Vitamin D Toxicity
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 treated too aggressively.
Vitamin D has 2 main forms:
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 developed 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, and colon cancers has not been proved, nor has its efficacy in treating various other nonskeletal disorders (1, 2) or preventing falls (3, 4, 5) in the elderly. Whether vitamin D supplementation is useful in preventing fractures in the frail or healthy elderly is under study (6).
(See also Overview of Vitamins.)
Actions of Vitamin D and Its Metabolites
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. Cummings SR, Kiel DP, Black DM: Vitamin D supplementation and increased risk of falling: A cautionary tale of vitamin supplements retold. JAMA Intern Med 176 (2):171–172, 2016.
4. Uusi-Rasi K, Patil R, Karinkanta S, Kannus P, et al: Exercise and vitamin D in fall prevention among older women: A randomized clinical trial. JAMA Intern Med 75 (5):703–711, 2015.
5. LeBlanc ES, Chou R: Vitamin D and falls—Fitting new data with current guidelines. JAMA Intern Med 175 (5):712–713, 2015.
6. 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 318:2466–2482, 2017.
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.
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.
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.