Description

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

Criteria

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

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.

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