Methylmalonic acid (MMA)
Methylmalonic acid rises in blood when cells are short of vitamin B12. WHO puts the cut-off at above 271 nmol/L and a later expert panel at above 376. US survey upper reference limits rise with age, from 254 under age 40 to 317 from age 70. Reduced kidney function raises the level too. Higher levels were linked to more deaths.
- Status
- A blood test ordered by a clinician, usually after a vitamin B12 result that is low or borderline. The one FDA device classification that names methylmalonic acid covers nonquantitative urine tests used for an inherited disorder, methylmalonic aciduria, as class II devices exempt from premarket notification [1].
- Measures
- The concentration in serum or plasma of methylmalonic acid, a substance that builds up when cells are short of vitamin B12 and that the kidneys clear from blood.
- Also called
- MMA, serum methylmalonic acid, plasma methylmalonic acid, methylmalonic acid serum, methylmalonic acid quantitative, methylmalonate, MMA blood test, serum MMA
- Tested for
- vitamin B12 deficiency, borderline B12 result, numbness and tingling, anemia workup, vegan or vegetarian diet, nitrous oxide use, checking B12 treatment
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Linked in research2
Reported risks0
No risks sourced yet.
Reference ranges
Each range is the one its source published, in nmol/L. Also reported in µmol/L. Where sources differ, each is shown.
World Health Organization and Food and Agriculture Organization fortification guidelines, 2006
All population groups, as a cut-off for assessing vitamin B12 status at the population level, in serum or plasma · [2]
| Range | What the source calls it |
|---|---|
| 271 or below nmol/L | No name given |
| above 271 nmol/L | "deficiency" |
The table lists above 271 nmol/L as the cut-off to define deficiency and calls methylmalonic acid the preferred indicator because increased levels are highly specific to vitamin B12 deficiency. The same guidelines note that it is more difficult and expensive to measure than vitamin B12. The table gives one cut-off for all ages and makes no mention of kidney function. The guidelines also mention urinary methylmalonic acid, a different test, and give no cut-off for it [2].
Biomarkers of Nutrition for Development (BOND) expert panel, 2018
Adults · [3]
| Range | What the source calls it |
|---|---|
| 376 or below nmol/L | No name given |
| above 376 nmol/L | "deficient" |
The panel's text describes above 376 nmol/L as the cut-off for adults, a concentration found in 2.4% of US elderly people with normal kidney function, and reports that above 271 is seen in 5.9% of the same group. Its table of cut-offs also prints 271 for adults, and the copy read here did not show under which heading, so only the cut-off named in the text is given. The panel states that renal insufficiency greatly increases serum methylmalonic acid and that concentrations begin to rise when serum B12 is below 287 pmol/L. It prints ranges for infants that are not shown here for the same reason [3].
US National Library of Medicine, MedlinePlus Medical Encyclopedia, reviewed 2025
People having the test, as an example of a laboratory normal range · [4]
| Range | What the source calls it |
|---|---|
| below 70 nmol/L | No name given |
| 70 to 270 nmol/L | "normal values" |
| above 270 nmol/L | "higher than normal" |
An encyclopedia entry licensed to the National Library of Medicine, not a guideline. It prints the range as 0.07 to 0.27 micromoles per liter, converted here. It states that normal value ranges may vary slightly among different laboratories and that a higher than normal value may be due to vitamin B12 deficiency or methylmalonic acidemia, an inherited disorder. It gives no meaning for a value under the range [4].
US national survey reference intervals, Mineva and colleagues, 2019, ages 20 to 39
Adults aged 20 to 39 with vitamin B12 of 300 pmol/L or more and no chronic kidney disease · [5]
| Range | What the source calls it |
|---|---|
| below 63.5 nmol/L | No name given |
| 63.5 to 254 nmol/L | "reference interval" |
| above 254 nmol/L | No name given |
The central 95% interval in 2,178 participants in the 2011 to 2014 US National Health and Nutrition Examination Survey, measured by mass spectrometry, excluding pregnant and breastfeeding women. In all 3,373 survey participants of this age, without those exclusions, the interval was 65.1 to 304. The authors derived the intervals for epidemiologic research and state that age-specific intervals are needed. No meaning is attached to a value under the interval [5].
US national survey reference intervals, Mineva and colleagues, 2019, ages 40 to 59
Adults aged 40 to 59 with vitamin B12 of 300 pmol/L or more and no chronic kidney disease · [5]
| Range | What the source calls it |
|---|---|
| below 70.5 nmol/L | No name given |
| 70.5 to 293 nmol/L | "reference interval" |
| above 293 nmol/L | No name given |
From 1,988 participants, derived the same way. In all 3,429 survey participants of this age the interval was 72.8 to 442 [5].
US national survey reference intervals, Mineva and colleagues, 2019, ages 60 to 69
Adults aged 60 to 69 with vitamin B12 of 300 pmol/L or more and no chronic kidney disease · [5]
| Range | What the source calls it |
|---|---|
| below 72.4 nmol/L | No name given |
| 72.4 to 281 nmol/L | "reference interval" |
| above 281 nmol/L | No name given |
From 824 participants, derived the same way. In all 1,667 survey participants of this age the interval was 77.0 to 497 [5].
US national survey reference intervals, Mineva and colleagues, 2019, ages 70 and older
Adults aged 70 and older with vitamin B12 of 300 pmol/L or more and no chronic kidney disease · [5]
| Range | What the source calls it |
|---|---|
| below 84.3 nmol/L | No name given |
| 84.3 to 317 nmol/L | "reference interval" |
| above 317 nmol/L | No name given |
From 491 participants, derived the same way. In all 1,551 survey participants of this age the interval was 92.5 to 758, and 85.9 to 571 in the 672 with normal kidney function whatever their B12 level [5].
Hordaland Homocysteine Study, Norway, Vogiatzoglou and colleagues, 2009, ages 47 to 49
Adults aged 47 to 49 with plasma vitamin B12 of 400 pmol/L or more · [6]
| Range | What the source calls it |
|---|---|
| below 100 nmol/L | No name given |
| 100 to 280 nmol/L | "reference limits" |
| above 280 nmol/L | No name given |
The 2.5th to 97.5th percentiles in the B12-replete members of a Norwegian population study, printed as 0.10 to 0.28 µmol/L and converted here. The authors found that methylmalonic acid rose when plasma B12 was below 400 pmol/L, and plotted the upper limit against plasma creatinine as nomograms [6].
Hordaland Homocysteine Study, Norway, Vogiatzoglou and colleagues, 2009, ages 71 to 74
Adults aged 71 to 74 with plasma vitamin B12 of 400 pmol/L or more · [6]
| Range | What the source calls it |
|---|---|
| below 100 nmol/L | No name given |
| 100 to 360 nmol/L | "reference limits" |
| above 360 nmol/L | No name given |
Printed as 0.10 to 0.36 µmol/L and converted here. Plotted against creatinine, the 97.5th percentile was about 0.15 µmol/L (150 nmol/L) higher in the older group than in the middle-aged group, a difference the authors report is only partly explained by creatinine and B12 [6].
Swiss SENIORLAB study decision limits, Risch and colleagues, 2015
Adults aged 60 and older · [7]
| Range | What the source calls it |
|---|---|
| 216 or below nmol/L | "probable vitamin B12 sufficiency" |
| 217 to 485 nmol/L | "grey zone" |
| above 485 nmol/L | "probable vitamin B12 deficiency" |
Cut-offs chosen by the authors from 1,143 Swiss adults aged 60 and older whom they describe as "subjectively healthy", 1,063 of them with methylmalonic acid measured, set against a combined index of four B12 markers that itself includes methylmalonic acid. The authors call the middle band a grey zone of diagnostic uncertainty. It is shown here on the high side, where it lies, and not as in range: the source does not clear a result in it. Median levels rose from 207 at ages 60 to 69 to 244 at 80 and older, which the authors attribute more to kidney function than to B12 [7].
Reference limits in pregnancy, British Columbia, Schroder and colleagues, 2019, first trimester
Pregnant women sampled between 8.3 and 13.9 weeks of pregnancy · [8]
| Range | What the source calls it |
|---|---|
| 371 or below nmol/L | No name given |
| above 371 nmol/L | "may indicate B-12 deficiency" |
The upper limit of the central 95% interval in 723 pregnant women of European and South Asian ethnicity in Canada, sampled at a median 11.4 weeks. The authors report that the upper limits differed significantly by ethnicity, and call for the cut-offs to be validated. The lower limit is not given in the abstract read here [8].
Reference limits in pregnancy, British Columbia, Schroder and colleagues, 2019, second trimester
Pregnant women sampled between 14.9 and 20.9 weeks of pregnancy · [8]
| Range | What the source calls it |
|---|---|
| 374 or below nmol/L | No name given |
| above 374 nmol/L | "may indicate B-12 deficiency" |
From the same 723 women, sampled again at a median 16.1 weeks [8].
What has been shown to move it
Tested, and not shown to change it1
B12 status on a vegan diet
One small trial found a multinutrient with B12 raised blood B12 markers in healthy vegan adults over 4 months.
Methylmalonic acid and homocysteine did not differ between groups.
The numbers and sources
- Effect
- After 4 months, a multinutrient supplement with 82 µg of B12 a day raised serum B12, holotranscobalamin and a combined B12 status indicator against placebo. Methylmalonic acid and homocysteine did not differ between groups [10].
- Population
- 72 healthy vegan adults aged 19 to 57 in Germany [10].
- Sources
- [10]
- Caveats
- One small trial of a supplement with several nutrients, measuring blood markers only [10].
How it compares with the reference method
Mixed results4
Detecting vitamin B12 deficiency
Mixed results: the area under the curve for detecting B12 deficiency ran from 0.78 to 0.92 across three studies that defined deficiency differently.
The numbers and sources
- Compared with
- Red cell cobalamin below 33 pmol/L in one study, and a combined index of four B12 markers in two
- Effect
- In 700 older adults, the area under the curve for detecting deficiency was 0.78 (95% CI 0.72 to 0.83) for methylmalonic acid, 0.90 for holotranscobalamin and 0.80 for serum B12. Half of the methylmalonic acid results fell in an indeterminate zone, and renal dysfunction compromised its accuracy and not that of the other two [13]. Against a combined index, the area under the curve was 0.916 (0.897 to 0.932) in Swiss adults aged 60 and older [7] and 0.91 in a mixed patient population [14]. In US survey data, the choice among commonly used cut-offs moved the share of adults classed as low from 2% to 6% for methylmalonic acid, against 3% to 26% for serum B12 [15].
- Population
- 700 adults aged 63 to 97 [13]. 1,143 Swiss adults aged 60 and older, 1,063 with methylmalonic acid measured [7]. 11,833 patient samples with all four markers measured [14]. 12,612 US adults older than 19 [15].
- Sources
- [13], [7], [14], [15]
- Caveats
- No accepted reference test for B12 deficiency exists [13]. The combined index used in two of the studies includes methylmalonic acid itself, which favors it in the comparison [7][14].
Reduced kidney function
Linked to levels about 50% to 70% higher in US adults with impaired kidney function than in those with normal function.
The numbers and sources
- Compared with
- Adults with normal kidney function in the same survey
- Effect
- In the US national survey, impaired kidney function went with methylmalonic acid about 50% to 70% higher in both survey periods. Geometric means were 140 and 145 nmol/L with normal function and 235 and 249 with chronic kidney disease stages 3 to 5. Serum B12 showed little change [5]. In a Norwegian population, age, plasma creatinine, B12 and sex were the strongest determinants and together accounted for 16% of the variation [6].
- Population
- 10,020 US adults aged 20 and older, surveyed from 2011 to 2014 [5]. 6,946 Norwegian adults aged 47 to 49 or 71 to 74 [6].
- Sources
- [5], [6]
- Caveats
- Cross-sectional. The surveys state no threshold for agreement, so the result is given as numbers only. A raised level in a person with reduced kidney function may not reflect B12 status [5].
Fasting against not fasting
One US survey found methylmalonic acid about 10% higher in people who had fasted less than 3 hours than in those who had fasted 8 hours or more.
The numbers and sources
- Compared with
- A sample taken after 8 or more hours of fasting
- Effect
- Shorter fasting time was significantly associated with about 10% higher methylmalonic acid in both survey periods after controlling for age, sex, race and Hispanic origin, supplement use and kidney function. It showed no association with serum B12 [5].
- Population
- US adults aged 20 and older in the 2011 to 2014 national survey, with fasting time self-reported [5].
- Sources
- [5]
- Caveats
- A comparison between people, not the same person tested twice. The survey states no threshold for agreement [5].
Variation from one draw to the next in one person
One study in a European laboratory database found methylmalonic acid varied about 7% from draw to draw within the same person.
The numbers and sources
- Compared with
- The same person's results on repeated venous draws
- Effect
- The European Federation of Clinical Chemistry and Laboratory Medicine database gives a within-person variation of 7.2% (limits 6.2% to 8.5%) and a variation between people of 21.1% (15.3% to 33.4%), from the one study it includes [16]. At 250 nmol/L, 7.2% is 18 nmol/L. The US survey laboratory reported long-term assay imprecision of 3% to 5% at 96 to 560 nmol/L [5].
- Population
- Volunteers in the one study the database includes [16].
- Sources
- [16], [5]
- Caveats
- One study. The database states no threshold for agreement, so the result is given as numbers only [16].
What studies tie it to
Linked in research2
Death from any cause
Linked to more deaths at higher levels in US and Dutch cohorts, 62% more at 250 nmol/L or above than below 120.
The numbers and sources
- Effect
- In a US national survey cohort, adults with methylmalonic acid of 250 nmol/L or more, compared with below 120, had hazard ratios of 1.62 (95% CI 1.43 to 1.84) for death from any cause and 1.66 (1.22 to 2.27) for cardiovascular death after adjustment. The association was especially marked in people with normal B12 and was repeated in a later round of the survey [9]. In a Dutch cohort, each doubling of methylmalonic acid had a hazard ratio for death of 1.67 (95% CI 1.25 to 2.22), independent of vitamin B12, kidney function and sex, and more pronounced in people with impaired kidney function [10].
- Population
- 23,437 US adults, with 3,019 deaths over a median 13.5 years in the 1999 to 2004 rounds [9]. 1,533 Dutch adults aged 60 to 75 followed for 8.5 years, 72 deaths [10].
- Sources
- [9], [10]
- Caveats
- Observational. In the Dutch cohort, vitamin B12, kidney function, age and sex together explained 22% of the variation in methylmalonic acid, so a raised level reflects more than B12 status. No trial cited here tested whether lowering it changes survival [10].
Cognitive decline in older adults
Limited evidence: one Oxford cohort linked a doubling of methylmalonic acid to cognitive decline more than 50% faster over 10 years.
The numbers and sources
- Effect
- A doubling of methylmalonic acid from 250 to 500 nmol/L went with a rate of cognitive decline more than 50% faster on the Mini-Mental State Examination. The association remained significant after adjustment for the other vitamin markers. Holotranscobalamin and homocysteine also predicted decline, and folate did not [11].
- Population
- 1,648 older adults in Oxford, United Kingdom, tested on 3 or more occasions over 10 years [11].
- Sources
- [11], [12]
- Caveats
- Observational, from one cohort. The authors state that randomized trials are required to determine whether B12 supplementation is relevant to preventing dementia [11]. In a meta-analysis of 11 trials with 22,000 participants, B vitamins given to lower homocysteine had no significant effect on global cognitive function (z score difference -0.01, 95% CI -0.03 to 0.02). Those trials did not select people by methylmalonic acid and were not trials of treating B12 deficiency [12].
Related
Sources
- US Food and Drug Administration. 21 CFR 862.1509, Methylmalonic acid (nonquantitative) test system. Electronic Code of Federal Regulations. https://www.ecfr.gov/current/title-21/section-862.1509
- Allen L, de Benoist B, Dary O, Hurrell R, eds. Guidelines on food fortification with micronutrients. Geneva: World Health Organization and Food and Agriculture Organization of the United Nations, 2006. ISBN 92-4-159401-2. https://iris.who.int/handle/10665/43412
- Allen LH, Miller JW, de Groot L, et al. Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review. The Journal of Nutrition. 2018. https://doi.org/10.1093/jn/nxy201
- US National Library of Medicine. Methylmalonic acid blood test. MedlinePlus Medical Encyclopedia, review date October 1, 2025. https://medlineplus.gov/ency/article/003565.htm
- Mineva EM, Sternberg MR, Zhang M, et al. Age-specific reference ranges are needed to interpret serum methylmalonic acid concentrations in the US population. The American Journal of Clinical Nutrition. 2019. https://doi.org/10.1093/ajcn/nqz045
- Vogiatzoglou A, Oulhaj A, Smith AD, et al. Determinants of Plasma Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status. Clinical Chemistry. 2009. https://doi.org/10.1373/clinchem.2009.128678
- Risch M, Meier DW, Sakem B, et al. Vitamin B12 and folate levels in healthy Swiss senior citizens: a prospective study evaluating reference intervals and decision limits. BMC Geriatrics. 2015. https://doi.org/10.1186/s12877-015-0060-x
- Schroder TH, Tan A, Mattman A, et al. Reference intervals for serum total vitamin B12 and holotranscobalamin concentrations and their change points with methylmalonic acid concentration to assess vitamin B12 status during early and mid-pregnancy. Clinical Chemistry and Laboratory Medicine. 2019. https://doi.org/10.1515/cclm-2018-1337
- Wang S, Liu Y, Liu J, et al. Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population. Redox Biology. 2020. https://doi.org/10.1016/j.redox.2020.101741
- Riphagen IJ, Minović I, Groothof D, et al. Methylmalonic acid, vitamin B12, renal function, and risk of all-cause mortality in the general population: results from the prospective Lifelines-MINUTHE study. BMC Medicine. 2020. https://doi.org/10.1186/s12916-020-01853-x
- Clarke R, Birks J, Nexo E, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. The American Journal of Clinical Nutrition. 2007. https://doi.org/10.1093/ajcn/86.5.1384
- Clarke R, Bennett D, Parish S, et al. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. The American Journal of Clinical Nutrition. 2014. https://doi.org/10.3945/ajcn.113.076349
- Valente E, Scott JM, Ueland PM, et al. Diagnostic Accuracy of Holotranscobalamin, Methylmalonic Acid, Serum Cobalamin, and Other Indicators of Tissue Vitamin B12 Status in the Elderly. Clinical Chemistry. 2011. https://doi.org/10.1373/clinchem.2010.158154
- Jarquin Campos A, Risch L, Nydegger U, et al. Diagnostic Accuracy of Holotranscobalamin, Vitamin B12, Methylmalonic Acid, and Homocysteine in Detecting B12 Deficiency in a Large, Mixed Patient Population. Disease Markers. 2020. https://doi.org/10.1155/2020/7468506
- Bailey RL, Carmel R, Green R, et al. Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12. The American Journal of Clinical Nutrition. 2011. https://doi.org/10.3945/ajcn.111.015222
- European Federation of Clinical Chemistry and Laboratory Medicine. EFLM Biological Variation Database, meta-analysis estimates, read 2026-11-13. https://biologicalvariation.eu/