VITAMIN D TESTING CLINICAL GUIDELINES. Policy Number: PDS Effective Date: January 1, Table of Contents

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1 CLINICAL GUIDELINES VITAMIN D TESTING Policy Number: PDS Effective Date: January 1, 2013 Table of Contents Page Guidelines 1 BACKGROUND 3 CLINICAL EVIDENCE 5 U.S. FOOD AND DRUG ADMINISTRATION (FDA) 9 CENTERS FOR MEDICARE AND MEDICAID SERVICES 9 APPLICABLE CODING 9 REFERENCES 10 POLICY HISTORY/REVISION INFORMATION 12 INSTRUCTIONS FOR USE Physician Decision Support (PDS) is a lab ordering tool operated by BeaconLBS. This Clinical Guideline supports the Questions and Answers that appear in PDS for tests referenced in this document. UnitedHealthcare reserves the right, in its sole discretion, to modify its Clinical Guidelines as necessary. This Clinical Guideline is provided for informational purposes. It does not constitute a Medical Policy or medical advice. Guidelines Vitamin D 25-hydroxy [25(OH)D] is recommended as the appropriate test for diagnosing vitamin D deficiency. Testing and screening for vitamin D deficiency with 1,25 dihydroxyvitamin D [1,25(OH) 2 D] serum testing is not recommended. 25(OH)D testing is not recommended for routine or initial screening in the absence of clinical documentation of an underlying disease or condition specifically associated with vitamin D deficiency. Vitamin D testing is recommended for patients with a clinically documented underlying disease/condition or belonging to the following populations which are specifically associated with vitamin D deficiency or decreased bone density/osteoporosis including: Rickets Osteomalacia Osteoporosis or at risk for osteoporosis Hepatic disease or failure Malabsorption syndromes (including: Cystic fibrosis, inflammatory bowel disease, Crohn s disease, bariatric surgery, radiation enteritis, short bowel syndrome, pancreatitis, amyloidosis, celiac sprue) 1

2 Hyperparathyroidism Medications (including: anti-seizure, glucocorticoids, AIDS medications, anti-fungals, 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/m 2 ) Granuloma-forming disorders (i.e., sarcoidosis, tuberculosis, histoplasmosis, coccidiomycosis, berylliosis) Lymphomas 1,25(OH) 2 D is recommended for evaluation of patients with a clinically documented underlying disease or condition associated with increased or decreased 1,25(OH) 2 D, including: Hypercalcemia with a low parathyroid hormone Acquired and/or inherited disorders in the metabolism of 25(OH)D and phophate Tumor induced osteomalacia (oncogenic osteomalacia) Hereditary phosphate-losing disorders Vitamin D-dependent rickets type 1 (also known as pseudo-vitamin D deficient rickets) Vitamin D-resistant rickets Chronic granuloma-forming disorders (i.e., sarcoidosis and some lymphomas) These recommendations are based on current guidelines/recommendations from the Endocrine Society and the Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. BACKGROUND Vitamin D has a key role in calcium homeostasis and the development and maintenance of bone structure. 1 Vitamin D is responsible for increasing calcium and phosphorus absorption from the intestine, promotion of bone osteoid mineralization, stimulation of proximal tubular phosphate reabsorption and maintenance of calcium reabsorption by the kidneys and decreasing parathyroid hormone synthesis and secretion. 2,3 Vitamin D also has non-calciotropic autocrine and paracrine functions, for example, in regulation of cell differentiation and proliferation. Vitamin D receptors have been discovered in multiple tissues, including cells of pancreas, immune system, macrophages, vascular endothelium, stomach, epidermis, colon, and placenta. Therefore, in recent years, there is an emerging interest in possible non-skeletal functions of vitamin D. 2,3 The term "vitamin D" refers to several different forms of this vitamin and the most important in humans are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Sunlight and nutrition are the two sources of vitamin D. When skin is exposed to ultraviolet light, vitamin D3 is synthesized. Nutritional sources of vitamin D3 include fatty fish such as salmon, mackerel, and herring, fish liver oils and egg yolks. Vitamin D2 is present in yeast and plants. Both forms of vitamin D are converted to 25-hydroxy vitamin D [25(OH)D] in the liver and later hydroxylated in the kidney and other tissues to 1,25-dihydroxyvitamin D [1,25(OH) 2 D(calcitrol)]. The synthesis of 2

3 1,25(OH) 2 D is tightly regulated and stimulated primarily by serum parathyroid hormone, as well as low serum calcium or phosphorus levels, and inhibited by circulating fibroblast growth factors produced by osteocytes. With a half-life of 2-3 weeks, 25(OH)D is the main circulating form of vitamin D. Serum quantities are measured in ng/ml. In contrast, 1,25(OH) 2 D, the most active metabolite of vitamin D, has a half-life of about 4 hours and serum concentrations are measured in pg/ml, which is a thousand times less than 25(OH)D. Categorizing vitamin D status The serum level of 25(OH)D is measured to determine the adequacy of vitamin D status. 2,3 Although a number of publications have debated the actual cutoff values for diagnosing vitamin D deficiency, data supports levels of 25(OH)D less than 20 ng/ml to be considered a deficiency, between ng/ml vitamin D insufficiency, and levels greater than 30 ng/ml vitamin D sufficiency. 4,5 Sometimes the deficiency category is subdivided by into severe (reported range <5 <10 ng/ml) and mild deficiency (reported range 10 and 20 ng/ml). 6,7 Serum concentrations of greater than 150 ng/ml is indicative of vitamin D intoxication, although >80 ng/ml has also been described as possibly toxic. 7,8 Vitamin D toxicity is rare and generally found in individuals consuming more than 10,000 IU per day of exogenous vitamin D. Vitamin D deficiency Vitamin D deficiency results in abnormalities in calcium, phosphorus, and bone metabolism and is associated with osteopenia, osteoporosis, bone pain, as well as muscle weakness and aches, and increased risk of falls. Classic vitamin D deficiency diseases include rickets in children and osteomalacia in adults. Rickets can often result in skeletal deformities and osteomalacia can lead to muscular weakness in addition to weak bones. As the major source of vitamin D for children and adults is exposure to natural sunlight, vitamin D deficiency can be found in individuals who use sunscreen, hats and long sleeve shirts and people who are housebound. Hispanic and African Americans are also at higher risk than Caucasians, because of the affect of skin pigmentation from melanin. 5 As, 25(OH)D is usually measured to assess nutritional adequacy, it may be decreased in dietary vitamin D deficiency and liver disease. Other causes for vitamin D deficiency include, patients with gastrointestinal problems, malabsorption syndromes, and bariatric patients, as these patients are unable to absorb the fatsoluble vitamin D. 5 There is an inverse association of serum 25(OH)D and body mass index (BMI) greater than 30 kg/m 2, and thus, obesity is associated also with vitamin D deficiency. 5 Patients with nephrotic syndrome and severe renal disease lose 25(OH)D bound to the vitamin D-binding protein in the urine. 5 Patients on a wide variety of medications, including anticonvulsants and medications to treat AIDS/HIV, are at risk because these drugs can enhance the catabolism of 25(OH)D and 1,25(OH) 2 D. 5 Patients with chronic granuloma-forming disorders, some lymphomas, and primary hyperparathyroidism who have increased metabolism of 25(OH)D to 1,25(OH) 2 D are also at high risk for vitamin D deficiency. 5 Vitamin D 1,25(OH) 2 As serum concentrations of 1,25(OH) 2 D are often normal or elevated in the presence of vitamin D deficiency. 1,25(OH) 2 D should not be used to assess vitamin D levels and the only appropriate marker to assess 3

4 vitamin D status is 25(OH)D. 9 Serum 1,25(OH) 2 D is frequently either normal or even elevated in those with vitamin D deficiency, due to secondary hyperparathyroidism. Thus, 1,25(OH) 2 D measurement does not accurately reflect vitamin D status. The measurement of serum 1,25(OH) 2 D may however be useful for certain conditions including acquired and inherited disorders in the metabolism of 25(OH)D and phosphate, chronic kidney disease, hereditary phosphatelosing disorders, oncogenic osteomalacia, pseudovitamin D-deficiency rickets, vitamin D-resistant rickets, as well as chronic granuloma-forming disorders such as sarcoidosis and some lymphomas. 5 Low levels of 1,25(OH) 2 D may be seen in severe vitamin D deficiency, renal osteodystrophy, or renal failure. However, 25(OH)D remains the appropriate test and will detect the deficiency. Low 1,25(OH) 2 D levels may also be seen in the setting of pseudohyperparathyroidism and hyperparathyroidism, where measurement of parathyroid hormone along with serum calcium is a better testing scheme. High levels of 1,25(OH) 2 D are found with 1,25(OH) 2 D intoxication and hyperparathyroidism. There are very few indications for measurements of 1,25(OH) 2 D levels. 5,9 These include: Hypercalcemia with a low parathyroid hormone Tumor induced osteomalacia (oncogenic osteomalacia) Hereditary phosphate-losing disorders Vitamin D-dependent rickets type 1 (also known as pseudo-vitamin D deficient rickets) Vitamin D-resistant rickets Acquired and/or inherited disorders in the metabolism of 25(OH)D and phophate Chronic granuloma-forming disorders (i.e., sarcoidosis and some lymphomas) CLINICAL EVIDENCE The role of vitamin D has recently received considerable media attention for a number of indications other than bone health, including cardiovascular disease and hypertension, diabetes and metabolic syndrome, colon, prostate, and breast cancer, reproductive health, immune function, and neuropsychological function. 1 However, whether low 25(OH)D is the cause or result of ill health has not been elucidated. It is not known how or why vitamin D impacts the risk of developing any of these conditions, or whether altering exposure to vitamin D provides a protective effect. 1 Large, randomized, controlled trials will be required to identify the role of vitamin D in these and other conditions to determine if low vitamin D levels are part of pathogenesis or just a marker for a corresponding non-skeletal condition. Epidemiology Multiple epidemiological studies have reported on vitamin D deficiency. Using the NHANES data sources, the prevalence of 25(OH)D levels less than 10 ng/ml increased from 2% in the NHANES III population ( ) to 6% in the NHANES population with the highest increase observed in the non-hispanic blacks (from 9% to 29% respectively). 10 4

5 Following the definitions by the IOM and Endocrine Society for Vitamin D deficiency and insufficiency, it has been estimated that a high percentage of elderly men and women still living in the community are vitamin D deficient. 5 Similarly, one study reported the prevalence of vitamin D deficiency in the routine patient populations is as high as 25 50% among nursing home or housebound residents; 44% among elderly ambulatory women, aged >80; 30% among women with osteoporosis, aged 70 79; 23% among patients with hip fractures, mean age 77; 42% among African American women, aged 15 49; 57% among adult hospitalized patients, mean age Children and young and middle-aged adults are at equally high risk vitamin D deficiency and insufficiency worldwide Pregnant and lactating women who take a prenatal vitamin and a calcium supplement with vitamin D remain at high risk for vitamin D deficiency. 5 Vitamin D and Bone Health Several studies correlate vitamin D levels and bone health. In one meta-analysis of vitamin D supplementation and fall prevention, high dose supplemental vitamin D reduced fall risk by 19%, whereas serum 25(OH)D concentrations of > 26 ng/dl resulted in a 23% fall reduction. 13 Falls were not notably reduced by low dose supplemental vitamin D or by lower achieved serum 25(OH) D concentrations. Likewise, an observational study of participants in NHANES III (ages 65 years and older) found that 25(OH)D levels of greater than 24 ng/ml are significantly associated with lower hip fracture risk. 14 Another meta-analysis on the anti-fracture efficacy of supplemental vitamin D, the authors concluded that non-vertebral fracture prevention with vitamin D is dose dependent, and a higher dose (greater than 400 IU/day) should reduce fractures by at least 20% for individuals aged 65 years or older. 15 Vitamin D and other adverse health outcomes Throughout the past decade, there have been numerous publications on vitamin D levels and/or supplementation and health outcomes. Cancer has been studied by several researchers to determine any associations with levels of vitamin D and cancer risk Similarly, the role of cardiovascular disease and vitamin D levels has also been studied Other studies have surveyed vitamin D levels and musculoskeletal function, neuropathic pain, and even respiratory tract infection However, a recent systemic review was compiled of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes. 1 The investigators found that most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. 1 However, results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence. The authors conclude that the discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. They hypothesize that inflammatory processes involved in disease occurrence and clinical course reduce 25(OH)D, which explains why low vitamin D status is reported in a wide range of disorders. A Summary of Existing Guidelines and Recommendations Endocrine Society 5 5

6 In 2011, the Endocrine Society published Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. 5 A summary of the recommendations states that 5 : We recommend screening for vitamin D deficiency in individuals at risk for deficiency. We do not recommend population screening for vitamin D deficiency in individuals who are not at risk. We 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, and vitamin D insufficiency as a 25(OH)D of ng/ml. We recommend against using the serum 1,25-dihydroxyvitamin D [1,25(OH) 2 D] assay for this purpose and are in favor of using it only in monitoring certain conditions, such as acquired and inherited disorders of vitamin D and phosphate metabolism. 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. 5 Candidates for screening include persons with the following conditions or belonging to the following populations: Rickets Osteomalacia Osteoporosis Chronic kidney disease Hepatic failure Malabsorption syndromes (i.e, Cystic fibrosis, inflammatory bowel disease, Crohn s disease, bariatric surgery, radiation enteritis) Hyperparathyroidism Medications (including: anti-seizure, glucocorticoids, AIDS medications, anti-fungals, 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/m 2 ) Granuloma-forming disorders (i.e., sarcoidosis, tuberculosis, histoplasmosis, coccidiomycosis, berylliosis) Some lymphomas Institute of Medicine 4 In 2010, the Institute of Medicine (IOM) tasked a committee of experts with reviewing the evidence regarding the health outcomes associated with vitamin D. 4 The IOM report stressed that its recommendations for vitamin D were based primarily on the intake [and serum 25(OH)D concentration] needed to ensure skeletal health and that, in the panel s judgment, there was insufficient evidence to make any recommendations with respect to non-skeletal benefits. The IOM also identified specific subgroups (older, institutionalized people, and dark skinned people) who are at increased risk of getting too little vitamin D. 6

7 American Academy of Pediatrics 30 In 2008, the American Academy of Pediatrics (AAP) issued guidelines Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents that defined vitamin D deficiency in adults as 25(OH)D concentration of <20 ng/ml and insufficiency as concentration of ng/ml. 30 The guideline recommended that 25(OH)D serum concentration in infants and children should be greater or even 20 ng/ml. It also stated that a mother should be supplemented with adequate amounts of vitamin D 3 to ensure that her 25(OH)D levels are in a sufficient range (>32 ng/ml). 30 Vitamin D International Summit 8 In 2009, a Vitamin D International Summit Meeting issued clinical practice recommendations Vitamin D and Musculoskeletal Health, Cardiovascular disease, Autoimmunity and Cancer: Recommendations for Clinical Practice. The expert panel clearly outlined recommendations as listed below 8 : Individuals with or at risk for musculoskeletal health problems, cardiovascular disease, autoimmune disease, and cancer in whom it is recommended to measure serum 25(OH)D level in clinical practice include: Individuals with or at risk for osteoporosis Elderly subjects with a recent fall accident Pregnant women Patients with chronic kidney disease stage 4 5D Transplant patients Patients with conditions or treatments that can lead to bone loss Obese individuals Patients with diabetes Hospitalized patients Patients with bone/muscle pain or aches All individuals with hypertension Patients with autoimmune disease Subjects at high risk for autoimmune disease Patients starting or already on corticosteroids All cancer patients undergoing treatment Mayo Foundation 7 In 2010, the Mayo Foundation published a review for clinicians Vitamin D Deficiency in Adults: When to Test and How to Treat. The review pointed out the clinical risk factors for vitamin D severe deficiency that included 7 : Inadequate oral intake of vitamin D Malnutrition Limited sun exposure Malabsorption including Short bowel syndrome 7

8 Pancreatitis Inflammatory Bowel Disease Amyloidosis Celiac Sprue Malabsorptive bariatric surgery procedures Some antiepileptic medications Severe liver disease or failure Aging Renal insufficiency, glomerular filtration rate <60 ml/min Nephrotic syndrome US FOOD AND DRUG ADMINISTRATION (US FDA) There are multiple Vitamin D assays that are FDA approved. Additionally, the FDA has created recommendations regarding supplementation and appropriate levels. CENTERS FOR MEDICARE AND MEDICAID (CMS) For Medicare beneficiaries, screening tests are governed by statute. Vitamin D testing may not be used for routine screening. Once a beneficiary has been shown to be vitamin D deficient, further testing is medically necessary only to ensure adequate replacement has been accomplished. Thereafter, annual testing may be appropriate depending upon the indication and other mitigating factors. APPLICABLE CODING CPT Code Description Vitamin D; 25 hydroxy [25(OH)D], includes fraction(s), if performed Dihydroxyvitamin D, 1, 25 dihydroxy [1,25(OH) 2 D], includes fraction(s), if performed 8

9 REFERENCES 1. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014; 2: Thacher TD, Clarke BL. Vitamin D Insufficiency. Mayo Clin Proc. 2011;86(1): Cranney A, et al. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No.158. AHRO Publication No. 07-E013. August Institute of Medicine of the National Academies. Dietary Reference Intakes for Calcium and Vitamin D. Report Brief. November 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;96(7): National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis. 2003;42:S1-S202 (suppl 3). 7. Kennel KA, Drake MT, Hurley DL. Vitamin D Deficiency in Adults: Who to Test and How to Test. Mayo Clin Proc. 2010;85(8): Souberbielle J-C, Body JJ, Lappe JM, et al. Vitamin D and Musculoskeletal Health, Cardiovascular Disease, Autoimmunity, and Cancer: Recommendations for Clinical Practice. Autoimmun Rev. 2010;9: Kleerekoper M, Schleicher RL, Eisman J, et al. Clinical applications for vitamin d assays: what is known and what is wished for. Clin Chem Sep;57(9): Ginde AA, Liu MC, Camargo CA Jr. Demographic Differences and Trends of Vitamin D Insufficiency in the US Population. Arch Intern Med. 2009;169(6): Kumar J, Muntner P, Kaskel FJ, et al. Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES Pediatrics. 2009;124(3):e1-e Cole CR, Grant FK, Tangpricha V, et al. 25-Hydroxyvitamin D Status of Healthy, Low-Income, Minority Children in Atlanta, Georgia. Pediatrics. 2010;125(4): Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692. doi: /bmj.b Looker AC, Mussolino ME. Serum 25-Hydroxyvitamin D and Hip Fracture Risk in Older U.S. White Adults. J Bone Miner Res. 2008;23: Bischoff-Ferrari HA, Willett WC, Wong JB, et al Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(6):

10 16. Wu K, Feskanich D, Fuchs CS, et al. A Nested Case-Control Study of Plasma 25-Hydroxyvitamin D Concentrations and Risk of Colorectal Cancer. J Natl Cancer Inst. 2007;99(14): Giovannucci E, Liu Y, Rimm EB, et al. Prospective Study of Predictors of Vitamin D Status and Cancer Incidence and Mortality in Men. J Natl Cancer Inst. 2006;98(7): Ng K, Meyerhardt JA, Wu K, et al. Circulating 25-Hydroxyvitamin D Levels and Survival in Patients With Colorectal Cancer. J Clin Oncol. 2008;26: IARC. Vitamin D and Cancer. IARC Working Group Reports Vol.5, International Agency for research on Cancer, Lyon, 25 November Chen P, Hu P, Xie D, et al. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat Jun;121(2): Lee JE, Li H, Chan AT, et al. Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies. Cancer Prev Res May;4(5): Martins D, Wolf M, Pan D, et al. Prevalence of Cardiovascular Risk Factors and the Serum Levels of 25- Hydroxyvitamin D in the United States. Arch Intern Med. 2007;167: Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and Risk of Myocardial Infarction in Men. Arch Intern Med. 2008;168(11): Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D Deficiency and Risk of Cardiovascular Disease. Circulation. 2008;117: Wolf M, Shah A, Gutierrez O, et al. Vitamin D Levels and Early Mortality Among Incident Hemodialysis Patients. Kidney Intl. 2007;72: Dobnig H, Pilz S, Scharnagl H, et al. Independent Association of Low Serum 25-Hydroxyvitamin D and 1,25- Dihydroxyvitamin D Levels With All-Cause and Cardiovascular Mortality. Arch Intern Med. 2008;168(12): Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher 25-Hydroxyvitamin D Concentrations are Associated With Better Lower-Extremity Function in Both Active and Inactive Persons Aged >60y. Am J Clin Nutr. 2004;80: Lee P, Chen R. Vitamin D as an Analgesic for Patients With Type 2 Diabetes and Neuropathic Pain. Arch Intern Med. 2008;168(7): Ginde AA, Mansbach JM, Camargo CA Jr. Association between Serum 25-Hydroxyvitamin D Level and Upper Respiratory Tract Infection in the Third National Health and Nutrition Examination Study. Arch Intern Med. 2009;169(4): Wagner CL, Greer FR, and the Section on Breastfeeding and Committee on Nutrition. Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents. Pediatrics. 2008;122(5):

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