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Vitamin B₁₂ Deficiency: Recognition and Direction

ROBERT C. LANGAN, MD, FAAFP, and ANDREW J. GOODBRED, Medico, St. Luke's Family unit Medicine Residency Program, Bethlehem, Pennsylvania

Am Fam Physician. 2017 Sep fifteen;96(6):384-389.

Patient information: A handout on this topic is available at https://familydoctor.org/vitamin-b-12.

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Author disclosure: No relevant financial affiliations.

Abstract
Manifestations
Screening and Diagnosis
Treatment
Prevention
Vitamin B12 and Hyperhomocysteinemia
References

Commodity Sections

Abstract
Manifestations
Screening and Diagnosis
Handling
Prevention
Vitamin B12 and Hyperhomocysteinemia
References

Vitamin B₁₂ deficiency is a common cause of megaloblastic anemia, various neuropsychiatric symptoms, and other clinical manifestations. Screening average-take chances adults for vitamin B₁₂ deficiency is not recommended. Screening may exist warranted in patients with one or more chance factors, such every bit gastric or small intestine resections, inflammatory bowel affliction, use of metformin for more than than iv months, apply of proton pump inhibitors or histamine H₂ blockers for more than 12 months, vegans or strict vegetarians, and adults older than 75 years. Initial laboratory cess should include a complete claret count and serum vitamin B₁₂ level. Measurement of serum methylmalonic acrid should exist used to ostend deficiency in asymptomatic loftier-take chances patients with low-normal levels of vitamin B₁₂. Oral assistants of high-dose vitamin B₁₂ (1 to 2 mg daily) is as effective as intramuscular assistants for correcting anemia and neurologic symptoms. Intramuscular therapy leads to more rapid comeback and should be considered in patients with severe deficiency or severe neurologic symptoms. Absorption rates improve with supplementation; therefore, patients older than 50 years and vegans or strict vegetarians should consume foods fortified with vitamin B₁₂ or take vitamin B₁₂ supplements. Patients who accept had bariatric surgery should receive i mg of oral vitamin B₁₂ per day indefinitely. Use of vitamin B₁₂ in patients with elevated serum homocysteine levels and cardiovascular disease does not reduce the risk of myocardial infarction or stroke, or change cerebral turn down.

Vitamin B₁₂ (cobalamin) is a h2o-soluble vitamin obtained through the ingestion of fish, meat, and dairy products, too as fortified cereals and supplements.1,2 It is coabsorbed with intrinsic factor, a product of the stomach's parietal cells, in the concluding ileum after beingness extracted by gastric acid1,two (Figure one 3). Vitamin B₁₂ is crucial for neurologic function, red blood cell production, and DNA synthesis, and is a cofactor for three major reactions: the conversion of methylmalonic acid to succinyl coenzyme A; the conversion of homocysteine to methionine; and the conversion of v-methyltetrahydrofolate to tetrahydrofolate.1,2

SORT: Central RECOMMENDATIONS FOR PRACTICE

Clinical recommendation	Evidence rating	References
Patients with risk factors for vitamin B₁₂ deficiency should be screened with a complete blood count and serum vitamin B₁₂ level.	C	18
A serum methylmalonic acid level may be used to confirm vitamin B₁₂ deficiency when information technology is suspected but the serum vitamin B₁₂ level is normal or low-normal.	C	eighteen
Oral and injectable vitamin B₁₂ are effective ways of replacement, only injectable therapy leads to more rapid improvement and should exist considered in patients with severe deficiency or severe neurologic symptoms.	B	18
Patients who accept had bariatric surgery should receive one mg of oral vitamin B₁₂ per day indefinitely.	C	31

Figure 1

Vitamin B₁₂ assimilation and transport.

Reprinted with permission from Oh R, Brown DL. Vitamin B₁₂ deficiency. Am Fam Doctor. 2003;67(five):981.

In the United States and the Uk, the prevalence of vitamin B₁₂ deficiency is approximately six% in persons younger than 60 years, and nearly 20% in those older than 60 years.1 Latin American countries have a clinical or subclinical deficiency rate of approximately twoscore%.one The prevalence is seventy% in Kenyan schoolhouse children, 80% in Eastward Indian preschool-aged children, and 70% in East Indian adults.1 Certain risk factors increment the prevalence of vitamin B₁₂ deficiency (Table 1).4,v Dietary insufficiency, pernicious anemia (i.e., an autoimmune process that reduces available intrinsic factor and subsequent absorption of vitamin B₁₂one,2,6,7), and long-term use of metformin or acid-suppressing medications have been implicated in B₁₂ deficiency.8,9

A multicenter randomized controlled trial of 390 patients with diabetes mellitus showed that those taking 850 mg of metformin three times per 24-hour interval had an increased risk of vitamin B₁₂ deficiency (number needed to damage = 14 per 4.3 years) and low vitamin B₁₂ levels (number needed to impairment = 9 per 4.3 years) vs. placebo.8 This effect increased with elapsing of therapy, and patients had an unclear rubber supplementation response. 8 A instance-control study that compared 25,956 patients who had vitamin B₁₂ deficiency with 184,199 command patients institute a significantly increased risk of vitamin B₁₂ deficiency in patients who had taken proton pump inhibitors (odds ratio = 1.65) or histamine H₂ blockers (odds ratio = 1.25) for at least 2 years.9 In lite of these findings, long-term utilise of these medications should be periodically reassessed, particularly in patients with other adventure factors for vitamin B₁₂ deficiency.8,nine

Tabular array 1

Risk Factors for Vitamin B₁₂ Deficiency

Decreased ileal absorption

Crohn affliction

Ileal resection

Tapeworm infection

Decreased intrinsic gene

Atrophic gastritis

Pernicious anemia

Postgastrectomy syndrome (includes Roux-en-Y gastric bypass)

Genetic

Transcobalamin Ii deficiency

Inadequate intake

Booze abuse

Patients older than 75 years

Vegans or strict vegetarians (including exclusively breastfed infants of vegetarian/vegan mothers)

Prolonged medication apply

Histamine H_ii blocker employ for more than 12 months

Metformin use for more than four months

Proton pump inhibitor use for more than 12 months

Manifestations

Abstract
Manifestations
Screening and Diagnosis
Treatment
Prevention
Vitamin B12 and Hyperhomocysteinemia
References

Vitamin B₁₂ deficiency affects multiple systems, and sequelae vary in severity from balmy fatigue to severe neurologic impairment 1,2,vi,10 (Table 2iv,10). The substantial hepatic storage of vitamin B₁₂ tin filibuster clinical manifestations for upwardly to 10 years after the onset of deficiency.11 Bone marrow suppression is common and potentially affects all cell lines, with megaloblastic anemia being virtually mutual.1,ii,6 The resultant abnormal erythropoiesis tin trigger other notable abnormal laboratory findings, such as decreased haptoglobin levels, loftier lactate dehydrogenase levels, and elevated reticulocyte count.1,2,six Symptoms typically include beingness hands fatigued with exertion, palpitations, and skin pallor.1,2,six Pare hyperpigmentation, glossitis, and infertility have besides been reported.ane,2,vi Neurologic manifestations are caused by progressive demyelination and can include peripheral neuropathy, areflexia, and the loss of proprioception and vibratory sense. Areflexia can exist permanent if neuronal decease occurs in the posterior and lateral spinal cord tracts.1,2,6,12 Dementia-similar illness, including episodes of psychosis, is possible with more severe and chronic deficiency.one,12 Clinical evaluation seems to show an inverse human relationship between the severity of megaloblastic anemia and the degree of neurologic impairment.2

Tabular array ii

Clinical Manifestations of Vitamin B₁₂ Deficiency

Cutaneous

Hyperpigmentation

Jaundice

Vitiligo

Gastrointestinal

Glossitis

Hematologic

Anemia (macrocytic, megaloblastic)

Leukopenia

Pancytopenia

Thrombocytopenia

Thrombocytosis

Neuropsychiatric

Areflexia

Cerebral impairment (including dementia-similar symptoms and acute psychosis)

Gait abnormalities

Irritability

Loss of proprioception and vibratory sense

Olfactory damage

Peripheral neuropathy

Maternal vitamin B₁₂ deficiency during pregnancy or while breastfeeding may pb to neural tube defects, developmental delay, failure to thrive, hypotonia, ataxia, and anemia.4,xiii–xvi Women at high risk or with known deficiency should supplement with vitamin B₁₂ during pregnancy or while breastfeeding.4,14–16

Screening and Diagnosis

Abstract
Manifestations
Screening and Diagnosis
Treatment
Prevention
Vitamin B12 and Hyperhomocysteinemia
References

Screening persons at average take chances of vitamin B₁₂ deficiency is not recommended.17 Screening should exist considered in patients with risk factors, and diagnostic testing should be considered in those with suspected clinical manifestations.1,ii,6,18

The recommended laboratory evaluation for patients with suspected vitamin B₁₂ deficiency includes a complete blood count and serum vitamin B₁₂ level.2,19–21 A level of less than 150 pg per mL (111 pmol per 50) is diagnostic for deficiency.1,two Serum vitamin B₁₂ levels may exist artificially elevated in patients with alcoholism, liver affliction, or cancer considering of decreased hepatic clearance of transport proteins and resultant college circulating levels of vitamin B₁₂; physicians should use caution when interpreting laboratory results in these patients.22,23 In patients with a normal or low-normal serum vitamin B₁₂ level, consummate claret count results demonstrating macrocytosis, or suspected clinical manifestations, a serum methylmalonic acrid level is an advisable next step 1,2,vi,18 and is a more straight measure of vitamin B₁₂'southward physiologic activeness.i,2 Although not clinically validated or available for widespread apply, measurement of holotranscobalamin, the metabolically active course of vitamin B₁₂, is an emerging method of detecting deficiency.ane,2,eighteen Tabular array 3 lists the relative sensitivities and specificities of diverse laboratory tests.24

Tabular array 3

Estimated Sensitivity and Specificity of Serum Laboratory Tests for Vitamin B₁₂ Deficiency

Criteria	Sensitivity (%)	Specificity
Decreased serum vitamin B₁₂ level (< 200 pg per mL [148 pmol per Fifty])	95 to 97	Uncertain
Elevated serum methylmalonic acid level	> 95	Uncertain

Pernicious anemia refers to i of the hematologic manifestations of chronic auto-immune gastritis, in which the allowed system targets the parietal cells of the tum or intrinsic cistron itself, leading to decreased absorption of vitamin B₁₂.1 Asymptomatic autoimmune gastritis likely precedes gastric cloudburst by ten to xx years, followed past the onset of iron-deficiency anemia that occurs as early as 20 years before vitamin B₁₂ deficiency pernicious anemia.25

Patients diagnosed with vitamin B₁₂ deficiency whose history and concrete exam do not suggest an obvious dietary or malabsorptive etiology should be tested for pernicious anemia with anti-intrinsic factor antibodies (positive predictive value = 95%), particularly if other autoimmune disorders are present.1,ii,6,18 Patients with pernicious anemia may accept hematologic findings consequent w ith normocytic anemia.i If anti-intrinsic factor results are negative only suspicion for pernicious anemia remains, an elevated serum gastrin level is consistent with the diagnosis.2 The Schilling examination, which was once the diagnostic standard for pernicious anemia, is no longer available in the United States. Figure ii presents an approach to diagnosing vitamin B₁₂ deficiency and pernicious anemia.eighteen,26

Evaluation of Suspected Vitamin B₁₂ Deficiency

Figure ii

Suggested arroyo to the patient with suspected vitamin B₁₂ deficiency.

Information from references 18 and 26.

Treatment

Abstruse
Manifestations
Screening and Diagnosis
Handling
Prevention
Vitamin B12 and Hyperhomocysteinemia
References

Vitamin B₁₂ deficiency can exist treated with intramuscular injections of cyanocobalamin or oral vitamin B₁₂ therapy. Approximately 10% of the standard injectable dose of 1 mg is absorbed, which allows for rapid replacement in patients with severe deficiency or severe neurologic sy mptoms.ii Guidelines from the British Guild for Haematology recommend injections three times per week for two weeks in patients without neurologic deficits.18 If neurologic deficits are present, injections should be given every other mean solar day for upwardly to 3 weeks or until no farther improvement is noted. Tabular array 4 lists the usual times until improvement for abnormalities associated with vitamin B₁₂ deficiency.27 In general, patients with an irreversible cause should exist treated indefinitely, whereas those with a reversible crusade should exist treated until the deficiency is corrected and symptoms resolve.1 If vitamin B₁₂ deficiency coexists with folate deficiency, vitamin B₁₂ should be replaced kickoff to forbid subacute combined degeneration of the spinal cord.one The British Society for Haematology does not recommend retesting vitamin B₁₂ levels subsequently treatment has been initiated, and no guidelines address the optimal interval for screening high-risk patients.18

Table iv

Time to Comeback of Abnormalities in Vitamin B₁₂ Deficiency After Initiation of Handling

Aberration	Expected time until improvement
Homocysteine or methylmalonic acid level, or reticulocyte count	One week
Neurologic symptoms	Six weeks to iii months
Anemia, leukopenia, mean corpuscular volume, or thrombocytopenia	Eight weeks

A 2005 Cochrane review involving 108 patients with vitamin B₁₂ deficiency found that loftier-dose oral replacement (1 mg to 2 mg per day) was as effective as parenteral assistants for correcting anemia and neurologic symptoms.28 Still, oral therapy does not better serum methylmalonic acid levels every bit well every bit intramuscular therapy, although the clinical relevance is unclear.29 There is besides a lack of data on the long-term do good of oral therapy when patients exercise non take daily doses.2 There is insufficient information to recommend other formulations of vitamin B₁₂ replacement (eastward.chiliad., nasal, sublingual, subcutaneous).ii The British Society for Haematology recommends intramuscular vitamin B₁₂ for severe deficiency and malabsorption syndromes, whereas oral replacement may be considered for patients with asymptomatic, mild disease with no absorption or compliance concerns.eighteen

Prevention

Abstract
Manifestations
Screening and Diagnosis
Handling
Prevention
Vitamin B12 and Hyperhomocysteinemia
References

Because of potential interactions from prolonged medication use, physicians should consider screening patients for vitamin B₁₂ deficiency if they have been taking proton pump inhibitors or H₂ blockers for more than than 12 months, or metformin for more than four months.5 The boilerplate intake of vitamin B₁₂ in the United States is iii.4 mcg per twenty-four hour period, and the recommended dietary allowance is 2.iv mcg per day for adult men and nonpregnant women, and 2.6 mcg per day for pregnant women.30 Patients older than 50 years may not be able to adequately absorb dietary vitamin B₁₂ and should swallow nutrient fortified with vitamin B₁₂.30 Vegans and strict vegetarians should be counseled to swallow fortified cereals or supplements to prevent deficiency. The American Society for Metabolic and Bariatric Surgery recommends that patients who have had bariatric surgery have 1 mg of oral vitamin B₁₂ per twenty-four hour period indefinitely.31

Vitamin B₁₂ and Hyperhomocysteinemia

Abstract
Manifestations
Screening and Diagnosis
Treatment
Prevention
Vitamin B12 and Hyperhomocysteinemia
References

Vitamin B₁₂ deficiency is a much more mutual cause of hyperhomocysteinemia in adult countries than folate deficiency because of widespread fortification of food with folate. Although epidemiologic studies accept shown an association between vascular affliction and hyperhomocysteinemia, large randomized controlled trials have shown that lowering homocysteine levels in these patients does non reduce the number of myocardial infarctions or strokes, or improve mortality rates.32 Similarly, an association between elevated homocysteine levels and cerebral harm has been noted, just subsequent vitamin B₁₂ replacement does not have preventive or therapeutic benefit.33

Data Sources: A PubMed search was completed in Clinical Queries using the key terms vitamin B₁₂, cobalamin, deficiency, and handling. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were the Agency for Healthcare Enquiry and Quality evidence reports, Clinical Testify, the Cochrane database, Essential Testify, the Institute for Clinical Systems Improvement, the National Guideline Clearinghouse database, and the U.S. Preventive Services Task Force. Search dates: March 1, 2016; October 20, 2016; and June 9, 2017.

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The Authors

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ROBERT C. LANGAN, Medico, FAAFP, is the plan director at St. Luke's Family unit Medicine Residency Program, Bethlehem, Pa., and an offshoot acquaintance professor in the Department of Family and Community Medicine at Temple Academy School of Medicine, Philadelphia, Pa....

ANDREW J. GOODBRED, MD, is a faculty member at St. Luke's Family Medicine Residency Plan and an adjunct banana professor in the Department of Family and Community Medicine at Temple Academy School of Medicine.

Address correspondence to Robert C. Langan, Doctor, St. Luke's Hospital, 2830 Easton Ave., Bethlehem, PA 18017 (e-mail: robert.langan@sluhn.org). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

REFERENCES

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1. Hunt A, Harrington D, Robinson Due south. Vitamin B₁₂ deficiency. BMJ. 2014;349g5226. ...

2. Stabler SP. Clinical practise. Vitamin B₁₂ deficiency. N Engl J Med. 2013;368(two):149–160.

iii. Brown DL, Oh R. Vitamin B₁₂ deficiency. Am Fam Physician. 2003;67(v):979–986.

4. Langan RC, Zawistoski KJ. Update on vitamin B₁₂ deficiency. Am Fam Physician. 2011;83(12):1425–1430.

5. Agency for Healthcare Enquiry and Quality. Guideline summary: cobalamin (vitamin B₁₂) deficiency—investigation and direction. Jan 1, 2012. https://www.guideline.gov/summaries/summary/38881. Accessed October thirteen, 2016.

6. Dali-Youcef N, Andrès E. An update on cobalamin deficiency in adults. QJM. 2009;102(ane):17–28.

7. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. 1997;337(20):1441–1448.

eight. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with blazon two diabetes and risk of vitamin B₁₂ deficiency: randomised placebo controlled trial. BMJ. 2010;340c2181.

9. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist employ and vitamin B₁₂ deficiency. JAMA. 2013;310(22):2435–2442.

10. Derin S, Koseoglu S, Sahin C, Sahan M. Effect of vitamin B₁₂ deficiency on olfactory function. Int Forum Allergy Rhinol. 2016;6(10):1051–1055.

11. Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51357–375.

12. Reynolds E. Vitamin B₁₂, folic acid, and the nervous system. Lancet Neurol. 2006;5(11):949–960.

xiii. Molloy AM, Kirke PN, Troendle JF, et al. Maternal vitamin B₁₂ status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Pediatrics. 2009;123(iii):917–923.

14. Dror DK, Allen LH. Event of vitamin B₁₂ deficiency on neurodevelopment in infants: current cognition and possible mechanisms. Nutr Rev. 2008;66(v):250–255.

15. Centers for Disease Control and Prevention (CDC). Neurologic harm in children associated with maternal dietary deficiency of cobalamin—Georgia, 2001. MMWR Morb Mortal Wkly Rep. 2003;52(4):61–64.

16. Hay Grand, Johnston C, Whitelaw A, Trygg Chiliad, Refsum H. Folate and cobalamin status in relation to breastfeeding and weaning in healthy infants. Am J Clin Nutr. 2008;88(one):105–114.

17. U.S. Preventive Services Task Force. A-Z topic guide. http://world wide web.uspreventiveservicestaskforce.org/uspstopics.htm#AZ. Accessed May 24, 2016.

eighteen. Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496–513.

19. Carmel R, Light-green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Programme. 200362–81.

20. Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Md. 2009;79(3):203–208.

21. Stabler SP, Allen RH. Megaloblastic anemias. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia, Pa.: Saunders; 2004:1050–1057.

22. Arendt JF, Nexo Due east. Cobalamin related parameters and illness patterns in patients with increased serum cobalamin levels. PLoS I. 2012;seven(9):e45979.

23. Andrès Due east, Serraj Thou, Zhu J, Vermorken AJ. The pathophysiology of elevated vitamin B₁₂ in clinical practice. QJM. 2013;106(6):505–515.

24. Oberley MJ, Yang DT. Laboratory testing for cobalamin deficiency in megaloblastic anemia. Am J Hematol. 2013;88(6):522–526.

25. Toh BH. Pathophysiology and laboratory diagnosis of pernicious anemia. Immunol Res. 2017;65(1):326–330.

26. Moridani Chiliad, Ben-Poorat Due south. Laboratory investigation of vitamin B₁₂ deficiency. Lab Med. 2006;37(3):166–174.

27. Carmel R. How I treat cobalamin (vitamin B₁₂) deficiency. Blood. 2008;112(xvi):2214–2221.

28. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B₁₂ versus intramuscular vitamin B₁₂ for vitamin B₁₂ deficiency. Cochrane Database Syst Rev. 2005(three):CD004655.

29. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Constructive treatment of cobalamin deficiency with oral cobalamin. Claret. 1998;92(4):1191–1198.

30. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B_vi, Folate, Vitamin B₁₂, Pantothenic Acid, Biotin, and Choline. Washington, DC: National University Printing; 1998.

31. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical back up of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Guild for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013;9(2):159–191.

32. Yang HT, Lee Thousand, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acrid supplementation in cardiovascular illness prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med. 2012;23(viii):745–754.

33. Nachum-Biala Y, Troen AM. B-vitamins for neuroprotection: narrowing the show gap. Biofactors. 2012;38(2):145–150.

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