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UBC Theses and Dissertations

Derivation of pediatric reference intervals for vitamin B-12 biomarkers and comparison of their diagnostic ability in children at risk of vitamin B-12 deficiency St-Cyr, Camille


Background: Early detection of vitamin B-12 (B-12) deficiency through reliable biomarkers is critical to prevent poor development and life-long health consequences. Children with short bowel syndrome (SBS) are at risk of B-12 deficiency. Serum total B-12 is the most commonly used B-12 biomarker but there is ambiguity to its performance. Holotranscobalamin (holoTC), the B-12 form taken up by cells, may be a more sensitive biomarker. Methylmalonic acid (MMA) is a functional and sensitive biomarker, but lacks availability in clinical laboratories. Overall, the utility of B-12 biomarkers in the pediatric population is limited, in part due to the lack of age-specific cutoffs. Objectives: 1) To derive age- and sex-specific reference intervals for serum holoTC and MMA concentrations in healthy children, and 2) to compare the diagnostic ability of total B-12 and holoTC to detect functional B-12 deficiency in pediatric SBS patients. Methods: The project consisted of 1) the secondary analysis of bio-banked serum samples for MMA and holoTC from 337 healthy Canadian children aged 0-18 years, and of 2) a descriptive, prospective study with 26 SBS patients from the BC Children’s Hospital in Vancouver, BC. Clinical and dietary data, and blood samples for quantitation of B-12 biomarkers, were collected over 2 years. Results: 1) Age-group partitions but no sex partitions were identified for MMA and holoTC. Upper reference limits (97.5th percentiles) for MMA were calculated for infants aged 0-<1 year and children aged 1-<19 years, and lower reference limits for holoTC were estimated for infants aged 0-<1 year, children aged 1-<14 years and adolescents aged 14-<19 years. 2) The diagnostic ability to detect functional B-12 deficiency was higher for holoTC compared to total B-12. HoloTC identified 4 out of 5 cases and total B-12 identified 1 of 5 cases of elevated MMA in our cohort of children with SBS. Conclusion: This is the first study to provide age-specific reference intervals for serum MMA and holoTC, that are required given the high variability of MMA and holoTC concentration across childhood. Serum holoTC may be a more reliable indicator than serum total B-12 at identifying functional B-12 deficiency in children with SBS.

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