Medicare Advantage

Medical Policy

Title:

Cobalamin (Vitamin B12), Folic Acid, and Homocysteine Testing

Policy #:

MA06.032a

Policy

MEDICALLY NECESSARY

TESTING OF METHYLMALONIC ACID (MMA)

Testing of methylmalonic acid (MMA) is considered medically necessary and, therefore, covered for the diagnosis of vitamin B12 deficiency when vitamin B12 levels are borderline-low* or low*.

* Vitamin B12 is assessed using a serum blood test and is assessed using the following ranges:

200-900 pg/mL: Normal
200-300 pg/mL: Borderline low
<200 pg/mL: Low – consistent with vitamin B12 deficiency

TESTING OF COBALAMIN (VITAMIN B12), FOLIC ACID TESTING, AND HOMOCYSTEINE

Testing of cobalamin (vitamin B12), folic acid, or homocysteine levels is considered medically necessary and, therefore, covered per the frequency limits listed in this policy section for individuals who are clinically symptomatic or considered high-risk for deficiency due to certain medical conditions.

Medically Necessary Frequencies

Testing of cobalamin (vitamin B12) or folic acid levels is considered medically necessary and, therefore, covered for up to three (3) times per year for each type of test; and one time per year for homocysteine for the ICD-10-CM codes listed under the CPT Codes 82607, 82746, AND 83090 in the coding table of this policy.

NOT MEDICALLY NECESSARY

All other uses, including routine screening, for testing cobalamin (vitamin B12) and folic acid levels are considered not medically necessary and, therefore, not covered.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for testing of homocysteine are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

Testing of holo-transcobalamin as a marker of vitamin B12 is considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

Subject to the terms and conditions of the applicable evidence of coverage, methylmalonic acid (MMA), cobalamin (vitamin B12), folic acid, and homocysteine testing are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

However, services that are identified in this policy as not medically necessary or experimental/investigational are not eligible for coverage or reimbursement by the Company.

Description

HOMOCYSTEINE

Homocysteine is an amino acid used to make protein and to build and maintain tissue. Excess levels in the blood are purported to increase the risk of stroke, certain types of heart disease or peripheral artery disease (PAD).

Homocysteine (Hcy), a sulphur-containing amino acid, is formed from the conversion of methionine into cysteine. It is usually rapidly metabolized via 1 of 2 pathways:

I. a vitamin B12- and folate-dependent re-methylation pathway that regenerates methionine, or

II. a vitamin B6-dependent trans-sulphuration pathway that converts Hcy to cysteine.

1. a vitamin B12- and folate-dependent re-methylation pathway that regenerates methionine, or

2. a vitamin B6-dependent trans-sulphuration pathway that converts Hcy to cysteine.

Thus, low levels of these vitamins/co-factors are associated with hyper-homocysteinemia, which can be classified as moderate (15 to 30 micromol/L), intermediate (31 to 100 micromol/L), or severe (greater than 100 micromol/L). Measurements of Hcy levels are usually performed after fasting; levels of 12 micromol/L are considered normal, and levels below 10 micromol/L are considered desirable. Increases in plasma Hcy concentration (pHcy) can arise from various causes:

I. genetic defects in the enzymes involved in Hcy metabolism,

II. nutritional deficiencies in vitamin co-factors, and

III. 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 nicotinic acid) (Rosenson and Kang, 2007).

1. genetic defects in the enzymes involved in Hcy metabolism,

2. nutritional deficiencies in vitamin co-factors, and

3. 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 nicotinic acid) (Rosenson and Kang, 2007).

The most common form of genetic hyper-homocysteinemia results from production of a thermo-labile variant of methylene tetrahydrofolate reductase (MTHFR) with reduced enzymatic activity. The gene encoding for this variant contains an alanine-to-valine substitution at amino acid 677 (C677T). The responsible gene is common, with a population frequency estimated between 5 % to 14 %. Homozygosity for the thermo-labile variant of MTHFR (TT genotype) is a relatively common cause of mildly elevated pHcy in the general population, often occurring in association with low serum folate levels (Rosenson and Kang, 2007). Harmon and colleagues (1996) quantified the contribution of the thermo-labile mutation to the hyper-homocysteinemic phenotype in a working male population (n = 625). Serum folate and vitamin B12 concentrations were measured and their relationship with Hcy status and MTHFR genotype were assessed. They found that 11.5 % of the subjects were homozygous for the TT genotype. However, for those in the top 5 to 10 % of pHcy, the frequency rose to 48 % and 36 %, respectively. Homozygotes also had the lowest serum folate concentrations.

However, the role of screening for MTHFR variants during pregnancy to ascertain risks of neural tube defects (NTDs) and/or recurrent pregnancy loss is unclear.

METHYLMALONIC ACID (MMA)

MMA is a four-carbon molecule that is a product of the metabolic break-down of valine, isoleucine, and propionic acid. Vitamin B12 is a critical cofactor for the conversion of MMA to succinate. As a result, vitamin B12 deficiency causes an accumulation of MMA in the serum. MMA concentrations will often become elevated in the early stages of vitamin B12 while serum vitamin B12 levels are in normal range. Consequently, MMA measurement is used as a diagnostic test for vitamin B12 deficiency in persons with a low or low normal serum vitamin B12 concentration. Follow-up measurement of MMA can also be of value in assessing the effectiveness of vitamin B12 supplementation of deficient individuals.

Vitamin B12 deficiency causes macrocytic anemias and decreased erythrocyte survival due to abnormal maturation of erythrocyte precursors in the bone marrow. Pernicious anemia is a form of vitamin B12 deficiency that is caused by a lack of intrinsic factor. Low vitamin B12 intake, gastrectomy, malabsorption, and transcobalamin deficiency can also cause vitamin B12 deficiency. Although severe vitamin B12 deficiency is associated with anemia, hematologic signs are not always observed in individuals with biochemically confirmed deficiency. Elderly individuals with cobalamin deficiency may present with peripheral neuropathy, ataxia, memory impairment, depression, and dementia in the absence of anemia.

A generally agreed on cutoff for elevated plasma MMA is 370 nmol/L.Approximately 2% of the US population and 7% of elderly persons have MMA concentrations above this threshold.

VITAMIN B12

Vitamin B12 is a water-soluble vitamin that is required for proper red blood cell formation, neurological function, and DNA synthesis.

Vitamin B12, or cyanocobalamin, is a complex corrinoid compound containing four pyrrole rings that surround a single cobalt atom. Humans obtain vitamin B12 exclusively from animal dietary sources, such as meat, eggs, and milk. Vitamin B12 requires intrinsic factor, a protein secreted by the parietal cells in the gastric mucosa, for absorption. Vitamin B12 and intrinsic factor form a complex that attaches to receptors in the ileal mucosa, where proteins known as transcobalamins transport the vitamin B12 from the mucosal cells to the blood and tissue. Most vitamin B12 is stored in the liver as well as in the bone marrow and other tissues.

Vitamin B12 and folate are critical to normal DNA synthesis, which in turn affects erythrocyte maturation. Vitamin B12 is also necessary for myelin sheath formation and maintenance. The body uses its Vitamin B12 stores very economically, reabsorbing vitamin B12 from the ileum and returning it to the liver so that very little is excreted.

Clinical and laboratory findings for vitamin B12 deficiency include neurological abnormalities, decreased serum vitamin B12 levels, and increased excretion of methylmalonic acid. The impaired synthesis associated with vitamin B12 deficiency causes macrocytic anemias. These anemias are characterized by abnormal maturation of erythrocyte precursors in the bone marrow, which results in the presence of megaloblasts and in decreased erythrocyte survival.

Pernicious anemia is a macrocytic anemia caused by vitamin B12 deficiency that is due to lack of intrinsic factor. Low vitamin B12 intake, alcoholism, gastrectomy, diseases of the small intestine, malabsorption, and transcobalamin deficiency can also cause vitamin B12 deficiency.

The main characteristics of vitamin B12 deficiency include megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, weight loss and neurological changes. Common symptoms associated with deficiency include difficulty with gait and balance, depression, confusion, dementia, impaired memory, and mouth and tongue soreness. Populations who are most at risk for deficiency include older adults, individuals with pernicious anemia, individuals with gastrointestinal disorders, individuals who have undergone bariatric surgery, and strict vegetarians/vegans.

Vitamin B12 is assessed using a serum blood test and is assessed using the following ranges:

200-900 pg/mL: Normal
200-300 pg/mL: Borderline low
<200 pg/mL: Low – consistent with vitamin B12 deficiency

Serum transport of vitamin B12 is accomplished by normally occurring proteins termed transcobalamins including I (an á-globulin), II (a â-globulin), and III (a group of transport factors − “R-type” binders or binder III − found also in some tissues, saliva, milk, and tears). The term “R-type” refers to binding protein with “rapid” mobility on electrophoresis. A family of immunologically identical proteins is known, not all of which have the initially described rapid mobility. They are known also as cobalophilins. Transcobalamin I is the major vitamin B12 transport protein and bears immunologic identity to granulocyte cobalophilin. Isoelectric focusing has shown that the cobalophilins are a microheterogenous group of plasma binding proteins. Stenman has reviewed this subject in detail. Cobalophilin is increased in diseases characterized by excess granulocyte production, reactive leukocytosis, chronic myelogenous leukemia, and other myeloproliferative states, in particular polycythemia vera. UBBC levels were increased in over two-thirds of cases with polycythemia vera, while nearly 90% of secondary/relative polycythemia patients had normal levels. Very high levels have been reported in some patients with hepatoma. The transcobalamins are normally about 25% saturated with vitamin B12.

FOLIC ACID

Note: Folate is the generic name for a type of B vitamin. Folate is naturally found in foods as folate. Folic acid is the manmade version sold as supplements and added to fortified foods. Folate and folic acid have the same effects.

Folates are compounds of pteroylglutamic acid (PGA) that function as coenzymes in metabolic reactions involving the transfer of single-carbon units from a donor to a recipient compound. Folate, with vitamin B12, is essential for DNA synthesis, which is required for normal red blood cell maturation. Humans obtain folate from dietary sources including fruits, green and leafy vegetables, yeast, and organ meats. Folate is absorbed through the small intestine and stored in the liver.

Low folate intake, malabsorption as a result of gastrointestinal diseases, pregnancy, and drugs such as phenytoin are causes of folate deficiency. Folate deficiency is also associated with chronic alcoholism. Folate and vitamin B12 deficiency impair DNA synthesis, causing macrocytic anemias. These anemias are characterized by abnormal maturation of red blood cell precursors in the bone marrow, the presence of megaloblasts, and decreased red blood cell survival.

Since both folate and vitamin B12 deficiency can cause macrocytic anemia, appropriate treatment depends on the differential diagnosis of the deficiency. A serum folate concentration <3 ng/mL is considered to represent clinical deficiency by the World Health Organization and numerous subsequent clinical studies. Serum folate measurement provides an early index of folate status; however, folate is much more concentrated in red blood cells than in serum so the red blood cell folate measurement more closely reflects tissue stores. Erythrocytes incorporate folate as they are formed, and levels remain constant throughout the life span of the cell. RBC folate levels are less sensitive to short-term dietary effects than are serum folate levels. Red blood cell folate concentration is considered the most reliable indicator of folate status.

Low serum folate during pregnancy has been associated with neural tube defects in the fetus.

In the 1990s mandatory increased fortification of enriched cereal-grain products along with the requirement of folate-related health and nutrient content claims on food and dietary supplement products significantly increased the folic acid content of the US food supply. Several reports have shown that serum folate concentrations have increased in the general US population since these measures were implemented.

HOLO-TRANSCOBALAMIN

It has been hypothesized that the response of holo-transcobalamin (holo-TC) to oral vitamin B12 may be used to assess absorption; however clinical validity and utility date are lacking to support this hypothesis at this time.

References

Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: A randomized trial. JAMA. 2008;299(17):2027-2036.

Allen RH. Human vitamin B12 transport proteins. Prog Hematol. 1975; 9:57-84 (review). PubMed 766076.

Almeida OP, McCaul K, Hankey GJ, et al. Homocysteine and depression in later life. Arch Gen Psychiatry. 2008;65(11):1286-1294.

American Academy of Family Physicians (AAFP). Summary of recommendations for clinical preventive services. Leawood, KS: American Academy of Family Physicians (AAFP); May 2012.

American College of Obstetricians and Gynecologists (ACOG). Inherited thrombophilias in pregnancy. Practice Bulletin No. 138. Obstet Gynecol. 2013;122:706-717.

Araki A, Ito H, Hosoi T, Orimo H. Plasma homocysteine and cognitive function in elderly patients with diabetes mellitus. Geriatr Gerontol Internat. 2003;3(2):86-92.

Badawy A, State O, El Gawad SSh, El Aziz OA. Plasma homocysteine and polycystic ovary syndrome: The missed link. Eur J Obstet Gynecol Reprod Biol. 2007;131(1):68-72.

Battaglia C, Mancini F, Cianciosi A, et al. Vascular risk in young women with polycystic ovary and polycystic ovary syndrome. Obstet Gynecol. 2008;111(2 Pt 1):385-395.

Beuerlein FJ. Testing strategies for anemias. Lab Mgmnt. 1988; 23-29.

Boxmeer JC, Macklon NS, Lindemans J, et al. IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Hum Reprod. 2009;24(5):1059-1066.

Brewster MA. Vitamins. In: Kaplan LA, Pesce AJ, eds. Clinical Chemistry: Theory, Analysis, and Correlation. St. Louis, Mo: CV Mosby;1989:543-568.

Burtis AC, Ashwood ER, eds. "Vitamin B12. Textbook of Clinical Chemistry. Philadelphia, Pa: WB Sanders Co;1996: 2047-2048.

Bushnell CD, Goldstein LB. Homocysteine testing in patients with acute ischemic stroke. Neurology. 2002;59(10):1541-1546.

B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: A review of the design and power of the large randomized trials. Am Heart J. 2006;151(2):282-287.

Carlsen SM, Kjøtrød S, Vanky E, Romundstad P. Homocysteine levels are unaffected by metformin treatment in both nonpregnant and pregnant women with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2007;86(2):145-150.

Carmel R. Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr. 2011 Jul; 94(1):348S-358S. PubMed 21593511.

Chen IW, Sperling MI, Heminger LA. Vitamin B12. In: Pesce AJ, Kaplan LA, eds.Methods in Clinical Chemistry. St Louis, Mo: CV Mosby;1987: 569-573.

Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF. Folic acid intake from fortification in United States exceeds predictions. J Nutr. 2002 Sep;132(9):2792-2798. PubMed 12221247.

Ciclitira PJ. Management of celiac disease in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2016.

Clarke R, Bennett DA, Parish S, et al.; MTHFR Studies Collaborative Group. Homocysteine and coronary heart disease: Meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med. 2012;9(2):e1001177.

Clarke R, Refsum H, Birks J, et al. Screening for vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr. 2003 May; 77(5):1241-1247. PubMed 12716678.

Coban-Karatas M, Erol I, Ozkale Y, Yazýcý N. Central retinal artery occlusion in a 13-year-old child as a presenting sign of hyperhomocysteinemia together with high lipoprotein(a) level. Pediatr Neurol. 2013;49(2):138-140.

Fairbanks VF, Klee GG. Biochemical aspects of hematology. In: Burtis CA, Ashwood ER, eds.Tietz Textbook of Clinical Chemistry. WB Saunders Co;1999:1642-1710.

Farrell RJ, Peppercorn MA. Overview of the medical management of mild to moderate Crohn disease in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2016.

Finnell RH, Shaw GM, Lammer EJ, Volcik KA. Does prenatal screening for 5,10-methylenetetrahydrofolate reductase (MTHFR) mutations in high-risk neural tube defect pregnancies make sense? Genet Test. 2002 Spring;6(1):47-52.

Folate on Elecsys 1010/2010 and Modular Analytics E170, package insert 2007-02, V 1, Indianapolis, Ind: Roche Diagnostics; 2007.

Fowler B, Leonard JV, Baumgartner MR. Causes of and diagnostic approach to methylmalonic acidurias. J Inherit Metab Dis. 2008 Jun; 31(3):350-360. PubMed 18563633.

Front Mol Biosci. 2016 Jun 27;3:27. doi: 10.3389/fmolb.2016.00027. eCollection 2016. Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency. Hannibal L1, Lysne V2, Bjørke-Monsen AL3, Behringer S1, Grünert SC1, Spiekerkoetter U1, Jacobsen DW4, Blom HJ1.

Ganji V, Kafai MR. Trends in serum folate, RBC folate, and circulating total homocysteine concentrations in the United States: Analysis of data from National Health and Nutrition Examination Surveys, 1988-1994, 1999-2000, and 2001-2002. J Nutr. 2006 Jan; 136(1):153-158. PubMed 16365075.

Genest J Jr, Audelin MC, Lonn E. Homocysteine: To screen and treat or to wait and see? CMAJ. 2000;163(1):37-38.

Gilbert HS, Krauss S, Pasternack B, Herbert V, Wasserman LR. Serum vitamin B12 content and unsaturated vitamin B12 binding capacity in myeloproliferative disease. Value in differential diagnosis and as indicators of disease activity. Ann Intern Med. 1969 Oct; 71(4):719-729. PubMed 5360286.

Gjesdal CG, Vollset SE, Ueland PM, et al. Plasma homocysteine, folate, and vitamin B 12 and the risk of hip fracture: The hordaland homocysteine study. J Bone Miner Res. 2007;22(5):747-756.

Gulhan I, Bozkaya G, Bilgir F, et al. Serum homocysteine and asymmetric dimethylarginine levels in patients with premature ovarian failure: A prospective controlled study. Gynecol Endocrinol. 2011;27(8):568-571.

Haapaniemi E, Helenius J, Soinne L, et al. Serial measurements of plasma homocysteine levels in early and late phases of ischemic stroke. Eur J Neurol. 2007;14(1):12-17.

Hachem RR. Lung transplantation: An overview. UpToDate Inc., Waltham, MA. Last reviewed June 2018a.

Hachem RR. Lung transplantation: General guidelines for recipient selection. UpToDate Inc., Waltham, MA. Last reviewed June 2018b.

Hague WM. Homocysteine and pregnancy. Best Pract Res Clin Obstet Gynaecol. 2003;17(3):459-469.

Hall CA, Horch C, Begley JA. The forms and transport of plasma cobalamins in normal man and in myeloproliferative states. J Lab Clin Med. 1979 Nov; 94(5):772-783. PubMed 501204.

Hankey GJ. Is plasma homocysteine a modifiable risk factor for stroke? Nat Clin Pract Neurol. 2006;2(1):26-33.

Harmon DL, Woodside JV, Yarnell JW, et al. The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM. 1996;89(8):571-577.

Hegges TR, III. Central and branch retinal artery occlusion. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed July 2015.

Ho RC, Cheung MW, Fu E, et al. Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression. Am J Geriatr Psychiatry. 2011;19(7):607-617.

Hoey PL, Strain JJ, McNulty H. Studies of biomarker responses to intervention with vitamin B-12: A systematic review of randomized controlled trials. Am J Clin Nutr. 2009 Jun; 89(6):1981S-1996S. PubMed 19403638.

Hølleland G, Schneede J, Ueland PM, Lund PK, Refsum H, Sandberg S. Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem. 1999 Feb; 45(2):189-198. PubMed 9931040.

Hong IH, Ahn JK, Chang S, Park SP. Diagnostic efficacy of total homocysteine and C-reactive protein for ocular ischemic syndrome. Eye (Lond). 2011;25(12):1650-1654.

Hooshmand B, Solomon A, Kareholt I, et al. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: A longitudinal study. Neurology. 2010;75(16):1408-1414.

Houston D, Lee D, Mant M. Hyperhomocysteinemia. The Thrombosis Interest Group of Canada. October 2006. Availalbe at: http://www.tigc.org/eguidelines/hyperhomocysteinemia.htm. Accessed March 31, 2008.

Huang X, Li Y, Li P, et al. Association between percent decline in serum total homocysteine and risk of first stroke. Neurology. 2017;89(20):2101-2107.

Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency- An update. Haematologica. 2006 Nov; 91(11):1506-1512. PubMed 17043022.

Institute for Clinical Systems Improvement (ICSI). Biochemical markers of cardiovascular disease risk. Technology Assessment Report No. 66. Bloomington, MN: ICSI; 2003.

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. 2007;298(10):1163-1170.

Janel N, Alexopoulos P, Badel A, et al. Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease. Transl Psychiatry. 2017;7(6):e1154.

Jerzak M, Putowski L, Baranowski W. Homocysteine level in ovarian follicular fluid or serum as a predictor of successful fertilization. Ginekol Pol. 2003;74(9):949-952.

Klee GG. Cobalamin and folate evaluation: Measurement of methylmalonic acid and homocysteine vs vitamin B12 and folate. Clin Chem. 2000 Aug; 46(8 Pt 2):1277-1283. PubMed 10926922.

Krabbendam I, Franx A, Bots ML, et al. Thrombophilias and recurrent pregnancy loss: A critical appraisal of the literature. Eur J Obstet Gynecol Reprod Biol. 2005;118(2):143-153.

Langan RC, Zawistoski KJ. Update on vitamin B12 deficiency. Am Fam Physician. 2011 Jun 15; 83(12):1425-1430. PubMed 21671542.

Lazzerini PE, Capecchi PL, Selvi E, et al. Hyperhomocysteinemia: A cardiovascular risk factor in autoimmune diseases? Lupus. 2007;16(11):852-862.

Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C-->T polymorphism and coronary heart disease: Does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ. 2005;331(7524):1053.

Local Coverage Determination (LCD): Local Coverage Article: Billing and Coding: Assays for Vitamins and Metabolic Function (A56416). https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=56416&ver=6&name=331*1&UpdatePeriod=829&bc=AAAAEAAAAAAA&. Accessed April 25, 2019.

Local Coverage Determination (LCD): Assays for Vitamins and Metabolic Function (L34914). https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=34914&ver=62&name=314*1&UpdatePeriod=826&bc=AAAAEAAAAAAA&. Accessed April 25, 2019.

Lonn E. Homocysteine in the prevention of ischemic heart disease, stroke and venous thromboembolism: Therapeutic target or just another distraction? Curr Opin Hematol. 2007;14(5):481-487.

Lonn E. Homocysteine-lowering B vitamin therapy in cardiovascular prevention -- wrong again? JAMA. 2008;299(17):2086-2087.

MacDermott RP. Management of mild to moderate ulcerative colitis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2016.

Makino A, Nakanishi T, Sugiura-Ogasawara M, et al. No association of C677T methylenetetrahydrofolate reductase and an endothelial nitric oxide synthase polymorphism with recurrent pregnancy loss. Am J Reprod Immunol. 2004;52(1):60-66.

Mangoni AA, Woodman RJ. Homocysteine and cardiovascular risk: An old foe creeps back. J Am Coll Cardiol. 2011;58(10):1034-1035.

Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2009;(4):CD006612.

McGimpsey SJ, Woodside JV, Cardwell C, et al. Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism, and risk of retinal vein occlusion: A meta-analysis. Ophthalmology. 2009;116(9):1778-1787.

McNeely MD. Folic acid. In: Pesce AJ, Kaplan LA, eds.Methods in Clinical Chemistry. St Louis, Mo: CV Mosby;1987:539-542.

McNulty H, Cuskelly GJ, Ward M. Response of red blood cell folate to intervention: implications for folate recommendations for the prevention of neural tube defects. Am J Clin Nutr. 2000 May; 71(5 Suppl);1308S-1311S. PubMed 10799407.

Mei W, Rong Y, Jinming L, et al. Effect of homocysteine interventions on the risk of cardiocerebrovascular events: A meta-analysis of randomised controlled trials. Int J Clin Pract. 2010;64(2):208-215.

Miale JB. Hematology. Laboratory Medicine. St Louis, Mo: CV Mosby;1989: 416-440.

Milani RV, Lavie CJ. Homocysteine: The Rubik's cube of cardiovascular risk factors. Mayo Clin Proc. 2008;83(11):1200-1202.

Molloy AM, Kirke PN, Troendle JF, et al. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Pediatrics. 2009 Marl 123(3):917-923. PubMed 19255021.

Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Vitamin B12 and folate depletion in cognition: A review. Neurol India. 2004 Sep; 52(3):310-318. PubMed 15472418.

Morris AA, Kozich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40(1):49-74.

Nafiye Y, Sevtap K, Muammer D, et al. The effect of serum and intrafollicular insulin resistance parameters and homocysteine levels of nonobese, nonhyperandrogenemic polycystic ovary syndrome patients on in vitro fertilization outcome. Fertil Steril. 2010;93(6):1864-1869.

Nathan SR. Branch retinal artery occlusion. eMedicine. Last updated September 26, 2014. Available at: http://emedicine.medscape.com/article/1223362-overview. Accessed August 4, 2015.

Nexo E, Olesen H, Norredam K, Schwartz M. A rare case of megaloblastic anaemia caused by disturbances in the plasma cobalamin binding proteins in a patient with hepatocellular carcinoma. Scand J Haematol. 1975 Jun; 14(5):320-327. PubMed 175433.

Nutritional anemias. Report of a WHO group of experts. World Health Organ Tech Rep Ser. 1972; 503:1-29. PubMed 4626525.

O'Leary VB, Mills JL, Pangilinan F; Members of the Birth Defects Research Group. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol Genet Metab. 2005;85(3):220-227.

Oterino A, Toriello M, Valle N, et al. The relationship between homocysteine and genes of folate-related enzymes in migraine patients. Headache. 2010;50(1):99-168.

Pacchiarotti A, Mohamed MA, Micara G, et al. The possible role of hyperhomocysteinemia on IVF outcome. J Assist Reprod Genet. 2007;24(10):459-462.

Parchand S, Bhalekar S, Gupta A, Singh R. Primary branch retinal artery occlusion in idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome associated with hyperhomocysteinemia. Retin Cases Brief Rep. 2012;6(4):349-352.

Peterson M, Grossman S. Managing celiac disease for women: Implications for the primary care provider. Gastroenterol Nurs. 2016;39(3):186-194.

Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: Results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr. 2005 Aug; 82920:442-450. PubMed 16087991.

Pfeiffer CM, Johnson CL, Jain RB, et al. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988 2004. Am J Clin Nutr. 2007 Sep; 86(3)718-727. PubMed 17823438.

Picker JD, Levy HL. Homocystinuria caused by cystathionine beta-synthase deficiency. GeneReviews. Seattle, WA: GeneTests, University of Washington at Seattle; Last updated March 29, 2006.

Pinna A, Zaccheddu F, Boscia F, et al. Homocysteine and risk of age-related macular degeneration: A systematic review and meta-analysis. Acta Ophthalmol. 2018;96(3):e269-e276.

Pinna A, Zinellu A, Franconi F, et al. Decreased plasma cysteinylglycine and taurine levels in branch retinal vein occlusion. Ophthalmic Res. 2010;43(1):26-32.

Ramsaransing GS, Fokkema MR, Teelken A, et al. Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006;77(2):189-192.

Rosenson RS, Kang DS. Overview of homocysteine. UpToDate [online serial]. Waltham, MA: UpToDate; 2007.

Roversi FM, Galdieri LC, Grego BH, et al. Blood oxidative stress markers in Gaucher disease patients. Clin Chim Acta. 2006;364(1-2):316-320.

Ruisi P, Makaryus JN, Ruisi M, Makaryus AN. Inflammatory bowel disease as a risk factor for premature coronary artery disease. J Clin Med Res. 2015;7(4):257-261.

Ryan-Harshman M, Aldoori W. Vitamin B12 and health. Can Fam Physician. 2008 Apr; 54(4):536-541. PubMed 18411381.

Sachdev PS. Homocysteine and brain atrophy. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(7):1152-1161.

Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: A randomized controlled trial. JAMA. 2005 Mar 2;293(9):1082-1088.

Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med. 1994 Mar; 96(3):239-246. PubMed 8154512.

Schachter M, Raziel A, Strassburger D, et al. Prospective, randomized trial of metformin and vitamins for the reduction of plasma homocysteine in insulin-resistant polycystic ovary syndrome. Fertil Steril. 2007;88(1):227-230.

Selhub J, Morris MS, Jacques PF, Rosenberg IH. Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr. 2009 Feb; 89(2):702S-706S. PubMed 19141696.

Selhub J. The many facets of hyperhomocysteinemia: Studies from the Framingham cohorts. J Nutr. 2006;136(6 Suppl):1726S-1730S.

Shane B. Folate status assessment history: Implications for measurement of biomarkers In NHANES. Am J Clin Nutr. 2011 Jul; 94(1):337S-342S. PubMed 10386505.

Silbert B, Evered L, Scott DA, et al. Homocysteine and C-reactive protein are not markers of cognitive impairment in patients with major cardiovascular disease. Dement Geriatr Cogn Disord. 2008;25(4):309-136.

Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: A guide for the primary care physician. Arch Intern Med. 1999 Jun 28; 159(12):1289-1298. PubMed 10386505.

Spijkerman AM, Smulders YM, Kostense PJ, et al. S-adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: The Hoorn Study. Arterioscler Thromb Vasc Biol. 2005;25(4):778-784.

Steinkamp RC. Vitamin B12 and folic acid: Clinical and pathophysiological considerations. In: Brewster MA, Naito HK, eds. Nutritional Elements and Clinical Biochemistry. New York, NY: Plenum Publishing Corp;1980:169-240.

Stenman U-H. Intrinsic Factor and the Vitamin B12 Binding Proteins. In: Hoffbrand AV, ed. Megaloblastic Anemia, Clinics in Haematology. Philadelphia, Pa: WB Saunders Co;1976: 5:473-495.

Tangney CC, Tang Y, Evans DA, Morris MC. Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline. Neurology. 2009 Jan 27; 72(4):361-367. PubMed 19171834.

Tanpaiboon P. Methylmalonic acidemia (MMA). Mol Genet Metab. 2005 May; 85(1):2-6. PubMed 15959932.

Teper E, O'Brien JT. Vascular factors and depression. Int J Geriatr Psychiatry. 2008;23(10):993-1000.

The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. A metaanalysis. JAMA. 2002;288:2015-2022.

Thompson MA, Bauer BA, Loehrer LL, et al. Dietary supplement S-adenosyl-L-methionine (AdoMet) effects on plasma homocysteine levels in healthy human subjects: A double-blind, placebo-controlled, randomized clinical trial. J Altern Complement Med. 2009;15(5):523-529.

Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291(5):565-575.

U.S. National Institutes of Health (NIH), National Library of Medicine. Homocystinuria. Genetics Home Reference. Bethesda, MD: NIH; reviewed January 2008.

U.S. Preventive Services Task Force (USPSTF). Using nontraditional risk factors in coronary heart disease risk assessment. Recommendations. Rockville, MD: USPSTF; October 2009.

UpToDate Website. Overview of homocysteine. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed August 2015.

van Meurs JB, Uitterlinden AG. Homocysteine and fracture prevention. JAMA. 2005;293(9):1121-1122.

Vashi P, Edwin P, Popiel B, et al. Methylmalonic acid and homocysteine as indicators of vitamin B-12 deficiency in cancer. PLoS One. 2016;11(1):e0147843.

Veeranna V, Zalawadiya SK, Niraj A, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol. 2011;58(10):1025-1033.

Vitamin B12 on Elecsys 1010/2010 and Modular Analytics E170, 2007-08, V 4 [package insert]. Indianapolis, Ind: Roche Diagnostics; 2007.

Vrethem M, Mattsson E, Hebelka H, et al. Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler. 2003;9(3):239-245.

Waxman S, Gilbert HS. A tumor-related vitamin B12 binding protein in adolescent hepatoma. N Engl J Med. 1973 Nov 15; 289(20):1053-1056. PubMed 4126370.

Weger M, Stanger O, Deutschmann H, et al. The role of hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T mutation in patients with retinal artery occlusion. Am J Ophthalmol. 2002;134(1):57-61.

Wolff T, Witkop CT, Miller T, Syed SB; U.S. Preventive Services Task Force. Folic acid supplementation for the prevention of neural tube defects: An update of the evidence for the US Preventive Services Task Force. Ann Interv Med. 2009 May 5:150(9):632-639. PubMed 19414843.

Zittoun J, Farcet JP, Marquet J, Sultan C, Zittoun R. Cobalamin (vitamin B12) and B12 binding proteins in hypereosinophilic syndromes and secondary eosinophilia. Blood. 1984 Apr; 63(4):779-783. PubMed 6704540.

Zoccolella S, Martino D, Defazio G, et al. Hyperhomocysteinemia in movement disorders: Current evidence and hypotheses. Curr Vasc Pharmacol. 2006;4(3):237-243.

Coding

CPT Procedure Code Number(s)

MEDICALLY NECESSARY

82607, 82746, 83090

THE FOLLOWING CODE IS USED TO REPRESENT METHYLMALONIC ACID (MMA)

83921

EXPERIMENTAL/ INVESTIGATIONAL

THE FOLLOWING CODE IS USED TO REPRESENT HOLO-TRANSCOBALAMIN

84999

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

COBALAMIN (VITAMIN B12), FOLIC ACID, AND/OR HOMOCYSTEINE TESTING (CPT CODES 82607, 82746, AND 83090) ARE MEDICALLY NECESSARY WHEN REPORTED WITH THE DIAGNOSIS CODES IN ATTACHMENT A.

REPORT THE MOST APPROPRIATE DIAGNOSIS CODE IN SUPPORT OF MEDICALLY NECESSARY CRITERIA AS LISTED IN THE POLICY FOR HOMOCYSTEINE (CPT CODE 83090) AND METHYLMALONIC ACID (MMA) TESTING (CPT CODE 83921).

HCPCS Level II Code Number(s)

N/A

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA06.032a:

11/26/2025	This policy has been reissued in accordance with the Company's annual review process.
07/10/2024	This policy has been reissued in accordance with the Company's annual review process.
01/01/2024	Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.
01/25/2023	This policy has been reissued in accordance with the Company's annual review process.
10/01/2022	This version of the policy is a result of code updates effective 10/01/2022. Narrative for the following diagnosis code was revised in the policy: F03.90 Following diagnosis codes were deleted from the policy because they were termed: F03.91 Following diagnosis codes were added to the policy: F03.911 F03.918 F03.92 F03.93 F03.94 F03.A0 F03.A11 F03.A18 F03.A2 F03.A3 F03.A4 F03.B0 F03.B11 F03.B18 F03.B2 F03.B3 F03.B4 F03.C0 F03.C11 F03.C18 F03.C2 F03.C3 F03.C4

Revisions From MA06.032:

11/17/2021	This policy has been reissued in accordance with the Company's annual review process.
07/15/2020	This policy has been reissued in accordance with the Company's annual review process.
05/28/2019	This new policy will become effective on 05/28/2019. Main focuses in this medical policy are placed on medical necessity criteria, (including applicable ICD-10 requirements), and frequencies for coverage of Cobalamin (Vitamin B12), Folic Acid, and Homocysteine Testing as detailed by the Centers for Medicare & Medicaid Services (CMS). Testing of methylmalonic acid (MMA) and holo-transcobalamin (holo-TC) are also addressed in this medical policy.

11/17/2021

This policy has been reissued in accordance with the Company's annual review process.

07/15/2020

This policy has been reissued in accordance with the Company's annual review process.

05/28/2019

This new policy will become effective on 05/28/2019.

Main focuses in this medical policy are placed on medical necessity criteria, (including applicable ICD-10 requirements), and frequencies for coverage of Cobalamin (Vitamin B12), Folic Acid, and Homocysteine Testing as detailed by the Centers for Medicare & Medicaid Services (CMS).

Testing of methylmalonic acid (MMA) and holo-transcobalamin (holo-TC) are also addressed in this medical policy.

Version Effective Date:

1/1/2024

Version Issued Date: