Vitamin Biomarkers: Methylmalonic Acid

Optimal Takeaways

Methylmalonic acid (MMA) production is associated with vitamin B12 insufficiency, oxidative stress, mitochondrial dysfunction, decreased renal function, and alteration of propionic acid metabolism. Although elevated MMA is associated with compromised B12 status, it is not a standalone biomarker for a B12 deficiency which should be assessed using at least two biomarkers, including MMA, holotranscobalamin, homocysteine, and serum B12. The disorders associated with elevated MMA include renal dysfunction, diabetes, neuropathy, migraines, and increased mortality risk. A low MMA does not appear to be clinically significant.

Standard Range: 0.00 – 318 nmol/L

The ODX Range: 0.00 – 260.00 nmol/L

Low methylmalonic acid suggests vitamin B12 sufficiency.

High methylmalonic acid is associated with B12 insufficiency, low serum B12, decreased hemoglobin, impaired renal function, kidney disease (Wolffenbuttel 2020), metformin use, diabetic peripheral neuropathy (Wile 2010), migraines (Togha 2019), heart failure, oxidative stress, hypertension, atrial fibrillation, thyroid dysfunction, diabetes mellitus (Polytarchou 2020), excess production and metabolism of propionic acid, and increased mortality especially combined with decreased renal function (Riphagen 2020).

Overview

Methylmalonic acid (MMA) is considered an early indicator of B12 insufficiency but also serves as a biomarker of mitochondrial dysfunction and oxidative stress (Polytarchou 2020). MMA is formed when a lack of vitamin B12 leads to the impairment of methylmalonyl-CoA mutase, the enzyme that converts methylmalonyl-CoA to succinyl-CoA in the citric acid cycle (Harrington 2017). Methylmalonyl-CoA is a byproduct of the metabolism of propionic acid, which is produced by the breakdown of branch-chain amino acids, odd-chain fatty acids, and cholesterol sidechains and by bacterial fermentation in the colon. Accumulating methylmalonyl-CoA and intermediary propionyl-CoA is toxic to the cell and contributes to impaired gluconeogenesis, fatty acid oxidation, pyruvate oxidation, and ureagenesis (Riphagen 2020).

NHANES studies have used a cut-off of 271 nmol/L and above to categorize elevated MMA, although levels are expected to increase with age (Allen 2018), possibly due to declining kidney function. Elevated MMA is more prevalent at lower levels of serum B12. A review of NHANES data from 9,645 adults over age 19 found that MMA above 300 nmol/L occurred in 56% of those with serum B12 below 189.75 pg/mL (140 pmol/L) but in only 4.1% of those with an adequate serum B12 of 407.97-1355.38 pg/mL (301-1000 pmol/L). Methylmalonic acid was more strongly associated with impaired functional status, muscle strength, and physical performance than serum B12 was. However, MMA is not considered a standalone indicator of B12 status as 25% of individuals with a serum B12 below 135.54 pg/mL (100 pmol/L) and 63% with a holoTC below 20 pmol/L had an MMA within the conventional range. Researchers emphasize that neurological complications and symptoms associated with B12 deficiency are often evident without the telltale signs of anemia (Wolffenbuttel 2020).  

The neurological role that vitamin B12 plays in scavenging excess nitric oxide and reducing serum homocysteine may be relevant to the prevention of migraine headaches. A case-control study of 140 subjects found that levels of MMA were significantly higher and serum B12 was significantly lower in those suffering from migraines. Those with the highest MMA had a five-fold increased risk of migraines in the study (Togha 2019).

Elevated MMA is also observed in both acute and chronic heart failure. In a study of 105 patients with heart failure and 51 healthy controls, those with heart failure had significantly higher MMA, creatinine, NT-proBNP, white blood cells, AST, ALT, GGT, folate, and free T4; and significantly lower hemoglobin, hematocrit, MCV, iron, and total T3. Although 43.8% of those with heart failure had elevated MMA, only 10.5% of patients had “overt B12 deficiency” with a serum B12 below 189.9 pg/mL (140.11 pmol/L). Researchers suggest that additional factors, such as oxidative stress and decreased renal function, can contribute to elevated MMA in heart failure patients (Polytarchou 2020).

Measuring methylmalonic acid helps detect B12 insufficiency in cancer patients. A cross-sectional study of 316 cancer patients found that a cut-off of 260 nmol/L was superior for identifying B12 deficiency compared to a cut-off above 12 umol/L for homocysteine or a cut-off below 300 pg/mL (221.34 pmol/L) for serum B12 (Vashi 2016).

Drug-induced nutrient depletion is often overlooked or goes undetected. Use of the oral hypoglycemic metformin is associated with vitamin B12 deficiency and a decrease in serum B12 can be seen within 3 months of initiation. Using a normal upper cut-off of 150 nmol/L, a prospective case-control study of 122 type 2 diabetics with peripheral neuropathy found that MMA was significantly higher at 180 nmol/L in those on metformin versus 110 nmol/L with no metformin. Homocysteine was also significantly higher, and serum was B12 significantly lower in the metformin group. Researchers recommend screening and monitoring for B12 deficiency in diabetic patients exposed to metformin (Wile 2010).

Severely elevated serum MMA may be caused by various genetic anomalies and is characterized by low bicarbonate, glucose dysregulation, acidosis, ketosis, neutropenia, and elevated serum ammonia (Keyfi 2016).

Normalization of MMA levels may require vitamin B12 supplementation with high doses of 500 ug/day or higher. In one study of older individuals with B12 deficiency, a dose of 1,000 ug/day of cyanocobalamin was needed to lower MMA levels, although lower doses of methylcobalamin or hydroxocobalamin may suffice (Smith 2018).

References

Harrington, Dominic J. “Laboratory assessment of vitamin B12 status.” Journal of clinical pathology vol. 70,2 (2017): 168-173. doi:10.1136/jclinpath-2015-203502

Keyfi, Fatemeh et al. “Methylmalonic Acidemia Diagnosis by Laboratory Methods.” Reports of biochemistry & molecular biology vol. 5,1 (2016): 1-14.

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Polytarchou, Kali et al. “Methylmalonic acid and vitamin B12 in patients with heart failure.” Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese vol. 61,5 (2020): 330-337. doi:10.1016/j.hjc.2019.10.010

Riphagen, Ineke J 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 vol. 18,1 380. 10 Dec. 2020, doi:10.1186/s12916-020-01853-x

Smith, A David et al. “Vitamin B12.” Advances in food and nutrition research vol. 83 (2018): 215-279. doi:10.1016/bs.afnr.2017.11.005

Togha, Mansoureh et al. “Serum Vitamin B12 and Methylmalonic Acid Status in Migraineurs: A Case-Control Study.” Headache vol. 59,9 (2019): 1492-1503. doi:10.1111/head.13618

Vashi, Pankaj et al. “Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer.” PloS one vol. 11,1 e0147843. 25 Jan. 2016, doi:10.1371/journal.pone.0147843

Wile, Daryl J, and Cory Toth. “Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy.” Diabetes care vol. 33,1 (2010): 156-61. doi:10.2337/dc09-0606

Wolffenbuttel, B H R et al. “Association of vitamin B12, methylmalonic acid, and functional parameters.” The Netherlands journal of medicine vol. 78,1 (2020): 10-24.