Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: A critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II

American Journal of Clinical Nutrition

Volumn 94, Issue 1, 2011, Pages

  Carmel, Ralph ^a,b  

^a NEW YORK METHODIST HOSPITAL   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; ANTIBODY; COBALAMIN; CYANOCOBALAMIN; CYSTATIN C; FUCOSYLTRANSFERASE; HOLOTRANSCOBALAMIN II; HOLOTRANSCOBALAMIN II ANTIBODY; HOMOCYSTEINE; INTRINSIC FACTOR ANTIBODY; METHYLMALONIC ACID; TRANSCOBALAMIN; UNCLASSIFIED DRUG;

AMINO ACID BLOOD LEVEL; ANALYTICAL ERROR; ANEMIA; ARTIFACT; CAPILLARY GAS CHROMATOGRAPHY; CHRONIC MYELOID LEUKEMIA; COGNITIVE DEFECT; CONFERENCE PAPER; CYANOCOBALAMIN DEFICIENCY; DIAGNOSTIC ACCURACY; DIAGNOSTIC ERROR; DIAGNOSTIC TEST; DIAGNOSTIC VALUE; FOLIC ACID DEFICIENCY; GAS CHROMATOGRAPHY; GLOMERULUS FILTRATION; HELICOBACTER INFECTION; IMMUNOASSAY; KIDNEY DYSFUNCTION; MACROCYTIC ANEMIA; MALABSORPTION; MEGALOBLASTIC ANEMIA; MEGALOCYTOSIS; METHYLMALONIC ACIDURIA; NEUROPATHY; NORMOCHROMIC NORMOCYTIC ANEMIA; PATHOPHYSIOLOGY; PERNICIOUS ANEMIA; PREDICTIVE VALUE; PUBLIC HEALTH; SENSITIVITY AND SPECIFICITY; SPINAL CORD DISEASE; VITAMIN BLOOD LEVEL; VITAMIN SUPPLEMENTATION;

BIOLOGICAL MARKERS; HOMOCYSTEINE; HUMANS; METHYLMALONIC ACID; PUBLIC HEALTH; TRANSCOBALAMINS; VITAMIN B 12; VITAMIN B 12 DEFICIENCY;

EID: 79959439256     PISSN: 00029165     EISSN: 19383207     Source Type: Journal    
DOI: 10.3945/ajcn.111.013441     Document Type: Conference Paper

References (86)

1. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood 2008;112:2214-21.
2. Carmel R. The disappearance of cobalamin absorption testing: a critical diagnostic loss. J Nutr 2007;137:2481-4. (Pubitemid 350058720)
3. 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;96:239-46. (Pubitemid 24099223)
4. Chanarin I. The megaloblastic anaemias, 2nd ed. Oxford, United Kingdom: Blackwell Scientific Publishing, 1979.
5. Cox EV, White AM. Methylmalonic acid excretion: index of vitamin B12 deficiency. Lancet 1962;2:853-6.
6. Metz J, Kelly A, Swett VC, Waxman S, Herbert V. Deranged DNA synthesis by bone marrow from vitamin B12-deficient humans. Br J Haematol 1968;14:575-92.
7. Carmel R, Karnaze DS. The deoxyuridine suppression test identifies subtle cobalamin deficiency in patients without typical megaloblastic anemia. JAMA 1985;253:1284-7. (Pubitemid 15127844)
8. Carmel R, Sinow RM, Karnaze DS. Atypical cobalamin deficiency: subtle biochemical evidence of deficiency is commonly demonstrable in patients without megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption. J Lab Clin Med 1987;109:454-63. (Pubitemid 17064448)
9. Karnaze DS, Carmel R. Low serum cobalamin levels in primary degenerative dementia: Do some patients harbor atypical cobalamin deficiency states? Arch Intern Med 1987;147:429-31.
10. Carmel R, Sinow RM, Siegel ME, Samloff IM. Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels. Arch Intern Med 1988;148:1715-9.
11. Carmel R. Subtle and atypical cobalamin deficiency states. Am J Hematol 1990;34:108-14. (Pubitemid 20180102)
12. Carmel R. Reversal by cobalamin therapy of minimal defects in the deoxyuridine suppression test in patients without anemia: further evidence for a subtle metabolic cobalamin deficiency. J Lab Clin Med 1992;119:240-4.
13. 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. Br J Haematol 1996;93:311-8. (Pubitemid 26150024)
14. Carmel R. Malabsorption of food cobalamin. Baillieres Clin Haematol 1995;8:639-55.
15. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Assay of methylmalonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography-mass spectrometry. J Clin Invest 1986;77:1606-12. (Pubitemid 16047105)
16. Rasmussen K. Solid-phase sample extraction for rapid determination of methylmalonic acid in serum and urine by a stable-isotope-dilution method. Clin Chem 1989;35:260-4. (Pubitemid 19075603)
17. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency. I. Usefulness of serum methylmalonic acid and total homocysteine levels. Am J Hematol 1990;34:90-8.
18. 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. (Pubitemid 20180101)
19. Carmel R. Cobalamin, the stomach, and aging. Am J Clin Nutr 1997;66:750-9. (Pubitemid 27415557)
20. Carmel R, Sarrai M. Diagnosis and management of clinical and sub-clinical cobalamin deficiency: advances and controversies. Curr Hematol Rep 2006;5:23-33.
21. Hvas AM, Ellegaard J, Nexo E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med 2001;161:1534-41. (Pubitemid 32679567)
22. Andres E, Kurtz JE, Perrin AE, et al. Oral cobalamin therapy for the treatment of patients with food cobalamin malabsorption. Am J Med 2001;111:126-9. (Pubitemid 32728405)
23. Lindenbaum J, Rosenberg IH, Wilson PWF, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly. Am J Clin Nutr 1994;60:2-11.
24. 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;70:904-10. (Pubitemid 29512918)
25. Clarke R, Sherliker P, Hin H, et al. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin. Clin Chem 2007;53:963-70. (Pubitemid 46744255)
26. Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996;156:1097-100. (Pubitemid 26158066)
27. Carmel R. Mean corpuscular volume and other concerns in the study of vitamin B-12 deficiency: epidemiology with physiology. Am J Clin Nutr 2008;87:1962-3. (Pubitemid 351872669)
28. Carmel R. Does high folic acid intake affect unrecognized cobalamin deficiency, and how will we know it if we see it? Am J Clin Nutr 2009;90:1449-50.
29. Brouwer I, Verhoef P. Folic acid fortification: is masking of vitamin B12 deficiency what we should really worry about? Am J Clin Nutr 2007;86:897-8.
30. Selhub J, Morris MS, Jacques PF, Rosenberg IH. Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr 2009;89(suppl):702S-6S.
31. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr 2010;91:1733-44.
32. Loikas S, Koskinen P, Irjala K, et al. Renal impairment compromises the use of total homocysteine and methylmalonic acid but not total vitamin B12 and holotranscobalamin in screening for vitamin B12 deficiency in the aged. Clin Chem Lab Med 2007;45:197-201. (Pubitemid 46294679)
33. Lewerin C, Ljungman S, Nilsson-Ehle H. Glomerular filtration rate as measured by serum cystatin C is an important determinant of plasma homocysteine and serum methylmalonic acid in the elderly. J Intern Med 2007;261:65-73. (Pubitemid 46046473)
34. Carmel R, Vasireddy H, Aurangzeb I, George K. High serum cobalamin levels in the clinical setting: clinical associations and holotranscobalamin changes. Clin Lab Haematol 2001;23:365-71. (Pubitemid 34093997)
35. Kolhouse JF, Kondo H, Allen NC, Podell E, Allen RH. Cobalamin analogues are present in human plasma and can mask cobalamin deficiency because current radioisotope dilution assays are not specific for true cobalamin. N Engl J Med 1978;299:785-92. (Pubitemid 9044521)
36. Emancipator K, Mansbach L, Robert T, Waskiewicz D. Failure of assay to identify low cobalamin concentration. Representatives of Bayer Diagnostics respond. Clin Chem 2000;46:2018-9.
37. Vogeser M, Lorenzl S. Comparison of automated assays for the determination of vitamin B12 in serum. Clin Biochem 2007;40:1342-5. (Pubitemid 47570042)
38. Carmel R, Brar S, Agrawal A, Penha PD. Failure of assay to identify low cobalamin concentrations. Clin Chem 2000;46:2017-8.
39. 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;52:157-8.
40. Hamilton MS, Blackmore S, Lee A. Possible cause of false normal B-12 assays. BMJ 2006;333:654-5.
41. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105:978-85. (Pubitemid 40170864)
42. Carmel R. Is testing for clinical cobalamin deficiency truly unreliable? Blood 2005;106:1136-7.
43. Drammeh BS, Schleicher RL, Pfeiffer CM, Jain RB, Zhang M, Nguyen PH. Effects of delayed sample processing and freezing on serum concentrations of selected nutritional indicators. Clin Chem 2008;54:1883-91.
44. Lowrey I, Smith G. Elevated results in a vitamin B12 assay when using serum separator blood collection tubes. Ann Clin Biochem 2003;40:560-2. (Pubitemid 37157969)
45. Bolann BJ, Solli JD, Schneede J, et al. Evaluation of indicators of cobalamin deficiency defined as cobalamin-induced reduction in increased serum methylmalonic acid. Clin Chem 2000;46:1744-50.
46. Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc 1992;40:1197-204.
47. van Asselt DZB, de Groot LCPGM, van Staveren WA, et al. Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older Dutch subjects. Am J Clin Nutr 1998;68:328-34.
48. Bernard MA, Nakonezny PA, Kashner TM. The effect of vitamin B12 deficiency on older veterans and its relationship to health. J Am Geriatr Soc 1998;46:1199-206. (Pubitemid 28467421)
49. Stabler SP, Allen RH, Fried LP, et al. Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women. Am J Clin Nutr 1999;70:911-9. (Pubitemid 29512919)
50. Vogiatzoglou A, Oulhaj A, Smith AD, et al. Determinants of plasma methylmalonic acid in a large population: implications for assessment of vitamin B12 status. Clin Chem 2009;55:2198-206.
51. Johnson MA, Hausman DB, Davey A, Poon LW, Allen RH, Stabler SP. Vitamin B12 deficiency in African American and white octogenarians and centenarians in Georgia. J Nutr Health Aging 2010;14:339-45.
52. Carmel R, Brar S, Frouhar Z. Plasma total transcobalamin. I. Ethnic/ racial patterns and comparison with lactoferrin. Am J Clin Pathol 2001;116:576-80.
53. Carmel R. Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin Chem 2003;49:1367-74. (Pubitemid 36900624)
54. Carmel R, Parker J, Kelman Z. Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels. Br J Haematol 2009;147:386-91.
55. Carmel R, Baril L. Circulating immunoglobulin-transcobalamin I (R binder) complexes. J Lab Clin Med 1978;91:769-79.
56. Carmel R, Tatsis B, Baril L. Circulating antibody to transcobalamin II causing retention of vitamin B12 in the blood. Blood 1977;49:987-1000. (Pubitemid 8123866)
57. Skouby AP, Hippe E, Olesen H. Antibody to transcobalamin II and B12 binding capacity in patients treated with hydroxocobalamin. Blood 1971;38:769-74.
58. Jeffery J, Millar H, MacKenzie P, Fahie-Wilson M, Hamilton M, Ayling RM. An Ig complexed form of vitamin B12 is a common cause of elevated serum concentrations. Clin Biochem 2010;43:82-8.
59. Carmel R. Ethnic and racial factors in cobalamin metabolism and its disorders. Semin Hematol 1999;36:88-100. (Pubitemid 29048615)
60. Hazra A, Kraft P, Selhub J, et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet 2008;40:1160-2.
61. Norman EJ, Berry HK, Denton MD. Identification and quantitation of urinary dicarboxylic acids as their dicyclohexyl esters in diseasee states by gas chromatography-mass spectrometry. Biomed Mass Spectrom 1979;6:546-53. (Pubitemid 10150071)
62. Goringe A, Ellis R, McDowell I, et al. The limited value of methyl-malonic acid, homocysteine and holotranscobalamin in the diagnosis of early B12 deficency. Haematologica 2006;91:231-4.
63. Sentongo TA, Azzam R, Charrow J. Vitamin B12 status, methyl-malonic acidemia, and bacterial overgrowth in short bowel syndrome. J Pediatr Gastroenterol Nutr 2009;48:495-7.
64. Rasmussen K, Nathan E. The clinical evaluation of cobalamin deficiency by determination of methylmalonic acid in serum or urine is not invalidated by the presence of heterozygous methylmalonicacidaemia. J Clin Chem Clin Biochem 1990;28:419-21. (Pubitemid 20195610)
65. Monsen AL, Refsum H, Markestad T, Ueland PM. Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years. Clin Chem 2003;49:2067-75. (Pubitemid 37449480)
66. Bjørke-Monsen AL, Torsvik I, Saetran H, Markestad T, Ueland PM. Common metabolic profile in infants indicating impaired cobalamin status responds to cobalamin supplementation. Pediatrics 2008;122:83-91.
67. Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr 2005;82:442-50.
68. Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G. The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status. Food Nutr Bull 2008;29:S67-73.
69. Carmel R. Measuring and interpreting holo-transcobalamin (holotranscobalamin II). Clin Chem 2002;48:407-9.
70. Chen X, Remacha AF, Sarda MP, Carmel R. Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holotranscobalamin II. Am J Clin Nutr 2005;81:110-4. (Pubitemid 43073382)
71. Lindemans J, Schoester M, van Kapel J. Application of a simple immunoadsorption assay for the measurement of saturated and unsaturated transcobalamin II and R-binders. Clin Chim Acta 1983;132:53-61. (Pubitemid 13069697)
72. Ulleland M, Eilertsen I, Quadros EV, et al. Direct assay for cobalamin bound to transcobalamin (holo-transcobalamin) in serum. Clin Chem 2002;48:526-32. (Pubitemid 34174583)
73. Nexo E, Christensen AL, Hvas AM, Petersen TE, Fedosov S. Quantification of holo-transcobalamin, a marker of vitamin B12 deficiency. Clin Chem 2002;48:561-2. (Pubitemid 34174588)
74. Brady J, McGregor L, Valente E, Orning L. Active B12: a rapid, automated assay for holotranscobalamin on the Abbott AxSYM analyzer. Clin Chem 2008;54:567-73. (Pubitemid 351348161)
75. Miller JW, Garrod MG, Rockwood AL, et al. Measurement of total vitamin B12 and holotranscobalamin, singly and in combination, in screening for metabolic vitamin B12 deficiency. Clin Chem 2006;52:278-85. (Pubitemid 43185490)
76. Morkbak AL, Heimdal RM, Emmens K, et al. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project. Clin Chem Lab Med 2005;43:1058-64. (Pubitemid 41581961)
77. Namour F, Olivier JL, Abdelmoutalleb I, et al. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood. Blood 2001;97:1092-8. (Pubitemid 32154298)
78. Miller JW, Ramos MI, Garrod MG, Flynn MA, Green R. Transcobalamin II 775G>C polymorphism and indices of vitamin B12 status in healthy older adults. Blood 2002;100:718-20. (Pubitemid 34761145)
79. 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;49:1195-8. (Pubitemid 36751113)
80. Carmel R. The distribution of endogenous cobalamin among cobalamin- binding proteins in the blood in normal and abnormal states. Am J Clin Nutr 1985;41:713-9. (Pubitemid 15092878)
81. Wickramasinghe SN, Ratnayaka ID. Limited value of serum holotranscobalamin II measurements in the differential diagnosis of macrocytosis. J Clin Pathol 1996;49:755-8. (Pubitemid 26297702)
82. Morkbak AL, Hvas AM, Milman N, Nexo E. Holotranscobalamin remains unchanged during pregnancy. Longitudinal changes of cobalamins and their binding proteins during pregnancy and postpartum. Haematologica 2007;92:1711-2.
83. Refsum H, Johnston C, Guttormsen AB, Nexo E. Holotranscobalamin and total transcobalamin in human plasma: determination, determinants, and reference values in healthy adults. Clin Chem 2006;52:129-37. (Pubitemid 43032476)
84. Green R, Miller JW. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population. Clin Chem Lab Med 2005;43:1048-51. (Pubitemid 41581959)
85. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004;50:3-32. (Pubitemid 38125696)
86. Gimsing P, Hippe E, Helleberg-Rasmussen I, et al. Cobalamin forms in plasma and tissue during treatment of vitamin B12 deficiency. Scand J Haematol 1982;29:311-8. (Pubitemid 12037579)