Usually, vitamin D toxicity results from taking excessive amounts. In vitamin D toxicity, resorption of bone and intestinal absorption of calcium is increased, resulting in hypercalcemia. Marked hypercalcemia commonly causes symptoms. Diagnosis is typically based on elevated blood levels of 25(OH)D. Treatment consists of stopping vitamin D, restricting dietary calcium, restoring intravascular volume deficits, and, if toxicity is severe, giving corticosteroids or bisphosphonates.
Because synthesis of 1,25-dihydroxyvitamin D (the most active metabolite of vitamin D) is tightly regulated, vitamin DVitamin D toxicity can occur iatrogenically when hypoparathyroidism is overtreated.
Physiology of Vitamin D Toxicity
Vitamin D has 2 main forms:
D2 (ergocalciferol)
D3 (cholecalciferol): The naturally occurring form and the form used for low-dose supplementation
Vitamin D3 is synthesized in skin by exposure to direct sunlight (ultraviolet B radiation) and is obtained in the diet chiefly in fish liver oils and salt water fish (see table Sources, Functions, and Effects of Vitamins). In some countries, milk and other foods are fortified with vitamin D. Human breast milk is low in vitamin D, containing an average of only 10% of the amount in fortified cow’s milk.
Vitamin D levels may decrease with age because skin synthesis declines. Sunscreen use and dark skin pigmentation also reduce skin synthesis of vitamin D.
Vitamin D is a prohormone with several active metabolites that act as hormones. It is metabolized by the liver to 25(OH)D (calcifediol, calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D), which is then converted by the kidneys to 1,25-dihydroxyvitamin D (1,25-dihydroxycholecalciferol, calcitriol, or active vitamin D hormone). 25(OH)D, the major circulating form, has some metabolic activity, but 1,25-dihydroxyvitamin D is the most metabolically active. The conversion to 1,25-dihydroxyvitamin D is regulated by its own concentration, parathyroid hormone (PTH), and serum concentrations of calcium and phosphate.
Vitamin D affects many organ systems (see table ), but mainly it increases calcium and phosphate absorption from the intestine and promotes normal bone formation and mineralization.
Vitamin D and related analogs may be used to treat psoriasis, hypoparathyroidism, and renal osteodystrophy. Its usefulness in reducing all-cause mortality or in preventing leukemia and breast, prostate, colon, or other cancers has not been proved, nor has its efficacy in treating various other nonskeletal disorders in adults (1–3). Vitamin D supplementation does not effectively treat or prevent depression or cardiovascular disease (4, 5) and has minimal effects on preventing acute respiratory infections (67) in patients who are vitamin D deficient, especially those who are institutionalized. However, large doses of vitamin D may increase fracture risk (8, 9). Because the causes of falls are multifactorial, other studies have not found that vitamin D supplements alone reduce falls and fractures in older adults (10, 11).
(See also Overview of Vitamins.)
Actions of Vitamin D and Its Metabolites
Organ | Actions |
|---|---|
Bone | Promotes bone formation by maintaining appropriate calcium and phosphate concentrations |
Immune system | Stimulates immunogenic and antitumor activity Decreases risk of autoimmune disorders |
Intestine | Enhances calcium and phosphate transport (absorption) |
Kidneys | Enhances calcium reabsorption by the tubules |
Parathyroid glands | Inhibits parathyroid hormone secretion |
Pancreas | Stimulates insulin production |
Physiology references
1. Autier P, Mullie P, Macacu A, et al: Effect of vitamin D supplementation on non-skeletal disorders: A systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol 5 (12):986–1004, 2017. doi: 10.1016/S2213-8587(17)30357-1
2. Manson JE, Cook NR, Lee IM, et al: Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 380(1):33-44, 2019. doi: 10.1056/NEJMoa1809944
3. Cianferotti L, Bertoldo F, Bischoff-Ferrari HA, et al: Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European Society for Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO). Endocrine 56:245-261, 2017. doi:10.1007/s12020-017-1290-9
4. Okereke OI, Reynolds CF 3rd, Mischoulon D, et al: Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: A randomized clinical trial. JAMA 324(5):471-480, 2020. doi: 10.1001/jama.2020.10224
5. Barbarawi M, Kheiri B, Zayed Y, et al: Vitamin D supplementation and cardiovascular disease risks in more than 83,000 individuals in 21 randomized clinical trials: A meta-analysis [published correction appears in JAMA Cardiol 2019 Nov 6]. JAMA Cardiol 4(8):765-776, 2019. doi: 10.1001/jamacardio.2019.1870
6. Jolliffe DA, Camargo CA Jr, Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021;9(5):276-292. doi:10.1016/S2213-8587(21)00051-6
7. Ling Y, Xu F, Xia X, et al: Vitamin DClin Nutr 40:5531-5537, 2021. doi:10.1016/j.clnu.2021.09.031
8. Yao P, Bennett D, Mafham M, et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019;2(12):e1917789. Published 2019 Dec 2. doi:10.1001/jamanetworkopen.2019.17789
9. Zhao JG, Zeng XT, Wang J, Liu L. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA. 2017;318(24):2466-2482. doi:10.1001/jama.2017.19344
10. Appel LJ, Michos ED, Mitchell CM, et al: The effects of four doses of vitamin D supplements on falls in older adults: a response-adaptive, randomized clinical trial. Ann Intern Med 174:145-156, 2021. doi:10.7326/M20-3812
11. LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults. N Engl J Med. 2022;387(4):299-309. doi:10.1056/NEJMoa2202106
Symptoms and Signs of Vitamin D Toxicity
The main symptoms of vitamin D toxicity result from hypercalcemia. Anorexia, nausea, and vomiting can develop, often followed by polyuria, polydipsia, weakness, nervousness, pruritus, and eventually renal failure. Proteinuria, urinary casts, azotemia, and metastatic calcifications (particularly in the kidneys) can develop.
Diagnosis of Vitamin D Toxicity
Hypercalcemia plus risk factors or elevated serum 25(OH)D levels
A history of excessive vitamin D intake may be the only clue differentiating vitamin D toxicity from other causes of hypercalcemia. Elevated serum calcium levels of 12 to 16 mg/dL (3 to 4 mmol/L) are a constant finding when toxic symptoms occur. Serum 25(OH)D levels are usually elevated to > 150 ng/mL (> 375 nmol/L). Levels of 1,25-dihydroxyvitamin D, which do not need to be measured to confirm the diagnosis, may be normal.
Serum calcium should be measured often (weekly at first, then monthly) in all patients receiving large doses of vitamin D, particularly the potent 1,25-dihydroxyvitamin D.
Treatment of Vitamin D Toxicity
IV hydration plus corticosteroids or bisphosphonates
After stopping vitamin D intake, hydration (with IV normal saline) and corticosteroids or bisphosphonates (which inhibit bone resorption) are used to reduce blood calcium levels. (See Treatment of Hypercalcemia.)
Kidney damage or metastatic calcifications, if present, may be irreversible.
