This Academy member benefit temporarily has been made public to allow all practitioners access to content that may assist in patient care during the national pandemic response. Click here for information on joining the Academy. 

Recommendations Summary

Search Plan and Results

Search Plan and Results

Evidence Analysis Question

What is B12 status among vegetarians, as measured by methylmalonic acid (MMA) across the lifespan?

What is the vitamin B-12 status of children of vegetarians, as measured by methylmalonic acid (MMA)?

What is the vitamin B-12 status among adolescent vegetarians, as measured by methylmalonic acid (MMA)?

What is the vitamin B12 status among adult vegetarians, as measured by methylmalonic acid (MMA)?

What is the vitamin B-12 status among vegetarian older adults (>55 years) as measured by methylmalonic acid (MMA)?

Date of Literature Review

November 2010

Inclusion Criteria

  • Age: Adults and children
  • Setting: Free living individuals.
  • Health status: Otherwise healthy
  • Diet: Vegetarian
  • Nutrition-related problem/condition:
    • Vitamin B12 deficiency
    • B12 status measured by MMA
  • Study design preferences: Epidemiological designs
  • Size of study groups: The sample size must equal 10 individuals for each study group.
  • Study dropout rate: Studies with attrition less than 20%
  • Year range: 2000 to November 2010
  • Authorship:
    • If an author is included on more than one review article or primary research article that is similar in content, the most recent review or article will be accepted and earlier versions will be rejected
    • If an author is included on more than one review article or primary research article and the content is different, then both reviews may be accepted
  • Language: Limited to articles in English.

Exclusion Criteria

  • Diet: 
    • Non-vegetarian: "Plant-based" diets are not considered vegetarian unless they specify within the article that the diet includes no meat
    • Did not use MMA to measure B12 status
  • Type of articles: 
    • Commentary
    • Case studies.

Search Terms: Search Vocabulary

  • Health condition: Vegetarian, vegan, macrobiotic diet
  • Intervention or exposure: Cobalamine, with outcome variable of methylmalonic acid
  • Study design: Not specified for search.

Electronic Databases 

  • Database: PubMed
  • Search Terms:  "Methylmalonic Acid"[Mesh] AND "Diet, Vegetarian"[Mesh] Limits: English, Publication Date from 1990/01/01 to 2010/03/18
  • Hits: 17
  • Articles to review: Six. 


  • B12 levels in healthy vegetarians
  • (((vegetarian) OR (vegan) OR (plant based diet) OR (plant based diets)) AND ((vitamin B12) OR (vitamin B12 deficiency)) AND (English[lang] AND "last 10 years"[PDat])) not (Case Reports[ptyp]))
  • Inclusion:
    • 10 years
    • Vegetarian group with at least 10 subjects
    • No limit on MMA
  • Exclusion:
    • Review articles
    • Unhealthy patients (e.g., renal disease, cancer)
    • Treatment studies with no baseline data on vegetarian group.

Total articles identified to review from electronic databases: 64

Articles Identified from other sources:


Inclusion List:

List of Included Articles  

Dhonukshe-Rutten RA, van Dusseldorp M, Schneede J, de Groot LC, van Staveren WA. Low bone mineral density and bone mineral content are associated with low cobalamin status in adolescents. Eur J Nutr. 2005 Sep; 44(6): 341-347. Epub: 2004 Aug 30. PMID: 15338248.  

Donaldson MS. Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab. 2000; 44(5-6): 229-234. PMID: 11146329.  

Geisel J, Hübner U, Bodis M, Schorr H, Knapp JP, Obeid R, Herrmann W. The role of genetic factors in the development of hyperhomocysteinemia. Clin Chem Lab Med. 2003 Nov; 41(11): 1, 427-1, 434. Review. PMID: 14656021.

Geisel J, Schorr H, Bodis M, Isber S, Hübner U, Knapp JP, Obeid R, Herrmann W. The vegetarian lifestyle and DNA methylation. Clin Chem Lab Med. 2005; 43(10): 1, 164-1, 169. PMID: 16197315.  

Gibson RS, Abebe Y, Stabler S, Allen RH, Westcott JE, Stoecker BJ, Krebs NF, Hambidge KM. Zinc, gravida, infection, and iron, but not vitamin B-12 or folate status, predict hemoglobin during pregnancy in Southern Ethiopia. J Nutr. 2008 Mar; 138(3): 581-586. PMID: 18287370. 

Herrmann W, Obeid R, Schorr H, Hübner U, Geisel J, Sand-Hill M, Ali N, Herrmann M. Enhanced bone metabolism in vegetarians: The role of vitamin B12 deficiency. Clin Chem Lab Med. 2009; 47(11): 1, 381-1, 387. PMID: 19817650.   

Herrmann W, Obeid R, Schorr H, Geisel J. Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med. 2003 Nov; 41(11): 1, 478-1, 488. PMID: 14656029.   

Herrmann W, Schorr H, Obeid R, Geisel J.  Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul; 78(1): 131-136. PMID: 12816782.  

Herrmann W, Schorr H, Purschwitz K, Rassoul F, Richter V. Total homocysteine, vitamin B(12), and total antioxidant status in vegetarians. Clin Chem. 2001 Jun; 47(6): 1, 094-1, 101. PMID: 11375297.  

Kwok T, Cheng G, Lai WK, Poon P, Woo J, Pang CP. Use of fasting urinary methylmalonic acid to screen for metabolic vitamin B12 deficiency in older persons. Nutrition. 2004 Sep; 20(9): 764-768. PMID: 15325684.   

Kwok T, Cheng G, Woo J, Lai WK, Pang CP. Independent effect of vitamin B12 deficiency on hematological status in older Chinese vegetarian women. Am J Hematol. 2002 Jul; 70(3): 186-90. PMID: 12111763. 

Miller DR, Specker BL, Ho ML, Norman EJ. Vitamin B-12 status in a macrobiotic community. Am J Clin Nutr. 1991 Feb; 53(2): 524-529. PMID: 1989421.

Mørkbak AL, Hvas AM, Lloyd-Wright Z, Sanders TA, Bleie O, Refsum H, Nygaard OK, Nexø E. Effect of vitamin B12 treatment on haptocorrin. Clin Chem. 2006 Jun; 52(6): 1, 104-1, 111. Epub: 2006 Apr 13. PMID: 16613998.   

Obeid R, Geisel J, Schorr H, Hübner U, Herrmann W. The impact of vegetarianism on some haematological parameters. Eur J Haematol. 2002 Nov-Dec; 69(5-6): 275-279. PMID: 12460231.

Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug; 74(2): 233-241. PMID: 11470726.

Schneede J, Dagnelie PC, van Staveren WA, Vollset SE, Refsum H, Ueland PM. Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets. Pediatr Res. 1994 Aug; 36(2): 194-201. PMID: 7970934.

van Dusseldorp M, Schneede J, Refsum H, Ueland PM, Thomas CM, de Boer E, van Staveren WA. Risk of persistent cobalamin deficiency in adolescents fed a macrobiotic diet in early life. Am J Clin Nutr. 1999 Apr ;69(4): 664-671. PMID: 10197567.

Articles Considered, but Excluded

List of Excluded Articles with Reason 


Article (A–H) Reason for Exclusion
Ambroszkiewicz J, Klemarczyk W, Chéchowska M, Gajewska J, Laskowska-Klita T. Serum homocysteine, folate, vitamin B12 and total antioxidant status in vegetarian children. Adv Med Sci. 2006; 51: 265-268. PMID: 17357323.  B12 was not measured using MMA.
Atamasirikul K, Kajanachumpol S, Wilairat P, Tantibhedhyangkul P. Clinical usefulness of a HPLC method for simultaneous quantitation of plasma homocysteine and cysteine. J Med Assoc Thai. 2008 Mar; 91(3): 338-344. PMID: 18575286.  B12 was not measured using MMA.
Barghouti FF, Younes NA, Halaseh LJ, Said TT, Ghraiz SM. High frequency of low serum levels of vitamin B12 among patients attending Jordan University Hospital. East Mediterr Health J. 2009 Jul-Aug; 15(4): 853-860. PMID: 20187536.  B12 was not measured using MMA
Bissoli L, Di Francesco V, Ballarin A, Mandragona R, Trespidi R, Brocco G, Caruso B, Bosello O, Zamboni M. Effect of vegetarian diet on homocysteine levels. Ann Nutr Metab. 2002; 46(2): 73-79. PMID: 12011576.   B12 was not measured using MMA
Carmel R, Mallidi PV, Vinarskiy S, Brar S, Frouhar Z.Hyperhomocysteinemia and cobalamin deficiency in young Asian Indians in the United States. Am J Hematol. 2002 Jun; 70(2): 107-114. PMID: 12111783.  B12 was not measured using MMA; no vegetarian subjects.
Chen CW, Lin YL, Lin TK, Lin CT, Chen BC, Lin CL. Total cardiovascular risk profile of Taiwanese vegetarians. Eur J Clin Nutr. 2008 Jan; 62(1): 138-144. Epub: 2007 Mar 14. PMID: 17356561.   B12 was not measured using MMA.
Cheng PJ, Chu DC, Chueh HY, See LC, Chang HC, Weng DR. Elevated maternal midtrimester serum free beta-human chorionic gonadotropin levels in vegetarian pregnancies that cause increased false-positive Down syndrome screening results. Am J Obstet Gynecol. 2004 Feb; 190(2): 442-447. PMID: 14981387. B12 was not measured using MMA.
Gamble MV, Ahsan H, Liu X, Factor-Litvak P, Ilievski V, Slavkovich V, Parvez F, Graziano JH. Folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh. Am J Clin Nutr. 2005 Jun; 81(6): 1, 372-1, 377. PMID: 15941889.  B12 was not measured using MMA.
Ganpule A, Yajnik CS, Fall CH, Rao S, Fisher DJ, Kanade A, Cooper C, Naik S, Joshi N, Lubree H, Deshpande V, Joglekar C. Bone mass in Indian children--relationships to maternal nutritional status and diet during pregnancy: The Pune Maternal Nutrition Study. J Clin Endocrinol Metab. 2006 Aug; 91(8): 2, 994-3, 001. Epub: 2006 May 30. PMID: 16735496.  Did not report baseline MMA levels.

Gilsing AM, Crowe FL, Lloyd-Wright Z, Sanders TA, Appleby PN, Allen NE, Key TJ. Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians and vegans: Results from a cross-sectional analysis of the EPIC-Oxford cohort study. Eur J Clin Nutr. 2010 Sep; 64(9): 933-939. Epub: 2010 Jul 21. PMID: 20648045. 

B12 was not measured using MMA.

Grant R, Bilgin A, Zeuschner C, Guy T, Pearce R, Hokin B, Ashton J. The relative impact of a vegetable-rich diet on key markers of health in a cohort of Australian adolescents. Asia Pac J Clin Nutr. 2008; 17(1): 107-115. PMID: 18364335. 

B12 was not measured using MMA.

Gupta AK, Damji A, Uppaluri A. Vitamin B12 deficiency. Prevalence among South Asians at a Toronto clinic. Can Fam Physician. 2004 May; 50: 743-747. PMID: 15171677. 

B12 was not measured using MMA; used serum B12 as the outcome. 
Hanumante NM, Wadia RS, Deshpande SS, Sanwalka NJ, Vaidya MV, Khadilkar AV. Vitamin B12 and homocysteine status in asymptomatic Indian toddlers. Indian J Pediatr. 2008 Jul; 75(7): 751-753. Epub: 2008 Aug 21. PMID: 18716749.   B12 was not measured using MMA.

Herrmann W, Geisel J. Vegetarian lifestyle and monitoring of vitamin B-12 status. Clin Chim Acta. 2002 Dec; 326(1-2): 47-59. Review. PMID: 12417096.

Review article. 
Huang YC, Chang SJ, Chiu YT, Chang HH, Cheng CH. The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians. Eur J Nutr. 2003 Apr; 42(2): 84-90. PMID: 12638029.  B12 was not measured using MMA. 
Hung CJ, Huang PC, Lu SC, Li YH, Huang HB, Lin BF, Chang SJ, Chou HF. Plasma homocysteine levels in Taiwanese vegetarians are higher than those of omnivores. J Nutr. 2002 Feb; 132(2): 152-158. PMID: 11823571.  B12 was not measured using MMA. 



Article (K–M) Reason for Exclusion
Kalita J, Kumar G, Bansal V, Misra UK. Relationship of homocysteine with other risk factors and outcome of ischemic stroke. Clin Neurol Neurosurg. 2009 May; 111(4): 364-367. Epub: 2009 Jan 30. PMID: 19185985.  B12 was not measured using MMA
Karabudak E, Kiziltan G, Cigerim N. A comparison of some of the cardiovascular risk factors in vegetarian and omnivorous Turkish females. J Hum Nutr Diet. 2008 Feb; 21(1): 13-22. PMID: 18184390.  B12 was not measured using MMA. 
Kazimírová A, Barancoková M, Krajcovicová-Kudlácková M, Volkovová K, Staruchová M, Valachovicová M, Pauková V, Blazícek P, Wsólová L, Dusinská M. The relationship between micronuclei in human lymphocytes and selected micronutrients in vegetarians and non-vegetarians. Mutat Res. 2006 Dec 10; 611(1-2): 64-70. Epub: 2006 Sep 15. PMID: 16978915.  B12 was not measured using MMA. 
Koebnick C, Hoffmann I, Dagnelie PC, Heins UA, Wickramasinghe SN, Ratnayaka ID, Gruendel S, Lindemans J, Leitzmann C. Long-term ovo-lacto vegetarian diet impairs vitamin B-12 status in pregnant women. J Nutr. 2004 Dec; 134(12): 3, 319-3, 326. PMID: 15570032. B12 was not measured using MMA 
Koebnick C, Garcia AL, Dagnelie PC, Strassner C, Lindemans J, Katz N, Leitzmann C, Hoffmann I. Long-term consumption of a raw food diet is associated with favorable serum LDL cholesterol and triglycerides but also with elevated plasma homocysteine and low serum HDL cholesterol in humans. J Nutr. 2005 Oct; 135(10): 2, 372-2, 378. PMID: 16177198. Did not report MMA levels.
Konstantinova SV, Vollset SE, Berstad P, Ueland PM, Drevon CA, Refsum H, Tell GS. Dietary predictors of plasma total homocysteine in the Hordaland Homocysteine Study. Br J Nutr. 2007 Jul; 98(1): 201-210. Epub: 2007 Mar 29. PMID: 17391553. B12 was not measured using MMA. 
Krajcovicova-Kudlackova M, Blazicek P, Mislanova C, Valachovicova M, Paukova V, Spustova V.Nutritional determinants of plasma homocysteine. Bratisl Lek Listy. 2007; 108(12): 510-515. PMID: 18309641. B12 was not measured using MMA. 
Krajcovicová-Kudlácková M, Blazícek P, Babinská K, Kopcová J, Klvanová J, Béderová A, Magálová T. Traditional and alternative nutrition: Levels of homocysteine and lipid parameters in adults. Scand J Clin Lab Invest. 2000 Dec; 60(8): 657-664. PMID: 11218148.   B12 was not measured using MMA. 
Krivosíková Z, Krajcovicová-Kudlácková M, Spustová V, Stefíková K, Valachovicová M, Blazícek P, N'mcová T. The association between high plasma homocysteine levels and lower bone mineral density in Slovak women: The impact of vegetarian diet. Eur J Nutr. 2010 Apr; 49(3): 147-153. Epub: 2009 Oct 7. PMID: 19809862.  B12 was not measured using MMA. 
Kumar J, Das SK, Sharma P, Karthikeyan G, Ramakrishnan L, Sengupta S. Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population. J Hum Genet. 2005; 50(12): 655-663. Epub: 2005 Oct 22. PMID: 16244782.   B12 was not measured using MMA. 
Kumar J, Garg G, Sundaramoorthy E, Prasad PV, Karthikeyan G, Ramakrishnan L, Ghosh S, Sengupta S. Vitamin B12 deficiency is associated with coronary artery disease in an Indian population. Clin Chem Lab Med. 2009; 47(3): 334-338. PMID: 19676146.    Did not report MMA levels.
Larsson CL, Johansson GK. Dietary intake and nutritional status of young vegans and omnivores in Sweden. Am J Clin Nutr. 2002 Jul; 76(1): 100-106. PMID: 12081822.  B12 was not measured using MMA.  
Leung SS, Lee RH, Sung RY, Luo HY, Kam CW, Yuen MP, Hjelm M, Lee SH. Growth and nutrition of Chinese vegetarian children in Hong Kong. J Paediatr Child Health. 2001 Jun; 37(3): 247-253. PMID: 11468039.   B12 was not measured using MMA; children.  
Levin SM, Ferdowsian HR, Hoover VJ, Green AA, Barnard ND. A worksite programme significantly alters nutrient intakes. Public Health Nutr. 2010 Oct; 13(10): 1, 629-1, 635. Epub: 2010 Jan 15. PMID: 20074388.   B12 was not measured using MMA.  
Majchrzak D, Singer I, Männer M, Rust P, Genser D, Wagner KH, Elmadfa I. B-vitamin status and concentrations of homocysteine in Austrian omnivores, vegetarians and vegans. Ann Nutr Metab. 2006; 50(6): 485-491. Epub: 2006 Sep 19. PMID: 16988496.   B12 was not measured using MMA.  
Misra A, Vikram NK, Pandey RM, Dwivedi M, Ahmad FU, Luthra K, Jain K, Khanna N, Devi JR, Sharma R, Guleria R. Hyperhomocysteinemia, and low intakes of folic acid and vitamin B12 in urban North India. Eur J Nutr. 2002 Apr; 41(2): 68-77. PMID: 12083316.   B12 was not measured using MMA.   
Mohanty D, Kakkar N, Cherian J, Das S, Britt RP. Elevated red cell volume in North Indian students. Southeast Asian J Trop Med Public Health. 2006 Nov; 37(6): 1, 224-1, 228. PMID: 17333781.   B12 was not measured using MMA.   
Morad M, Gringols M, Kandel I, Merrick J.Vitamin B12 deficiency in persons with intellectual disability in a vegetarian residential care community.Scientific World Journal. 2005 Jan 21; 5: 58-61. PMID: 15674451.  B12 was not measured using MMA.  


Article (N–Z) Reason for Exclusion
Nakamoto K, Watanabe S, Kudo H, Tanaka A. Nutritional characteristics of middle-aged Japanese vegetarians. J Atheroscler Thromb. 2008 Jun; 15(3): 122-129. PMID: 18603818. B12 was not measured using MMA.
Rush EC, Chhichhia P, Hinckson E, Nabiryo C. Dietary patterns and vitamin B(12) status of migrant Indian preadolescent girls. Eur J Clin Nutr. 2009 Apr; 63(4): 585-587. Epub: 2007 Dec 19. PMID: 18091765. Small sample size.
Su TC, Jeng JS, Wang JD, Torng PL, Chang SJ, Chen CF, Liau CS. Homocysteine, circulating vascular cell adhesion molecule and carotid atherosclerosis in postmenopausal vegetarian women and omnivores. Atherosclerosis. 2006 Feb; 184(2): 3563-62. Epub: 2005 Jul 6. PMID: 16005009.   B12 was not measured using MMA.
Sebeková K, Krajcovicová-Kudlácková M, Blazícek P, Parrák V, Schinzel R, Heidland A. Functional hyperhomocysteinemia in healthy vegetarians: no association with advanced glycation end products, markers of protein oxidation, or lipid peroxidation after correction with vitamin B(12). Clin Chem. 2003 Jun; 49(6 Pt 1): 983-986. No abstract available. PMID: 12766005. B12 was not measured using MMA.
Specker BL. Nutritional concerns of lactating women consuming vegetarian diets. Am J Clin Nutr. 1994 May; 59(5 Suppl): 1, 182S-1, 186S. Review. PMID: 8172121. Review article.
Specker BL, Black A, Allen L, Morrow F. Vitamin B-12: Low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. Am J Clin Nutr. 1990 Dec; 52(6): 1, 073-1, 076. PMID: 2239784. Small sample size.
Sütterlin MW, Bussen SS, Rieger L, Dietl J, Steck T. Serum folate and Vitamin B12 levels in women using modern oral contraceptives (OC) containing 20 microg ethinyl estradiol. Eur J Obstet Gynecol Reprod Biol. 2003 Mar 26; 107(1): 57-61. PMID: 12593896.  B12 was not measured using MMA.
Tiahou G, Dupuy AM, Jaussent I, Sees D, Cristol JP, Badiou S. Determinants of homocysteine levels in Ivorian rural population. Int J Vitam Nutr Res. 2009 Sep; 79(5-6): 319-327. PMID: 20533218. B12 was not measured using MMA; used serum cobalamin.
Waldmann A, Koschizke JW, Leitzmann C, Hahn A. German vegan study: diet, life-style factors, and cardiovascular risk profile. Ann Nutr Metab. 2005 Nov-Dec; 49(6): 366-372. Epub: 2005 Oct 11. PMID: 16219987.  B12 was not measured using MMA; used serum cobalamin.
Waldmann A, Koschizke JW, Leitzmann C, Hahn A.Homocysteine and cobalamin status in German vegans. Public Health Nutr. 2004 May; 7(3): 467-472. PMID: 15153278. B12 was not measured using MMA.
Yajnik CS, Lubree HG, Thuse NV, Ramdas LV, Deshpande SS, Deshpande VU, Deshpande JA, Uradey BS, Ganpule AA, Naik SS, Joshi NP, Farrant H, Refsum H. Oral vitamin B12 supplementation reduces plasma total homocysteine concentration in women in India. Asia Pac J Clin Nutr. 2007; 16(1): 103-109. PMID: 17215186.  B12 was not measured using MMA.
Yajnik CS, Deshpande SS, Lubree HG, Naik SS, Bhat DS, Uradey BS, Deshpande JA, Rege SS, Refsum H, Yudkin JS. Vitamin B12 deficiency and hyperhomocysteinemia in rural and urban Indians. J Assoc Physicians India. 2006 Oct; 54: 775-782. PMID: 17214273.  B12 was not measured using MMA; measured plasma B12.
Yen CE, Yen CH, Cheng CH, Huang YC. Vitamin B-12 status is not associated with plasma homocysteine in parents and their preschool children: Lacto-ovo, lacto, and ovo vegetarians and omnivores. J Am Coll Nutr. 2010 Feb; 29(1): 7-13. PMID: 20595640.  B12 was not measured using MMA.

Summary of Articles Identified to Review

Number of Included Primary Research Articles Identified from all sources: 17

Number of Included Review Articles Identified from all sources: 0

Total Number of Included Articles: 17

Number of Articles Considered but Excluded: 47

Total Number of Articles Considered: 64