Methylmalonic acid

Methylmalonic acid is an organic acid of which the blood levels are usually raised in case of a B12 deficiency. Adenosylcobalamin – one of the two active forms of B12 – is a cofactor of the enzyme L-methylmalonyl-CoA- mutase, which converts L-methylmalonyl-Coa into succinyl-CoA. If adenosylcobalamin is lacking, excess D-methylmalonyl-CoA (precursor of L-methylmalonyl-CoA) is converted into methylmalonic acid(MMA) which causes raised blood levels of MMA. In short: a B12 deficiency (usually) causes high MMA.

High MMA serum values are also found in people with renal insufficiency, hypovolemia (decreased volume of circulating blood) and intestinal bacterial overgrowth. In these cases MMA levels cannot be used to diagnose B12 deficiency though a B12 deficiency might simultaneously exist. In the case of kidney disease ( or hypovolemia) MMA levels in urine can be tested.

MMA values can be false-normal in people with B12 deficiency who take (or recently took) antibiotics, for these destroy the intestinal flora needed to make propionic acid (an organic acid, precursor to MMA). MMA should be tested before starting treatment..

In case of a B12 deficiency treatment will rather quickly lower MMA levels. Testing sometime after starting treatment, for instance after one or two months, may serve as a confirmation of the B12 deficiency diagnosis. This can also be done when people before treatment have a MMA value which is not distinctly above reference values.

MMA and homocysteine are considered more sensitive tests than serum B12. However, Solomon1 previously reported on patients with normal values of MMA, homocysteine and serum B12 who still had clinical symptoms of a B12 deficiency and responded favourably to treatment with vitamin B12. When patients show serious symptoms that relate to B12 deficiency, Hvas and Nexo2 , too, advise treatment regardless the test results. With patients having values (of serum B12 and MMA) in the grey area and complaints that could indicate a B12 deficiency, treatment should be started and, in case of clinical improvement, continued.
Subsequently, one could consider retesting homocysteine and MMA to see if they decrease.

For diagnosing B12 deficiency there is no golden standard test and non-treatment because of normal values can have very serious consequences.
An additional problem is the variety of MMA reference values as used by specific laboratories. In the Netherlands MMA reference values vary from <0.31µmol/L (Free University Medical Center in Amsterdam) to < 0.45µmol/L (Erasmus Medical Center in Rotterdam) The other laboratories use values between these two. In medical literature even lower MMA values are used: from <0.21µmol/L to<0.318µmol/L and the most widely used value is 0.27µmol/L as well as B12 symptoms.

Additionally, patients with values in the grey area and distinct B12 problems should be treated and, if improvement occurs, treatment should be continued.


1. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Solomon LR. Blood 2005;105:978-85.
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10. Methylmalonic acid as an indicator of vitamin B12 deficiency in patients on metformin. Norbert Shtaynberg, Manjinder Singh, Phillip Sohn, Michael Goldman*, Neil Cohen Journal of Diabetes Mellitus Vol.2, No.1, 72-75 (2012)
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