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




Homocysteine testing (measurements of plasma homocysteine) is considered medically necessary and, therefore, covered for the following indications:
  • Assessment of borderline vitamin B12 deficiency*, where the results will impact the member's management; OR
  • Assessment of homocystinuria caused by cystathionine beta synthase deficiency, (for newborn screening, measurements of plasma homocysteine/total homocysteine are performed only when hyper-methioninemia has been confirmed); OR
  • Assessment of idiopathic venous thrombo-embolism, recurrent venous thrombo-embolism, thrombosis occurring at a young age (i.e., less than 45 years of age), or thrombosis at an unusual site.

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 cobalamin (vitamin B12) and folic acid 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, including:
  • Abnormalities of gait, mobility, or coordination
  • Achlorhydia
  • Alcohol dependence
  • Alzheimer’s disease
  • Amnesia
  • Anemia
  • Anhedonia
  • Anorexia
  • Blind loop syndrome
  • Celiac disease
  • Crohn’s disease
  • Dependence on renal dialysis
  • Diabetes mellitus with neuropathy, amyotrophy, or neurologic complication
  • Disease of the blood or blood-forming organs
  • Disturbances of skin sensation
  • Eating disorders
  • Endocrine, nutritional, or metabolic disease
  • Failure to thrive (child)
  • Glossitis
  • Glossodynia
  • Homocystinuria
  • Human immunodeficiency virus (HIV) disease
  • Hypergammaglobulinemia
  • Malabsorption
  • Malnutrition
  • Marasmus
  • Neuropathy
  • Osteomyelofibrosis
  • Pancreatic steatorrhea
  • Pernicious anemia
  • Prolonged drug use (e.g., proton pump inhibitors (PPI), Metformin)
  • Senile dementia
  • Sulfur-bearing amino-acid metabolism disorders
  • Tropical sprue
  • Veganism
  • Vitamin deficiency or other B-complex deficiencies
  • Whipple’s disease
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 for the ICD-10-CM codes listed under the CPT Codes 82607, 82608, 82746, AND 82747 in the coding table of this policy.


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


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.


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.


Subject to the terms and conditions of the applicable benefit contract, homocysteine, methylmalonic acid (MMA), cobalamin (vitamin B12), and folic acid 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.



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.


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 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.


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.


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.


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CPT Procedure Code Number(s)

82607, 82608, 82746, 82747, 83090





ICD - 10 Procedure Code Number(s)

ICD - 10 Diagnosis Code Number(s)


HCPCS Level II Code Number(s)

Revenue Code Number(s)

Coding and Billing Requirements

Policy History

Medical Policy Bulletin
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