Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease and Venous Thromboembolic Disease

Section: Laboratory
Effective Date: July 01, 2018
Revised Date: November 14, 2019


Homocysteine is a sulfur-containing amino acid that is rapidly oxidized in plasma into homocysteine and cysteine-homocysteine disulfide. Measurement of total plasma homocysteine is the sum of homocysteine and its oxidized forms.

Plasma levels of homocysteine have been actively researched as a risk factor for cardiovascular disease (CVD), initially based on the observation that individuals with hereditary homocystinuria, an inborn error of metabolism associated with high plasma levels of homocysteine, had a markedly increased risk of CVD. Subsequently, prospective epidemiologic studies were conducted to determine if an elevated plasma level of homocysteine was an independent risk factor for CVD and could be used to improve current risk prediction models. Several case-control studies have also suggested that elevated homocysteine is a risk factor for venous thromboembolism (VTE; pulmonary embolism, deep vein thrombosis).

Interest in homocysteine as a potentially modifiable risk factor has been stimulated by the epidemiologic finding that levels of homocysteine inversely correlate with levels of folate. This finding has raised the possibility that treatment with folic acid might lower homocysteine levels and, in turn, reduce the risk of CVD and thrombotic events. Therefore, homocysteine has potential utility both as a risk predictor and as a target of treatment.

Determination of homocysteine concentration may be offered as a component of a comprehensive cardiovascular risk assessment that may include evaluation of small-density lipoproteins, subclassification of high-density lipoproteins, evaluation of lipoprotein (a), high-sensitivity C-reactive protein, and genotyping of apolipoprotein E. Determination of homocysteine concentration may also be offered as part of risk assessment for individuals at high risk of VTE events or who have experienced idiopathic VTE, recurrent VTE, thrombosis occurring at a young age, or thrombosis at an unusual site.

Regulatory Status

Several of the homocysteine test systems have been cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process. Food and Drug Administration product code: LPS. Examples are listed in Table 1.

Table 1. Homocysteine Test Systems



Approval Date

Homocysteine Enzymatic Assay

Roche Diagnostics


Diazyme Enzymatic Homocysteine Assay

Diazyme Laboratories


A/C Automatic Enzymatic Hcy [Homocysteine] Assay

AntiCancer Inc.


Teco Enzymatic Homocysteine Assay

Teco Diagnostics



Measurement of plasma levels of homocysteine is considered not medically necessary in the screening, evaluation, and management of patients for cardiovascular disease

Measurement of plasma levels of homocysteine is considered investigational in the screening, evaluation, and management of patients with venous thromboembolism or risk of venous thromboembolism.

Procedure Codes


Diagnosis Codes

I25.110 I25.111 I25.118 I25.119 I25.700 I25.701 I25.708
I25.709 I25.710 I25.711 I25.718 I25.719 I25.720 I25.721
I25.728 I25.729 I25.730 I25.731 I25.738 I25.739 I25.750
I25.751 I25.758 I25.759 I25.760 I25.761 I25.768 I25.769
I25.790 I25.791 I25.798 I25.799 I82.210 I82.211 I82.220
I82.221 I82.290 I82.291 I82.401 I82.402 I82.403 I82.409
I82.411 I82.412 I82.413 I82.419 I82.421 I82.422 I82.423
I82.429 I82.431 I82.432 I82.433 I82.439 I82.441 I82.442
I82.443 I82.449 I82.451 I82.452 I82.453 I82.459 I82.461
I82.462 I82.463 I82.469 I82.491 I82.492 I82.493 I82.499
I82.4Y1 I82.4Y2 I82.4Y3 I82.4Y9 I82.4Z1 I82.4Z2 I82.4Z3
I82.4Z9 I82.501 I82.502 I82.503 I82.509 I82.511 I82.512
I82.513 I82.519 I82.521 I82.522 I82.523 I82.529 I82.531
I82.532 I82.533 I82.539 I82.541 I82.542 I82.543 I82.549
I82.551 I82.552 I82.553 I82.559 I82.561 I82.562 I82.563
I82.569 I82.591 I82.592 I82.593 I82.599 I82.5Y1 I82.5Y2
I82.573 I82.5Y9 I82.5Z1 I82.5Z2 I82.5Z3 I82.5Z9 I82.601
I82.602 I82.603 I82.609 I82.611 I82.612 I82.613 I82.619
I82.621 I82.622 I82.623 I82.629 I82.701 I82.702 I82.703
I82.709 I82.711 I82.712 I82.713 I82.719 I82.721 I82.722
I82.723 I82.729 I82.A11 I82.A12 I82.A13 I82.A19 I82.A21
I82.A22 I82.A23 I82.A29 I82.B11 I82.B12 I82.B13 I82.B19
I82.B21 I82.B22 I82.B23 I82.B29 I82.C11 I82.C12 I82.C13
I82.C19 I82.C21 I82.C22 I82.C23 I82.C29 I82.811 I82.812
I82.813 I82.819 I82.890 I82.891 I82.90 I82.91 Z13.6

Professional Statements and Societal Positions Guidelines

Practice Guidelines and Position Statements

Cardiovascular Disease

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (2016) updated its guidance on risk assessment and reduction of cardiovascular disease (CVD), including lipid modification. The guidance asserted that full formal risk assessments should use a combination of risk assessment tools as well as informed clinical judgment. Homocysteine testing was not mentioned.

American Heart Association and American Stroke Association

The American Heart Association and the American Stroke Association (2014) issued joint guidelines on the primary prevention of stroke. These guidelines were endorsed by the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the Preventive Cardiovascular Nurses Association. The guidelines stated that individuals with hyperhomocysteinemia may be treated with B-complex vitamins to prevent ischemic stroke, but that the effectiveness was not clearly established (class IIb; level of evidence B).

American College of Cardiology and American Heart Association

The American College of Cardiology and the American Heart Association (2013) issued joint guidelines on the assessment of. These guidelines were endorsed by 6 medical specialty associations. The guidelines developed multivariable equations to estimate age- and race-specific arteriosclerotic cardiovascular risk. The equations included age, total and high-density cholesterol levels, systolic blood pressure, antihypertensive treatment use, diabetes history, and current smoking status. The use of homocysteine screening for assessing the arteriosclerotic cardiovascular risk was not considered in these guidelines.

National Academy of Clinical Biochemistry

The National Academy of Clinical Biochemistry (2009) published guidelines on biomarkers for primary prevention of CVD.The Academy concluded that while homocysteine is a modest independent CVD risk factor, homocysteine screening for primary prevention and assessment in healthy individuals was unwarranted.

Venous Thromboembolism

Agency for Healthcare Research and Quality

The Agency for Healthcare Research and Quality (2016) issued guidelines for effective quality improvement on preventing hospital-associated. The venous thromboembolism prevention protocol recommended involves a venous thromboembolism risk assessment, a bleeding risk assessment, and a clinical decision support on prophylactic choices. Homocysteine testing was not mentioned in these guidelines.

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (2018) issued guidance on reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. Homocysteine testing was not mentioned in this guidance.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (2009) issued a recommendation stating that the evidence was insufficient to assess the benefits and harms of using nontraditional risk factors to screen asymptomatic adults with no history of coronary heart disease to prevent coronary heart disease events. Homocysteine was one of the nontraditional risk factors considered in the recommendation.The Task Force (2018) issued an assessment of CVD risk with nontraditional risk factors. Homocysteine levels were not mentioned in this recommendation.