mp-448 - Medical Policies - Alabama
Serum Holotranscobalamin as a Marker of Vitamin B12 (Cobalamin) Status
Policy Number: MP-448
Latest Review Date: September 2019
Policy Grade: Effective 08/29/2013: Active Policy but no longer scheduled for regular literature reviews and updates.
Measurement of holotranscobalamin (HoloTC) is considered not medically necessary and investigational in the diagnosis and management of Vitamin B12 deficiency.
DESCRIPTION OF PROCEDURE:
Holotranscobalamin (holo-TC) is a transcobalamin-vitamin B12 complex which has been investigated as a diagnostic test for vitamin B12 deficiency in symptomatic and at-risk populations, as well as an assay for monitoring response to therapy.
Vitamin B12 is also called cobalamin (Cbl). It is present in foods derived from animal products. IT is an essential vitamin that is required for DNA synthesis affecting red blood cell formation, and methionine synthesis affecting neurological functioning. The endogenous forms of Vitamin B12 include cobalamin and holotranscobalamin, which represent the active fraction of plasma cobalamin. Cobalamin deficiency can result from nutritional deficiencies or malabsorption. Dietary insufficiency is most common among vegetarians and the elderly. Malabsorption of vitamin B12 may be associated with autoantibodies as in pernicious anemia or can occur after gastrectomy, or in other gastrointestinal conditions such as celiac disease, Whipple’s disease and Zollinger-Ellison syndrome. Clinical signs and symptoms of cobalamin deficiency include megaloblastic anemia, paresthesias and neuropathy, and psychiatric symptoms such as irritability, dementia, depression, or psychosis. While the hematologic abnormalities disappear promptly after treatment, neurologic disorders may become permanent if treatment is delayed.
The diagnosis of cobalamin deficiency has traditionally been based on low levels of total serum cobalamin, typically less than 200 pg/ml, in conjunction with clinical evidence of disease. However, this laboratory test has been found to be poorly sensitive and specific. Therefore, attention has turned to measuring metabolites of cobalamin as a surrogate marker. For example, in humans only two enzymatic reactions are known to be dependent on cobalamin: the conversion of methylmalonic acid (MMA) to succinyl-CoA, and the conversion of homocysteine and folate to methionine. Therefore, in the setting of cobalamin deficiency, serum levels of MMA and homocysteine are elevated, and have been investigated as surrogate markers.
There also is interest in the direct measurement of the subset of biologically-active cobalamin. Cobalamin in serum is bound to two proteins, transcobalamin and haptocorrin. Transcobalamin-cobalamin complex (called holotranscobalamin, or holo-TC) functions to transport cobalamin from its site of absorption in the ileum to specific receptors throughout the body. Less than 25% of the total serum cobalamin exists as holo-TC, but this is considered the clinically relevant biologically active form. Serum levels of holo-TC can be measured using a radioimmunoassay or enzyme immunoassay.
This policy is based on a review of current literature as of September 23, 2019.
Summary of Evidence
Holotranscobalamin (holo-TC) is a transcobalamin-vitamin B12 complex that has been investigated as a diagnostic test for vitamin B12 deficiency in symptomatic and at-risk populations, as well as an assay for monitoring response to therapy. Holo-TC seems more suitable than total vitamin B-12 for the diagnosis of vitamin B-12 deficiency. There is currently no gold standard or true reference method to diagnose subtle vitamin B-12 deficiency, which makes evaluation of the clinical usefulness of holoTC and the estimation of sensitivity and specificity problematic. There is a need for studies that can prove or disprove this technology’s clinical utility. Evidence of the clinical utility of the test is currently lacking, and therefore is considered investigational.
Practice Guidelines and Position Statements
Many societies have recommended vitamin B12 supplementation for specific clinical conditions or evaluation for vitamin B12 deficiency in the workup for clinical indication without specifying a methodology. An exception is in a practice parameter for peripheral neuropathy by the American Academy of Neurology (AAN), who has specified a methodology (evidence level C): “serum B12 level with metabolites (methylmalonic acid with or without homocysteine)” in the evaluation for vitamin B12 deficiency.
U.S. Preventive Services Task Force Recommendations
Holo-TC, Vitamin B12 Deficiency, Holotranscobalamin, Transcobalamin, Axis-Shield, HoloTC RIA
APPROVED BY GOVERNING BODIES:
In January 2004, the device “HoloTC RIA” (Axis-Shield plc, Dundee, UK) is an example of a radioimmunoassay for holo-TC that was cleared for marketing by the FDA through the 510(k) process. The FDA determined that this device was substantially equivalent to existing devices for use in:
“Quantitative measurement of the fraction of cobalamin (vitamin B12) bound to the carrier protein transcobalamin in the human serum or plasma. Measurements obtained by this device are used in the diagnosis and treatment of vitamin B12 deficiency.”
In November 2006, the device “Axis-Shield HoloTC Assay” (Axis-Shield, Dundee, UK),an enzyme immunoassay for holo-TC, was cleared for marketing by the FDA through the 510(k) process. The FDA determined that this device was substantially equivalent to existing devices for use in:
“Quantitative determination of holotranscobalamin…in human serum and plasma on the AxSym® System. HoloTC is used as an aid in the diagnosis and treatment of vitamin B12 deficiency.”
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
Pre-certification requirements: Not applicable
Unlisted chemistry procedure.
- Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. Engl J Med. 2012;367(4):385.
- 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; 94(1):348S-58S.
- Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med 2000; 51:357-75.
- Collin SM, Metcalfe C, Refsum H, et al. Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: A case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 2010; 19(6):1632-42.
- Dullemeijer C, Souverein OW, Doets EL et al. Systematic review with dose-response meta-analyses between vitamin B-12 intake and European Micronutrient Recommendations Aligned's prioritized biomarkers of vitamin B-12 including randomized controlled trials and observational studies in adults and elderly persons. Am J Clin Nutr 2013; 97(2):390-402.
- Elin RJ and Winter WE. Methylmalonic acid: A test whose time has come? Arch Pathol Lab Med 2001; 125(6):824-7.
- England JD, Gronseth GS, Franklin G, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009; 72(2):185-92.
- Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: A randomized, placebo-controlled trial. Am J Clin Nutr 2006; 84(2):361-70.
- Eussen SJ, Ueland PM, Hiddink GJ, et al. Changes in markers of cobalamin status after cessation of oral B-vitamin supplements in elderly people with mild cobalamin deficiency. Eur J Clin Nutr 2008; 62(10):1248-51.
- Fedosov SN. Metabolic signs of vitamin B(12) deficiency in humans: computational model and its implications for diagnostics. Metabolism 2010;59:1124–38.
- Hardlei TF, Mørkbak AL, Bor MV, Bailey LB, Hvas AM, Nexo E. Assessment of vitamin B(12) absorption based on the accumulation of orally administered cyanocobalamin on transcobalamin. Clin Chem 2010;56:432–6
- Hay G, Clausen T, Whitelaw A, et al. Maternal folate and cobalamin status predicts vitamin status in newborns and 6-month-old infants. J Nutr 2010; 140(3):557-64.
- Heil SG, de Jonge R, de Rotte MC et al. Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study. Ann Clin Biochem 2012; 49(Pt 2):184-9.
- Hill MH, Flatley JE, Barker ME et al. A vitamin B-12 supplement of 500 mug/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status. J Nutr 2013; 143(2):142-7.
- Hoey L, Strain JJ and McNulty H. Studies of biomarker responses to intervention with vitamin B-12: A systematic review of randomized controlled trials. Am J Clin Nutr 2009; 89(6):1981S-96S.
- Hvas AM, Ellegaard J and Nexo E. Vitamin B12 treatment normalizes metabolic markers but has limited clinical effect: A randomized placebo-controlled study. Clin Chem 2001; 47(8):1396-404.
- Hvas AM and Nexo E. Holotranscobalamin--a first choice assay for diagnosing early vitamin B deficiency? J Intern Med 2005; 257(3):289-98.
- Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990; 34:99.
- Loikas S, Lopponen M, Suominen P, et al. RIA for serum holo-transcobalamin: Method evaluation in the clinical laboratory and reference interval. Clin Chem 2003; 49(3):455-62.
- Matchar DB, McCrory DC, Millington DS, Feussner JR. Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci 1994; 308:276.
- Nexo E, Hoffmann-Lucke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr 2011; 94(1):359S-65S.
- Nexo E, Hvas AM, Bleie O, et al. Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clin Chem 2002; 48(10):1768-71.
- Norman EJ, Morrison JA. Screening elderly populations for cobalamin (vitamin B12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry. Am J Med 1993; 94:589.
- Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003; 67(5):979-86.
- O'Leary F, Allman-Farinelli M, Samman S. Vitamin B(1)(2) status, cognitive decline and dementia: a systematic review of prospective cohort studies. Br J Nutr 2012; 108(11):1948-61.
- Robinson D, O'Luanaigh C, Tehee E, et al. Associations between holotranscobalamin, vitamin B12, homocysteine and depressive symptoms in community-dwelling elders. Int J Geriatr Psychiatry 2010.
- 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; 96:239.
- Stabler SP. Clinical practice. Vitamin B12 deficiency. Engl J Med. 2013 Jan;368(2):149-60.
- Sumner AE, Chin MM, Abrahm JL, et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery. Ann Intern Med 1996; 124(5):469-76.
- Valente E, Scott JM, Ueland PM et al. Diagnostic accuracy of holotranscobalamin, methylmalonic acid, serum cobalamin, and other indicators of tissue vitamin B(1)(2) status in the elderly. Clin Chem 2011; 57(6):856-63.
Medical Policy Group, September 2010 (3)
Medical Policy Administration Committee, September 2010
Available for comment September 22-November 5, 2010
Medical Policy Group, September 2012 (3): 2012 Update to Key Points and References
Medical Policy Panel, August 2013
Medical Policy Group, August 2013 (1) Update to Key Points and References; no change to policy statement
Effective August 29, 2013: Active Policy but no longer scheduled for regular literature reviews and updates.
Medical Policy Group, November 2015: 2016 Annual Coding Update. Created previous coding section and moved CPT code 0103T under this section. Added cpt code 84999 to current coding.
Medical Policy Group, September 2019 (9): Updated Description, Key Points, and References. Added clarifying notation to policy statement (HoloTC), no change to policy statement intent.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
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As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
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1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
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1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
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