Medical Policy: 02.04.22
Original Effective Date: December 2009
Reviewed: September 2014
Revised: September 2014
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Homocysteine is an amino acid found normally in the body. Several vitamins, including B6, B12, and folic acid aid in the metabolism of homocysteine. Evidence suggests that elevated levels of homocysteine provoke an inflammatory response in the arteries and increase the potential for thrombosis contributing to the development of atherosclerosis.
Plasma levels of homocysteine have been researched as a risk factor for cardiovascular disease, initially based on the observation that patients with hereditary homocystinuria, an inborn error of metabolism associated with high plasma levels of homocysteine, had a markedly increased risk of cardiovascular disease. Interest in homocysteine, as a potentially modifiable risk factor, has been stimulated by the epidemiologic finding that levels of homocysteine are inversely correlated with levels of folate. This has raised the possibility that treatment with folic acid might lower homocysteine levels and, in turn, reduce the risk of coronary artery disease (CAD). While there is significant evidence for a relationship between plasma homocysteine and cardiovascular disease, studies have not shown a clinical benefit to lowering plasma levels. Despite the evidence suggesting an increased intake of folic acid will reduce homocysteine levels; it has not been proven that reduction in homocysteine by vitamin therapy and/or dietary modification will reduce cardiovascular disease risk. Additionally, no studies have demonstrated an effect of homocysteine-lowering therapy on mortality or major cardiovascular events in patients with known coronary artery disease.
Recently, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial revealed that, despite lowering blood homocysteine levels for up to 7 years, supplementation with folic acid and vitamin B12, had no beneficial effects on major vascular events such as stroke and coronary events. While there is a known association between increased homocysteine levels and increased risk of heart disease, the most recent evidence indicates the association is not causal.
Homocysteine levels are elevated in vitamin B12 (cobalamin,Cbl) deficiency due to decreased rate of metobolism. Measurement of the serum concentrations of homocysteine appear to be more sensitive for the diagnosis of this deficiency then serum vitamin levels alone. Deficiency of vitamin B12 (cobalamin,Cbl) ) can lead to hematologic, neurologic or psychiatric disorders that can often be reversed with early diagnosis and treatment.
Homocystinuria also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected.
Homocystinuria is usually asymptomatic in the neonate. If untreated, these children eventually develop mental retardation, ectopia lentis, a marfanoid appearance including arachnodactyly, osteoporosis, other skeletal deformities and thromboembolism.
Practice Guidelines and Position Statements
U.S. Preventative Services Task Force
In 2009 the U.S. Preventative Services Task Force issued a recommendation that the current evidence is insufficient to assess the balance of the benefits and harms of using the nontraditional risk factors discussed in this statement to screen asymptomatic men and women with no history of CHD to prevent CHD events.
The nontradiational risk factors included in this recommendation are high sensitivity C-reactive protein (hs-CRP), ankle-brachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness (carotid IMT), coronary artery calcification (CAC) score on electron-beam computed tomography (EBCT), homocysteine level, and lipoprotein(a) level.
American Heart Association
January 2012 a statement issued by the American Heart Association states that the organization does not consider hyperhomoscyteinemia (high homocysteine level in the blood) a major risk factor for cardiovascular disease.
American College of Cardiology Foundation and the American Heart Association
A 2010 guideline from the American College of Cardiology Foundation and the American Heart Association for assessment of cardiovascular risk in asymptomatic adults did not address measurement of homocysteine levels.
American College of Obstetricians and Gynecologist (ACOG)
September 2013 ACOG Practice Bulliten; no. 138, Inherited Thrombophilias in Pregnancy. The guideline objective was as follows: To review common thrombophilias and their association with maternal venous thromboembolism risk and adverse pregnancy outcomes, indications for screening to detect these conditions, and management options in pregnancy. The recommendations incude:
- “Because of the lack of association between either heterozygosity or homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and any negative pregnancy outcomes, including any increased risk for venous thromboembolism, screening with either MTHFR mutation analyses or fasting homocysteine levels is not recommended.”
Homocysteine testing may be considered medically necessary for the following non-cardiovascular indications:
- Management of patients with borderline vitamin B12 deficiency
- Assessment of patients with homocystinuria
- Assessment of patients with venous thromboembolism
Measurement of plasma homocysteine is considered not medically necessary in the screening, diagnosis, and management of cardiovascular disease.
Due to the large amount of evidence from placebo-controlled RCTs that homocysteine-lowering interventions do not have a statistically significant effect on the rate of major cardiovascular events, routine testing of homocysteine for cardiovascular indications is considered not medically necessary.
Measurement of plasma homocysteine is considered not medically necessary in the evaluation of recurrent pregnancy loss. In evaluation of recurrent pregnancy loss homocysteine testing has been shown to be of no value.
Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- 83090 Homocysteine
- Eikelboom JW, Lonn E, Genest J Jr et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999 Sep 7; 131(5):363-75.
- Lonn E, Yusuf S, Arnold MJ et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13; 354(15):1567-77.
- Jamison RL, Hartigan P, Kaufman JS et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2008 Sep 12; 298(10):1163-70.
- Ebbing M, Bleie O, Ueland PM et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008 Aug 20; 300(7): 795-804.
- Song Y, Cook NR, Albert CM et al. Effects of homocysteine-lowering treatment with folic acid and B vitamins on risk of type-2 diabetes mellitus in women: a randomized controlled trial. Diabetes. 2009 Jun 2. [Epub ahead of print]
- Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23; 325(7374):1202.
- Grundy SM, Cleeman JI, Merz CN et al. Implications of recent trials for the National Cholesterol Education program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13; 110(2):227-39.
- Moat SJ. Plasma total homocysteine: instigator or indicator of cardiovascular disease? Ann Clin Biochem. 2008 Jul; 45(Pt 4):345-8.
- Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L, Clarke RJ et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010;303(24):2486-94.
- Veeranna V, Zalawadiya SK, Niraj A, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol 2011; 58(10):1025-33.
- Clark R, Halsey J, Bennett D, et al. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis 2011; 34(1):83-91.
- Refsum H, Smith AD, Ueland PM, et al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion. Clinical Chemistry 2004;50(1):3-32.
- Stanislawska-Sachadyn A, Woodside JV, Sayers CM, Yarnell JW, et al. The transcobalamin (TCH2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin b12 status. Eur J Clin Nutr. 2010;64:1138-1343.
- Varga EA, Sturm AC, Misita CP and Moll S. Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease. Circulation 2005;11:e289-e293.
- Deshmukh US, Joglekar CV, Lubree HG, et al. Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-blind trial in India. Eur J Clin Nutr. 2010 May;64(5):495-502.
- Kokturk N, Kanbay A, Aydogdu M, et al. Hyperhomocysteinemia prevalence among patients with venous thromboembolism. Clin Appl Thromb Hemost. 2011 Oct;17(5):487-93.
- Ray JG, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Ann Intern Med. 2007 Jun 5;146(11):761-7.
- Van der Molen EF, Verbruggen B, Novakova I, et al. Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy. BJOG. 2000 Jun;107(6):785-91.
- Bergen NE, Jaddoe VW, Timmermans S, et al. Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. BJOG. 2012 May;119(6):739-51.
- U.S. Preventative Services Task Force. October 2009. Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment, Recommendation Statement.
- American Heart Association. January 20, 2012. Homocysteine, Folic Acid and Cardiovascular Disease.
- American College of Cardiology Foundation and American Heart Association. November 2010. Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults.
- American Journal of Obstetrics and Gynecology vol.197, issue 5, November 2007. Antithrombotic Therapy and Pregnancy: Consensus Report and Recommendations for Preventative and Treatment of Venous Embolism and Adverse Pregnancy Outcomes.
- American College of Obstetricians and Gynecologists (ACOG). Inherited thrombophilias in pregnancy. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2013 Sep. 12 p. (ACOG practice bulletin; no. 138).
Date Reason Action
August 2011 Annual review Policy renewed
July 2012 Annual review Policy renewed
December 2012 Annual review Policy revised
October 2013 Annual review Policy renewed
September 2014 Annual review Policy revised
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.