Vitamin D is an important prohormone that plays a vital role in calcium homeostasis and bone mineralisation. Vitamin D also sub subserves in a wide range of fundamental biological functions, such as cell differentiation and the inhibition of cell growth, as well as immunomodulation. Vitamin D deficiency leads to a defect of bone mineralization and to increased risks of several extra skeletal complications such as cardiovascular diseases, hypertension, obesity, metabolic syndrome, chronic obstructive pulmonary disease, autoimmune diseases and cancer. Vitamin D deficiency [25-hydroxyvitamin D – 25(OH)D level < 20 ng/ml] and insufficiency [25(OH)D level 21-29 mg/ml] is a worldwide problem that is widely prevalent (1).

Because of the increased awareness of vitamin D deficiency in recent years, the use of vitamin D supplements by the population has increased, as well as use of high doses of vitamin D prescribed by physicians to treat vitamin D deficiency. This increased use of vitamin D supplements by the general population and the growing number of prescriptions of therapeutic doses without any monitoring may result in a greater risk of hypervitaminosis D, also known as vitamin D toxicity (VDT) (2). This article presents some of the problems associated with VDT.

Vitamin D toxicity (VDT), also called hypervitaminosis D, is a rare but potentially serious condition that occurs when an individual is exposed to excessive amounts of vitamin D for prolonged period of time.

Vitamin D toxicity is usually caused by mega doses of vitamin D supplements, not by diet or exposure to the sun. This is because the human body regulates the amount of previtamin D produced by UVB, and even fortified foods do not contain large amounts of vitamin D (3).

VDT may be defined as a state when markedly elevated 25(OH)D levels (> 150 ng/mL) coinciding with hypercalcemia, hypercalciuria and very low or even undetectable PTH activity. However, the major clinical worries related to VDT most often focus on elevated calcium levels (hypercalcemia) and a variety of nonspecific symptoms (see below).

The literature reports that hypercalcemia due to an overdose of vitamin D may appear if serum levels of 25(OH)D reach a range of 150-200 ng/ml (3, 4). For this reason, it is generally accepted that serum 25(OH)D level above 150 ng/ml should be observed before a diagnosis of vitamin D toxicity. The lower 25(OH)D levels (up to 100 ng/mL) are considered perfectly safe for most children and adults, with the exception of individuals who have a hypersensitivity to vitamin D, such as children and adults with idiopathic infantile hypercalcemia, Williams-Beuren syndrome, granulomatous disorders and some lymphomas (5).

The existing knowledge related to VDT is based on case reports, series courses and animal experiments. The experimental analysis of VDT in humans is impossible due to ethical problems. In the 1930s to the 1950s, public health officials in USA and Great Britain recommended the routine fortification of milk and other foods with vitamin D initially as prophylactic for rickets in children and later to improve the general condition of adults. In the 1940s, massive doses of vitamin D (200,000 to 300,000 IU/D) were considered as an effective treatment strategy for many chronic illnesses from tuberculosis to rheumatoid arthritis. In 1950s, the incidence of hypercalcemia significantly increased, mainly in Great Britain as well as in some other countries in Europe. This unexpected and unexplained (at that time) increase of incidence of hypercalcemia resulted in the discontinuation of the fortification of food with vitamin D. Because hypercalcemia was observed at early stages of treatment, the therapy was discontinued and symptoms of vitamin D intoxication disappeared after a few months. This experience alerted physicians to the potential of vitamin D toxicity, and that concern persists to this day (5, 6). During the 1930s to the 1950s, there was no reliable assay for vitamin D and its metabolite, so symptoms of hypercalcemia in some children were based on a survey of dietary intake.

Vitamin D toxicity involves an increased concentration of vitamin D metabolites reaching the VDR in the nucleus of target cells and causing exaggerated gene expressions. The three mechanisms are suggested to explain vitamin D toxicity (3, 7):

1. Toxicity mediated by the increased levels of plasma 1,25(OH)₂D (active hormonal form of vitamin D) leads to its increased intracellular concentration. This hypothesis is not strongly supported, as only Mewar et al. reported elevated 1,25(OH)₂D levels at VDT, and many other studies revealed that 1,25(OH)₂D levels were only marginally elevated or normal.

2. 1,25(OH)₂D has low affinity to the vitamin D binding protein (DBP, transport protein) and high affinity to VDR making it an important ligand with access to the transcriptional signal transduction machinery. At the state of hypervitaminosis D, the levels of various vitamin D metabolites are markedly increased compromising the capacity of the DBP, and in term enable other vitamin D metabolites to enter the cell nucleus. Among these inactive metabolites 25(OH)D has the strongest affinity to the VDR, so at high concentrations 25(OH)D itself may stimulate transcription.