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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter / Tate, Jillian R.

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1437-4331
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Volume 53, Issue 8

Issues

Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points

Sergey N. Fedosov
  • Corresponding author
  • Department of Clinical Chemistry, Aarhus University, Science Park, Gustav Wieds Vej 10C, 8000, Aarhus C, Denmark
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Alex Brito / Joshua W. Miller
  • Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
  • Department of Pathology and Laboratory Medicine, University of California, Davis, CA, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ralph Green / Lindsay H. Allen
Published Online: 2015-01-14 | DOI: https://doi.org/10.1515/cclm-2014-0818

Abstract

Background: A novel approach to determine vitamin B12 status is to combine four blood markers: total B12 (B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). This combined indicator of B12 status is expressed as cB12=log10[(holoTC·B12)/(MMA·Hcy)]–(age factor). Here we calculate cB12 in datasets with missing biomarkers, examine the influence of folate status, and revise diagnostic cut-points.

Methods: We used a database with all four markers (n=5211) plus folate measurements (n=972). A biomarker Z (assumed missing) was plotted versus X (a combination of other markers) and Y (age). Each chart was approximated by a function Ztheor, which predicted the potentially absent value(s). Statistical distributions of cB12 were aligned with physiological indicators of deficiency and used to determine cut-offs.

Results: The predictive functions Ztheor allowed assessment of the “incomplete” indicators, 3cB12 (three markers known) and 2cB12 (two markers known). Predictions contained a systematic deviation associated with dispersion along two axes Z and X (and unaccounted by the least squares fit). Increase in tHcy at low serum folate was corrected (cB12folate) based on the function of Δfolate=log10(Hcyreal/Hcytheor) versus folate. Statistical distributions of cB12 revealed the boundaries of groups with B12 deficiency, i.e., cB12<–0.5.

Conclusions: We provide equations that combine two, three or four biomarkers into one diagnostic indicator, thereby rescaling unmatched data into the same coordinate system. Adjustment of this indicator is required if serum folate is <10 nmol/L and tHcy is measured. Revised cut-points and guidelines for using this approach are provided.

This article offers supplementary material which is provided at the end of the article.

Keywords: cobalamin; deficiency; diagnostics; folate; markers; vitamin B12

References

  • 1.

    Allen LH. Vitamin B12. Adv Nutr 2012;3:54–5.Google Scholar

  • 2.

    Herrmann W, Obeid R. Cobalamin deficiency. Subcell Biochem 2012;56:301–22.CrossrefPubMedGoogle Scholar

  • 3.

    Andrès E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AR, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. Can Med Assoc J 2004;171:251–9.Google Scholar

  • 4.

    Lachner C, Steinle NI, Regenold WT. The neuropsychiatry of vitamin B12 deficiency in elderly patients. J Neuropsychiatry Clin Neurosci 2012;24:5–15.CrossrefWeb of ScienceGoogle Scholar

  • 5.

    Green R. Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies. Food Nutr Bull 2008;29:S52–63.Google Scholar

  • 6.

    Elin RJ, Winter WE. Methylmalonic acid: a test whose time has come? Arch Pathol Lab Med 2001;125:824–7.PubMedGoogle Scholar

  • 7.

    Scott JM. Folate and vitamin B12. Proc Nutr Soc 1999;58:441–8.CrossrefGoogle Scholar

  • 8.

    Carmel R, Green R, Rosenblatt S, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program 2003:62–81.Google Scholar

  • 9.

    Obeid R, Schorr H, Eckert R, Herrmann W. Vitamin B12 status in the elderly as judged by available biochemical markers. Clin Chem 2004;50:238–41.CrossrefGoogle Scholar

  • 10.

    Lindgren A. Elevated serum methylmalonic acid. How much comes from cobalamin deficiency and how much comes from the kidneys? Scand J Clin Lab Invest 2002;62:15–9.CrossrefPubMedGoogle Scholar

  • 11.

    Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B12 status: analytical aspects and clinical utility. Am J Clin Nutr 2011;94:359S–65S.CrossrefGoogle Scholar

  • 12.

    Herbert V, Fong W, Gulle V, Stopler T. Low holotranscobalamin II is the earliest serum marker for subnormal vitamin B12 (cobalamin) absorption in patients with AIDS. Am J Hematol 1990;34:132–9.CrossrefGoogle Scholar

  • 13.

    Carmel R. Biomarkers of cobalamin (vitamin B12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr 2011;94:348S–58S.Web of ScienceCrossrefGoogle Scholar

  • 14.

    Chatthanawaree W. Biomarkers of cobalamin (vitamin B12) deficiency and its application. J Nutr Health Aging 2011;15: 227–31.CrossrefWeb of ScienceGoogle Scholar

  • 15.

    Wuerges J, Garau G, Geremia S, Fedosov SN, Petersen TE, Randaccio L. Structural basis for mammalian vitamin B12 transport by transcobalamin. Proc Natl Acad Sci 2006;103:4386–91.CrossrefGoogle Scholar

  • 16.

    Fedosov SN. Physiological and molecular aspects of cobalamin transport. Subcell Biochem 2012;56:347–67.PubMedCrossrefGoogle Scholar

  • 17.

    Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105:978–85.PubMedGoogle Scholar

  • 18.

    Remacha AF, Sardà MP, Canals C, Queraltò JM, Zapico E, Remacha J, et al. Role of serum holotranscobalamin (holoTC) in the diagnosis of patients with low serum cobalamin. Comparison with methylmalonic acid and homocysteine. Ann Hematol 2014;93:565–9.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 19.

    Palacios G, Sola R, Barrios L, Pietrzik K, Castillo MJ, González M. Algorithm for the early diagnosis of vitamin B12 deficiency in elderly people. Nutr Hosp 2013;28:1447–52.Web of ScienceGoogle Scholar

  • 20.

    Miller JW, Garrod MG, Rockwood AL, Kushnir MM, Allen LH, Haan MN, 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.Google Scholar

  • 21.

    Fedosov SN. Metabolic signs of vitamin B12 deficiency in humans: computational model and its implications for diagnostics. Metabolism 2010;59:1124–38.Web of ScienceCrossrefGoogle Scholar

  • 22.

    Lildballe DL, Fedosov S, Sherliker P, Hin H, Clarke R, Nexo E. Association of cognitive impairment with combinations of vitamin B12-related parameters. Clin Chem 2011;57:1436–43.CrossrefWeb of ScienceGoogle Scholar

  • 23.

    Fedosov SN. Biochemical markers of vitamin B12 deficiency combined in one diagnostic parameter: the age-dependence and association with cognitive function and blood haemoglobin. Clin Chim Acta 2013;422:47–53.Web of ScienceGoogle Scholar

  • 24.

    Hvas AM, Mørkbak AL, Nexø E. Plasma holotranscobalamin compared with plasma cobalamins for assessment of vitamin B12 absorption; optimization of a non-radioactive vitamin B12 absorption test (CobaSorb). Clin Chim Acta 2007;376:150–4.Web of ScienceGoogle Scholar

  • 25.

    Hvas AM, Nexø E. Holotranscobalamin – a first choice assay for diagnosing early vitamin B12 deficiency? J Intern Med 2005;257:289–98.Google Scholar

  • 26.

    Wright ZL, Hvas AM, Møller J, Sanders TA, Nexø E. Holotranscobalamin as an indicator of dietary vitamin B12 deficiency. Clin Chem 2003;49:2076–8.CrossrefGoogle Scholar

  • 27.

    Hin H, Clarke R, Sherliker P, Sherliker P, Atoyebi W, Emmens K, et al. Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age Ageing 2006;35:416–22.CrossrefGoogle Scholar

  • 28.

    Campbell AK, Miller JW, Green R, Haan MN, Allen LH. Plasma vitamin B12 concentrations in an elderly Latino population are predicted by serum gastrin concentrations and crystalline vitamin B12 intake. J Nutr 2003;133:2770–6.Google Scholar

  • 29.

    Sánchez H, Albala C, Lera L, Castillo JL, Verdugo R, Lavados M, et al. Comparison of two modes of vitamin B12 supplementation on neuroconduction and cognitive function among older people living in Santiago, Chile: a cluster randomized controlled trial, a study protocol. Nutr J 2011;10:100.Web of ScienceCrossrefGoogle Scholar

  • 30.

    Brito A, Allen LH, Verdugo R, Sánchez H, Hertrampf E, Albala C, et al. Cyanocobalamin treatment improves vitamin B12 status and peripheral neuroconduction in deficient Chilean elderly. [Abstract]. FASEB J 2012;26:126.2.Google Scholar

  • 31.

    Stone N, Pangilinan F, Molloy AM, Shane B, Scott J, Ueland PM, et al. Bioinformatic and genetic association analysis of microRNA target sites in one-carbon metabolism genes. PLoS One 2011;6:e21851.CrossrefGoogle Scholar

  • 32.

    Shahab-Ferdows S, Anaya-Loyola MA, Vergara-Castañeda H, Rosado JL, Keyes WR, Newman JW. Vitamin B-12 supplementation of rural Mexican women changes biochemical vitamin B-12 status indicators but does not affect hematology or a bone turnover marker. J Nutr 2012;142:1881–7.Google Scholar

  • 33.

    Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 1988;81:466–74.PubMedCrossrefGoogle Scholar

  • 34.

    Søreide K. Receiver-operating characteristic curve analysis in diagnostic, prognostic and predictive biomarker research. J Clin Pathol 2009;62:1–5.PubMedCrossrefGoogle Scholar

  • 35.

    Hansjörg S, Wilmanns W. Cobalamin dependent methionine synthesis and methyl-folate-trap in human vitamin B12 deficiency. Br J Haematol 1977;36:189–98.Google Scholar

  • 36.

    Arendt J, Nexo E. Unexpected high plasma cobalamin/Proposal for a diagnostic strategy. Clin Chem Lab Med 2013;51:489–96.PubMedGoogle Scholar

  • 37.

    Allen LH. Guidelines on food fortification with micronutrients. World Health Organization. Geneva: Department of Nutrition for Health and Development, 2006.Google Scholar

  • 38.

    Murphy MM, Molloy AM, Ueland PM, Fernandez-Ballart JD, Schneede J, Arija V, et al. Longitudinal study of the effect of pregnancy on maternal and fetal cobalamin status in healthy women and their offspring. J Nutr 2007;137:1863–7.Google Scholar

  • 39.

    Greibe E, Andreasen BH, Lildballe DL, Morkbak AL, Hvas AM, Nexo E. Uptake of cobalamin and markers of cobalamin status: a longitudinal study of healthy pregnant women. Clin Chem Lab Med 2011;49:1877–82.PubMedWeb of ScienceGoogle Scholar

About the article

Corresponding author: Sergey N. Fedosov, Department of Clinical Chemistry, Aarhus University, Science Park, Gustav Wieds Vej 10C, 8000, Aarhus C, Denmark, E-mail: ;


Received: 2014-08-14

Accepted: 2014-12-07

Published Online: 2015-01-14

Published in Print: 2015-07-01


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2014-0818.

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