immune system targets the parietal cells of the abdomen or intrinsic issue itself, resulting in decreased absorption of vitamin B12.1 Asymptomatic autoimmune gastritis doubtless precedes gastric atrophy by 10 to twenty years, adopted by the onset of iron-deficiency anemia that happens as early as 20 years earlier than vitamin B12 deficiency pernicious anemia.25
Sufferers recognized with vitamin B12 deficiency whose historical past and bodily examination don’t counsel an apparent dietary or malabsorptive etiology ought to be examined for pernicious anemia with anti-intrinsic issue antibodies (optimistic predictive worth = 95%), significantly if different autoimmune issues are current.1,2,6,18 Sufferers with pernicious anemia might have hematologic findings constant w ith normocytic anemia.1 If anti-intrinsic issue outcomes are adverse however suspicion for pernicious anemia stays, an elevated serum gastrin stage is per the analysis.2 The Schilling take a look at, which was as soon as the diagnostic commonplace for pernicious anemia, is now not obtainable in the US. Determine 2 presents an method to diagnosing vitamin B12 deficiency and pernicious anemia.18,26
Remedy
Vitamin B12 deficiency might be handled with intramuscular injections of cyanocobalamin or oral vitamin B12 remedy. Roughly 10% of the usual injectable dose of 1 mg is absorbed, which permits for fast substitute in sufferers with extreme deficiency or extreme neurologic sy mptoms.2 Tips from the British Society for Haematology suggest injections thrice per week for 2 weeks in sufferers with out neurologic deficits.18 If neurologic deficits are current, injections ought to be given each different day for as much as three weeks or till no additional enchancment is famous. Desk 4 lists the same old instances till enchancment for abnormalities related to vitamin B12 deficiency.27 Typically, sufferers with an irreversible trigger ought to be handled indefinitely, whereas these with a reversible trigger ought to be handled till the deficiency is corrected and signs resolve.1 If vitamin B12 deficiency coexists with folate deficiency, vitamin B12 ought to be changed first to stop subacute mixed degeneration of the spinal twine.1 The British Society for Haematology doesn’t suggest retesting vitamin B12 ranges after therapy has been initiated, and no pointers deal with the optimum interval for screening high-risk sufferers.18
A 2005 Cochrane overview involving 108 sufferers with vitamin B12 deficiency discovered that high-dose oral substitute (1 mg to 2 mg per day) was as efficient as parenteral administration for correcting anemia and neurologic signs.28 Nonetheless, oral remedy doesn’t enhance serum methylmalonic acid ranges in addition to intramuscular remedy, though the medical relevance is unclear.29 There’s additionally a scarcity of knowledge on the long-term good thing about oral remedy when sufferers don’t take every day doses.2 There’s inadequate knowledge to suggest different formulations of vitamin B12 substitute (e.g., nasal, sublingual, subcutaneous).2 The British Society for Haematology recommends intramuscular vitamin B12 for extreme deficiency and malabsorption syndromes, whereas oral substitute could also be thought of for sufferers with asymptomatic, delicate illness with no absorption or compliance issues.18
Prevention
Due to potential interactions from extended remedy use, physicians ought to take into account screening sufferers for vitamin B12 deficiency if they’ve been taking proton pump inhibitors or H2 blockers for greater than 12 months, or metformin for greater than 4 months.5 The typical consumption of vitamin B12 in the US is 3.4 mcg per day, and the advisable dietary allowance is 2.4 mcg per day for grownup males and nonpregnant girls, and a pair of.6 mcg per day for pregnant girls.30 Sufferers older than 50 years might not have the ability to adequately soak up dietary vitamin B12 and will eat meals fortified with vitamin B12.30 Vegans and strict vegetarians ought to be recommended to eat fortified cereals or dietary supplements to stop deficiency. The American Society for Metabolic and Bariatric Surgical procedure recommends that sufferers who’ve had bariatric surgical procedure take 1 mg of oral vitamin B12 per day indefinitely.31
Vitamin B12 and Hyperhomocysteinemia – “b vitamin therapy”
Vitamin B12 deficiency is a way more widespread explanation for hyperhomocysteinemia in developed international locations than folate deficiency due to widespread fortification of meals with folate. Though epidemiologic research have proven an affiliation between vascular illness and hyperhomocysteinemia, massive randomized managed trials have proven that decreasing homocysteine ranges in these sufferers doesn’t cut back the variety of myocardial infarctions or strokes, or enhance mortality charges.32 Equally, an affiliation between elevated homocysteine ranges and cognitive impairment has been famous, however subsequent vitamin B12 substitute doesn’t have preventive or therapeutic profit.33
This text updates earlier articles on this subject by Langan and Zawistoski,4 and by Oh and Brown.3
Information Sources: A PubMed search was accomplished in Medical Queries utilizing the important thing phrases vitamin B12, cobalamin, deficiency, and therapy. The search included meta-analyses, randomized managed trials, medical trials, and opinions. Additionally searched have been the Company for Healthcare Analysis and High quality proof experiences, Medical Proof, the Cochrane database, Important Proof, the Institute for Medical Programs Enchancment, the Nationwide Guideline Clearinghouse database, and the U.S. Preventive Providers Process Pressure. Search dates: March 1, 2016; October 20, 2016; and June 9, 2017.
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