Medical Policy: 02.04.22
Original Effective Date: December 2009
Reviewed: July 2016
Revised: July 2016
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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 (Hcy), is an intermediary amino acid and is formed by the conversion of methionine to cysteine. It is usually rapidly metabolized by one of two pathways: 1) a vitamin B12 and folate dependent remethylation pathway that regenerates methionine, or 2) a vitamin B6 and folate dependent trans-sulphuration pathway that converts homocysteine (Hcy) to cysteine. Thus, low levels of these vitamins/co-factors are associated with hyperhomocysteinemia.
Measurements of homocysteine (Hcy) levels are usually performed fasting. Normal homocysteine concentrations range between 5 and 15 micromol/L, and levels below 10 micromol/L are considered desirable. Hyperhomocysteinemia has been classified as follows:
- Moderate 15 to 30 micromol/L
- Intermediate 31 to 100 micromol/L
- Severe >100 micromol/L
Elevations in the plasma homocysteine concentration (pHcy) can arise from various causes: genetic defects in the enzymes involved in homocysteine (Hcy) metabolism, nutritional deficiencies in vitamin co-factors, and other factors such as chronic conditions/diseases (e.g. obesity, smoking, physical inactivity, hypertension, hypercholesterolemia, diabetes mellitus and chronic kidney failure) and medications (e.g. fenofibrate, methotrexate, and nicotine acid).
Vitamin supplementation with folate lowers homocysteine levels. In patients who are treated to lower homocysteine levels treatment may consist of folic acid (1mg/day), vitamin B6 (10mg/day) and vitamin B12 (0.4mg/day). Normalization of the homocysteine concentration has been reported within two weeks, but further lowering of homocysteine levels occur by six weeks. The dose of folic acid should be increased up to 5 mg/day as needed to lower the homocysteine concentration below 15 micromol/L. In patients with homocysteine concentation >30 micromol/L or chronic renal failure the initial dose of folic acid is 5mg/day. A diet rich in fruits, vegetables, and low-fat dairy products and low in saturated and total fat also can lower fasting serum homocysteine.
Vitamin B12 Deficiency
Vitamin B12 deficiency often co-exist and are not easily differentiated on a clinical basis. Accordingly such patients should be evaluated for both deficiencies. The first step should entail determination of vitamin B12 and folate concentrations. Serum vitamin B12 levels can be interpreted as follows:
- Normal result: >300 pg/mL (>221 pmo/L) vitamin B12 deficiency unlikely
- Borderline result: 200 to 300 pg/mL (148 to 221 pmo/L) vitamin B12 deficiency possible
- Low result: <200 pg/mL (<148 pmo/L) – consistent with vitamin b12 deficiency
Patients with serum vitamin B12 values at the lower end of the normal range or in the borderline range (described above) may be vitamin B12 deficient and respond to replacement therapy. Measurement of serum homocysteine appears to be more sensitive for the diagnosis of these deficiencies than serum vitamin levels alone, and is helpful in clarifying the diagnosis when serum vitamin B12 or folate concentrations are equivocal. Serum concentrations of homocysteine are elevated in vitamin B12 deficiency due to a decreased rate of metabolism.
Homocystinuria also known as cystathionine beta synthase deficiency or CBS deficiency, is an autosomal recessively inherited disorder in which patients are unable to properly process certain amino acids. The principal biochemical features of this condition are markedly elevated plasma homocysteine concentration (pHcy), total homocysteine (tHcy), plasma concentrations of methionine as well as increased urinary concentration of homocysteine (Hcy). The most common form of homocystinuria is caused by the lack of cystathionine beta synthase (CBS), a vitamin B6 dependent enzyme. Homocystinuria caused by CBS deficiency effects at least 1 in 200,000 or 335,000 people worldwide. Other forms of homocystinuria are much rarer.
Early diagnosis and interventions have helped prevent some of the complications of homocystinuria, including ectopia lentis (dislocation of the ocular lens) and/or severe myopia, developmental delay/mental retardation, skeletal abnormalities and thromboembolic events.
There are two phenotypic variants of homocystinuria: 1) B6-responsive, 2) B6-non-responsive. The former is typically milder than the latter. In the majority of untreated affected individuals, ectopia lentis occurs by 8 years of age. Patients are often tall and slender build with asthenic habitus (long limbs, an angular profile, and prominent muscles or bones) and are prone to osteoporosis. Thromboembolism is the major cause of early death and morbidity. Intelligence quotient (IQ) in individuals with homocystinuria usually ranges from 10 to 138; with the mean IQ in individuals with B6-responsiveness being 79 versus 57 for those who are B6-non-responsive. Other features that may occur include seizures, psychiatric problems, extra-pyramidal signs such as dystonia, hypo-pigmentation, pancreatitis, malar flush (redness of cheeks), and livedo reticularis (mottled discolouration of the skin).
Laboratory studies for homocystinuria include serum homocysteine level. Treatments should aim to correct the biochemical abnormalities and to normalize homocysteine levels. Individuals identified by newborn screening are treated shortly after birth to maintain plasma homocysteine (pHcy) below 11 micromol/L. For newborn screening, measurements of homocysteine (Hcy) are performed only when hyper-methioninemia has been confirmed. Complications of homocystinuria should be treated appropriately (e.g. surgical intervention for ectopia lentis).
The most common presentation of venous thrombosis are deep vein thrombosis (DVT) of the lower extremities and pulmonary embolism. The causes of venous thrombosis can be divided into two groups; hereditary and acquired, and are often multiple in a given patient.
Inherited thrombophilia is a genetic tendency to venous thromboembolism. Acquired risk factors or predisposing conditions for thrombosis include a prior thrombotic event, recent major surgery, presence of central venous catheter, trauma, immobilization, malignancy, pregnancy, the use of oral contraceptives, antiphospholipid syndrome (APS) and myeloproliferative disorders.
A major theory delineating the pathogenesis of venous thromboembolism (VTE), often called Virchow’s triad, which proposes that VTE occurs as a result of:
- Alterations in blood flow (i.e. stasis)
- Vascular endothelial injury
- Alternations in the constitutents of the blood (i.e. inherited or acquired hypercoaguable state)
Hyperhomocysteinemia (elevation of homocysteine level in blood) has been associated with an increased risk for venous thromboembolic disease (pulmonary embolism and deep vein thrombosis), but is currently considered a relatively weak prothrombotic factor. While screening for hyperhomocysteinemia is not difficult, a benefit from lowering the homocysteine concentration and venous thromboembolic disease remains unproven.
It is still unclear whether administration of vitamins, that reduce homocysteine levels acting as co-factors of the enzymes involved in the methionine metabolism, may decrease the risk of arterial and/or venous thromboembolic events. Further randomized clinical trials are needed to help clarify the use of supplementation for prevention of VTE.
Cardiovascular Disease Risk
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 of homocysteine. 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.
Evidence suggesting improved clinical outcomes of reduced cardiac risk and adverse events as a result of lowering homocysteine levels with treatment is lacking. Patient selection criteria and target levels or safe levels of homocysteine for determining cardiac risk have not been clearly defined. There is insufficient evidence in peer reviewed literature to support routine measurement of homocysteine testing for screening, diagnosing and management of cardiovascular disease. Further randomized controlled clinical trials are needed to support the potential clinical utility of lowering homocysteine levels and therefore is considered investigational.
Recurrent Pregnancy Loss
In normal pregnancy, homocysteine concentrations fall. Disturbance of maternal and fetal homocysteine metabolism has been associated with fetal neural tube defects, with various conditions characterized by placental vasculopathy, such as pre-eclampsia and abruption, and with recurrent pregnancy loss. Apart from folate supplementation, which has been clearly shown to halve the risk of fetal neural tube defects, no other strategies have been identified in relation to homocysteine metabolism that will reliably reduce the frequency of these other common obstetric pathologies. Routine testing of women with recurrent pregnancy loss for inherited thrombophilias to include fasting homocysteine levels is not currently recommended because there is lack of association between this testing and negative pregnancy outcomes and therefore is considered investigational.
Role of Homocysteine Testing in Other Conditions
Osteoporosis – homocystinuria is associated with the early onset of osteoporosis. High homocysteine levels in adults have been associated with osteoporotic fractures in some, but not all studies. It is not clear, however, whether high levels of homocysteine have a direct effect on bone or whether the effect is mediated through another factor, such as poor nutrition, and its uncertain whether folic acid supplementation is beneficial for osteoporosis and therefore homocysteine testing would be considered investigational for this indication.
Dementia and Cognitive Impairment – There is conflicting evidence about whether homocysteine is an independent risk factor for dementia or cognitive impairment. The potential mechanisms whereby homocysteine might mediate cognitive decline and dementia include: Neurotoxicity induced by activation of N-methl-D-aspartate (NMDA receptors; promotion of apoptosis; vascular injury from promotion of atherogenesis and proliferation of smooth muscle cells; platelet activation; increased burden of ischemic strokes and white matter lesions. However, some studies suggest that the association between abnormal homocysteine levels as well as other changes in serum vitamin concentrations reflects early weight loss as a manifestation of early dementia rather than its cause. Homocysteine lowering therapy using supplementation with vitamins B12 and B6 has not been shown to improve cognitive function or prevent cognitive decline. Also, homocysteine testing is generally not recommended or included in the standard evaluation of dementia. Therefore, homocysteine testing for dementia and/or cognitive impairment is considered investigational.
Autism: Based on peer reviewed medical literature homocysteine testing is not supported for the assessment and treatment of autism and is considered investigational.
Multiple Sclerosis: Elevated homocysteine levels have been observed in patients with MS. Studies have examined why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course. Findings indicated that regardless of significant increase in plasma homocysteine levels in MS patients, the disease is not generally associated with vitamin B12 deficiency. Therefore, homocysteine testing is considered investigational because the effectiveness of this testing for this indication has not been established.
Practice Guidelines and Position Statements
U.S. Preventative Services Task Force
In 2009 the U.S. Preventative Services Task Force issued a recommendation, Coronary Heart Disease: Screening Using Non-Traditional Risk Factors, which concluded 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 non-tradiational 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 College of Cardiology Foundation (ACCF) and the American Heart Association (AHA)
In 2010 the American College of Cardiology Foundation and the American Heart Association guideline on the assessment of cardiovascular risk in asymptomatic adults, did not address measurement of homocysteine levels.
American College of Cardiology (ACC)/American Heart Association (AHA)
In 2013 the American College of Cardiology and the American Heart Association guideline on the assessment of cardiovascular risk, did not address measurement of homocysteine levels.
American Society for Reproductive Medicine (ASRM)
Inherited Thrombophilias: Screening for inherited thrombophilias (specifically, Factor V Leiden and the prothrombin gene mutations, protein C, protein S and antithrombin deficiencies) may be clinically justified when a patient has a personal history of venous thromboembolism in the setting of a non-recurrent risk factor (such as surgery) or a first degree relative with a known or suspected high risk thrombophilia. Although an association between hereditary thrombophilias and fetal loss has been suggested, prospective cohort studies have failed to confirm this. Routine testing of women with recurrent pregnancy loss for inherited thrombophilias is not currently recommended.
American College of Obstetricians and Gynecologist (ACOG)
In 2013 ACOG issued a Practice Bulliten; no. 138, Inherited Thrombophilias in Pregnancy and the recommendations included:
- Testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption is not recommended because it is unclear if anticoagulation reduces recurrence.
- 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.
See Related Medical Policy:
- 02.04.04 Cardiovascular Disease Risk Test
- 02.04.46 Genetic Testing for Inherited Thrombophilia
Homocysteine testing (measurement of plasma levels of homocysteine) may be considered medically necessary for the following indications:
- Assessment of patients with borderline vitamin B12 deficiency
- Assessment of patients with homocystinuria (also known as cystathionine beta synthase deficiency or CBS deficiency)
Homocysteine testing is considered investigational for all other indications including but not limited to the following:
- Screening, evaluation and management of cardiovascular disease (CVD)
- Assessment of recurrent pregnancy loss
- Assessment of cognitive impairment and dementia
- Assessment of osteoporosis - fracture risk
- Assessment of Autism
- Assessment of multiple sclerosis
- Assessment of venous thromboembolism, inherited or acquired
Based on peer reviewed medical literature there is insufficient evidence to support conclusions concerning the health outcomes or benefits associated with homocysteine testing for the above indications (not an all inclusive list) and therefore, considered investigational.
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 ForceExternal Site. October 2009. Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment, Recommendation Statement.
- American Heart AssociationExternal Site. 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. Am Coll Cardiol 2010:56(25):e50-e103
- 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).
- American Society for Reproductive MedicineExternal Site, Evaluation and Treatment of Recurrent Pregnancy Loss: Committee Opinion 2012. Fertil Steril 2012;98:1103-11
- MedScapeExternal Site. Homocystinuria/Homocysteinemia. Updated November 4, 2014.
- UpToDateExternal Site. Overview of Homocysteine, Robert S. Rosenson, M.D., David S. Kang, M.D., PhD. Topic last updated July 23, 2015.
- UpToDateExternal Site. Diagnosis and Treatment of Vitamin B12 and Folate Deficiency, Stanley L. Schrier, M.D., Topic last updated April 14, 2015.
- UpToDateExternal Site. Overview of the Possible Risk Factors for Cardiovascular Disease, Peter Wilson, M.D., Topic last updated April 8, 2016.
- UpToDateExternal Site. Risk Factors for Cognitive Decline and Dementia, Eric B. Larson, M.D., MPH, Topic last updated May 4, 2016.
- ACC/AHA 2013 Guideline on the Assessment of Cardiovascular Risk, Journal of the American College of Cardiology Vol. 63, No. 25. 2014
- UpToDate. Overview of the Causes of Venous Thrombosis, Kenneth A Bauer M.D., Gregroy YH Lip, M.D., FRCPE, FESC, FACC. Topic last updated June 3, 2016. Also available at www.uptodate.com
- Picker J, Levy H. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency, Gene Reviews last updated November 13, 2014. NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. www.ncbi.nlm.nih.gov
- U.S. National Institute of Health (NIH), National Library of Medicine. Homocystinuria. Genetics Home Reference. Bethesda, MD: Also available at http://ghr.nlm.nih.gov/condition=homocystinuria
- Wang C, Han L, Wu Q, et al. Association between homocysteine and incidence of ischemic stroke in subjects with essential hypertension: A matched case-control study. Clin Exp Hypertens. Nov 2015;37(7):557-562. PMID 25992490
- Catena C, Colussi G, Nait F, et al. Elevated Homocysteine Levels Are Associated With the Metabolic Syndrome and Cardiovascular Events in Hypertensive Patients. Am J Hypertens. Jul 2015;28(7):943-950. PMID 25498997
- Marti-Carvajal AJ, Sola I, Lathyris D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2015;1:CD006612. PMID 25590290
- Yi X, Zhou Y, Jiang D, et al. Efficacy of folic acid supplementation on endothelial function and plasma homocysteine concentration in coronary artery disease: A meta-analysis of randomized controlled trials. Exp Ther Med. May 2014;7(5):1100-1110. PMID 24940394
- Liu Y, Tian T, Zhang H, et al. The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: a meta-analysis of randomized controlled trials. Atherosclerosis. Jul 2014;235(1):31-35. PMID 24814647
- van Dijk SC, Enneman AW, Swart KM, et al. Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial. J Hypertens. Sep 2015;33(9):1897-1906; discussion 1906. PMID 26147383
July 2016 - Annual Review, Policy Revised
August 2015 - Annual Review, Policy Revised
September 2014 - Annual Review, Policy Revised
October 2013 - Annual Review, Policy Renewed
December 2012 - Annual Review, Policy Revised
July 2012 - Annual Review, Policy Renewed
August 2011 - Annual Review, Policy Renewed
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.