Blood Reviews
Volume 21, Issue 3 , Pages 113-130 , May 2007

Disorders of cobalamin (Vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and treatment

References 

  1. Green R, Kinsella L. Current concepts in the diagnosis of cobalamin deficiency. Neurology. 1995;45:1435–1440
  2. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency. A guide for the primary care physician. Arch Intern Med. 1999;159:1289–1298
  3. Baik HW, Russell RM. Vitamin B12 Deficiency in the Elderly. Annu Rev Nutr. 1999;19:357–377
  4. Carmel R. Current Concepts in Cobalamin Deficiency. Annu Rev Med. 2000;51:357–375
  5. Carmel R, Rasmussen K, Jacobsen DW, Green R. Comparison of the deoxyuridine suppression test with serum levels of methylmalonic acid and homocysteine in mild cobalamin deficiency. Brit J Haematol. 1996;93:311–318
  6. Choi S-W, Friso S, Ghandour H, Bagley PJ, Selhub J, Mason JB. Vitamin B12 deficiency induces anomalies of base substitution and methylation in the DNA of rat colonic epithelium. J Nutr. 2004;134:750–755
  7. Herbert V. Recommended dietary intakes (RDI) of vitamin B12 in humans. Am J Clin Nutr. 1987;45:671–678
  8. Bailey LB. Folate and vitamin B12 recommended intakes and status in the United States. Nutr Rev. 2004;62:S14–S20
  9. Fenech MF, Dresoti IE, Rinaldi JR. Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis. 1997;18:1329–1336
  10. Fenech M, Aitken C, Rinaldi J. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis. 1998;19:1163–1171
  11. Kapiszewska M, Kalemba M, Wojciech U, Milewicz T. Uracil misincorporation into DNA of leukocytes of young women with positive folate balance depends on plasma vitamin B12 concentrations and methylenetetrahydrofolate reductase polymorphisms. A pilot study. J Nutr Biochem. 2005;16:467–478
  12. Pfohl-Leszkowicz A, Keith G, Dirheimer G. Effect of cobalamin derivatives on in vitro enzymatic DNA methylation: methylcobalamin can act as a methyl donor. Biochem. 1991;30:8045–8051
  13. Lorsch JR, Szostak JW. In vitro selection of RNA aptmers specific for cyanocobalamin. Biochem. 1994;33:973–982
  14. Lott WB, Takyar SS, Tuppen J, et al. Vitamin B12 and hepatitis C: molecular biology and human pathology. Proc Natl Acad Sci. 2001;98:4916–4921
  15. Takyar SS, Gowans EJ, Lott WB. Vitamin B12 stalls the 80 S ribosomal complex on the hepatitis C internal ribosome entry site. J Mol Biol. 2002;319:1–8
  16. Li D, Lott WB, Martyn J, Haqshenas G, Gowans EJ. Differential effects on the hepatitis C virus (HCV) internal ribosome entry site by vitamin B12 and the HCV core protein. J Virol. 2004;78:12075–12081
  17. Gulati S, Brody LC, Banerjee R. Posttranscriptional regulation of mammalian methionine synthase by B12. Biochem Biophys Res Commun. 1999;259:436–442
  18. Oltean S, Banerjee R. Nutritional modulation of gene expression and homocysteine utilization by vitamin B12. J Biol Chem. 2003;278:20778–20784
  19. Oltean S, Banerjee R. A B12-responsive IRES element in human methionine synthase. J Biol Chem. 2005;280:32662–32668
  20. Yamada K, Kawata T, Wada M, et al. Extremely low activity of methionine synthase in vitamin B12-deficient rats may be related to effects on coenzyme stabilization rather than to changes in coenzyme function. J Nutr. 2000;130:1894–1900
  21. Solomon LR, Hillman RS. Vitamin B6 metabolism in human red cells: I. Variations in human red cells. Enzyme. 1978;23:262–273
  22. Solomon LR, Hillman RS. Regulation of vitamin B6 metabolism in human red cells. Am J Clin Nutr. 1979;32:1824–1831
  23. Solomon LR, Hillman RS. Vitamin B6 metabolism in idiopathic sideroblastic anaemia and related disorders. Brit J Haematol. 1979;42:239–253
  24. Brouwer M, Chamulitrat W, Ferruzzi G, Sauls DL, Weinberg JB. Nitric oxide interactions with cobalamins: biochemical and functional consequences. Blood. 1996;88:1857–1864
  25. Wolak M, Zahl A, Schneppensieper T, Stochel G, van Eldik R. Kinetics and mechanism of the reversible binding of nitric oxide to reduced cobalamin B(12r)(Cob(II)alamin. J Am Chem Soc. 2001;123:9780–9791
  26. Sharma VS, Pilz RB, Boss GR, Magde D. Reactions of nitric oxide with vitamin B12 and its precursor, cobinamide. Biochem. 2003;42:8900–8908
  27. Weinberg JB, Chen YC, Beasley BE, Ghosh DK. Cobalamins and cobinamides inhibit nitric oxide synthase enzymatic activity. Blood. 2005;106:627a;Abstract
  28. Stucker M, Pieck C, Stoerb C, Niedner R, Hartung J, Altmeyer P. Topical vitamin B12 – a new therapeutic approach in atopic dermatitis – evaluation of efficacy and tolerability in a randomized placebo-controlled multicentre trial. Brit J Dermatol. 2004;150:977–983
  29. Weinberg JB, Shugars DC, Sherman PA, Sauls DL, Fyfe JA. Cobalamin inhibition of HIV-1 integrase and integration of HIV-DNA into cellular DNA. Biochem Biophys Res Commun. 1998;246:393–397
  30. Weinberg JB, Sauls DL, Misukonis MA, Shugars DC. Inhibition of productive human immunodeficiency virus-1 infection by cobalamins. Blood. 1995;86:1281–1287
  31. Tang AM, Graham NMH, Chandra RK, Saah AJ. Low serum vitamin B12 concentrations are associated with faster human immunodeficiency type 1 (HIV-1) disease progression. J Nutr. 1997;127:345–351
  32. Wickramasinghe SN, Fida S. Bone marrow cells from vitamin B12- and folate-deficient patients misincorporate uracil into DNA. Blood. 1994;83:1656–1661
  33. Wickramasinghe SN. The wide spectrum of unresolved issues of megaloblastic anemia. 1999;36:3–18.
  34. Ingram CF, Davidoff AN, Marais E, Sherman GG, Mendelow BV. Evaluation of DNA analysis for evidence of apoptosis in megalobalstic anemia. Brit J Haematol. 1997;96:576–583
  35. Perry J, Chanarin I, Deacon R, Lumb M. Methylation of DNA in megaloblastic anaemia. J Clin Pathol. 1990;43:211–212
  36. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine. 1991;70:229–246
  37. Aaron S, Sudhir K, Vijayan J, Jacob J, Alexander M, Gnanamuthu C. Clinical and laboratory features and response to treatment in patients presenting with vitamin B12 deficiency-related neurologic syndromes. Neurol India. 2005;53:55–58
  38. Lee M, Chang H-S, Wu H-T, Weng H-H, Chen C-M. Intractable epilepsy as the presentation of vitamin B12 deficiency in the absence of macrocytic anemia. Epilepsia. 2005;46:1147–1148
  39. Chatterjee A, Yapundich R, Palmer CA, Marson DC, Mitchell G. Leukoencephalopathy associated with cobalamin deficiency. Neruology. 1996;46:832–834
  40. Ahn T-B, Cho J-W, Jeon BS. Unusual neurological presentations of vitamin B12 deficiency. Europ J Neurol. 2004;11:339–341
  41. Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in the identification of cobalamin-deficiency polyneuropathy. Arch Neurol. 2003;60:1296–1301
  42. Beitzke M, Pfister P, Fortin J, Skrabal F. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Autonomic Neurosci: Basic and Clinical. 2002;97:45–54
  43. Al-Shubaili AF, Farah SA, Hussein JM, Trontelj JV, Khuraibet AJ. Axonal and demyelinating neuropathy with reversible proximal conduction block, an unusual feature of vitamin B12 deficiency. Muscle Nerve. 1998;21:1341–1343
  44. Hemmer B, Glocker FX, Schumacher M, Deuschl G, Lucking CH. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psych. 1998;65:822–827
  45. Yu MK, Rodgers GM. Detection of occult cobalamin deficiency by magnetic resonance imaging. Am J Hematol. 2000;65:83–84
  46. Lindenbaum J, Healton EB, Savage DG, Brust JCM, Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Eng J Med. 1988;318:1720–1728
  47. Metz J. Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr. 1992;12:59–79
  48. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J. 1993;7:1344–1353
  49. Carmel R, Karnaze DS, Weiner JM. Neurologic abnormalities in cobalamin deficiency are associated with higher cobalamin “analogue” values than are hematologic abnormalities. J Lab Clin Med. 1988;111:57–62
  50. Green R, Jacobsen DW. No discrepancy between vitamin B12 radioassays using purified intrinsic factor and R-binder in bats developing cobalamin deficiency. Clin Res. 1980;28:74A
  51. Kondo H, Osborne ML, Kolhouse JF, et al. Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats. J Clin Invest. 1981;67:1270–1283
  52. Van der Westhuyzen J, Fernandes-Costa F, Metz J, Kanazawa S, Drivas G, Herbert V. Cobalamin (vitamin B12) analogs are absent in plasma of fruit bats exposed to nitrous oxide. Proc Soc Exp Biol Med. 1982;171:88–91
  53. Carmel R, Melnyk S, James SJ. Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Blood. 2003;101:3302–3308
  54. Carmel R, Pullarrkat V. Gene polymorphisms associated with diminished activity of 5,10-methylenetetrahydrofolate reductase do not explain the clinical manifestations of cobalamin deficiency. Brit J Haematol. 2003;12:907–909
  55. Adachi K, Izumi M, Osano Y, et al. Polyamine concentrations in the brain of vitamin-B12 deficient rats. Exp Biol Med. 2003;228:1069–1071
  56. Scalabrino G, Buccellato FR, Veber D, Mutti E. New basis for the neurotrophic action of vitamin B12. Clin Chem Lab Med. 2003;41:1435–1437
  57. Scalabrino G. Cobalamin (vitamin B12) in subacute combined degeneration and beyond: traditional interpretations and novel theories. Exp Neurol. 2005;192:463–479
  58. Peracchi M, Bamonti Catena F, Pomati M, De Franceschi M, Scalabrino G. Human cobalamin deficiency: alterations in serum tumour necrosis factor-α and epidermal growth factor. Exp J Haematol. 2001;67:123–127
  59. Chanarin I, Stephenson E. Vegetarian diet and cobalamin deficiency: their association with tuberculosis. J Clin Pathol. 1988;41:759–762
  60. Fata F, Herzlich BC, Schiffman G, Ast AL. Impaired antibody responses to pneumococcal polysaccharide in elderly patients with low serum vitamin B12 levels. Ann Int Med. 1996;124:299–304
  61. Imamura M, Fujimura K, Kuramoto A. Lymphocyte subpopulations in pernicious anemia. N Eng J Med. 1984;311:56
  62. Wodzinski MA, Forrest MJ, Barnett D, et al. Lymphocyte subpopulations in patients with hydroxocobalamin responsive megaloblastic anaemia. J Clin Pathol. 1985;38:582–584
  63. Gogos CA, Kapatais-Zoumbos KN, Zoumbos NC. Lymphocyte subpopulations in megaloblastic anemia due to vitamin B12 deficiency. Scand J Haematol. 1986;37:316–318
  64. Kubota K, Arai T, Tamura J, et al. Restoration of decreased suppressor cells by vitamin B12 therapy in patients with pernicious anemia. Am J Hematol. 1987;24:221–223
  65. Kubota K, Kurabayashi H, Kawada E, et al. Restoration of abnormally high CD4/CD8 ratio and low natural killer activity by vitamin B12 in a patient with post-gastrectomy megaloblastic anemia. Int Med. 1992;31:125–126
  66. Tamura J, Kubota K, Murakami H, et al. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment. Clin Exp Immunol. 1999;116:28–32
  67. Dhonukshe-Rutten RAM, Lips M, de Jong N, et al. Vitamin B12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. J Nutr. 2003;133:801–807
  68. Tucker KL, Hannan MT, Qiao N, et al. Low plasma vitamin B12 is associated with lower BMD: the Framingham osteoporosis study. J Bone Miner Res. 2005;20:152–158
  69. Carmel R, Lau K-HW, Baylink DJ, Saxena S, Singer FR. Cobalamin and osteoblast-specific proteins. N Eng J Med. 1988;319:70–75
  70. Kim GS, Kim C-H, Park JY, Lee K-U, Park CS. Effects of vitamin B12 on cell proliferation and cellular alkaline phosphatase activity in human bone marrow stromal osteoprogenitor cells and UMR106 osteoblastic cells. Metabolism. 1996;45:1443–1446
  71. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke – a randomized control trial. JAMA. 2005;239:1082–1088
  72. Nanes MS. Tumor necrosis factor α: molecular and cellular mechanisms in skeletal pathology. Gene. 2003;90:1–15
  73. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid and homocysteine testing. Blood. 2005;105:978–985
  74. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. 1990;76:871–881
  75. Matchar DB, McCrory DC, Millington DS, Feussner JR. Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci. 1994;308:276–283
  76. Carmel R, Vasireddy H, Aurangzeb I, George K. High serum cobalamin levels in the clinical setting – clinical associations and holo-transcobalamin changes. Clin Lab Haem. 2001;23:365–371
  77. Ermens AAM, Vlasveld LT, Lindemans J. Significance of elevated cobalamin (vitamin B12) levels in blood. Clin Biochem. 2003;36:585–590
  78. Faurschou M, Nielsen OJ, Jensen MK, Hasselbalch HC. High prevalence of hyperhomocysteinemia due to marginal deficiency of cobalamin or folate in chronic myeloproliferative disorders. Am J Hematol. 2000;65:136–140
  79. Baker H, Leevy CB, DeAngelis B, Frank O, Baker ER. Cobalamin (vitamin B12) and holotranscobalamin changes in plasma and liver tissue in alcoholics with liver disease. J Am Coll Nutr. 1998;17:235–238
  80. Lambert D, Benhayoun S, Adjalla C, et al. Alcoholic cirrhosis and cobalamin metabolism. Digestion. 1997;58:64–71
  81. Carmel R, Brar S, Frouhar Z. Plasma total transcobalamin I: Ethnic/Racial patterns and comparison with lactoferrin. Am J Clin Pathol. 2001;116:576–580
  82. Carmel R. Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin Chem. 2003;49:1367–1374
  83. Koebnick C, Hein UA, Dagnelie PC, et al. Longitudinal concentrations of vitamin B12 and vitamin B12-binding proteins during uncomplicated pregnancy. Clin Chem. 2002;48:928–933
  84. Pardo J, Peled Y, Hod M, Sela BA, Rafael ZB, Orvieto R. Evaluation of low serum vitamin B12 in the nonanemic pregnant patient. Human Reproduction. 2000;15:224–226
  85. Kalamegham R, Krishnaswamy K. Functional significance of low serum vitamin B12 levels in pregnancy. Int J Vit Nutr Res. 1977;47:52–56
  86. McMullin MF, Young PB, Bailie KEM, Savage GA, Lappin TRJ, White R. Homocysteine and methylmalonic acid as indicators of folate and vitamin B12 deficiency in pregnancy. Clin Lab Haem. 2001;23:161–165
  87. Monsen A-LB, Ueland PM, Vollset SE, et al. Determinants of cobalamin staus in newborns. Pediatrics. 2001;108:624–630
  88. Metz J, McGrath K, Bennett M, Hyland K, Bottiglieri T. Biochemical indices of vitamin B12 nutrition in pregnant patients with subnormal serum vitamin B12 levels. Am J Hematol. 1995;48:251–255
  89. Adams MJ, Khoury MJ, Scanlon KS, Stevenson RE, et al. Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects. Tetralogy. 1995;51:311–317
  90. Gardyn J, Mittelman M, Zlotnik J, Sela BA, Cohen AM. Oral contraceptives can cause falsely low vitamin B12 levels. Acta Haematologica. 2000;104:22–24
  91. Shojania AM. Oral contraceptives: effects on folate and vitamin B12 metabolism. CMA J. 1982;126:244–247
  92. Shojania AM, Wylie B. The effect of oral contraceptives on vitamin B12 metabolism. Am J Obst Gyn. 1979;135:129–134
  93. Riedel B, Bjorke Monsen A-L, Ueland PM, Schneede J. Effects of oral contraceptives and hormone replacement therapy on markers of cobalamin status. Clin Chem. 2005;51:778–781
  94. Sutterlin MW, Bussen SS, Rieger L, Dietl J, Steck T. Serum folate and vitamin B12 levels in women using modern oral contraceptives (OC) containing 20 μg ethinyl estradiol. Europ J Obstet Gyn Reproduc Biol. 2003;107:57–61
  95. Carmel R, Howard JM, Green R, Jacobsen DW, Azen C. Hormone replacement therapy and cobalamin status in elderly women. Am J Clin Nutr. 1996;64:856–859
  96. Hansen OP, Drivsholm A, Hippe E. Vitamin B12 metabolism in myelomatosis. Scand J Haematol. 1977;18:395–402
  97. Ermens AA, Sonneveid P, Michiels JJ, Lindemans J. Increased uptake and accumulation of cobalamin by multiple myeloma bone marrow cells as a possible cause of low serum cobalamin. Europ J Haematol. 1993;50:57–59
  98. Remacha AF, Cadafalch J. Cobalamin deficiency in patients infected with the human immunodeficiency virus. Semin Hematol. 1999;36:75–87
  99. Hansen M, Gimsing P, Ingeberg S, Jans H, Nexo E. Cobalamin binding in patients with HIV infection. Eur J Haematol. 1992;48:228–231
  100. Remacha AF, Cadafalch J, Sardar P, Barcelo M, Fuster M. Vitamin B12 metabolism in HIV-infected patients in the age of highly active retroviral therapy: role of homocysteine in assessing vitamin B12 status. Am J Clin Nutr. 2003;77:420–424
  101. Kieburtz KD, Giang DW, Schiffer RB, Vakil N. Abnormal vitamin B12 metabolism in human immunodeficiency virus infection: Association with neurologic dysfunction. Arch Neurol. 1991;48:312–314
  102. Puri V, Chaudry N, Goel S, Gulati P, Nehru R, Chowdhury D. Vitamin B12 deficiency: a clinical and electrophysiological profile. Electromyogr Clin Neurophysiol. 2005;273–284
  103. Namour F, Olivier J-L, Abdelmouttaleb A, et al. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells in Caucasians: relation to transcobalamin and homocysteine concentration in blood. Blood. 2001;97:1092–1098
  104. Miller JW, Ramos MI, Garrod MG, Flynn MA, Green R. Transcobalamin II 755G>C polymorphism and indices of vitamin B12 status in healthy older adults. Blood. 2002;100:718–720
  105. Lievers KJA, Afman LA, Kluijtmans LAJ, et al. Polymorphisms in the transcobalamin gene: association with plasma homocysteine in healthy individuals and vascular disease patients. Clin Chem. 2002;48:1383–1389
  106. von Castel-Dunwoody KM, Kauwell GPA, Shelnutt KP, et al. Transcobalamin 776G→C polymorphism negatively effects vitamin B12 metabolism. Am J Clin Nutr. 2005;81:1436–1441
  107. Gale DP, Cobbold JF, Chataway J. Steroid-responsive functional B12 deficiency in association with functional transcobalamin II polymorphism 766 C→G. Eur J Haematol. 2006;76:75–78
  108. Wans S, Schutter K, Jacuicza S, Muller A, Luley C, Dierkea J. Analysis of the transcobalamin II 776G>C (259P>R) single nucleotide polymorphism by denaturing HPLC in healthy elderly: associations with cobalamin, homocysteine and holotranscobalamin II. Clin Chem Lab Med. 2003;41:1532–1536
  109. Teplitsky V, Huminer D, Zoldan J, Pitlik S, Shohat M, Mittelman M. Hereditary partial transcobalamin II deficiency with neurologic mental and hematologic abnormalities in children and adults. Isr Med Assn J. 2003;5:868–872
  110. Zittoun J, Zittoun R. Modern clinical testing strategies in cobalamin and folate deficiency. Semin Hematol. 1999;36:35–46
  111. Carmel R, Brar S, Agrawal A, Penha PD. Failure of assay to identify low cobalamin concentrations (letter). Clin Chem. 2000;46:2017–2018
  112. Vlasveld LT, van’t Wout JW, Meeuwissen P, Castel A. High measured cobalamin (vitamin B12) concentration attributable to an analytical problem in testing serum from a patient with pernicious anemia. Clin Chem. 2006;52:157–158
  113. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid and total homocysteine concentrations. Am J Hematol. 1990;34:99–107
  114. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. 1990;76:871–881
  115. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med. 1994;96:239–246
  116. Moelby L, Rasmussen K, Jensen MK, Pedersen KO. The relationship between clinically confirmed cobalamin deficiency and serum methylmalonic acid. J Intern Med. 1990;228:3733–3738
  117. Rasmussen K, Moller J, Ostergaard K, Ostergaard KM, Jensen J. Methylmalonic acid concentrations in serum of normal subjects: Biologic variability and effect of oral L-isoleucine loads before and after intramuscular administration of cobalamin. Clin Chem. 1990;36:1295–1299
  118. Hvas AM, Juul S, Gerdes LU, Nexo E. The marker of cobalamin deficiency, plasma methylmalonic acid correlates to plasma creatinine. J Intern Med. 2000;247:507–512
  119. Moelby L, Rasmussen K, Ring T, Nielsen G. Relationship between methylmalonic acid and cobalamin in uremia. Kidney Intl. 2000;57:265–273
  120. Refsum H, Smith DA, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem. 2004;50:3–32
  121. Garg UC, Zheng Z-J, Folsom AR, et al. Short-term and long-term variability of plasma homocysteine measurement. Clin Chem. 1997;43:141–145
  122. Thirup P, Ekelund S. Day-to-day, postprandial, and orthostatic variation of total plasma homocysteine. Clin Chem. 1999;45:1280–1283
  123. Santhosh-Kumar CR, Deutsch JC, Ryder JW, Kolhouse JF. Unpredictable intra-individual variations in serum homocysteine levels on folic acid supplementation. Europ J Clin Nutr. 1997;51:188–192
  124. Herzlich B, Herbert V. Depletion of holotranscobalamin II: an early sign of negative vitamin B12 balance. Lab Invest. 1988;58:332–337
  125. Hvas A-M, Nexo E. Holotranscobalamin as a predictor of vitamin B12 status. Clin Chem Lab Med. 2003;41:1489–1492
  126. Hvas A-M, Nexo E. Holotranscobalamin – a first choice assay for diagnosing early vitamin B12 deficiency. J Int Med. 2005;257:289–298
  127. Chen X, Remacha AF, Pilar Sarda M, Carmel R. Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holo-transcobalamin II. Am J Clin Nutr. 2005;81:110–114
  128. Wickramasinghe SN, Ratnayaka ID. Limited value of serum holo-transcobalamin II measurements in the differential diagnosis of macrocytosis. J Clin Pathol. 1996;49:755–758
  129. Molad Y, Rachmilewitz B, Sidi Y, Pinkhas J, Weinberger A. Serum cobalamin and transcobalamin levels in systemic lupus erythematosis. Am J Med. 1990;88:141–144
  130. Carmel R, Hollander D. Extreme elevation of transcobalamin II levels in multiple myeloma and other disorders. Blood. 1978;51:1057–1063
  131. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate and homocysteine. Hematology. 2003;62–81
  132. Karnaze DS, Carmel R. Neurologic and evoked potential abnormalities in subtle cobalamin deficiency states including deficiency without anemia and with normal absorption of free cobalamin. Arch Neurol. 1990;47:1008–1012
  133. Louwman MWJ, van Dusseldorp M, van de Vijver FJR, et al. Signs of impaired cognitive function in adolescents with marginal cobalamin status. Am J Clin Nutr. 2000;72:762–769
  134. Carmel R, Gott PS, Waters CH, et al. The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities. Eur J Haematol. 1995;54:245–253
  135. Andres E, Affenberger S, Vinzio S, et al. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am J Clin Nutr. 2005;118:1154–1159
  136. Hvas A-M, Ellegaard J, Nexo E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Int Med. 2001;161:1534–1541
  137. Hvas A-M, Ellegaard J, Nexo E. Vitamin B12 treatment normalizes metabolic markers but has limited clinical effect: A randomized placebo-controlled study. Clin Chem. 2001;47:1396–1404
  138. Hvas A-M, Juul S, Nexo E, Ellegaard J. Vitamin B12 treatment has limited effect on health-related quality of life among individuals with elevated plasma methylmalonic acid: a randomized placebo-controlled study. J Int Med. 2003;253:146–152
  139. Marie RM, Le Biez E, Busson P, Schaeffer S. Nitrous oxide anesthesia-associated myelopathy. Arch Neurol. 2000;57:380–382
  140. Niyikza C, Baker SD, Seitz DE, Walling JM, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Molec Cancer Therapeutics. 2002;1:545–552
  141. Hazarika M, White RM, Johnson JR, Pazdur R. FDA drug approval summaries: premetrexed (Alimta). Oncologist. 2004;9:482–488
  142. Rasmussen K, Nathan E. The clinical evaluation of cobalamin determination of methylmalonic acid in serum or urine is not invalidated by the presence of heterozygous methylmalonic academia. J Clin Chem Clin Biochem. 1990;28:419–421
  143. Hvas AM, Ellegaard J, Lous J, Nexo E. Health technology assessment in clinical biochemistry. Methylmalonic acid: a Danish showcase. Scand J Clin Lab Invest. 2003;63:319–330
  144. Ledley FD, Levy HL, Shih VE, Benjamin R, Mahoney MJ. Benign methylmalonic aciduria. New Engl J Med. 1984;311:1015–1018
  145. Birn H, Nexo E, Christensen EI, Nielsen R. Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis. Nephrol Dial Transpl. 2003;18:1095–1100
  146. Marcus DL, Shadick N, Crantz J, Gray J, Hernandez F, Freedman ML. Low serum B12 levels in a hematologically normal elderly subpopulation. J Am Geriatr Soc. 1987;35:635–638
  147. van Asselt DZB, Thomas CMG, Segers MFG, Blom HJ, Wevers RA, Hoefnagels WHL. Cobalamin-binding proteins in normal and cobalamin-deficient older subjects. Ann Clin Biochem. 2003;40:65–69
  148. Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea M, Azen C. Serum cobalamin, homocysteine and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities. Am J Clin Nutr. 1999;70:904–910
  149. Clarke R, Refsum H, Birks J, et al. Screening for vitamin B12 and folate deficiency in older patients. Am J Clin Nutr. 2003;77:1241–1247
  150. Campbell AK, Miller JW, Green R, Haan MN, Allen LH. Plasma vitamin B12 concentations in an elderly Latino population are predicted by serum gastrin concentrations and by crystalline vitamin B12 intake. J Nutr. 2003;133:2770–2776
  151. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Elevated serum methylmalonic acid concentrations are common among elderly Americans. J Nutr. 2002;132:2799–2803
  152. Bates CJ, Schneede J, Mishra G, Prentice A, Mansoor MA. Relationship between methylmalinic acid, homocysteine, vitamin B12 intake and status and socio-economic indices in a subset of participants in the British National Diet and Nutrition Survey of people aged 65 years and older. Europ J Clin Nutr. 2003;57:349–359
  153. Wolters M, Hermann S, Hahn A. B vitamin status and concentrations of homocysteine and methylmalonic acid in elderly German women. Am J Clin Nutr. 2003;78:765–772
  154. Refsum H, Syajnik C, Gadkari M, et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001;74:233–241
  155. Wolters M, Hermann S, Hahn A. Effect of multivitamin supplementation on homocysteine and methylmalonic acid blood concentrations in women over the age of 60. Eur J Nutr. 2004;
  156. Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc. 1992;40:1197–1204
  157. Lindenbaum J, Rosenberg IH, Wilson PWF, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994;60:2–11
  158. Bjorkegren K, Svardsudd K. Elevated serum levels of methlymalonic acid and homocysteine in elderly people: a population-based intervention study. J Int Med. 1999;246:317–324
  159. Lewerin C, Nilsson-Ehle H, Matousek M, Steen B. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatement with folic acid, vitamin B12 and vitamin B6: a randomized trial. Europ J Clin Nutr. 2003;57:1426–1436
  160. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum H, Sandberg S. Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem. 1999;45:189–198
  161. Joosten E, van de Berg A, Riezler R, et al. Metabolic evidence that deficiences of vitamin B12 (cobalamin), folate and vitamin B6 occur commonly in elderly people. Am J Clin Nutr. 1993;58:468–476
  162. Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH, Lindenbaum J. Effects of vitamin B12, folate and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet. 1995;346:85–89
  163. Eussen SJPM, de Groot LCPGM, Clarke R, et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005;165:1167–1172
  164. Rajan S, Wallace JI, Brodkin KI, Beresford SA, Allen RH, Stabler SP. Response of elevated methylmalonic acid to three doses levels of oral cobalamin in older adults. J Am Geriatr Soc. 2002;50:1789–1795
  165. 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;41:1478–1488
  166. Anwar W, Gerard P, Moutabarrek A, Namour F, Gueant J-L. End-stage renal disease increases plasma transcobalamin and neutralizes influence of TCN 776C>G polymorphism. Kidney Intl. 2005;2092–2093letter
  167. Kaplan LN, Mamer OA, Hoffer LJ. Parenteral vitamin B12 reduces hyperhomocysteinemia in end-stage renal disease. Clin Invest Med. 2001;24:5–11
  168. Mann B, Hyndman E, Burgess E, et al. Oral vitamin B12 and high-dose folic acid in hemodialysis patients with hyper-homocysteinemia. Kidney Intl. 2001;59:1103–1109
  169. Elian KM, Hofer LJ. Hydroxocobalamin reduces hyperhomocysteinemia in end-stage renal disease. Metabolism. 2002;51:881–886
  170. Hofer LJ, Elian KM. Parenteral vitamin B12 therapy of hyperhomocysteinemia in end-stage renal disease. Med Clin Exp. 2004;27:10–13
  171. Nakhoul F, Abassi Z, Plawner M, et al. Comparative study of response to treatment with supraphysiologic doses of B-vitamins in hyperhomocysteinemic hemodialysis patients. IMAJ. 2004;6:213–217
  172. Hoffer LJ, Soboohi F, Golden M, Barre PE. Cobalamin dose regimen for maximum homocysteine reduction in end-stage renal disease. Metabolism. 2005;54:835–840
  173. Obeid R, Kuhlman MK, Kohler H, Herrmann W. Response of homocysteine, cystathionine and methylmalonic acid to vitamin treatment in dialysis patients. Clin Chem. 2005;51:196–201
  174. Obeid R, Kuhlmann M, Kirsch C-M, Herrmann W. Cellular uptake of vitamin B12 in patients with chronic renal failure. Nephron Clin Pract. 2005;99:c42–c48
  175. Koyama K, Yoshida A, Yakeda A, Morozumi K, Fujinami T. Efficacy of methylcobalamin in subclinical uraemic neuropathy as detected by measured vibration perception thresholds. Nephrology. 1996;2:25–28
  176. Bhatt HR, Linnell JC, Matthews DM. Can faulty vitamin B12 (cobalamin) metabolism produce diabetic neuropathy?. Lancet. 1983;2:572
  177. Bailey LB, Molloy A, Scott J, Rice D. Streptozotocin-induced diabetes is not a model for methylmalonic acidaemia. J Inherit Metab Dis. 1989;12:429–435
  178. Yagihashi S, Tokui A, Kashiwamura H, Takagi S, Imamura K. In vivo effect of methylcobalamin on the peripheral nerve structure in streptozotocin diabetic rats. Horm Metabol Res. 1982;14:10–13
  179. Sonobe M, Yasuda H, Hatanaka I, et al. Methylcobalamin improves nerve conduction in streptozotocin-diabetic rats without affecting sorbitol or myo-inositol contents of sciatic nerve. Homr Metab Res. 1988;20:717–718
  180. Solomon LR. Elevated methylmalonic acid (MMA) and homocysteine (HCys) levels in patients with normal serum cobalamin (Cbl) values: diabetes mellitus (DM) and age as possible causes of Cbl resistance. Blood. 2005;106:635a;abstract
  181. Smulders YM, Rakic M, Slaats EF, et al. Fasting and post-methionine homocysteine levels in NIDDM. Diabetes Care. 1999;22:125–132
  182. Ambrosch A, Dierkes I, Lobmann R, Kuhne W, Luley C, Lehnert H. Relation between homocysteinemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001;18:185–192
  183. Beitzke M, Pfister P, Fortin J, Skrabal F. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Autonomic Neurosci. 2002;97:45–54
  184. Yoshioka K, Tanaka K. Effect of methylcobalamin on diabetic autonomic neuropathy as assessed by power spectral analysis of heart rate variation. Horm Metab Res. 1995;27:41–42
  185. Utsunomiya K, Narabayashi I, Tamura K, et al. Effects of aldose reductase inhibitor and vitamin B12 on myocardial uptake of iodine-123 metaiodobenzylguanidine in patients with non-insulin-dependent diabetes mellitus. Eur J Nucl Med. 1998;25:1643–1648
  186. Kuwabra S, Nakazawa R, Azuma N, et al. Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients. Intern Med. 1999;38:472–475
  187. Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clin Neurol Neurosurg. 1992;94:105–111
  188. Ide H, Fujiya S, Asanuma Y, Tsuji M, Sakai H, Agishi Y. Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy. Clin Therapeutics. 1987;9:183–192
  189. Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endcorinol Diabetes. 1996;104:311–316
  190. Stacke H, Hammes HP, Werkman D, et al. Efficacy of benfotiamine versus thiamine on function and glycation productis of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabetes. 2001;109:330–336
  191. Setola E, Monti LD, Galluccio E, et al. Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia. Exp J Endocrinol. 2004;151:483–489
  192. Watanabe T, Kaji R, Oka N, Bara W, Kimura J. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurolog Sci. 1994;122:140–143
  193. Kikuchi M, Kahii S, Honda Y, Tamura Y, Kaneda K, Akaike A. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophtalm Vis Sci. 1997;38:848–854
  194. Kaji R, Kodama M, Imamura A, et al. Effect of ultrahigh-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study. Muscle Nerve. 1998;21:1775–1778
  195. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Amelioration by mecocobalamin of sublcinical carpal tunnel syndrome involving unaffected limbs in stroke patients. J Neurol Sci. 2005;231:13–18
  196. Fowler B. Genetic defects of folate and cobalamin metabolism. Eur J Pediatr. 1998;15(Suppl2):S60–S66
  197. Ames BN, Elson-Schwab I, Silver EA. High dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75:616–658
  198. McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B12 deficiency and Alzheimer disease. Neurology. 2002;58:1395–1399
  199. Miller A, Korem M, Almog R, Galboiz Y. Vitamin B12 demyelination, remyelination and repair in multiple sclerosis. J Neurol Sci. 2005;233:93–97
  200. Di Rocco A, Bottiglieri T, Werner P, et al. Abnormal cobalamin dependent transmethylation in AIDS-associated myelopathy. Neurology. 2002;58(march):2002
  201. Kira J, Tobimatsu S, Goto I. Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Intern Med. 1994;33:82–86
  202. Wade DT, Young CA, Chaudhuri KR, Davidson DLW. A randomized placebo controlled exploratory study of vitamin B12, lofeperamine and L-phenylalanine (the “Cari-Loser regime”) in the treatment of multiple sclerosis. J Neurol Neurosurg Psych. 2002;73:246–249
  203. Mastonardi FG, Min W, Wang H, et al. Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-β plus vitamin B12: treatment to modify notch-1/sonic hedgehog balance. J Immunol. 2004;172:6418–6426
  204. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B12 and folate in relation to the development of Alzheimer’s disease. Neurol. 2001;56:1188–1194
  205. McCaddon A, Hudson P, Abrahamsson L, Olofsson H, Regland B. Analogues, ageing and aberrant assimilation of vitamin B12 in Alzheimer’s disease. Dementia Geriatr Cognitive Disorders. 2001;12:133–137
  206. Zetterberg H, Nexo E, Regland B, et al. The transcobalamin (TC) codon 259 genetic polymorphism influences holo-TC concentration in cerebrospinal fluid from patients with Alzheimer Disease. Clin Chem. 2003;49:1195–1198
  207. Refsum H, Smith AD. Low vitamin B12 status in confirmed Alzheimer’s disease as revealed by holotranscobalamin. J Neurol Neurosurg Psychiatry. 2003;74:959–961
  208. McCaddon A, Blennow K, Hudson P, et al. Transcobalamin polymorphism and serum holo-transcobalamin in relation to Alzheimer’s disease. Dementia Geriatr Cognitive Disorders. 2004;17:215–221
  209. Kanazawa S, Herbert V. Noncobalamin vitamin B12 analogues in human red cells, liver and brain. Am J Clin Nutr. 1983;37:774–777
  210. Stabler SP, Brass EP, Marshall PD, Allen RH. Inhibition of cobalamin-dependent enzymes by cobalamin analogues in rats. J Clin Invest. 1991;87:1422–1430
  211. Malouf R, Aranea SA. Vitamin B12 for cognition (review). Cochrane Library. 2005;4:1–18
  212. Di Rocco A, Werner P, Bottiglieri T, et al. Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study. Neurol. 2004;63:1270–1275
  213. Olcay L, Irkkan C, Senbil N, Haci U, Basmaci M, Gurer YKY. Progressive vacuolar myelopathy and leukoencephalopathy in childhood acute lymphoblastic leukemia and transient improvement with vitamin B12. Pediatr Blood Cancer 2006; (in press).
  214. Berliner N, Rosenberg LE. Uptake and metabolism of free cyanocobalamin by cultured human fibroblasts from controls and a patient with transcobalamin II deficiency. Metabolism: Clin Exper. 1981;230–236
  215. Chalmers JNM, Shinton NK. Comparison of hydroxocobalamin and cyanocobalamin in the treatment of pernicious anemia. Lancet. 1965;2:1305–1308
  216. Boddy K, King P, Mervyn L, Macleod A, Adams JF. Retention of cyanocobalamin, hydroxocobalamin and coenzyme B12 after parenteral administration. Lancet. 1968;2:710–712
  217. Hall CA, Begley JA, Green-Colligan PD. The availability of therapeutic hydroxocobalamin to cells. Blood. 1984;63:335–341
  218. Andersson HC, Shapira E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic academia and homocystinuria (cblC). J Pediatrics. 1998;132:121–124
  219. Bastrup-Madsen P. Treatment of vitamin B12 deficiency: evaluation of therapy with cyanocobalamin, hydroxocobalamin and depot cobalamin Betolvex. Scand J Gastroenterol. 1974;(Suppl 29):89–95
  220. Tudhope GR, Swan HT, Spray GC. Patient variation in pernicious anaemia, as shown in a clinical trial of cyanocobalamin, hydroxocobalamin and cyanocobalamin-zinc tannate. Brit J Haematol. 1967;13:216–228
  221. Magnus EM. Cobalamin and unsaturated transcobalamin values in pernicious anaemia: relation to treatment. Scand J Haematol. 1986;36:457–465
  222. Chalmers JNM, Shinton NK. Absorption of orally administered vitamin B12 in pernicious anaemia. Lancet. 1958;2:1298–1302
  223. Hemsted EH, Mills J. Vitamin B12 in pernicious anaemia: intramuscular or oral?. Lancet. 1958;2:1302–1303
  224. Berlin R, Berlin H, Brante G, Pilbrant A. Vitamin B12 body stores during oral and parenteral treatment of pernicious anaemia. Acta Med Scand. 1978;204:81–84
  225. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12 versus intramuscular B12 for vitamin B12 deficiency (Review). The Cochrane Database of Systematic Reviews. 2005;3:1–21
  226. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92:1191–1198
  227. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized open-label study. Clin Therapeutics. 2003;25:3124–3134
  228. Andres E, Kaltenback G, Noel E, et al. Efficacy of short-term oral cobalamin therapy for the treatment of cobalamin deficiencies related to food-cobalamin malabsorption: a study of 30 patients. Clin Lab Haem. 2003;25:161–166
  229. Andres E, Kurtz J-E, Perrin A-E, et al. Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption. Am J Med. 2001;111:126–129
  230. Kondo H. Haematological effects of oral cobalamin preparations on patients with megaloblastic anaemia. Acta Haematol. 1998;99:200–205
  231. Solomon LR. Oral vitamin B12 therapy: a cautionary note. Blood. 2004;103:2863
  232. Green R. Unreliability of current assays to detect cobalamin deficiency: “nothing gold can stay”. Blood. 2005;105:910

PII: S0268-960X(06)00039-7

doi: 10.1016/j.blre.2006.05.001

Blood Reviews
Volume 21, Issue 3 , Pages 113-130 , May 2007

Article Tools

* Image Usage & Resolution