Biomarkers and Algorithms for the Diagnosis of Vitamin B ₁₂ Deficiency

Vitamin B ₁₂ (cobalamin, Cbl, B ₁₂) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B ₁₂ and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B ₁₂ status. Clinically, vitamin B ₁₂ deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B ₁₂ deficiency (usually defined as a total serum B ₁₂ of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B ₁₂ has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B ₁₂ not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B ₁₂. This review discusses the usefulness and limitations of current biomarkers of B ₁₂ status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B ₁₂ deficiency and unusual findings of vitamin B ₁₂ status in various human disorders.