Cigna Vitamin D Testing - (0526) Form

The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients.

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Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

This Coverage Policy addresses serum Vitamin D testing.

Coverage Policy

Vitamin D testing is considered medically necessary in a non-pregnant individual age 18 – 64 years for any of the following:

• previously documented Vitamin D deficiency
• known or suspected excessive Vitamin D blood levels (i.e., toxicity)
• condition or medical diagnosis associated with Vitamin D deficiency (See Appendix)

Vitamin D testing for any other indication including screening in the general population is not covered or reimbursable.

Vitamin D testing (CPT® 82306) more frequently than twice in 12 rolling months is not covered or reimbursable for any diagnosis other than chronic kidney disease (CKD) or intestinal malabsorption. Vitamin D testing utilizing both CPT® 82306 and CPT® 82652 in combination is not covered or reimbursable.

General Background

Vitamin D is a fat-soluble vitamin.

Very few foods naturally contain Vitamin D (fatty fish and eggs are the exception), so Vitamin D is obtained primarily through fortified foods or supplements and dermal synthesis from exposure to sunlight. Vitamin D has two forms, ergocalciferol (Vitamin D2) and cholecalciferol (Vitamin D3), and several metabolites. Vitamin D from the diet or sunlight is biologically inactive and requires enzymatic conversion to active metabolites. Vitamin D is converted enzymatically:

• in the liver to 25-hydroxyvitamin D (25[OH]D), the major circulating form of Vitamin D; and then
• in the kidney to 1,25-dihydroxyvitamin D (1,25[OH]2D), the active form of Vitamin D.

The concentration of 25(OH)D is almost 1000-fold that of 1,25(OH)2D, and the half-life of 25(OH)D is much longer, implying that its concentration is more stable. The most common type of vitamin D deficiency is 25-OH vitamin D. A much smaller percentage of 1, 25-dihydroxy vitamin D deficiency exists; mostly, in those with renal disease. Although it is not the active form of the hormone, 25-OH vitamin D is more commonly measured. It better reflects the sum total of vitamin D produced endogenously and absorbed from the diet than does the level of the active hormone 1, 25-dihydroxy vitamin D. Deficiency of 1, 25-dihydroxy vitamin D, which is present at much lower concentrations, does not necessarily reflect deficiency of 25-OH vitamin D. Its measurement should be limited to specific diseases such as acquired and inherited disorders in the metabolism of 25(OH)D and phosphate, including chronic kidney disease.

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25(OH)D (CPT® code 82306) The best laboratory indicator of Vitamin D adequacy is the serum 25(OH)D concentration. It is the measurement of choice to diagnose Vitamin D deficiency and to assess Vitamin D status. The lower limit of normal for 25(OH)D levels varies depending on the geographic location and sunlight exposure of the reference population. There is no consensus on the optimal 25(OH)D concentration for skeletal or extraskeletal health. The IOM concluded that a serum 25(OH)D concentration of 20 ng/mL (50 nmol/L) is sufficient for most individuals. Other experts (Endocrine Society, National Osteoporosis Foundation, and American Geriatrics Society) suggest that a minimum level of 30 ng/mL (75 nmol/L) is necessary in older adults to minimize the risk of falls and fracture. Additionally, 25(OH)D measurements have had widespread variation in the results. Serum 25-OH-D assays fall into two main categories:

1. those based on a separation step of chromatography, the most popular of which is liquid chromatography–tandem mass spectrometry (LC-MS/MS) and
2. nonchromatographic methods based on antibody or protein binding, such as radioimmunoassays.

Serum 25(OH)D should be assessed in persons at risk for Vitamin D deficiency or insufficiency. Vitamin D deficiency may result from:

• medications or disorders that affect the metabolism of Vitamin D and phosphate (e.g., glucocorticoids, chronic kidney disease)
• resistance to the effects of Vitamin D inadequate exposure to sunlight or intake of Vitamin D
• reduced absorption of Vitamin D (e.g., malabsorption syndromes)

Vitamin D Toxicity: Another reason to measure serum 25(OH)D is when there is a suspicion of excessive Vitamin D blood levels (toxicity). Because vitamin D increases calcium absorption in the gastrointestinal tract, vitamin D toxicity results in marked hypercalcemia (total calcium greater than 11.1 mg/dL, beyond the normal range of 8.4 to 10.2 mg/dL), hypercalciuria, and high serum 25(OH)D levels (typically greater than 375 nmol/l [150 ng/mL]) [155].

Hypercalcemia, in turn, can lead to nausea, vomiting, muscle weakness, neuropsychiatric disturbances, pain, loss of appetite, dehydration, polyuria, excessive thirst, and kidney stones (National Institute of Health, 2020).

1,25(OH)2D (CPT® code 82652) Serum 1,25(OH)2D is not suitable to assess Vitamin D status because it is kept within reference limits as long as possible by hormonal mechanisms (e.g., parathyroid hormone for stimulation and serum calcium and phosphate for suppression). Also, it has a short half-life measured in hours. Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe. Serum measurement of 1,25(OH)2D is useful in monitoring certain conditions, such as acquired and inherited disorders in the metabolism of 25(OH)D and phosphate, including chronic kidney disease, hereditary phosphate-losing disorders, oncogenic osteomalacia, pseudovitamin D- deficiency rickets, Vitamin D-resistant rickets, as well as chronic granuloma-forming disorders such as sarcoidosis and some lymphomas (Dawson-Hughes, et al., 2017; National Institute of Health, 2020; Pazirandeh, et al., 2016; Enko, et al., 2015; Jones, 2015; Holick, et al., 2011; Lip, et al., 2007).

Literature Review

There is a paucity of evidence evaluating the benefit and harm of testing for Vitamin D. Peer-reviewed scientific literature primarily investigates the effects of Vitamin D supplementation, not testing. Kahwati et al. (2021) conducted a systematic review for the U.S. Preventive Services Task Force (USPSTF) to assess the evidence about screening for vitamin D deficiency in adults. No studies Medical Coverage Policy: 0526 evaluated the direct benefits or harms of screening for vitamin D deficiency. Because no studies were identified that evaluated screening for vitamin D deficiency, the evidence report was limited to an evaluation of the benefits and harms of vitamin D treatment among participants at risk for deficiency based on low serum vitamin D levels. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.

The Agency for Healthcare Research and Quality (AHRQ) published a technology assessment (Newberry, et al., 2014) updating a previous technology assessment (Chung, et al., 2009) that assessed numerous factors related to Vitamin D. Data from nearly 250 new studies published between 2009 and 2013 was reviewed. The report concluded that it is not possible to specify a relationship between vitamin D and health outcomes other than bone health. Similarly, the Food and Nutrition Board (FNB) committee at the National Academies of Sciences, Engineering, and Medicine (NASEM) found that the evidence was inadequate or too contradictory to conclude that the vitamin had any effect on a long list of potential health outcomes (e.g., on resistance to chronic diseases or functional measures), except for measures related to bone health (National Institute of Health Office of Dietary Supplements, Fact Sheet for Health Professionals on Vitamin D; Updated August 12, 2022).

The Washington State Health Care Authority Health Technology Assessment Program (HTA) published a technology assessment on Vitamin D Screening and Testing in 2012. It was determined that no definitive conclusions can be drawn about the effectiveness of Vitamin D screening or testing since no trials have been conducted to directly assess the impact of screening or testing on health outcomes, patient behavior, or clinical decision making.

However, for some populations and outcomes, an association between serum levels and health outcomes and/or a positive effect of supplementation on health outcomes has been demonstrated. Thus, Vitamin D screening has potential utility for identifying individuals who could benefit from the preventive or disease-modifying effects of supplementation in these clinical situations. Both Vitamin D screening/testing and Vitamin D supplementation are generally safe interventions.

Professional Societies/Organizations

Endocrine Society

The Endocrine Society Clinical Practice Guideline on Evaluation, Treatment, and Prevention of Vitamin D Deficiency (Holick, et al., 2011) makes the following recommendations specific to Vitamin D testing:

• Recommend screening for Vitamin D deficiency in individuals at risk for deficiency.
• Do not recommend population screening for Vitamin D deficiency in individuals who are not at risk.
• Recommend using the serum circulating 25-hydroxyvitamin D [25(OH)D] level, measured by a reliable assay, to evaluate Vitamin D status in patients who are at risk for Vitamin D deficiency.

Vitamin D deficiency is defined as a 25(OH)D below 20 ng/ml (50 nmol/liter), and Vitamin D insufficiency as a 25(OH)D of 21–29 ng/ml (525–725 nmol/liter).

• Recommend against using the serum 1,25-dihydroxyvitamin D [1,25(OH)2D] assay for this purpose (patients at risk) and are in favor of using it only in monitoring certain conditions, such as acquired and inherited disorders of Vitamin D and phosphate metabolism.

Rationale/Evidence: There is no evidence demonstrating benefits of screening for Vitamin D deficiency at a population level. Such evidence would require demonstration of the feasibility and cost-effectiveness of such a screening strategy, as well as benefits in terms of important health outcomes. In the absence of this evidence, it is premature to recommend screening at large at this time. Currently, 25(OH)D measurement is reasonable in groups of people at high risk for Vitamin D deficiency and in whom a prompt response to optimization of Vitamin D status could be expected.

Indications for 25(OH)D measurement (candidates for screening):

• Rickets
• Osteomalacia
• Osteoporosis
• Chronic kidney disease
• Hepatic failure
• Malabsorption syndromes
  • Cystic fibrosis
  • Inflammatory bowel disease
  • Crohn's disease
  • Bariatric surgery
  • Radiation enteritis
• Hyperparathyroidism
• Medications
  • Antiseizure medications
  • Glucocorticoids
  • AIDS/HIV medications
  • Antifungals, e.g. ketoconazole
  • Cholestyramine
• African-American and Hispanic children and adults
• Pregnant and lactating women
• Older adults with history of falls
• Older adults with history of nontraumatic fractures
• Obese children and adults (BMI > 30 kg/m2)
• Granuloma-forming disorders
  • Sarcoidosis
  • Tuberculosis
  • Histoplasmosis
  • Coccidiomycosis
  • Berylliosis
• Some lymphomas

The Endocrine Society, in conjunction with the American Society for Bone and Mineral Research (ASBMR), Endocrine Society, American Association of Clinical Endocrinologists (AACE), European Calcified Tissue Society (ECTS), the National Osteoporosis Foundation (NOF), and the International Osteoporosis Foundation (IOF), released ‘Joint guidance on vitamin D in the era of COVID-19’ on July 09, 2020. It does not address testing for Vitamin D.

The Endocrine Society Guideline on Pharmacological Management of Osteoporosis in Postmenopausal Women including Section 8 on Calcium and Vitamin D, does not address testing for Vitamin D (Eastell, et al., 2019; Shoback, et al., 2020).

Professional Societies/Organizations

The Endocrine Society

The Endocrine Society Clinical Practice Guideline on Pediatric Obesity-Assessment, Treatment, and Prevention (Styne, 2017) states the following re pediatric bariatric surgery: Vitamin deficiencies are common, including deficiencies of vitamins B12, B1, and folate, as Roux-en-Y gastric bypass and vertical sleeve gastrectomy both reduce the surface of the distal portion of the stomach,

Medical Coverage Policy: 0526 resulting in inadequate secretion of intrinsic factor. Annual screening is recommended for patients at risk for developing vitamin deficiencies.

U.S. Preventive Services Task Force (USPSTF)

The 2021 Final Recommendation Statement on Screening for Vitamin D Deficiency in Adults states:

For asymptomatic, community-dwelling, non-pregnant adults: The USPSTF found that the evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency. (Insufficient)

This applies to community-dwelling, non-pregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended. It does not apply to persons who are hospitalized or living in institutions such as nursing homes. This recommendation is consistent with the 2014 USPSTF statement. In summary, there is insufficient evidence to recommend for or against screening for vitamin D deficiency.

American Academy of Neurology (AAN)

The AAN published a Practice Guideline titled Disease-modifying therapies for Adults with Multiple Sclerosis does not address testing for Vitamin D (Rae-Grant, et al., 2018; Reaffirmed September 18, 2021). The AAN Summary of evidence-based guideline on Complementary and Alternative medicine in Multiple Sclerosis does not address testing for Vitamin D (Yadav, et al., 2014; Reaffirmed January 11, 2020).

The Consensus-based Care Recommendations for Adults with Myotonic Dystrophy Type 2 (Schoser, et al., 2019) lists Vitamin D under \'Severe Symptoms, Endocrine and Metabolic\', under \'Recommendations to test for\'.

The Consensus-based Care Recommendations for Children with Myotonic Dystrophy Type 1 (Johnson, et al., 2019) does not address testing for Vitamin D.

American Academy of Pediatrics (AAP)

The AAP Committee on Nutrition (Golden, et al., 2014) states that evidence is insufficient to recommend universal screening for Vitamin D deficiency. The AAP report advises screening for Vitamin D deficiency \

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The AACE, American College of Endocrinology, Obesity Society, American Society for Metabolic & Bariatric Surgery (ASMBS), Obesity Medicine Association, and American Society of Anesthesiologists Clinical Practice Guidelines for the Perioperative nutrition, metabolic, and nonsurgical support of patients undergoing Bariatric procedures recommends:

• Baseline and annual postoperative evaluation for vitamin D deficiency is recommended after Roux-en-Y gastric bypass, sleeve gastrectomy, or laparoscopic biliopancreatic diversion without or with duodenal switch (Recommendation 53) (Grade B [strong]; BEL 2 [best evidence level 1= highest, 4 = lowest]) (Mechanick, et al., 2020).

The AACE/ACE Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity does not address testing for Vitamin D (Garvey, 2016).

American Association of Endocrine Surgeons (AAES)

The AAES Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults states ‘Check vitamin D 25-OH level and if low, replete preoperatively’ (Patel, et al., 2020). The AAES Guideline for Definitive Management of Primary Hyperparathyroidism (Wilhelm, et al., 2016) includes the following recommendation:

1. The biochemical evaluation of suspected primary hyperparathyroidism should include serum total calcium, PTH, creatinine, and 25-hydroxyvitamin D levels (strong recommendation; moderate quality evidence).

American College of Cardiology (ACC)/American Heart Association (AHA)

The 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease does not address Vitamin D testing (Arnett, et al., 2019). The 2013 ACC/AHA Guideline for the Management of Overweight and Obesity in Adults does not address testing for Vitamin D (Jensen, 2013).

American College of Gastroenterology (ACG)

The ACG Guidelines Update: Diagnosis and Management of Celiac Disease (CD) notes that Vitamin D testing may be included in the diagnosis of CD. Additionally, the ACG states Blood tests at follow-up should be individualized to verify correction of laboratory tests that were abnormal at baseline (Rubio-Tapia, et al., 2023). The ACG Clinical Guideline: Chronic Pancreatitis (Gardner, et al., 2020) states that ‘patients with chronic pancreatitis should have periodic evaluation for malnutrition, including tests for osteoporosis and fat-soluble vitamin deficiency’. The ACG Clinical Guideline Management of Crohn's Disease recommendations include “Routine laboratory investigation: Initial laboratory investigation should include evaluation for inflammation, anemia, dehydration, and malnutrition” (Lichtenstein, et al., 2018). The ACG Clinical Guideline on Primary Sclerosing Cholangitis (Lindor, et al., 2015) provides this recommendation: Patients with advanced liver disease should be screened and monitored for fat- soluble vitamin deficiencies. Fat-soluble vitamin deficiencies can occur in late stages of primary sclerosing cholangitis when patient becomes jaundiced. Levels of Vitamins A, E, and D should be assessed in patients with advanced disease (Conditional recommendation, moderate quality of evidence).

The following ACG guidelines do not address testing for Vitamin D:

• Diagnosis and Management of Gastrointestinal Subepithelial Lesions (Jacobson, et al., 2023)

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• Gastroparesis (Camilleri, et al., 2022)
• Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections (Kelly, et al., 2021)
• Upper Gastrointestinal and Ulcer Bleeding (Laine, et al., 2021)
• Management of Irritable Bowel Syndrome (Lacy, et al., 2021)

American College of Obstetricians and Gynecologists (ACOG)

The ACOG Clinical Practice Guideline on Management of Postmenopausal Osteoporosis (2022), under Initial Evaluation for Secondary Osteoporosis (Box 2), lists '25-hydroxyvitamin D'. The ACOG Committee Opinion on Vitamin D screening and supplementation during pregnancy (2011, reaffirmed 2021) states that there is insufficient evidence to support a recommendation for screening all pregnant women for Vitamin D deficiency. For pregnant women thought to be at increased risk of Vitamin D deficiency, maternal serum 25-hydroxyvitamin D levels can be considered and should be interpreted in the context of the individual clinical circumstance.

The ACOG Clinical Practice Guidelines on Osteoporosis Prevention, Screening, and Diagnosis (2021) cites the Endocrines Society and USPSTF, noting that they state there is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults.

American College of Physicians

The American College of Physicians Clinical Practice Guideline Update on Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women (Qaseem, et al., 2017) does not address testing for Vitamin D.

American College of Rheumatology (ACR)

The ACR Guideline Summary for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis (Updated November 9, 2022) does not address testing for Vitamin D. The ACR Guideline for the Treatment of Rheumatoid Arthritis (Fraenkel, et al., 2021) does not address testing for Vitamin D.

American Gastroenterological Association (AGA)

The AGA Clinical Practice Update on Management of Refractory Celiac Disease: Expert Review states that Celiac disease may be associated with both micronutrient and macronutrient deficiencies, recommending micronutrient status should also be evaluated objectively by testing for deficiency of fat-soluble vitamins (D) (Green, et al., 2022).

The following AGA guidelines do not address testing for Vitamin D:

• AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review (Sept 2022)
• AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease (Feuerstein, et al., 2021).
• AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis (Feuerstein, et al., 2020)
• AGA Institute Guideline on Initial Management of Acute Pancreatitis (Crockett, et. al., 2017)
• AGA Institute Guideline on the Management of Crohn’s Disease After Surgical Resection (Nguyen, et al., 2016/2017)

Bone Health & Osteoporosis FOUNDATION™

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The Bone Health & Osteoporosis FOUNDATION™ (previously known as the National Osteoporosis Foundation [NOF]) Clinician’s Guide to Prevention and Treatment of Osteoporosis (LeBoff, et al., 2022) notes the following specific to Vitamin D testing:

Synopsis of major recommendations to the clinician:

Note: These recommendations apply to postmenopausal women and men aged 50 years and older.

• Universal recommendations
• Monitor serum 25-hydroxyvitamin D levels.

Diagnostic studies for exclusion of secondary causes of osteoporosis (Table 3)

• 25(OH) vitamin D

The American Board of Internal Medicine’s (ABIM) Foundation Choosing Wisely® Initiative

• American Academy of Pediatrics – Section on Endocrinology: Avoid ordering Vitamin D concentrations routinely in otherwise healthy children, including children who are overweight or obese (October 2017).
• Endocrine Society: Don’t routinely measure 1,25-dihydroxyvitamin D unless the patient has hypercalcemia or decreased kidney function (October 2013)
• American Society for Clinical Pathology: Don’t perform population based screening for 25- OH-Vitamin D deficiency (February 21, 2013).