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. Read on to find out more about this test.
What is Methylmalonic Acid?
Methylmalonic acid (MMA) is normally produced in very small amounts when you digest protein and fat. It serves 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 levels, it is used as a functional indicator of 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 point out 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?
Methylmalonic acid test is not a part of routine health check-ups. Instead, doctors sometimes use it to follow up on people with normal B12 levels but with symptoms of vitamin B12 deficiency. It can also be 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 can point to an early or mild B12 deficiency.
Apart from blood, MMA can also 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.
Your doctor 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 and some labs also provide a low-normal limit.
The cut-off value that points to vitamin B12 deficiency has not been universally agreed upon. 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 (affecting MMA removal) 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). The normal range varies somewhat between laboratories.
Methylmalonic Acid 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 scientists 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
Other scientists 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, 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 study has found that a genetic mutation in people of European ancestry (in the HIBCH gene) can increase MMA levels by almost 50% regardless of vitamin B12 levels [22].
Bottom Line
An MMA test may be useful in addition to a B12 test.
| Low B12 | Normal/High B12 | |
| High MMA | Vitamin B12 deficiency | Possible mild B12 deficiency, but can also be due to other causes |
| Normal/Low MMA | Vitamin 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
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, 28]
- 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 [29]
- Common harmless genetic mutations [22]
- Genetic disorders [3]
Causes listed above are commonly associated with high MMA levels. Work with your doctor or another health care professional to get an accurate diagnosis.
Health Risks
MMA interferes with energy production in mitochondria and may harm the nervous system and kidneys [3].
High MMA has been associated with:
- Worse cognitive function and physical activity in older people (> 200 people) [30, 31]
- Hearing loss (93 people) [32]
- Early nerve damage in diabetes (176 people) [33]
- Increased neuropathic pain in Parkinson’s disease (58 people) [34]
Decreasing Methylmalonic Acid
The most important thing is to work with your doctor to find out what’s causing your high MMA levels.
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.
Discuss the additional lifestyle changes with your doctor. None of these strategies should ever be done in place of what your doctor recommends or prescribes:
- 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]. Remember that vitamin B12 deficiency is often caused by an underlying health issue, in which case simple dietary changes are unlikely to be of help. Work with your doctor to treat the underlying cause.
- Reduce or quit drinking alcohol. Alcohol can deplete vitamin B12 levels [10, 9, 38]
- Quit smoking as nicotine can also lower B12 levels [39]
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. Your doctor will interpret your levels, taking into account your medical history, symptoms, and other test results.
Genetics
Genetics probably plays 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].
