Laboratory Section - Vitamin D Testing

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

DESCRIPTION

Vitamin D is a fat-soluble vitamin that plays an essential role in mineral metabolism (e.g. calcium absorption) and is needed for normal bone growth and remodeling. In addition, the vitamin has several other roles, including but not limited to modulation of neuromuscular and immune functions.  Vitamin D intake (food and supplements) can be expressed in either International Units (IU) or micrograms (µg) (1 µg = 40 IU vitamin D).

Vitamin D is available from a limited number of dietary sources (fish liver oils, fatty fish, egg yolks, and fortified foods), supplementation, and from skin synthesis upon exposure to ultraviolet radiation from the sun.

There are 2 forms of activated vitamin D for which testing is performed:

• 25-hydroxyvitamin D [25(OH)D], calcidiol, is the most abundant circulating form of Vitamin D
• 1,25-dihydroxyvitamin D [1,25(OH)₂D], calcitriol, is the most metabolically active form; however it is not considered to be a good indicator of vitamin D levels

Serum Vitamin D Testing

Laboratory testing to determine Vitamin D serum levels may be performed for two purposes:

1. To assess serum levels in patients with signs and/or symptoms of toxicity or deficiency or with conditions strongly associated with vitamin D deficiency (eg, rickets, osteomalacia, hyperparathyroidism, osteoporosis, patients who have undergone surgical removal of the small intestine); or
   
2. To screen for potential deficiencies in:
   
   • Healthy individuals without signs or symptoms of an illness/disease (eg, vitamin D screening as a part of routine health exams);  or
   • Individuals with general symptoms that are not specific to or suggestive of vitamin D deficiency.

POLICY/CRITERIA

1. 25-hydroxyvitamin D [25(OH)D], calcidiol, serum testing
   
   
1. 25(OH)D serum testing may be considered medically necessary in patients with a clinically documented underlying disease or condition which is specifically associated with vitamin D deficiency or decreased bone density (see Appendix I).
   
   
2. 25(OH)D serum testing is considered not medically necessary for routine or initial screening in the absence of clinical documentation of an underlying disease or condition  specifically associated with vitamin D deficiency.
   
   
2. 1,25-dihydroxyvitamin D [1,25(OH)₂D] calcitriol, serum testing
   
   
   1. 1,25(OH)2D serum testing may be medically necessary in the evaluation or treatment of the conditions that may be associated with defects in vitamin D metabolism (see Appendix II).
      
      
   2. 1,25(OH)2D serum testing is considered not medically necessary for testing and screening for vitamin D deficiency because this test is not considered a reliable indicator of vitamin D serum levels.

SCIENTIFIC BACKGROUND

The following evidence summary is based on the Agency for Healthcare Research and Quality (AHRQ) evidence report on the effectiveness and safety of Vitamin D in relation to bone health, ^[1] the Institute of Medicine of the National Academies Dietary Reference Intakes for Calcium and Vitamin D ^[2] and National Institutes of Health Vitamin D Health Professional Fact Sheet.^[3]

Vitamin D Test Reliability and Clinical Utility

25-hydroxyvitamin D [25(OH)D] (calcidiol)

Although the serum concentration of 25(OH)D, the most abundant circulating form of Vitamin D,  is the best indicator of vitamin D status, there is considerable uncertainty associated with this measurement due to the following: ^[1-3]

• The tests that measure serum levels are not reliable.  
  
  25(OH)D tests are not standardized and there is substantial variability among the different assay types currently available on the market and among the different laboratories that carry out testing.
  
  
• The serum concentrations that define deficient, adequate, and optimal levels of 25(OH)D are not firmly established.
  
  The range of proposed cutoff points is very wide and not sufficiently supported by evidence. Consequently, different practitioners endorse different cutoff points. According to the 2010 Institute of Medicine (IOM) report, currently there is no central body that is responsible for establishing such values for clinical use.
  
  For the purposes of the 2010 report, the IOM specified a serum 25(OH)D concentration below 30 nmol/L as deficient. However, the report notes that variable definitions have been used in the literature, ranging from 40 to >80 nmol/L, and that there is potentially large variability in measurements, depending on the assay used.
  
  
• The serum concentrations that define toxic levels of 25(OH)D are not firmly established.
  
  Although toxicity from excessive vitamin D supplementation is possible, the 25(OH)D serum levels representing toxicity are not precisely defined due to the lack of evidence from reliable, controlled studies. In addition, the vitamin D intakes needed to bring about toxic symptoms are also not firmly established. According to the 2010 IOM report, the evidence suggests that daily intakes below 10 000 IU/day are not usually associated with toxicity, while daily intakes above 10 000 IU may be. However, these recommendations are based on short-term findings and are not adequate for setting upper intake levels for the general population for long-term/lifetime exposure.^[1,2] In addition, there is a lack of consensus on the toxicity of vitamin D doses prescribed at or above 50 000 IU/day (mega-doses), which are administered for a short period of time (eg, several weeks). While some textbooks consider this dose to be non-toxic (with the excess stored and used as needed), the 2010 IOM report identified evidence that suggests that doses this high are frequently associated with toxic side effects.
  
  
• The serum concentration of 25(OH)D reflects vitamin D produced in the skin and obtained from food and supplements, but it does not reflect vitamin D stores in other body tissues. In addition, confounders, such as such as adiposity, African-American ancestry, or size and frequency of dose can also affect 25(OH)D serum levels.
  

• The clinical utility of the test is not established.
  
  It is not clear how vitamin D test results guide treatment decisions compared to decisions that would be made in the absence of test results, especially for asymptomatic patients who are being prescribed vitamin D supplementation as a part of their wellness assessment or for patients with conditions where the role of vitamin D is not clearly defined.  Consequently, the tests may produce false results that in turn may mislead treatment decisions.

1,25-dihydroxyvitamin D 1,25(OH)₂D (calcitriol)

1,25(OH)₂D as a measure of vitamin D deficiency

Although the most metabolically active form, circulating 1,25(OH)₂D is generally not considered to be a reliable indicator of vitamin D as it has a very short half-life, production in the kidney is closely regulated by a number of different factors, and a significant decrease is observed only when deficiency is severe. 

It is uncertain how calcitriol serum testing may be used in the clinical setting to guide treatment decisions.

1,25(OH)₂D and other indications

Vitamin D Supplementation and Treatment

Vitamin D Supplementation

A 2010 comprehensive systematic review of the current evidence (IOM report) concludes that there is strong evidence from rigorous testing to support the importance of vitamin D in promoting bone growth and maintenance.^[2] The 2007 AHRQ report points out that research gaps exist even in this area. This review identified fair evidence of an association between circulating 25(OH)D concentrations with some bone outcomes (established rickets, parathyroid hormone (PTH) levels, bone mineral density) and inconsistent evidence for others (eg, bone mineral content in infants, fractures in adults).^[1] However, it is uncertain how much vitamin D is needed to maintain bone health and normal calcium metabolism in healthy people. Many factors, including age, gender, sun exposure, and dietary intake, play a role in determining adequate vitamin D intake for any given individual. In addition, the presence of certain medical conditions or treatments may further alter an individual’s vitamin D needs/sensitivity (eg, glucocorticoid therapy). The report notes that the optimal level of circulating 25(OH)D required for bone health may also vary depending on the functional outcome.^[1] The AHRQ report identifies the need for further research to better understand these modifiers of vitamin D effect.  

Despite uncertain evidence, the IOM report recommends a dietary allowance of 600 IU for males and females 1-70 years of age and 800 IU for adults 71 years and older (recommended dietary allowance is defined as average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%-98%) healthy people).^[2]

Vitamin D Treatment

The role of vitamin D has been investigated for numerous indications other than bone health, including but not limited to cancer (e.g. colon, prostate, and breast cancer), cardiovascular disease and hypertension, diabetes and metabolic syndrome, falls, immune response, neuropsychological functioning, physical performance, preeclampsia, and reproductive outcomes.  However, the IOM report does not specify any conditions for which testing of 25(OH)D serum levels may be indicated.

The reviewed studies of these conditions provided mixed and inconclusive results. Consequently, it cannot be reliably determined whether or how vitamin D affects the risk of these conditions, or whether changing the exposure to vitamin D provides a protective effect. Specifically, large well-designed and well-executed randomized controlled trials are needed in order to reliably investigate the role of vitamin D in these conditions.

Clinical Practice Guidelines

Summary

Although there is evidence that Vitamin D plays an essential role in promoting bone growth and maintenance, there is considerable uncertainty with respect to the reliability and clinical utility of testing. Specifically:

• Serum tests are unreliable.
• Toxic, deficient, and optimal Vitamin D serum levels have not been defined.
• In the absence of signs or symptoms specifically associated with diseases or conditions related to vitamin D deficiency, there is no evidence to demonstrate that testing results in improved health outcomes.

REFERENCES

1. Agency for Healthcare Research and Quality. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evaluation Report. 2007.   [cited 02-11-2011]; Available from: http://www.ahrq.gov/downloads/pub/evidence/pdf/vitamind/vitad.pdf
2. Institute of Medicine of the National Academies. Dietary Reference Intakes for Calcium and Vitamin D. November 2010.   [cited 12/03/2010]; Available from: http://www.iom.edu/Reports/2010/Dietary-Reference-In takes-for-Calcium-and-Vitamin-D.aspx
3. Office of Dietary Supplements, National Institutes of Health. Dietary Supplements Fact Sheet: Vitamin D Health Professional Fact Sheet.   [cited 02/08/2011]; Available from: http://ods.od.nih.gov/factsheets/vitamind.asp
4. Goldman, L, editor. Cecil Medicine. 23 ed. Philadelphia, PA: Saunders Elsevier; 2007.
5. Henry M. Kronenberg, Shlomo Melmed, Kenneth S. Polonsky, P. Reed Larsen, editors. Williams Textbook of Endocrinology. 11 ed. Philadelphia, PA: Saunders Elsevier; 2008.
6. Richard A. McPherson, Pincus, MR, editors. Henry's Clinical Diagnosis and Management by Laboratory Methods. 21 ed. Philadelphia, PA: Saunders Elsevier; 2007.
7. Ferri, FF, editor. Ferri's Clinical Advisor 2011. 1 ed. Philadelphia, PA: Mosby Elsevier; 2010.
8. Holick, MF, Binkley, NC, Bischoff-Ferrari, HA, et al. Evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30.  PMID: 21646368

Cross References

None

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