Causes of vitamin D deficiency and resistance
- Zalman S Agus, MD
Zalman S Agus, MD
- Emeritus Professor of Medicine and Physiology; Associate Dean, CME
- Perelman School of Medicine at the University of Pennsylvania
- Marc K Drezner, MD
Marc K Drezner, MD
- Section Editor — Bone Disease
- Professor of Medicine
- University of Wisconsin Medical School
Vitamin D has a variety of actions on calcium, phosphate, and bone metabolism. Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium and phosphorus, thereby promoting bone mineralization. At high vitamin D concentrations, under conditions of calcium and phosphate deficiency, it also stimulates bone resorption, thereby helping to maintain the supply of these ions to other tissues (figure 1). (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Calcitriol'.)
Vitamin D deficiency or resistance interferes with these processes, sometimes causing hypocalcemia and hypophosphatemia. Since hypocalcemia stimulates the release of parathyroid hormone (PTH), however, the development of hypocalcemia is often masked. The secondary hyperparathyroidism, via its actions on bone and the kidney, partially corrects the hypocalcemia but enhances urinary phosphate excretion, thereby contributing to the development of hypophosphatemia and osteomalacia. (See "Epidemiology and etiology of osteomalacia" and "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Laboratory findings'.)
This topic will review the major causes of vitamin D deficiency and resistance. Optimal serum vitamin D concentrations, the treatment of vitamin D deficiency, and the role of vitamin D therapy for osteoporosis are discussed in detail separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D supplementation in osteoporosis".) The major causes of hypophosphatemia and hypocalcemia are also reviewed elsewhere. (See "Causes of hypophosphatemia" and "Etiology of hypocalcemia in adults".)
The optimal serum 25-hydroxyvitamin D (25[OH]D) concentration for skeletal health and extraskeletal health is controversial, and it has not been rigorously established for the population in general or for specific ethnic groups. Clinicians variably consider the optimal serum 25(OH)D concentration to range between 20 and 40 ng/mL (50 to 100 nmol/L) or between 30 and 50 ng/mL (75 to 125 nmol/L). The range of common agreement is 30 to 40 ng/mL (75 to 100 nmol/L). This topic is reviewed in detail elsewhere. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D sufficiency'.)
VITAMIN D METABOLISM
Vitamin D (cholecalciferol) is normally synthesized in the skin under the influence of sunlight in a nonenzymatic manner. In addition, vitamin D (ergocalciferol) may be ingested from fish or plant sources. Vitamin D is then hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol, 25[OH]D), which is the major circulating form of vitamin D and the best index of vitamin D sufficiency. Calcidiol is hydroxylated primarily in the kidney to 1,25-dihydroxyvitamin D (calcitriol), which is the most active form (figure 1). 1,25-dihydroxyvitamin D is also formed in some other tissues but is used only within the tissues and not circulated. (See "Overview of vitamin D", section on 'Metabolism'.)
- Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 2007; 92:2130.
- Lamberg-Allardt CJ, Outila TA, Kärkkainen MU, et al. Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe? J Bone Miner Res 2001; 16:2066.
- Tsai KS, Wahner HW, Offord KP, et al. Effect of aging on vitamin D stores and bone density in women. Calcif Tissue Int 1987; 40:241.
- Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988; 67:373.
- MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985; 76:1536.
- Czernichow S, Fan T, Nocea G, Sen SS. Calcium and vitamin D intake by postmenopausal women with osteoporosis in France. Curr Med Res Opin 2010; 26:1667.
- Harris SS, Soteriades E, Coolidge JA, et al. Vitamin D insufficiency and hyperparathyroidism in a low income, multiracial, elderly population. J Clin Endocrinol Metab 2000; 85:4125.
- Passeri G, Pini G, Troiano L, et al. Low vitamin D status, high bone turnover, and bone fractures in centenarians. J Clin Endocrinol Metab 2003; 88:5109.
- Krall EA, Sahyoun N, Tannenbaum S, et al. Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women. N Engl J Med 1989; 321:1777.
- Gloth FM 3rd, Gundberg CM, Hollis BW, et al. Vitamin D deficiency in homebound elderly persons. JAMA 1995; 274:1683.
- Holick MF, Siris ES, Binkley N, et al. Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005; 90:3215.
- Callaghan AL, Moy RJ, Booth IW, et al. Incidence of symptomatic vitamin D deficiency. Arch Dis Child 2006; 91:606.
- Lawson M, Thomas M. Vitamin D concentrations in Asian children aged 2 years living in England: population survey. BMJ 1999; 318:28.
- Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002; 112:659.
- Sham L, Yeh EA, Magalhaes S, et al. Evaluation of fall Sun Exposure Score in predicting vitamin D status in young Canadian adults, and the influence of ancestry. J Photochem Photobiol B 2015; 145:25.
- Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338:777.
- Perin A, Zanatta E, Pigatto E, et al. Hypovitaminosis D in an hospitalized old population of Western Friuli. Reumatismo 2012; 64:166.
- Ramel A, Jonsson PV, Bjornsson S, Thorsdottir I. Vitamin D deficiency and nutritional status in elderly hospitalized subjects in Iceland. Public Health Nutr 2009; 12:1001.
- Guardia G, Parikh N, Eskridge T, et al. Prevalence of vitamin D depletion among subjects seeking advice on osteoporosis: a five-year cross-sectional study with public health implications. Osteoporos Int 2008; 19:13.
- Nitta K, Nagano N, Tsuchiya K. Fibroblast growth factor 23/klotho axis in chronic kidney disease. Nephron Clin Pract 2014; 128:1.
- LaClair RE, Hellman RN, Karp SL, et al. Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States. Am J Kidney Dis 2005; 45:1026.
- Taskapan H, Ersoy FF, Passadakis PS, et al. Severe vitamin D deficiency in chronic renal failure patients on peritoneal dialysis. Clin Nephrol 2006; 66:247.
- Elder GJ, Mackun K. 25-Hydroxyvitamin D deficiency and diabetes predict reduced BMD in patients with chronic kidney disease. J Bone Miner Res 2006; 21:1778.
- Compston JE. Hepatic osteodystrophy: vitamin D metabolism in patients with liver disease. Gut 1986; 27:1073.
- Dibble JB, Sheridan P, Losowsky MS. A survey of vitamin D deficiency in gastrointestinal and liver disorders. Q J Med 1984; 53:119.
- Kumar R. Hepatic and intestinal osteodystrophy and the hepatobiliary metabolism of vitamin D. Ann Intern Med 1983; 98:662.
- Shaker JL, Brickner RC, Findling JW, et al. Hypocalcemia and skeletal disease as presenting features of celiac disease. Arch Intern Med 1997; 157:1013.
- Peterson LA, Zeng X, Caufield-Noll CP, et al. Vitamin D status and supplementation before and after bariatric surgery: a comprehensive literature review. Surg Obes Relat Dis 2016.
- Awumey EM, Mitra DA, Hollis BW, et al. Vitamin D metabolism is altered in Asian Indians in the southern United States: a clinical research center study. J Clin Endocrinol Metab 1998; 83:169.
- Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003; 78:1463.
- Donovan DS Jr, Papadopoulos A, Staron RB, et al. Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 1998; 157:1892.
- Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in skin after burns. Lancet 2004; 363:291.
- Hahn TJ. Drug-induced disorders of vitamin D and mineral metabolism. Clin Endocrinol Metab 1980; 9:107.
- Sotaniemi EA, Hakkarainen HK, Puranen JA, Lahti RO. Radiologic bone changes and hypocalcemia with anticonvulsant therapy in epilepsy. Ann Intern Med 1972; 77:389.
- Välimäki MJ, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994; 9:631.
- Kovacs CS, Jones G, Yendt ER. Primary hyperparathyroidism masked by antituberculous therapy-induced vitamin D deficiency. Clin Endocrinol (Oxf) 1994; 41:831.
- Fortenbery EJ, McDermott MT, Duncan WE. Effect of theophylline on calcium metabolism and circulating vitamin D metabolites. J Bone Miner Res 1990; 5:321.
- Meier C, Kraenzlin ME. Antiepileptics and bone health. Ther Adv Musculoskelet Dis 2011; 3:235.
- Collins N, Maher J, Cole M, et al. A prospective study to evaluate the dose of vitamin D required to correct low 25-hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic drug-induced osteomalacia. Q J Med 1991; 78:113.
- Aggarwal A, Yadav AK, Ramachandran R, et al. Bioavailable vitamin D levels are reduced and correlate with bone mineral density and markers of mineral metabolism in adults with nephrotic syndrome. Nephrology (Carlton) 2015.
- Selewski DT, Chen A, Shatat IF, et al. Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study. Pediatr Nephrol 2016; 31:465.
- Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. N Engl J Med 1989; 320:980.
- Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin North Am 2010; 39:333.
- Wang X, Zhang MY, Miller WL, Portale AA. Novel gene mutations in patients with 1alpha-hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 2002; 87:2424.
- Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular basis of vitamin D-dependent rickets type I. Endocr J 2001; 48:427.
- Kato S. Genetic mutation in the human 25-hydroxyvitamin D3 1alpha-hydroxylase gene causes vitamin D-dependent rickets type I. Mol Cell Endocrinol 1999; 156:7.
- Li YC, Pirro AE, Amling M, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A 1997; 94:9831.
- Whitfield GK, Selznick SH, Haussler CA, et al. Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D3: point mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner. Mol Endocrinol 1996; 10:1617.
- Brooks MH, Bell NH, Love L, et al. Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D. N Engl J Med 1978; 298:996.
- Yagi H, Ozono K, Miyake H, et al. A new point mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Clin Endocrinol Metab 1993; 76:509.
- Malloy PJ, Weisman Y, Feldman D. Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets resulting from a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain. J Clin Endocrinol Metab 1994; 78:313.
- Rut AR, Hewison M, Kristjansson K, et al. Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA-binding domain crystal structures. Clin Endocrinol (Oxf) 1994; 41:581.
- Malloy PJ, Eccleshall TR, Gross C, et al. Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J Clin Invest 1997; 99:297.
- Sakai Y, Kishimoto J, Demay MB. Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice. J Clin Invest 2001; 107:961.
- Chen CH, Sakai Y, Demay MB. Targeting expression of the human vitamin D receptor to the keratinocytes of vitamin D receptor null mice prevents alopecia. Endocrinology 2001; 142:5386.
- Malloy PJ, Wang J, Srivastava T, Feldman D. Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor. Mol Genet Metab 2010; 99:72.
- Forghani N, Lum C, Krishnan S, et al. Two new unrelated cases of hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D receptor gene. J Pediatr Endocrinol Metab 2010; 23:843.
- Hewison M, Rut AR, Kristjansson K, et al. Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene. Clin Endocrinol (Oxf) 1993; 39:663.
- VITAMIN D METABOLISM
- NUTRITIONAL DEFICIENCY AND REDUCED CUTANEOUS SYNTHESIS
- Older adults
- Healthy adults in the winter
- Hospitalized patients
- Women treated for osteoporosis
- Chronic renal disease
- Gastrointestinal disease
- Gastric bypass
- Immigrants to cold climates from warm climates
- Patients who have musculoskeletal pain
- Cystic fibrosis
- Extensive burns
- DEFICIENCY RELATED TO ABNORMAL SYNTHESIS AND CATABOLISM
- Calcidiol (25-hydroxyvitamin D)
- - Decreased synthesis
- - Drugs
- - Renal loss
- Calcitriol (1,25-dihydroxyvitamin D)
- - Renal failure
- - Vitamin D dependent rickets type I
- VITAMIN D RESISTANCE
- INFORMATION FOR PATIENTS