Homocysteine and Methylmalonic Acid

Homocysteine and Methylmalonic Acid

Synonym/acronym: N/A.

Common use

To assist in evaluating increased risk for blood clots, plaque formation, and platelet aggregations associated with atherosclerosis and stroke risk.


Serum (4 mL) collected in a gold-, red-, or red/gray-top tube if methylmalonic acid and homocysteine are to be measured together. Alternatively, plasma collected in a lavender-top (EDTA) tube may be acceptable for the homocysteine measurement. The laboratory should be consulted before specimen collection because specimen type may be method dependent. Care must be taken to use the same type of collection container if serial measurements are to be taken.

Normal findings

(Method: Chromatography)
Conventional & SI Units
Homocysteine4.6–11.2 micromol/L
Methylmalonic Acid70–270 nmol/L


Homocysteine is an amino acid formed from methionine. Normally, homocysteine is rapidly remetabolized in a biochemical pathway that requires vitamin B12 and folate, preventing the buildup of homocysteine in the blood. Excess levels damage the endothelial lining of blood vessels; change coagulation factor levels, increasing the risk of blood clot formation and stroke; prevent smaller arteries from dilating, increasing the risk of plaque formation; cause platelet aggregation; and cause smooth muscle cells lining the arterial wall to multiply, promoting atherosclerosis.

Approximately one-third of patients with hyperhomocystinuria have normal fasting levels. Patients with a heterozygous biochemical enzyme defect in cystathionine B synthase or with a nutritional deficiency in vitamin B6 can be identified through the administration of a methionine challenge or loading test. Specimens are collected while fasting and 2 hr later. An increase in homocysteine after 2 hr is indicative of hyperhomocystinuria. In patients with vitamin B12 deficiency, elevated levels of methylmalonic acid and homocysteine develop fairly early in the course of the disease. Unlike vitamin B12 levels, homocysteine levels will remain elevated for at least 24 hr after the start of vitamin therapy. This may be useful if vitamin therapy is inadvertently begun before specimen collection. Patients with folate deficiency, for the most part, will only develop elevated homocysteine levels. A methylmalonic acid level can differentiate between vitamin B12 and folate deficiency, since it is increased in vitamin B12 deficiency, but not in folate deficiency. Hyperhomocysteinemia due to folate deficiency in pregnant women is believed to increase the risk of neural tube defects. Elevated levels of homocysteine are thought to chemically damage the exposed neural tissue of the developing fetus.

This procedure is contraindicated for



  • Evaluate inherited enzyme deficiencies that result in homocystinuria
  • Evaluate the risk for cardiovascular disease
  • Evaluate the risk for venous thrombosis

Potential diagnosis

Increased in

  • Cerebrovascular disease (CVD) (there is a relationship, but the pathophysiology is unclear)
  • Chronic renal failure (pathophysiology is unclear)
  • Coronary artery disease (CAD) (there is a relationship, but the pathophysiology is unclear)
  • Folic acid deficiency (folate is required for completion of biochemical reactions involved in homocysteine metabolism)
  • Homocystinuria (inherited disorder of methionine metabolism that results in accumulation of homocysteine)
  • Peripheral vascular disease (related to vascular wall damage and formation of occlusive plaque)
  • Vitamin B12 deficiency (vitamin B12 is required for completion of biochemical reactions involved in homocysteine metabolism)

Decreased in


Critical findings


Interfering factors

  • Drugs that may increase plasma homocysteine levels include anticonvulsants, cycloserine, hydralazine, isoniazid, methotrexate, penicillamine, phenelzine, and procarbazine.
  • Drugs that may decrease plasma homocysteine levels include folic acid.
  • Specimens should be kept at a refrigerated temperature and delivered immediately to the laboratory for processing.

Nursing Implications and Procedure


  • Positively identify the patient using at least two unique identifiers before providing care, treatment, or services.
  • Patient Teaching: Inform the patient this test can assist in screening for risk of cardiovascular disease and stroke.
  • Obtain a history of the patient’s complaints, including a list of known allergens, especially allergies or sensitivities to latex.
  • Obtain a history of the patient’s cardiovascular and hematopoietic systems, symptoms, and results of previously performed laboratory tests and diagnostic and surgical procedures.
  • Obtain a list of the patient’s current medications, including herbs, nutritional supplements, and nutraceuticals (see Effects of Natural Products on Laboratory Values online at DavisPlus).
  • Review the procedure with the patient. Inform the patient that specimen collection takes approximately 5 to 10 min. Address concerns about pain and explain that there may be some discomfort during the venipuncture.
  • Sensitivity to social and cultural issues, as well as concern for modesty, is important in providing psychological support before, during, and after the procedure.
  • Note that there are no food, fluid, or medication restrictions unless by medical direction.


  • Potential complications: N/A
  • Avoid the use of equipment containing latex if the patient has a history of allergic reaction to latex.
  • Instruct the patient to cooperate fully and to follow directions. Direct the patient to breathe normally and to avoid unnecessary movement.
  • Observe standard precautions, and follow the general guidelines in Patient Preparation and Specimen Collection. Positively identify the patient, and label the appropriate collection container with the corresponding patient demographics, initials of the person collecting the specimen, date, and time of collection. Perform a venipuncture; collect the specimen for combined methylmalonic acid and homocysteine studies in two 5-mL red-, green-, or red/gray-top tubes. If only homocysteine is to be measured, a 5-mL lavender-top tube is acceptable.
  • Remove the needle and apply direct pressure with dry gauze to stop bleeding. Observe/assess venipuncture site for bleeding or hematoma formation and secure gauze with adhesive bandage.
  • Promptly transport the specimen to the laboratory for processing and analysis.


  • Inform the patient that a report of the results will be made available to the requesting health-care provider (HCP), who will discuss the results with the patient.
  • Nutritional Considerations: Increased homocysteine levels may be associated with atherosclerosis and CAD. Nutritional therapy is recommended for the patient identified to be at risk for developing CAD or for individuals who have specific risk factors and/or existing medical conditions (e.g., elevated LDL cholesterol levels, other lipid disorders, insulin-dependent diabetes, insulin resistance, or metabolic syndrome). Other changeable risk factors warranting patient education include strategies to encourage patients, especially those who are overweight and with high blood pressure, to safely decrease sodium intake, achieve a normal weight, ensure regular participation in moderate aerobic physical activity three to four times per week, eliminate tobacco use, and adhere to a heart-healthy diet. If triglycerides also are elevated, the patient should be advised to eliminate or reduce alcohol. The 2013 Guideline on Lifestyle Management to Reduce Cardiovascular Risk published by the American College of Cardiology (ACC) and the American Heart Association (AHA) in conjunction with the National Heart, Lung, and Blood Institute (NHLBI) recommends a “Mediterranean”-style diet rather than a low-fat diet. The new guideline emphasizes inclusion of vegetables, whole grains, fruits, low-fat dairy, nuts, legumes, and nontropical vegetable oils (e.g., olive, canola, peanut, sunflower, flaxseed) along with fish and lean poultry. A similar dietary pattern known as the Dietary Approaches to Stop Hypertension (DASH) diet makes additional recommendations for the reduction of dietary sodium. Both dietary styles emphasize a reduction in consumption of red meats, which are high in saturated fats and cholesterol, and other foods containing sugar, saturated fats, trans fats, and sodium.
  • Nutritional Considerations: Diets rich in fruits, grains, and cereals, in addition to a multivitamin containing B12 and folate, may be recommended for patients with elevated homocysteine levels related to a dietary deficiency. Processed and refined foods should be kept to a minimum.
  • Nutritional Considerations: Instruct the folate-deficient patient (especially pregnant women), as appropriate, to eat foods rich in folate, such as liver, salmon, eggs, asparagus, green leafy vegetables, broccoli, sweet potatoes, beans, and whole wheat.
  • Nutritional Considerations: Instruct the patient with vitamin B12 deficiency, as appropriate, in the use of vitamin supplements. Inform the patient, as appropriate, that the best dietary sources of vitamin B12 are meats, fish, poultry, eggs, and milk.
  • Social and Cultural Considerations: Numerous studies point to the prevalence of excess body weight in American children and adolescents. Experts estimate that obesity is present in 25% of the population ages 6 to 11 yr. The medical, social, and emotional consequences of excess body weight are significant. Special attention should be given to instructing the child and caregiver regarding health risks and weight-control education.
  • Recognize anxiety related to test results, and be supportive of fear of shortened life expectancy. Discuss the implications of abnormal test results on the patient’s lifestyle. Provide teaching and information regarding the clinical implications of the test results, as appropriate. Educate the patient regarding access to counseling services. Provide contact information, if desired, for the American Heart Association (www.americanheart.org) or the NHLBI (www.nhlbi.nih.gov).
  • Reinforce information given by the patient’s HCP regarding further testing, treatment, or referral to another HCP. Answer any questions or address any concerns voiced by the patient or family. Educate the patient regarding access to nutritional counseling services. Provide contact information, if desired, for the Institute of Medicine of the National Academies (www.iom.edu).
  • Depending on the results of this procedure, additional testing may be performed to evaluate or monitor progression of the disease process and determine the need for a change in therapy. Evaluate test results in relation to the patient’s symptoms and other tests performed.

Related Monographs

  • Related tests include antiarrhythmic drugs, apolipoprotein A and B, AST, ANP, blood gases, BMD, BNP, BUN, calcitonin, calcium, cholesterol (total, HDL, and LDL), CBC, CBC RBC count, CBC RBC indices, CBC RBC morphology, CBC WBC count and differential, CRP, CK and isoenzymes, creatinine, folate, glucose, glycated hemoglobin, ketones, LDH and isoenzymes, lipoprotein electrophoresis, magnesium, myoglobin, osteocalcin, PTH, pericardial fluid analysis, potassium, prealbumin, renogram, triglycerides, troponin, US kidney, UA, and vitamin B12.
  • Refer to the Cardiovascular and Hematopoietic systems tables at the end of the book for related tests by body system.
Handbook of Laboratory and Diagnostic Tests, © 2013 Farlex and Partners
References in periodicals archive ?
According to the US National Institutes of Health, additional laboratory tests which include homocysteine and methylmalonic acid values may also be needed to reliably detect low levels of vitamin B-12.
Therefore, measurement of the levels of homocysteine and methylmalonic acid is helpful in the diagnosis of vitamin [B.sub.12] deficiency (7).
However, recent research has found that B12 deficiency may occur at B12 concentrations in the blood as high as 500-600 pg/mL She says that elevated serum homocysteine and methylmalonic acid levels are considered more reliable indicators of B12 deficiency than the concentration of B12 in blood.
Renal impairment compromises the use of total homocysteine and methylmalonic acid but not total vitamin [B.sub.12] and holotranscobalamin in screening for vitamin [B.sub.12] deficiency in the aged.
Vitamin supplementation and other variables affecting serum homocysteine and methylmalonic acid concentrations in elderly men and women.
Pennypacker et al (2) state that "the ultimate gold standard for vitamin [B.sub.12] deficiency may be the reduction in homocysteine and methylmalonic acid concentrations and improvement in clinical symptoms or signs in response to vitamin [B.sub.12] treatment."
Cobalamine absorption and serum homocysteine and methylmalonic acid in elderly subjects with low serum cobalamin.
Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler 2003;9:239-45.
If both the RBC folate and the [B.sub.12] levels are abnormal, further metabolic testing with serum or urine determination of homocysteine and methylmalonic acid levels may be necessary.
Results from persons with increased creatinine concentrations were excluded from the statistical evaluation because renal dysfunction is known to cause increases, independent of vitamin [B.sub.12] status, in both homocysteine and methylmalonic acid. Persons with holoTC above the upper limit of the calibration curve (>160 pmol/L) also were excluded.
Vitamin B12 decreases, but does not normalize, homocysteine and methylmalonic acid in end-stage renal disease: a link with glycine metabolism and possible explanation of hyperhomocysteinemia in end-stage renal disease.
Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy.