Demonstration of the clinical utility of holotc as an early marker of vitamin b12 deficiency

Guidelines for the evaluation of the technical performance of the holoTC assay were published together with information on sample handling and determinants of holoTC. Use of holoTC is simple and does not require either special sample collection or post-treatment. Neither is it, in contrast to the metabolic markers methylmalonic acid or homocysteine, more than marginally influenced by kidney function or age of the patient. HoloTC is a better marker than is plasma vitamin B12 in identifying persons with vitamin B12 deficiency, as defined by an increased level of MMA. In addition holoTC has the advantage of being easily standardized. This in contrast to total plasma vitamin B12, where a lack of standardisation requires laboratories to implement their own reference ranges and cut-off values. Further guidelines as to the use of holoTC are to be published in papers now in progress.

The project results have been described in several published peer reviewed reports and several more are in preparation. Two web sites have been established, both aimed for health professionals and clinicians who want to learn more about holo-transcobalamin. One is managed by the consortium and one by the commercial partner. A booklet on holoTC aimed at end-users of the HoloTC-assays has been produced. In addition, the results obtained have been disseminated at numerous scientific meetings, and marketing activities. These activities will be continued after project end.

The performance of the commercially available HoloTC RIA was evaluated. Total imprecision was 10% or less. No inter-laboratory deviations were observed in the range 10 to 200 pmol/L. The assay works well but has certain limitations: Such as the time and technical skill needed to perform the assay, the use of radioactivity, and the large sample volume needed, which severely limits the possibility to re-test samples. On the basis of these results the commercial partner intensified development of a more user-friendly non-isotopic method requiring less sample and adaptable to automatic clinical instruments. This assay, HoloTC AxSYM became available toward the end of the project.

The project found that holoTC is superior to plasma vitamin B12 in identifying individuals with vitamin B12 deficiency and disclosed the usefulness of the holoTC assay to investigate the uptake of vitamin B12. The latter will be further explored in order to devise a routine method for the use of holoTC to evaluate a patient's capacity to absorb vitamin B12. The project further found that usually analysis of total TC and TC saturation would not add information compared to analysing holoTC alone. However, measurement of total TC may be useful to identify individuals lacking the protein and to explore unusual holoTC results. The project identified a method whereby total TC can be measured employing the holoTC assay. Work to clarify the future of total TC will be continued.

The introduction of holoTC will have a positive socio-economic impact. The project has demonstrated that holoTC is superior to the measurement of vitamin B12 in plasma for correctly identifying both those with vitamin B12 deficiency and those without the condition, the condition being defined based on an elevated level of the metabolic marker methylmalonic acid. In addition holoTC has other advantages over plasma B12, such as being less influenced by common biological confounders and being more adaptable to standardization, which both positively affect diagnostic utility. A replacement of the new test for the old, plasma B12, will have a neutral cost impact as it requires no extra resources and will be run on the same automatic platforms. Thus, provided the analysis becomes generally available and competitively priced, general use of holoTC can be recommended.

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