Vitamin D is a fat soluble vitamin important in the regulation of calcium metabolism and bone health and deficiency of which cause rickets, a disease marked by lack of mineralization of bone. Conventional doses of vitamin D are well tolerated without appreciable adverse effects. High doses of vitamin D can be toxic, leading to a constellation of signs and symptoms but not liver injury or jaundice.


Vitamin D is typically referred to as a fat soluble vitamin, but actually represents two related fat soluble substances cholecalciferol (koe" le kal sif' er ol: vitamin D3) and ergocalciferol (er" goe kal sif’ er ol: vitamin D2), both of which can be used to cure or prevent rickets. These molecules are made from 7-dehydrocholesterol, referred to as pro-vitamin D, which is activated to vitamin D by ultraviolet light, generally in the dermis or epidermis. These sterols are then transported to the liver where they undergo 25-hydroxylation (to 25-OH vitamin D) and then to the kidney where they undergo a second hydroxylation to the fully active molecules: 1,25 dihydroxycholecalciferol (vitamin D3, calcitriol) and 1,25 dihydroxyergocalciferol (vitamin D2). Vitamin D is not a vitamin in the usual sense, in that humans synthesize adequate amounts given adequate exposure to sunlight. Furthermore, vitamin D acts more like a hormone than a vitamin. It acts by binding to specific cytosolic receptors, not only in intestinal epithelial cells and in osteocytes, but also in multiple other tissues such as hematopoietic cells, hair follicles, adipose tissue, muscles and brain. After binding to its cytosolic receptors, vitamin D is translocated to the nucleus where the vitamin-receptor complex interacts with DNA and modulates gene expression to increase calcium absorption. The effect of vitamin D on bone is complex, in that it directly causes mobilization of calcium and bone resorption. The effect of vitamin D on bone mineralization is indirect, being mediated by the increase in calcium absorption from the intestine. While the major effects of vitamin D are on calcium absorption and bone resorption, it clearly has many other activities, the clinical implications of which are not all fully known. Vitamin D is available in multiple forms, including tablets, capsules, oral solutions and syrups and solutions for injection; by prescription and over-the-counter; alone or in combination with calcium or in combination with other vitamins; as cholecalciferol, ergocalciferol and their hydroxylated forms as well as synthetic analogues. Common commercial (and generic) names include Rocaltrol (calcitriol), One-Alpha (alfacalcidol), Calderol (calcifediol), Caltrate (cholecaliciferol), Hectorol (doxercalcifedol), Calcidol (ergocalciferol) and Zemplar (paricalcitol). The recommended daily allowance (RDA) for vitamin D has been recently modified and is 600 IU (~15 µg) in persons 1 to 70 years of age and 800 IU (~20 µg) daily for those 71 years and older. An adequate blood level of vitamin D (measured as 25-OH vitamin D) is considered 20 ng/mL (50 nmol/L) and above, a level that can be achieved by most people through daily skin exposure to light. Levels above 60 ng/mL (150 nmol/L) are considered excessive and referred to as “hypervitaminosis D”. Levels above 150 ng/mL (375 nmol/L) generally lead to symptoms and signs of toxicity which is referred to as “vitamin D intoxication”.


Neither normal nor excessively high intakes of vitamin D are associated with liver injury or liver test abnormalities. Hypervitaminosis D and vitamin D intoxication generally arise with intakes above 50,000 IU daily, but lower doses may induce toxicity in susceptible individuals such as patients with renal osteodystrophy (secondary hyperparathyroidism), and a safer upper limit of recommended intake is 10,000 IU daily. Symptoms of vitamin D intoxication are caused by hypercalcemia and can include dehydration, thirst, polyuria, anorexia, nausea, vomiting, constipation, fatigue, bone pains and muscle cramps. Complications can include renal dysfunction, nephrocalcinosis, decreased consciousness and seizures. Symptoms arise a few weeks to several months after starting excess doses of vitamin D given orally or parenterally. A common cause of hypervitaminosis D is the mislabeling of an over-the-counter or locally prepared nutritional supplement, excessive fortification of milk or foods, and inadvertent prescription or dispensing errors. In clinical descriptions of vitamin D intoxication, typical laboratory findings are hypercalcemia, increase in serum creatinine, and high 25-OH vitamin D levels (usually above 200 ng/mL or 500 nmol/L). Serum aminotransferase and bilirubin levels are typically normal, while alkaline phosphatase levels may actually be lower than normal.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

Vitamin D in high doses increases absorption of dietary calcium, but also mobilizes calcium from bone. The symptoms of vitamin D intoxication are largely those of hypercalcemia. While hepatocytes, cholangiocytes, stellate cells and resident immune cells in the liver have vitamin D receptors, there is no evidence that vitamin D causes injury to the liver.

Drug Class: Vitamins

Other Drugs in the Class: Vitamin A, Vitamin B, Vitamin C, Vitamin E, Vitamin K, Folate, Niacin



Vitamin D – Generic, Rocaltrol® (Calcitriol, Vitamin D3)




Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 27 May 2021

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    (Among 65 patients with diabetes and nonalcoholic fatty liver treated with cholecalciferol [2000 IU/day] vs placebo for 24 weeks, changes in ALT, serum lipids, HbA1c and cytokine levels and measures of visceral or total fat were similar in the two groups).
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    (Among 3882 adults in a community based study of vitamin D supplementation in doses of 1000-15,000 IU per day [aiming to raise serum 25-OH vitamin D levels to above 100 nmol/L] there were no serious adverse events and mean serum calcium did not change and ALT and GGT levels decreased slightly).
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    (Among 2423 adults at high risk of type 2 diabetes treated with vitamin D [4000 IU daily] or placebo for a median of 2.5 years, the rate of new onset diabetes was similar in the two groups as were rates of total and serious adverse events and deaths; no specific mention of ALT levels or hepatotoxicity).
  • Billington EO, Burt LA, Rose MS, Davison EM, Gaudet S, Kan M, Boyd SK, et al. Safety of high-dose vitamin D supplementation: secondary analysis of a randomized controlled trial. J Clin Endocrinol Metab. 2020;105:dgz212. [PubMed: 31746327]
    (Among 373 adults [ages 55 to 70 years] treated with one of 3 doses of 25[OH] vitamin D per day for up to 3 years, mild hypercalcemia arose in none on 400 IU, 3% on 4000 IU and 9% on 10,000 IU daily, while adverse event rates were similar in all 3 groups including ALT or AST elevations above 1.5 times the ULN [2%, 2% and 4%] and there were no serious hepatic adverse events).
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    (Commentary on the safety and efficacy of high doses of vitamin D summarizing results from 3 recent randomized controlled trials, all of which demonstrated the safety of doses of 3000 to 10,000 IU daily [except for low rates of mild and transient hypercalcemia], but with no evidence of efficacy in reducing the risk of bone fractures, cardiovascular disease, diabetes, or cancer, indicating that doses at or above 4000 IU per day should not be used outside of clinical trials).