From the Guidelines
The most specific test to diagnose Vitamin B12 deficiency is methylmalonic acid (MMA) measurement in people who have symptoms or signs of vitamin B12 deficiency and an indeterminate total or active B12 test result. According to the latest guideline summary from the BMJ in 2024 1, the initial test for suspected vitamin B12 deficiency should be either total B12 (serum cobalamin) or active B12 (serum holotranscobalamin). However, in cases where the initial test results are indeterminate, measuring serum MMA concentrations can provide a more specific diagnosis, although this is based on very low certainty evidence 1.
Some key points to consider when diagnosing Vitamin B12 deficiency include:
- Using total B12 or active B12 as the initial test
- Considering further testing with serum MMA in people with symptoms or signs of vitamin B12 deficiency and an indeterminate initial test result
- Being aware that MMA testing has its own limitations and uncertainties, including the potential for overestimation of savings due to lack of evidence on model parameters 1
It's also important to note that while serum B12 levels can sometimes be normal despite a functional deficiency, MMA levels are a more sensitive and specific marker of B12 status at the tissue level. Therefore, measuring MMA concentrations can be a crucial step in diagnosing Vitamin B12 deficiency, especially in cases where the initial test results are unclear.
From the FDA Drug Label
Cyanocobalamin injection is also suitable for the Vitamin B12 absorption test (Schilling test). The most specific test to diagnose Vitamin B12 deficiency is the Schilling test 2.
From the Research
Diagnosis of Vitamin B12 Deficiency
The diagnosis of vitamin B12 deficiency can be challenging, and there is no single test that can conclusively determine the deficiency. However, several biomarkers can be used to evaluate vitamin B12 status, including:
- Serum vitamin B12 levels
- Holotranscobalamin (holoTC) levels
- Methylmalonic acid (MMA) levels
- Total plasma homocysteine (Hcy) levels
Most Specific Test for Diagnosing Vitamin B12 Deficiency
According to the studies, MMA is a functional marker of vitamin B12 status and a valuable diagnostic tool 3, 4, 5. The measurement of MMA levels can help detect vitamin B12 deficiency, especially in cases where serum vitamin B12 levels are borderline or normal 5. A study compared two methods for measuring MMA, gas chromatography mass spectrometry (GCMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS), and found that both methods showed a strong correlation, particularly at low holoTC levels 3.
Diagnostic Algorithm
A diagnostic algorithm has been proposed that uses holotranscobalamin as a first-line marker and MMA as a second-line marker 5. This approach can help detect vitamin B12 deficiency, especially in individuals with normal renal function. The algorithm suggests that testing for vitamin B12 deficiency should start with holotranscobalamin measurement, and if the levels are between 23 and 75 pM, MMA testing should be performed as a second-line marker.
Key Findings
- MMA levels are more strongly associated with poor functional status and physical performance than serum vitamin B12 levels 4
- Elevated MMA concentrations are more strongly associated with poor functional performance than serum vitamin B12 levels 4
- The measurement of MMA levels can help detect vitamin B12 deficiency, especially in cases where serum vitamin B12 levels are borderline or normal 5
- A diagnostic algorithm that uses holotranscobalamin as a first-line marker and MMA as a second-line marker can help detect vitamin B12 deficiency 5