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 D toxicity usually occurs only if excessive doses (prescription or megavitamin) are taken. Vitamin D 1000 mcg (40,000 units)/day causes toxicity within 1 to 4 months in infants. In adults, taking 1250 mcg (50,000 units)/day for several months can cause toxicity. Vitamin 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 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. Vitamin D 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 Actions of Vitamin D and Its Metabolites), 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. Vitamin D's usefulness 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). Some evidence suggests that taking the combined recommended daily allowance of both vitamin D and calcium reduces the risk of fractures (6, 7) and falls (8), but primarily in patients who are vitamin D deficient. As the causes of falls are multifactorial, other studies have not found that vitamin D supplements alone reduce falls in older adults (9).
(See also Overview of Vitamins.)
Дія вітаміну D та його метаболітів
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 |
Довідкові матеріали щодо фізіології
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. 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 2(12):e1917789, 2019. doi:10.1001/jamanetworkopen.2019.17789
7. Kong SH, Jang HN, Kim JH, et al: Effect of vitamin D supplementation on risk of fractures and falls according to dosage and interval: a meta-analysis. Endocrinol Metab 37:344-358, 2022. doi:10.3803/EnM.2021.1374
8. Ling Y, Xu F, Xia X, et al: Vitamin D supplementation reduces the risk of fall in the vitamin D deficient elderly: an updated meta-analysis. Clin Nutr 40:5531-5537, 2021. doi:10.1016/j.clnu.2021.09.031
9. 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
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 need not 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.
Kidney damage or metastatic calcifications, if present, may be irreversible.
