Methylmalonic acid (MMA) is normally made in the body in tiny amounts. It builds up only in the absence of vitamin B12 and can be used as a functional indicator of vitamin B12 status. However, testing MMA is still controversial and has some limitations, according to the latest research. Read on to find out if this test is right for you.

What is Methylmalonic Acid?

Methylmalonic acid (MMA) is normally produced in very small amounts when you digest protein and fat. It serves only as an intermediate compound that needs to be broken down further into succinate by Vitamin B12. When there’s not enough vitamin B12, MMA levels rise both in the blood and urine [1].

Since MMA builds up due to inadequate vitamin B12, it is used as a functional indicator of one’s vitamin B12 status [2].

Methylmalonic acid levels increase in the early stages of vitamin B12 deficiency, when vitamin B12 levels may still be in the normal range. Measuring MMA can tell you if you have a mild vitamin B12 deficiency that a standard B12 test might not pick up [3].

Methylmalonic Acid Test – When is It Ordered?

The methylmalonic acid test is not a part of routine health check-ups. Instead, it is sometimes used to follow up on people with normal B12 levels but with symptoms of vitamin B12 deficiency. It is also used to check if B12 supplements are working.

An MMA test is sometimes ordered along with homocysteine. This is because vitamin B12 is needed to metabolize both homocysteine and MMA. Having high MMA, high homocysteine and slightly low vitamin B12 points to an early or mild B12 deficiency.

MMA can be measured in the urine, which is more convenient as it doesn’t require a blood draw [1].

Newborns are often tested for high levels of MMA, which can help diagnose a rare metabolic disorder called methylmalonic acidemia.

You may want to test your MMA if you are at an increased risk of B12 deficiency. Groups at higher risk include:

  • Vegans and vegetarians [4, 5, 6]
  • Pregnant and breastfeeding women [7, 8]
  • Heavy alcohol drinkers [9, 10]
  • Obese people [11, 12]
  • People with gut disorders that reduce the absorption of dietary B12 [13, 14, 15]
  • AIDS/HIV patients [16, 17]
  • Elderly people, as the gut becomes less efficient at absorbing nutrients with age [18, 19, 14] – however, an MMA test is not recommended in older people

Normal Range

Blood MMA Test

Healthy people will have MMA below 370 nmol/L (nanomoles per liter) or 0.37 umol/L (micromoles per liter). The normal range varies somewhat between laboratories, while some also provide a low-normal limit.

The cut-off value that points to vitamin B12 deficiency has not been universally agreed on. Studies suggest that levels anywhere from > 243 to > 350 indicate possible B12 deficiency [20, 21, 22].

MMA levels can normally rise in pregnancy, especially in the third trimester [23].

Blood MMA levels also tend to increase after the age of 40, caused mainly by decreased kidney function and poorer vitamin B12 absorption [3, 24].

Urine MMA Test

The normal range of MMA in the urine is 0.4 – 2.5 μmol/mmol crt (micromoles per mmol of creatinine).

Methylmalonic Acid Test vs. Vitamin B12 Test

In Favor of MMA Testing

Is an MMA test better than a regular vitamin B12 blood test? The answer is not straightforward.

Some argue that people with low-normal vitamin B12 blood levels can show signs of tissue vitamin B12 deficiency, which can be discovered by testing MMA [3].

In a study of 581 patients with polyneuropathy (a disease that causes damage to multiple nerves, leading to weakness, numbness, and burning pain), 32% had a possible vitamin B12 deficiency. Although their B12 levels were normal, MMA was >243 nmol/L. In this group, treatment with vitamin B12 improved symptoms in 43% of the cases [21].

Against MMA Testing

Others take the stance that mild deficiencies do not necessarily need to be treated since they rarely progress and become more severe. What’s more, MMA can only indicate B12 deficiency but it reflects neither the severity nor the progression of the deficiency.

For example, a study monitored 432 elderly people who had increased MMA but were not treated with vitamin B12. Initially, high MMA values did not predict a further increase in the severity or symptoms of vitamin B12 deficiency even 1 – 4 years later [25].

MMA is a sensitive test – most B12-deficient people will have high MMA [26]. However, it is not specific – MMA can be high due to causes other than vitamin B12 deficiency. In fact, high MMA can be a “normal” finding. Many older people have elevated MMA that is NOT associated with low B12 levels, which is why this test is not recommended in the elderly [22, 27].

Finally, a genetic mutation in people of European ancestry (in the HIBCH gene) can increase MMA levels by almost 50% uninfluenced by vitamin B12 levels, according to a recent study [22].

Bottom Line

An MMA test can be useful in addition to a B12 test.

Low B12Normal/High B12
High MMAVitamin B12 deficiencyPossible mild B12 deficiency, but can also be due to other causes
Normal/Low MMAVitamin B12 deficiency (some people can be vitamin B12 deficient but have low MMA levels – e.g. urine MMA can decrease with impaired kidney function)Vitamin B12 sufficiency

 

High Methylmalonic Acid

Health Risks

Since MMA is usually quickly broken down in the body, its buildup can have a negative impact on health. MMA interferes with energy production in mitochondria and may harm the nervous system and kidneys [3].

High MMA is associated with:

  • Early nerve damage in diabetes (176 people) [28]
  • Worse cognitive function and physical activity in older people (> 200 people) [29, 30]
  • Hearing loss (93 people) [31]
  • Increased neuropathic pain in Parkinson’s disease (58 people) [32]

Causes

Causes of high MMA include:

  • B12 deficiency, most often due to a B12-poor diet, issues with nutrient absorption, or drugs that deplete B12 levels (e.g. metformin) [2, 33]
  • Poor kidney function. Kidneys that are not working properly can’t filter MMA into the urine, causing it to accumulate in the blood [3]
  • Small bowel bacterial overgrowth (SIBO) in short bowel syndrome [34]
  • Common harmless genetic mutations [22]
  • Genetic disorders [3]

How to Decrease Methylmalonic Acid

If you have high MMA but normal vitamin B12 levels, your doctor may decide to monitor your levels before recommending any interventions.

If a vitamin B12 deficiency is confirmed, your doctor may recommend increasing your intake of foods rich in B12, taking B12 supplements, or receiving B12 injections. You can take the following steps in this case:

  • Eat more vitamin B12-rich foods from animal sources such as red meat, fish, poultry, yogurt, and milk. Vitamin B12 found in eggs is poorly absorbed, making eggs a less ideal source [35, 36, 37]
  • Reduce or quit drinking alcohol. Alcohol can reduce vitamin B12 levels [10, 9, 38]
  • Quit smoking as nicotine can also lower B12 levels [39]
  • In women, the use of birth control pills is linked to lower B12 levels; switching to an alternative form of birth control may help [40]
  • Calcium improves vitamin B12 absorption in diabetic patients taking metformin [41, 42, 43]

Low Methylmalonic Acid

Low MMA has no known health implications.

Remember that it’s possible (although rare) to have low blood or urine MMA and still be vitamin B12 deficient.

Genetics

Genetics probably play a large role in MMA levels. In a large study with over 18,500 people living in the US, those of European ancestry (non-Hispanic) had higher MMA levels compared to those of African or Hispanic ancestry, despite using more vitamin/mineral supplements and having better kidney function (measured by creatinine) [3].

One SNP in the HIBCH gene (rs291466 C allele) was strongly linked with elevated MMA levels in the Irish white population (a genome-wide study of > 2,00 people). This mutation influences blood MMA concentrations independently of vitamin B12 status. People with the CC genotype in the study had, on average, 46% higher MMA levels [22].

Irregular Methylmalonic Acid Levels?

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About the Author

Biljana Novkovic - PHD (ECOLOGICAL GENETICS) - Writer at Selfhacked

Dr. Biljana Novkovic, PhD

PhD (Ecological Genetics)

Biljana received her PhD from Hokkaido University.

Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science & health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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