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Vitamin D Toxicity

By

Larry E. Johnson

, MD, PhD, University of Arkansas for Medical Sciences

Medically Reviewed Nov 2022
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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 Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more . 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 Hypoparathyroidism Hypoparathyroidism is a deficiency of parathyroid hormone often caused by an autoimmune disorder or by iatrogenic damage or removal of the glands during thyroidectomy or parathyroidectomy. Symptoms... read more 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 ). 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 ), 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 Psoriasis Psoriasis is an inflammatory disease that manifests most commonly as well-circumscribed, erythematous papules and plaques covered with silvery scales. Multiple factors contribute, including... read more Psoriasis , hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is a deficiency of parathyroid hormone often caused by an autoimmune disorder or by iatrogenic damage or removal of the glands during thyroidectomy or parathyroidectomy. Symptoms... read more , and renal osteodystrophy Calcium and phosphate Calcium and phosphate . 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 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ). Vitamin D supplementation does not effectively treat or prevent depression or cardiovascular disease (4, 5 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ). Some evidence suggests that taking the combined recommended daily allowance of both vitamin D and calcium reduces the risk of fractures (6, 7 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ) and falls (8 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ), 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 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ).

Table

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. 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 Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more . 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.

Drugs Mentioned In This Article

Drug Name Select Trade
Calcidol, Calciferol, D3 Vitamin, DECARA, Deltalin, Dialyvite Vitamin D, Dialyvite Vitamin D3, Drisdol, D-Vita, Ergo D, Fiber with Vitamin D3 Gummies Gluten-Free, Happy Sunshine Vitamin D3, MAXIMUM D3, PureMark Naturals Vitamin D, Replesta, Replesta Children's, Super Happy SUNSHINE Vitamin D3, Thera-D 2000, Thera-D 4000, Thera-D Rapid Repletion, THERA-D SPORT, UpSpring Baby Vitamin D, UpSpring Baby Vitamin D3
Calderol, RAYALDEE
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