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Thread: MMA (Methylmalonic Acid) tests

  1. #1
    Ex-admin Korn's Avatar
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    Default MMA (Methylmalonic Acid) tests

    MMA (Methylmalonic Acid) tests are often mentioned when B12 (and homocysteine) is discussed. Some claim that MMA tests is a 'gold standard' for measuring B12 deficiency.

    Just like homocysteine, MMA is a controversial topic. Here are some links to information about MMA and MMA tests.

    An improved assay for plasma methylmalonic acid using chemical ionization gas chromatography mass spectrometry

    Mehrdad Yazdanpanaha, Pak Cheung Chana, d, Jovan Evrovskia, d, Alex Romaschina and David E. C. Cole, , a, b, c, d
    a Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, Canada
    b Department of Medicine, University of Toronto, Toronto ON, Canada
    c Department of Pediatrics, University of Toronto, Toronto ON, Canada
    d Department of Clinical Pathology, Sunnybrook & Women's College Health Science Center, Toronto ON, Canada
    Received 3 May 2003; revised 13 July 2003; accepted 16 July 2003. ; Available online 18 November 2003.

    To develop a precise and sensitive assay for methylmalonic acid (MMA) using positive chemical ionization gas chromatography mass spectrometry (CI GC-MS), and to illustrate its clinical utility.


    Using the developed assay, reference intervals were determined with 108 ambulatory individuals, and potential clinical utility examined in 178 consecutive patients with possible cobalamin deficiency (serum B12 < 200 nmol/L).

    Results and conclusions

    Methylmalonic acid measured by CI GC-MS was precise (CV: 4–5%), and sensitive (limit of quantitation: 37 nmol/L). In a clinical reference set, 37% of individuals with serum B12 less than 200 pmol/L had plasma MMA concentrations within the reference interval (75–378 nmol/L), rendering cobalamin deficiency unlikely. The observation illustrates that MMA assay may be a useful adjunct test in assessing patients with low serum B12.
    Increased Plasma Methylmalonic Acid Level Does Not Predict Clinical Manifestations of Vitamin B12 Deficiency
    Anne-Mette Hvas, MD; J°rgen Ellegaard, MD; Ebba Nex°, MD
    Arch Intern Med. 2001;161:1534-1541.


    Background The prevalence of vitamin B12 deficiency, defined as an elevated concentration of plasma methylmalonic acid (P-MMA), has been estimated to be 15% to 44% in the elderly. However, we do not know whether an increased P-MMA level actually indicates or predicts a clinical condition in need of treatment.

    Participants and Methods In a follow-up study, 432 individuals not treated with vitamin B12 were examined 1.0 to 3.9 years after initial observation of an increased P-MMA concentration (>0.28 Ámol/L). The examination included laboratory tests, a structured interview to disclose symptoms, a food frequency questionnaire, and a clinical examination including a Neurological Disability Score.

    Results Variation in P-MMA levels over time was high (coefficient of variation, 34%). In only 16% of participants, P-MMA levels increased substantially, whereas 44% showed a decrease. Level of P-MMA was significantly but not strongly associated with levels of plasma cobalamins (r = -0.22, P<.001) and plasma total homocysteine (r = 0.37, P<.001). After adjustment for age and sex, we found no associations between P-MMA concentration and the total symptom score (P = .61), the total Neurological Disability Score (P = .64), or other clinical manifestations related to vitamin B12 deficiency.

    Conclusions An increased level of P-MMA did not predict a further increase with time and clinical manifestations related to vitamin B12 deficiency. We therefore challenge the use of an increased P-MMA concentration as the only marker for diagnosis of vitamin B12 deficiency.
    AIM: To compare serum analyses of vitamin B12 and methylmalonic acid (MMA) as indices of cobalt/vitamin B12 deficiency in lambs around weaning. METHODS: Lambs on five properties, considered to be cobalt-deficient, were supplemented with either cobalt bullets, or short- or long-acting vitamin B12 preparations. Blood samples, and in some cases liver biopsies, and liveweights were obtained at monthly intervals. Serum samples were assayed for vitamin B12 and MMA and liver for vitamin B12 concentrations. Pasture cobalt concentrations were measured on three of the properties. RESULTS: Pasture cobalt concentrations were generally maintained below 0.07 Ág/g dry matter (DM) on the properties sampled. Growth responses to supplementation were observed on only 2/5 properties, despite serum vitamin B12 concentrations being within the currently used 'marginal' reference range (336-499 pmol/L) for at least 3 months on all properties and in the deficient reference range (0-335 pmol/L) for at least 2 months on all farms except one. Serum MMA concentrations in supplemented lambs were <2 Ámol/L, except in those animals sampled 1 month after receiving treatment with a short-acting vitamin B12 injection. Serum MMA concentrations in unsupplemented animals on properties on which no growth response to supplementation occurred generally reached peak levels of between 4 and 7 Ámol/L at the nadir of serum vitamin B12 concentration. When a growth response was observed, differences in weight gain between supplemented and unsupplemented lambs occurred as mean serum MMA concentrations increased from 9 to 14 Ámol/L. On one property where supplementation commenced before weaning, normal growth rates were maintained despite serum vitamin B12 concentrations of 140 pmol/L and serum MMA concentrations in excess of 40 Ámol/L serum. CONCLUSIONS: The possibility that current serum vitamin B12 references ranges for diagnosis of cobalt deficiency are set too high and lead to over-diagnosis of responsiveness to cobalt/vitamin B12 supplementation is discussed. The suggestion is made that serum MMA concentrations in excess of 9-14 Ámol/L will provide a more reliable diagnostic test for cobalt deficiency. However, there was sufficient variation between properties in the relationships between cobalt concentrations of pasture and serum vitamin B12 or MMA concentrations to require more rigorous testing of the reliability of using serum MMA concentration for this purpose. The possibility that differences in rumen fermentation and therefore propionate and vitamin B12 production could be involved is discussed. The measurement of serum MMA and vitamin B12 appears to be of little value whilst the lamb is still suckling. CLINICAL SIGNIFICANCE: Serum MMA concentration may offer advantages over serum vitamin B12 concentrations in the diagnosis of a cobalt/vitamin B12 responsiveness in weaned lambs.
    Methylmalonic acid is a substance produced when proteins (amino acids) in the body break down. A test can be done to measure the amount of methylmalonic acid in your blood.

    This tests may also be done with other tests to check for vitamin B12 deficiency.

    Normal Results

    Normal values are 0.08 to 0.56 micromoles per liter.

    Note: Normal value ranges may vary slightly among different laboratories.

    Greater-than-normal values may be due to vitamin B12 deficiency or methylmalonic acidemia.
    Increased methylmalonic acid levels may indicate a vitamin B12 deficiency. However, it is sensitive without being specific. MMA is elevated in 90-98% of patients with B12 deficiency. This test may be overly sensitive, as 25-20% of patients over the age of 70 have elevated levels of MMA, but 25-33% of them do not have B12 deficiency. For this reason, MMA is not routinely recommended in the elderly. [1]
    An excess is associated with methylmalonic acidemia
    Many groups now recognize MMA and homocysteine tests as the most sensitive and specific indicators of functional vitamin B12 deficiency (2)(11)(12)(14)(15)(21)(27)(29)(30)(33)(34)(35)(36 ). MMA and homocysteine concentrations are increased in many patients with "normal" vitamin B12 concentrations. Fig. 1 shows MMA concentrations from a stratified sample of 72 patients measured at the Mayo Clinic. Increased MMA was found even with vitamin B12 concentrations as high as 400 ng/L. Similarly, Holleland et al. (37) found increased MMA or homocysteine concentrations (see Fig. 2 ) in >20% of patients with serum vitamin B12 concentrations within the reference interval. Some laboratory-based algorithms recommend initially testing serum vitamin B12 and following up low values with MMA measurements (2). The choice of the threshold vitamin B12 concentration for triggering follow-up is controversial. If the lower limit of normal (200 ng/L) is used, multiple patients with increased MMA would be missed. If higher values, such as 500 ng/L, are used (as advocated by some), the majority of the patients having vitamin B12 tests would have follow-up MMA tests (38). Fig. 3 shows the distribution of vitamin B12 results for the assay used at the Mayo Clinic with a reference range of 200–650 ng/L.
    Our proposed approach to cobalamin testing would be to define cobalamin deficiency as any cobalamin level less than 100 pg/mL. For patients with cobalamin levels between 100 and 299 pg/mL, MMA should be measured.22 If MMA levels are elevated in this equivocal group, then cobalamin replacement should be initiated. Although macrocytosis and hypersegmentation are useful findings when present, the absence of hematologic findings does not exclude cobalamin deficiency.
    Furthermore, serum MMA is commonly elevated in elderly North Americans,6 but lowering it through vitamin B12 supplementation does not appear to affect blood hemoglobin concentration, neurological disability score or quality of life.7 Like homocysteine, MMA has not been fully validated as a routine clinical test of cobalamin deficiency,8 especially in the face of increased folate fortification,2 and MMA testing is not routinely available in Canadian centres and community laboratories.
    Cobalamin and Folate Evaluation: Measurement of Methylmalonic Acid and Homocysteine vs Vitamin B12 and Folate
    George G. Klee1
    1 Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905. Fax 507-284-4542; e-mail

    Vitamin B12 and folate are two vitamins that have interdependent roles in nucleic acid synthesis. Deficiencies of either vitamin can cause megaloblastic anemia; however, inappropriate treatment of B12 deficiency with folate can cause irreversible nerve degeneration. Inadequate folate nutrition during early pregnancy can cause neural tube defects in the developing fetus. In addition, folate and vitamin B12 deficiency and the compensatory increase in homocysteine are a significant risk factor for cardiovascular disease. Laboratory support for the diagnosis and management of these multiple clinical entities is controversial and somewhat problematic. Automated ligand binding measurements of vitamin B12 and folate are easiest to perform and widely used. Unfortunately, these tests are not the most sensitive indicators of disease. Measurement of red cell folate is less dependent on dietary fluctuations, but these measurements may not be reliable. Homocysteine and methylmalonic acid are better metabolic indicators of deficiencies at the tissue level. There are no "gold standards" for the diagnosis of these disorders, and controversy exists regarding the best diagnostic approach. Healthcare strategies that consider the impact of laboratory tests on the overall costs and quality of care should consider the advantages of including methylmalonic acid and homocysteine in the early evaluation of patients with suspected deficiencies of vitamin B12 and folate.
    Methylmalonic Acid

    How is it used?
    MMA primarily is ordered, sometimes along with homocysteine, to help diagnose an early or mild B12 deficiency. It may be ordered as a follow-up to a vitamin B12 test for which the result is in the lower end of the normal range.
    Some researchers have suggested using MMA as a screening tool, especially among the elderly, who frequently have B12 deficiencies and may have few recognizable symptoms. However, this use is still controversial in the medical community and only a few doctors are using MMA for this purpose. MMA testing may not be suitable for monitoring because it is subject to variation and results do not reliably trend up or down in response to B12 treatment.

    Occasionally, MMA may be ordered along with other tests to help diagnose methylmalonic acidemia, a rare inherited metabolic disorder that occurs in about 1 in 25,000 to 48,000 people. Babies with this disease are unable to convert methylmalonyl CoA to succinyl CoA. They appear normal at birth but as they ingest protein, they begin to show symptoms such as seizures, failure to thrive, mental retardation, strokes, and severe metabolic acidosis.

    When is it ordered?
    Methylmalonic acid is not ordered frequently. Until there is more data supporting its use and consensus on its clinical utility and long-term benefits, it will probably not be routinely used by doctors.
    However, MMA may be ordered, sometimes along with a homocysteine test, when a vitamin B12 test result is in the lower portion of the normal range, especially if the patient has symptoms associated with B12 deficiency. An MMA test also may be ordered as a follow-up to an elevated homocysteine level if the two tests are not ordered together.

    Occasionally, MMA may be ordered when a doctor suspects that an acutely ill infant may have inherited methylmalonic acidemia.

    What does the test result mean?
    NOTE: A standard reference range is not available for this test. Because reference values are dependent on many factors, including patient age, gender, sample population, and test method, numeric test results have different meanings in different labs. Your lab report should include the specific reference range for your test. Lab Tests Online strongly recommends that you discuss your test results with your doctor. For more information on reference ranges, please read Reference Ranges and What They Mean.

    If MMA and homocysteine levels are increased and B12 concentrations are mildly decreased, then an early or mild B12 deficiency may be present. This may indicate a decrease in available B12 at the tissue level. (If only homocysteine levels are elevated, then folate concentrations should be checked). If MMA and homocysteine levels are normal, it is unlikely that there is a B12 deficiency.
    Blood MMA levels also can be increased with kidney disease, which results in decreased MMA excretion in the urine so MMA accumulates in the blood.

    Moderately to severely elevated levels of MMA may be seen in infants with the rare inherited disease methylmalonic acidemia.

    Is there anything else I should know?
    An elevated MMA test may indicate a B12 deficiency, but the amount of MMA measured does not necessarily reflect the severity of the deficiency, its likelihood of progressing, or the presence or severity of any symptoms.
    Some studies have found a high variation in MMA levels when they are measured over time.

  2. #2

    Default Re: MMA (Methylmalonic Acid) tests

    What is the reference value of urinary MMA concentration for adults ( mmol/mol creatinine ) ?

    Now my
    urinary MMA is 5.28 mmol/mol creatinine

  3. #3
    Ex-admin Korn's Avatar
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    Default Re: MMA (Methylmalonic Acid) tests

    Sorry, Ogi - I missed that post - and it's now three years old! I hope you have sorted it all out with those who took the test for you...


    Anemia occurs when the number of red blood cells and/or the amount of hemoglobin found in these red is too low. Since vitamin B12 is needed for the production of hemoglobin/the needs B12 to produce red blood cells, taking B12 is a normal way to deal with anemia. And MMA is currently considered the best way to check B12 levels in the body - even better than testing the actual B12 levels. This makes this new study relevant, at least for some people:

    Parenteral vitamin B12 in macrocytic hemodialysis patients reduced MMA levels but did not change mean red cell volume or hemoglobin (PMID: 21426888)

    It concludes that taking parenteral vitamin B12 causes "sustained decline in MMA levels in macrocytic patients", but that there still were "no significant changes in" the hemoglobin levels or in the mean red cell volume.
    I will not eat anything that walks, swims, flies, runs, skips, hops or crawls.

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    Ex-admin Korn's Avatar
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    Default Re: MMA (Methylmalonic Acid) tests

    Richard Ravel mentions in 'Clinical laboratory medicine: clinical application of laboratory data' that both serum and urine MMA 'are said to' be increased in 95% of patients with B12 deficiency, but that one study found that only 60% of patients with increased urine MMA has decreased serum B12 values. This means that one out of ten people will not see elevated MMA even if they are B12 deficient. It also suggests that since 40% of patients with increased MMA do not have decreased B12 levels, elevated MMA levels could suggest something else than a B12 deficiency.
    I will not eat anything that walks, swims, flies, runs, skips, hops or crawls.

  5. #5
    Ex-admin Korn's Avatar
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    Default Re: MMA (Methylmalonic Acid) tests

    From Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998), p. 314:
    Serum MMA values from older studies may not be comparable with those obtained recently because of improvements over time (Beck, 1991; Green and Kinsella, 1995). More importantly, no studies were found that examined directly the relationship of B12 intake and MMA concentrations.
    I will not eat anything that walks, swims, flies, runs, skips, hops or crawls.

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