Scientific Publications

The body of research on Holotranscobalamin continues to grow and peer-reviewed literature continues to suggest that it is the superior marker for assessing Vitamin B12status.

A selection of important academic publications on Active-B12 (Holotranscobalamin) are shown below along with a summary of their conclusions.

Publications of particular interest and relevance are also highlighted in the clinical utility section of this site.

Holotranscobalamin: in the middle of difficulty lies opportunity
Harrington D
CCLM 2016 Vol 54;9 1407-1409
Laboratory assessment of B12 status
Harrington D
J Clin Pathol 2016 May 11
In these two complementary publications, Dr Harrington describes the various options available to laboratories for the investigation of suspected B12 deficiency. He describes the difficulties involved in obtaining an accurate diagnosis and highlights the potential benefits of Active-B12 over the traditional Serum B12 test in light of the new International Standard which can be used for Active-B12.


Low holo-transcobalamin levels are prevalent in vegetarians and is associated with coronary artery disease in Indian population
Basak T et al
Biomarkers 2016 Jul;21(5)
This Indian study shows for the first time that holoTC levels are significantly lower in Coronary Artery Disease (CAD) cases as compared to controls.


An International Standard for holotranscobalamin (holoTC): international collaborative study to assign a holoTC value to the International Standard for vitamin B12 and serum folate
Thorpe S et al
CCLM 2016 54;9 1467-72
One of the main difficulties associated with traditional B12 tests is the lack of repeatability of results between different methods and different laboratories. With the introduction of this new International Standard for Active-B12, lab-to-lab results will become interchangeable giving further benefits over the Serum B12 test in addition to the clinical improvement offered by Active-B12.


Metabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke
Spence JD
Nutrition Research 2016 36;2 109-116
The author highlights the importance of sufficient Vitamin B12 and the difficulties associated with diagnosis of deficiency. He emphasises that serum B12 alone is insufficient for diagnosis and that other markers such as Active-12 are needed.


Diagnosis of Vitamin B12 Deficiency in Patients With Myeloproliferative Disorders
Cinemre H et al
J Inv Med 2015 63;4
The authors show that patients with myeloproliferative disorders had a high prevalence of vitamin B12 deficiency, despite the Serum B12 test giving normal results. They suggest that vitamin B12 status should be evaluated in these patients and that Active-B12 may be the best initial test as a replacement for Serum B12.


Guidelines for the diagnosis and treatment of cobalamin and folate disorders
Devalia V, Hamilton MS, Molloy AM
Brit J Haem 2014
These new guidelines from the British Committee for Standards in Haematology review the latest research on the diagnosis and treatment of Vitamin B12 deficiency. They highlight that there is no ‘gold standard’ test for Vitamin B12 deficiency and that Active-B12 has the potential to become the first-line test for assessment of deficiency.


Algorithm for the early diagnosis of vitamin B12 deficiency in elderly people
Palacios G et al
Nutricion Hospitalaria 2013 28;5
This Spanish study recognised that there are issues with the current algorithms for assessing B12 deficiency and suggest a new approach using Active-B12 and other markers in place of the Serum B12 test which showed no value in their investigations.


Falsely elevated cobalamin concentration in multiple assays in a patient with pernicious anaemia: a case study
van Rossum AP, Vlasvel LT, Castel A
Clin Chem Lab Med 2013 May 14:1-3
This case study demonstrated that 5 different Total B12 assays from 4 manufacturers all gave falsely elevated results in a patient with confirmed pernicious anaemia. The same failing described by Carmel and Agrawal and Yang and Cook (see below) is again apparent in this case study and demonstrates why Total B12 results can be unreliable.


Holotranscobalamin is not influenced by decreased renal function in elderly men: the MrOS Sweden study
Lewerin C et al
Ann Clin Biochem 2013 Nov;50(Pt 6):585-94
This important study from Sweden showed that levels of Active-B12 are not related to kidney function – an important advantage over other markers such as MMA and Homocysteine which can be falsely elevated in patients with renal disease.


Failures of Cobalamin Assays in Pernicious Anemia
Carmel R, Agrawal YP
N Eng J Med 2012 Jul 26:367(4):385-6
Spurious Elevations of Vitamin B12 with Pernicious Anemia
Yang DT, Cook RJ
N Eng J Med 2012 366;18
Doctors Carmel and Agrawal and Yang and Cook demonstrate that serious failings in the Total B12 assay mean that results should be interpreted with caution. They also emphasise that routine control and monitoring measures cannot detect these false results.


Utility and limitations of biochemical markers of vitamin B12 deficiency
Herrmann W, Obeid R
Eur J Clin Invest 2012 Nov 27
Professors Herrmann and Obeid emphasise the need for improvement in the current testing regimes for assessment of suspected B12 deficiency and suggest a new algorithm utilising Active-B12 as the first-line measurement.


Vitamin B12 status, cognitive decline and dementia: a systematic review of prospective cohort studies
O’Leary F, Allman-Farinelli M, Samman S
Br J Nutr 2012 Oct 19:1-14
This review showed that there was no association between cognitive decline or dementia and Vitamin B12 status as judged by the Total B12 test. However, in the studies whereActive-B12 was utilised, there was an association between an increased risk of dementia diagnosis and poor Vitamin B12 status.


Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency : a multi-centre study
Heil SG, de Jonge R, de Rotte MCFJ et al
Ann Clin Biochem 2012: 1-6
This Dutch group published their findings from the routine introduction of Active-B12testing into their hospital lab and concluded that Active-B12 gives better diagnostic accuracy. They now use Active-B12 in place of the outdated Total B12 assay.


Vitamin B12 absorption judged by measurement of holotranscobalamin, active vitamin B12: evaluation of a commercially available EIA kit.
Greibe E, Nexo E
Clin Chem Lab Med 2011 Nov;49(11):1883-5
The group at Aarhus University in Denmark have their own method to assess a patient’s ability to absorb therapeutic B12. They use Active-B12 as part of this assessment.


Serum homocysteine, holotranscobalamin, folate and cognition in the elderly : a longitudinal study
Hooshmand B, Solomon A et al.
J Intern Med 2011 Nov 12
This Swedish/Finnish study looked at the correlation between Vitamin B12 status as judged by Active-B12 and executive brain functions and psychomotor speed. They saw that Active-B12 levels are related to cognitive performance even in non-demented elderly.


Cobalamin Deficiency
W Herrmann and R Obeid
Water Soluble Vitamins, Subcellular Biochemistry 56 2012
In this review article, the authors highlight the lack of sensitivity and specificity of the Total B12 test and conclude that many deficient subjects would be overlooked by using this test as a status marker. They also suggest that Active-B12 is an earlier marker that would show a decrease before the Total B12 result.


Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies.
R. Green
AJCN Jul 2011;94(suppl):666S-72S
Professor Green reviews the available tests for assessment of B12 deficiency and suggests that growing evidence indicates that measurement of Active-B12 may improve the predictive power for detecting B12 deficiency.


Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility.
Nexo E, Hoffmann-Lucke E.
AJCN Jul 2011;94(1):359S-65S
This review focuses on Active-B12 and concludes that it may be more suitable than Total B12 for diagnosis of Vitamin B12 deficiency. The authors also predict that Active-B12 may be used for monitoring of the B12 status of populations.


Diagnostic Accuracy of Holotranscobalamin, Methylmalonic Acid, Serum Cobalamin, and Other Indicators of Tissue Vitamin B12 Status in the Elderly.
Valente E, Scott JM, Ueland PM, Cunningham C, Casey M, Molloy AM.
Clin Chem. 2011;57:6 856-863.
This novel study examined the performance of all tests that are currently used for the assessment of Vitamin B12 status and concluded that Active-B12 should be the front-line procedure.


Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study.
Hooshmand B, Solomon A, Kåreholt I, Leiviskä J, Rusanen M, Ahtiluoto S, Winblad B, Laatikainen T, Soininen H, Kivipelto M.
Neurology. 2010 Oct 19;75(16):1408-14
In this study to examine the link between Homocysteine levels and risk of Alzheimer’s disease, the authors suggest that the link may be partly explained by Active-B12 and go on to recommend that the role of Active-B12 in Alzheimer’s disease should be further investigated.


Relationship between the Levels of Holotranscobalamin and Vitamin B12.
Woo KS, Kim KE, Park JS, Park JI, Han JY.
Korean J Lab Med. 2010 Apr;30(2):185-9
This publication describes the introduction of Active-B12 into a Korean hospital laboratory. The authors show how Active-B12 levels were more sensitive than the Total B12 levels for indicating vitamin B12 status. They focus on the grey-zone of Total B12 results and suggest that in this area, Active-B12 either in isolation or in combination with Total B12 would be more useful than Total B12 alone.


Increases in Plasma Holotranscobalamin Can Be Used to Assess Vitamin B-12 Absorption in Individuals with Low Plasma Vitamin B-12
Dattatray S. Bhat, Nileema V. Thuse, Himangi G. Lubree, Charudatta V. Joglekar, Sadanand S. Naik, Lalita V. Ramdas, Carole Johnston, Helga Refsum, Caroline H. Fall and Chittaranjan S. Yajnik
J. Nutr. 139: 2119–2123, 2009
In a similar approach to the Aarhus group, this study examined the use of Active-B12 level in B12 replacement therapy and concluded that Active-B12 may be used to assess the ability of patients to absorb B12.


The Usefulness of Holotranscobalamin in Predicting Vitamin B12 Status in Different Clinical Settings
Wolfgang Herrmann, Rima Obeid, Heike Schorr, Jurgen Geisel
Current Drug Metabolism, 2005, 6, 47-53
This German study investigated the utility of Active-B12 in different patient groups and concluded that Active-B12 is a more accurate predictor of Vitamin B12 status than is the Total B12 test.


Diagnosis and treatment of vitamin B12 deficiency – an update
Anne-Mette Hvas, Ebba Nexo
Haematologica 2006; 91(11) 1508-1514
This review paper again describes why growing evidence indicates that Active-B12 may be superior to Total B12.


Holotranscobalamin remains unchanged during pregnancy. Longitudinal changes of cobalamins and their binding proteins during pregancy and postpartum
AL Morkbak, AM Hvas, N Milma, E Nexo
Haematologica 2007; 92: 1711-1712
This study shows that while Total B12 levels drop during normal pregnancy, the Active-B12 level remains unchanged. The authors conclude that Active-B12 but not Total B12 can be used to monitor B12 status during pregnancy.


Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid

R Obeid, W Herrmann
Clin Chem Lab Med 2007:45(12):1746-1750
In this study population it was shown that the majority of patients with combined low Active-B12 and elevated MMA had normal concentrations of Total B12. For this reason, the authors recommend that Active-B12 can be used as the first line parameter in detecting B12 deficiency.


To source more publications concerning Active-B12 in the peer reviewed literature visit PubMed and type “holotranscobalamin” into the search box. This will give a list of all articles related to Active B12. In some cases only the abstract of the publication is provided but in others the full publication is available at no charge. These publications vary in the level of scientific content and knowledge required to read them: some are straight -forward and relatively easy to understand reviews and some require a degree of technical knowledge.

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