Homocysteine: Optimal Testing Recommendations

To determine if a person may have folate or vitamin B12 deficiency or an inherited disorder of methionine metabolism.
May be used to assess risk of cardiovascular disease in high-risk individuals for heart attack or stroke without traditional risk factors, but this clinical utility is uncertain and controversial.

Guidelines for Test Utilization

What does the test tell me?

  • Homocysteine is an intermediary in the sulfur-amino acid metabolism pathways, linking the methionine cycle to the folate cycle.
  • Severe homocysteinemia is typically caused by a rare inborn errors of metabolism (e.g. cystathionine beta-synthase deficiency (homocystinuria) and disorders of methionine remethylation).
  • Homocystinuria, a rare condition detected by newborn screening, presents in children as developmental delay, Marfanoid appearance, osteoporosis, ocular abnormalities, severe premature atherothrombosis.
  • When suspecting an inborn error of methionine metabolism, this test can be used in conjunction with other biochemical genetics tests such as plasma amino acids, quantitative acylcarnitines, methylmalonic acid, and urine organic acids.
  • Nutritional deficiencies of vitamins B6, B12, and folate can result in abnormally high homocysteine levels. Homocysteine may rise before B12 and folate tests are abnormal.
  • Elevated homocysteine confers increased risk of cardiovascular disease, especially peripheral vascular disease.

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When should I order this test?

When suspecting vitamin B6, B12 or folate deficiency. Homocysteine is also a weak indicator of cardiovascular risk and may be used as an adjunctive test to assess cardiovascular risk in patients at high risk for heart disease (and no other known risk factors) or venous thromboembolism with family history but no other risk factors. [back to top]

When should I NOT order this test?

This test is not recommended for routine screening of cardiovascular risk in the population.
In populations with folic acid fortification, the clinical utility of serum homocysteine for assessment of cardiovascular risk is uncertain and controversial.

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How should I interpret the result?

An elevated homocysteine result is an indicator of acquired folate or vitamin B12 deficiency. >100 uM is indicative of severe hyperhomocysteinemia. [back to top]

Is the test result diagnostic/confirmatory of the condition?

Yes. Extremely high homocysteine levels are found in inborn errors of methionine metabolism, such as homocystinuria and can be confirmed using genetic tests. [back to top]

Are there factors that can affect the lab result?

Several conditions (vitamin deficiency, advanced age, hypothyroidism, impaired kidney function, smoking, and systemic lupus erythematosus) result in hyperhomocysteinemia. Medications including nicotinic acid, theophylline, methotrexate, and L-dopa also elevate homocysteine levels. Phenytoin and carbamazepine interfere with folate metabolism and increases homocysteine while oral contraceptives may raise homocysteine due to estrogen induced vitamin B6 deficiency. [back to top]

Are there considerations for special populations?

Not applicable. [back to top]

What other test(s) might be indicated?

Methylmalonic acid levels are a better indicator of vitamin B12 deficiency but may not be readily available compared to homocysteine. Measurement of methylmalonic acid (MMA) distinguishes between vitamin B12 (cobalamin) and folate deficiencies, as MMA is only elevated in vitamin B12 deficiency.[back to top]


Refsum H, Smith AD, Ueland PM, et al: Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004 January;50:3-32.

McCully KS. Homocysteine and vascular disease. Nat Med 1996; 2:386.

Humphrey LL, Fu R, Rogers K, et al. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc 2008; 83:1203.

Ospina-Romero M, Cannegieter SC, den Heijer M, et al. Hyperhomocysteinemia and Risk of First Venous Thrombosis: The Influence of (Unmeasured) Confounding Factors. Am J Epidemiol 2018; 187:1392.

Last reviewed: February 2022. The content for Optimal Testing: the Association for Diagnostics & Laboratory Medicine’s (ADLM) Guide to Lab Test Utilization has been developed and approved by the the Academy of Diagnostics & Laboratory Medicine and ADLM’s Science and Practice Core Committee.

As the fields of laboratory medicine and diagnostic testing continue to grow at an incredible rate, the knowledge and expertise of clinical laboratory professionals is essential to ensure that patients received the highest quality and most useful laboratory tests. ADLM’s Academy and Science and Practice Core Committee have developed a test utilization resource focusing on commonly misused tests in hospitals and clinics. Improper test utilization can result in poor patient outcomes and waste in the healthcare system. This important resource geared toward medical professionals recommends better tests and diagnostic practices. Always consult your laboratory director to make sure these recommendations are appropriate for your patient population.