From the Guidelines
The two products of metabolism that increase with low vitamin B12 are methylmalonic acid (MMA) and homocysteine. When B12 levels are insufficient, the body cannot properly convert methylmalonyl-CoA to succinyl-CoA, leading to increased MMA levels in the blood and urine. Similarly, B12 deficiency impairs the conversion of homocysteine to methionine, causing homocysteine levels to rise. These metabolic changes occur because vitamin B12 serves as a cofactor for the enzymes methylmalonyl-CoA mutase and methionine synthase, which are essential for these conversion processes. Measuring these metabolites in the blood provides a functional assessment of B12 status and can help diagnose deficiency even when serum B12 levels appear borderline, as suggested by the most recent guideline from the BMJ 1. Elevated MMA is considered more specific to B12 deficiency, while homocysteine can also increase with folate and vitamin B6 deficiencies. Some key points to consider when evaluating B12 deficiency include:
- Using either total B12 or active B12 as the initial test for suspected vitamin B12 deficiency 1
- Considering a further test to measure serum MMA concentrations in people who have symptoms or signs of vitamin B12 deficiency and an indeterminate total or active B12 test result 1
- Treating vitamin B12 deficiency immediately using hydroxocobalamin, with dosing regimens varying based on the presence of neurological involvement 1 These markers are particularly useful in detecting early or subclinical B12 deficiency before clinical symptoms develop.
From the Research
Metabolic Products of Low B12
The two products of metabolism that increase with low B12 are:
- Homocysteine
- Methylmalonic acid
Evidence from Studies
Studies have shown that low levels of vitamin B12 can lead to increased levels of homocysteine and methylmalonic acid in the body 2, 3, 4, 5.
- A study published in 1999 found that supplementation with vitamin B12 decreased homocysteine and methylmalonic acid levels in patients with end-stage renal disease 3.
- Another study published in 2016 found that high levels of methylmalonic acid and homocysteine were better indicators of vitamin B12 deficiency than serum vitamin B12 levels themselves 4.
- A 2009 study found that metabolic evidence of vitamin B12 deficiency, including high homocysteine and methylmalonic acid, was more pronounced in older adults with elevated plasma folate 5.
- A 2021 review discussed the importance of vitamin B12 in metabolic pathways and the potential pitfalls of testing for deficiency 2.
- A 2024 study compared the kinetics of cellular cobalamin uptake and conversion, and found that methylcobalamin and 5'-deoxyadenosylcobalamin metabolize homocysteine and methylmalonic acid, respectively 6.