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Editorial |
1 Department of Medicine, New York Methodist Hospital, Brooklyn, NY 11215, and Weill Medical College of Cornell University, New York, NY 10021
aAddress for correspondence: NY Methodist Hospital, 506 Sixth St., Brooklyn, NY 11215. Fax 718-780-3259; e-mail rac9001@nyp.org.
At one time, diagnosing cobalamin deficiency was fairly simple, usually involving a patient with clinical problems, and was usually settled by determining whether the serum cobalamin concentration was low or not. As reviewed elsewhere (1), things began to change after sensitive metabolic tests were introduced and as attention extended to the cobalamin status of asymptomatic persons. Metabolic studies confirmed that most low cobalamin concentrations in asymptomatic patients and seemingly healthy persons represented subclinical cobalamin insufficiency, but 
30–40% of these cobalamin concentrations did not represent insufficiency and thus could be considered "falsely low". The diagnostic reliability of serum cobalamin was further challenged by metabolic demonstrations of "falsely normal" cobalamin concentrations; these too occurred most often, but not exclusively, in asymptomatic persons.
The search continues for the optimal test to diagnose deficiency because the metabolic tests also have disadvantages. Increased plasma total homocysteine is too nonspecific; methylmalonic acid determination, although posing fewer problems of specificity, is complex and expensive; and the deoxyuridine suppression test is too unwieldy for practical use.
Interest has been drawn to the possible benefit of measuring only the cobalamin attached to transcobalamin (TC; also called TC II; the TC-cobalamin complex is called holo-TC or holo-TC II) rather than the total cobalamin content of plasma. The concept, suggested by Lindemans et al. in 1983 (2), is simple and attractive: holo-TC contains the biologically available cobalamin because only TC promotes specific uptake of its cobalamin by all cells. The much larger fraction of serum cobalamin carried by haptocorrin (HC; also called TC I, R binder, or sometimes cobalophilin) is considered metabolically inert because no cellular receptors exist for holo-HC (also called holo-TC I).
However, the physiologic cycle of holo-TC is quite complex: (a) ileal holo-TC enters the portal circulation, carrying cobalamin absorbed from the
Malabsorption and deficiency are not identical, nor are their clinical implications.
Does the evidence favor cobalamin deficiency or impaired absorption as the determinant of low holo-TC?
Specificity of the low holo-TC concentration.
Clinical utility of holo-TC measurement.
Methodologic issues.
Acknowledgments
References
The following articles in journals at HighWire Press have cited this article:
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  R. Clarke, P. Sherliker, H. Hin, E. Nexo, A. M. Hvas, J. Schneede, J. Birks, P. M. Ueland, K. Emmens, J. M. Scott, et al. Detection of Vitamin B12 Deficiency in Older People by Measuring Vitamin B12 or the Active Fraction of Vitamin B12, Holotranscobalamin Clin. Chem., May 1, 2007; 53(5): 963 - 970. [Abstract] [Full Text] [PDF]
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 M. Tettamanti, M. T. Garri, A. Nobili, E. Riva, and U. Lucca Low Folate and the Risk of Cognitive and Functional Deficits in the Very Old: The Monzino 80-plus Study J. Am. Coll. Nutr., December 1, 2006; 25(6): 502 - 508. [Abstract] [Full Text] [PDF]
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H. Refsum, C. Johnston, A. B. Guttormsen, and E. Nexo Holotranscobalamin and Total Transcobalamin in Human Plasma: Determination, Determinants, and Reference Values in Healthy Adults Clin. Chem., January 1, 2006; 52(1): 129 - 137. [Abstract] [Full Text] [PDF]
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 K. M von Castel-Dunwoody, G. P. Kauwell, K. P Shelnutt, J. D Vaughn, E. R Griffin, D. R Maneval, D. W Theriaque, and L. B Bailey Transcobalamin 776C->G polymorphism negatively affects vitamin B-12 metabolism Am. J. Clinical Nutrition, June 1, 2005; 81(6): 1436 - 1441. [Abstract] [Full Text] [PDF]
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W. Herrmann, H. Schorr, R. Obeid, J. Makowski, B. Fowler, and M. K. Kuhlmann Disturbed Homocysteine and Methionine Cycle Intermediates S-Adenosylhomocysteine and S-Adenosylmethionine Are Related to Degree of Renal Insufficiency in Type 2 Diabetes Clin. Chem., May 1, 2005; 51(5): 891 - 897. [Abstract] [Full Text] [PDF]
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X. Chen, A. F Remacha, M P. Sarda, and R. Carmel Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holo-transcobalamin II Am. J. Clinical Nutrition, January 1, 2005; 81(1): 110 - 114. [Abstract] [Full Text] [PDF]
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Z. Lloyd-Wright, A.-M. Hvas, J. Moller, T. A.B. Sanders, and E. Nexo Holotranscobalamin as an Indicator of Dietary Vitamin B12 Deficiency Clin. Chem., December 1, 2003; 49(12): 2076 - 2078. [Full Text] [PDF]
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A. McCaddon, P. Hudson, C. McCracken, R. Ellis, and A. McCaddon Biological Variation of Holo-Transcobalamin in Elderly Individuals Clin. Chem., September 1, 2003; 49(9): 1542 - 1544. [Full Text] [PDF]
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A. C Antony Vegetarianism and vitamin B-12 (cobalamin) deficiency Am. J. Clinical Nutrition, July 1, 2003; 78(1): 3 - 6. [Full Text] [PDF]
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W. Herrmann, H. Schorr, R. Obeid, and J. Geisel Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians Am. J. Clinical Nutrition, July 1, 2003; 78(1): 131 - 136. [Abstract] [Full Text] [PDF]
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S. Loikas, M. Lopponen, P. Suominen, J. Moller, K. Irjala, R. Isoaho, S.-L. Kivela, P. Koskinen, and T.-T. Pelliniemi RIA for Serum Holo-Transcobalamin: Method Evaluation in the Clinical Laboratory and Reference Interval Clin. Chem., March 1, 2003; 49(3): 455 - 462. [Abstract] [Full Text] [PDF]
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 R. Carmel, R. Green, D. S. Rosenblatt, and D. Watkins Update on Cobalamin, Folate, and Homocysteine Hematology, January 1, 2003; 2003(1): 62 - 81. [Abstract] [Full Text] [PDF]
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R. Obeid, M. Jouma, and W. Herrmann Cobalamin Status (Holo-Transcobalamin, Methylmalonic Acid) and Folate as Determinants of Homocysteine Concentration Clin. Chem., November 1, 2002; 48(11): 2064 - 2065. [Full Text] [PDF]
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E. Nexo, A.-M. Hvas, O. Bleie, H. Refsum, S. N. Fedosov, S. E. Vollset, J. Schneede, J. E. Nordrehaug, P. M. Ueland, and O. K. Nygard Holo-Transcobalamin Is an Early Marker of Changes in Cobalamin Homeostasis. A Randomized Placebo-controlled Study Clin. Chem., October 1, 2002; 48(10): 1768 - 1771. [Abstract] [Full Text] [PDF]
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M. M. Kushnir, B. Shushan, W. L. Roberts, and M. Pasquali Serum Acylcarnitines and Vitamin B12 Deficiency Clin. Chem., July 1, 2002; 48(7): 1126 - 1128. [Full Text] [PDF]
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