Medical Policy: 02.04.22
Original Effective Date: December 2009
Reviewed: August 2015
Revised: August 2015
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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 a sulphur-containing amino acid and is formed from the conversion of methionine into cysteine. It is metabolized by one of two pathways: transsulfuration and remethylation. The transsulfuration of homocysteine to cysteine is catalyzed by cystathionine-B-synthase, a process that requires pyridoxal phosphate (vitamin B6) as a cofactor. Remethylation of homocysteine produces methionine. This reaction is catalyzed either by methionine synthase or by betaine-homocysteine methyltransferase. Vitamin B12 (cobalamin) is the precursor of methylcobalamin, which is the cofactor for methionine synthase.
Elevations in the plasma homocysteine concentration can occur due to genetic defects in the enzymes involved in homocysteine metabolism, to nutritional deficiencies in vitamin cofactors, or other factors including some chronic medical 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).
Measurements of homocysteine levels are usually performed fasting. Levels of 12 micromol/L are considered normal, 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
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 the transsulfation pathway (homocystinuria I) or methylation pathway (homocystinuria II and III). Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine.
Early diagnosis and interventions have helped prevent some of the complications of homocystinuria, including ectopia lentis, mental retardation and thromboembolic events. Laboratory studies for homocystinuria include serum homocysteine level. Treatment to normal homocysteine levels improves outcomes in individuals with homocystinuria.
There is increasing evidence that hyperhomocysteinemia (elevation of homocysteine level in blood) is a risk factor for venous thromboembolic disease (pulmonary embolism and deep vein thrombosis). Meta-analyses of case control studies have found an odds ratio of 2.5 to 2.95 for venous thromboembolic disease in patients with homocysteine levels more than two standard deviations above the mean value of control groups.
Moderate hyperhomocysteinemia (15 to 30 micromol/L) may also be a risk factor for recurrent venous thrombosis. This was illustrated in a multicenter study in which patients with a single episode of idiopathic venous thromboembolism were prospectively followed after discontinuation of oral anticoagulants. Recurrent venous thromboembolism was significantly more likely in the 66 patients with hyperhomocysteinemia than in the 198 with normal levels (18.2 percent versus 8.1 percent respectively).
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: Cardiovascular Disease Risk Test 02.04.04
Homocysteine testing (measurement of plasma homocysteine)may be considered medically necessary for the following indications:
- Assessment of patients with borderline vitamin B12 deficiency
- Assessment of patients with homocystinuria
- Assessment of patients with venous thromboembolism
Homocysteine testing is considered investigational for all other indications including but not limited to the following:
- Screening, evaluation and management of cardiovascular disease (CVD)
- Recurrent pregnancy loss
- Cognitive impairment and dementia
- Osteoporosis - fracture risk
- Multiple Sclerosis
Based on peer reviewed medical literature there is insufficient evidence to support a conclusion 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.
- 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.
- 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 June 2, 2015.
- UpToDateExternal Site. Risk Factors for Cognitive Decline and Dementia, Eric B. Larson, M.D., MPH, Topic last updated July 16, 2015.
- ACC/AHA 2013 Guideline on the Assessment of Cardiovascular Risk, Journal of the American College of Cardiology Vol. 63, No. 25. 2014
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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