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

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.

More sensitive

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.

No gold standard

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.

References:

1. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Solomon LR. Blood 2005;105:978-85.
2. Diagnosis and treatment of vitamin B12 deficiency. An update. Anne-Mette Hvas, Ebba Nexo Haematologica 2006; 91:1506-1512
3. Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin. Ralph Carmel Am J Clin Nutr July 2011 vol. 94 no. 1 348S-358S
4. Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12 Regan L Bailey, Ralph Carmel, Ralph Green, Christine M Pfeiffer, Mary E Cogswell, John D Osterloh, Christopher T Sempos, and Elizabeth A Yetley Am J Clin Nutr. 2011 Aug;94(2):552-61.
5. Determinants of Plasma Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status. Anna Vogiatzoglou, Abderrahim Oulhaj, A. David Smith, Eha Nurk, Christian A. Drevon, Per M. Ueland, Stein E. Vollset, Grethe S. Tell, Helga Refsum Clinical Chemistry December 2009 vol. 55 no. 12 2198-2206
6. Measurement of methylmalonic acid, homocysteine and methionine in cobalamin and folate deficiencies and homocysteinuria. Ueland PM, Schneede J. Tidsskr Nor Laegeforen. 2008 Mar 13;128(6):690-3.
7. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Am J Clin Nutr. 2005; 82(2): 442–450.
8. Causes and early diagnosis of vitamin B12 deficiency. Dtsch. Herrmann W, Rima O. Arztebl Int. 2008; 105(40): 680-685.
9. Role of homocysteine, cystathionine and methylmalonic acid measurement for diagnosis of vitamin deficiency in high-aged subjects. Herrmann W, Schorr H, Bodis M, Knapp JP, Müller A, Stein G, Geisel J, European Journal Of Clinical Investigation, 0014-2972, 2000 Dec, Vol. 30, Issue 12
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)
11. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Martha Savaria Morris, Paul F Jacques, Irwin H Rosenberg, and Jacob Selhub Am J Clin Nutr January 2007 vol. 85 no. 1 193-200
12. Vitamin B12 and methylmalonic acid levels in patients presenting with polyneuropathy. Rachel A. Nardin MD*, Amy N.H. Amick MD, Elizabeth M. Raynor MD Muscle & Nerve Volume 36, Issue 4, pages 532–535, October 2007