Post N Med 2016; XXIX(10): 756-759 ©Borgis *Ewa Marcinowska-Suchowierska1, Paweł Płudowski2 Vitamin D toxicity Zatrucie witaminą D 1Department of Geriatric, Internal Medicine and Metabolic Bone Disease, Centre of Postgraduate Medical Education, Warsaw Head of Department: Professor Marek Tałałaj, MD, PhD 2Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, Warsaw Head of Department: Professor Roman Janas, PhD Keywords Summary vitamin D, 25(OH)D, toxicity, clinical Vitamin D toxicity (VDT), also called hypervitaminosis D, is a rare but potentially serious symptoms and management condition that occurs when an individual has excessive 25(OH)D levels in the bloodstream. Vitamin D toxicity is usually caused by extremely high doses of vitamin D supplements, not by diet or skin exposure to the sun. The main clinical consequence of VDT is elevated Słowa kluczowe serum calcium level (hypercalcemia) and a variety of nonspecific symptoms. The literature witamina D, 25(OH)D, toksyczność, reports that hypercalcemia due to overdosed vitamin D may appear if serum 25(OH)D objawy kliniczne, leczenie levels are higher than 150-200 ng/ml. Many different mechanisms have been proposed to account for VDT, including the vitamin D metabolite itself, VDR number, activity of 1 al- fa-hydroxylase, inhibition of vitamin D catabolism, and the capacity of VDBP. Mounting evidence that higher levels of vitamin D may have beneficial effects on bone and cellular health may predispose to enhanced administration of vitamin D and increased frequency of VDT. Hypercalcemia from VDT is rare, but a dangerous state for the organism and should receive adequate and sensible treatment. Conflict of interest Konflikt interesów Streszczenie None Brak konfliktu interesów Zatrucie witaminą D (VDT), zwane także hiperwitaminozą D, jest rzadkim powikła- niem, będącym najczęściej następstwem podaży dużej ilości witaminy D jako suplemen- tu, a nie skutkiem diety lub ekspozycji na promienie UVB. Następstwem klinicznym VDT Address/adres: może być hiperkalcemia oraz inne niespecyficzne objawy. Dane literaturowe wskazują, że do hipercalcemii w VDT dochodzi, jeśli stężenie 25(OH)D w surowicy jest większe niż *Ewa Marcinowska-Suchowierska 150-200 ng/ml. Wiele różnych mechanizmów może być odpowiedzialnych za powstanie Department of Geriatric, Internal Medicine objawów VDT, w tym wzrost: stężenia metabolitów witaminy D, ilości receptorów dla wita- and Metabolic Bone Disease miny D (VDR) i białka wiążącego witaminę D (VDBP). Dostępna dokumentacja wskazująca Centre of Postgraduate Medical Education na korzystny wpływ wyższych stężeń witaminy D zarówno na tkankę kostną, jak i wiele ul. Czerniakowska 231, 00-416 Warszawa innych komórek, zachęca niektóre osoby do przyjmowania (niekontrolowanego) większej tel. +48 (22) 584-11-01 ilości witaminy D niż zalecane, co zwiększa ryzyko wystąpienia VDT. Hiperkalcemia wsku- [email protected] tek VDT występuje rzadko, ale jest niebezpieczna i wymaga rozważnego leczenia. INTRODUCTION droxyvitamin D – 25(OH)D level < 20 ng/ml] and in- Vitamin D is an important prohormone that plays sufficiency [25(OH)D level 21-29 mg/ml] is a worldwide a vital role in calcium homeostasis and bone minerali- problem that is widely prevalent (1). sation. Vitamin D also sub subserves in a wide range of Because of the increased awareness of vitamin D fundamental biological functions, such as cell differen- deficiency in recent years, the use of vitamin D sup- tiation and the inhibition of cell growth, as well as immu- plements by the population has increased, as well as nomodulation. Vitamin D deficiency leads to a defect of use of high doses of vitamin D prescribed by physi- bone mineralization and to increased risks of several cians to treat vitamin D deficiency. This increased use extra skeletal complications such as cardiovascular of vitamin D supplements by the general population diseases, hypertension, obesity, metabolic syndrome, and the growing number of prescriptions of therapeu- chronic obstructive pulmonary disease, autoimmune tic doses without any monitoring may result in a great- diseases and cancer. Vitamin D deficiency [25-hy- er risk of hypervitaminosis D, also known as vitamin D 756 Vitamin D toxicity toxicity (VDT) (2). This article presents some of the calcemia in some children were based on a survey of problems associated with VDT. dietary intake. WHAT IS VITAMIN D TOXICITY AND HOW OFTEN MECHANISM OF VITAMIN D TOXICITY DOES IT OCCUR? Vitamin D toxicity involves an increased concentra- Vitamin D toxicity (VDT), also called hypervitamino- tion of vitamin D metabolites reaching the VDR in the sis D, is a rare but potentially serious condition that nucleus of target cells and causing exaggerated gene occurs when an individual is exposed to excessive expressions. The three mechanisms are suggested to amounts of vitamin D for prolonged period of time. explain vitamin D toxicity (3, 7): Vitamin D toxicity is usually caused by mega doses 1. Toxicity mediated by the increased levels of of vitamin D supplements, not by diet or exposure to plasma 1,25(OH)2D (active hormonal form of vi- the sun. This is because the human body regulates tamin D) leads to its increased intracellular con- the amount of previtamin D produced by UVB, and centration. This hypothesis is not strongly sup- even fortified foods do not contain large amounts of ported, as only Mewar et al. reported elevated vitamin D (3). 1,25(OH)2D levels at VDT, and many other studies VDT may be defined as a state when markedly el- revealed that 1,25(OH)2D levels were only margin- evated 25(OH)D levels (> 150 ng/mL) coinciding with ally elevated or normal. hypercalcemia, hypercalciuria and very low or even 2. 1,25(OH)2D has low affinity to the vitamin D bind- undetectable PTH activity. However, the major clinical ing protein (DBP, transport protein) and high af- worries related to VDT most often focus on elevated finity to VDR making it an important ligand with calcium levels (hypercalcemia) and a variety of non- access to the transcriptional signal transduction specific symptoms (see below). machinery. At the state of hypervitaminosis D, the The literature reports that hypercalcemia due to an levels of various vitamin D metabolites are mark- overdose of vitamin D may appear if serum levels of edly increased compromising the capacity of the 25(OH)D reach a range of 150-200 ng/ml (3, 4). For this DBP, and in term enable other vitamin D metabo- reason, it is generally accepted that serum 25(OH)D lites to enter the cell nucleus. Among these inac- level above 150 ng/ml should be observed before a di- tive metabolites 25(OH)D has the strongest affin- agnosis of vitamin D toxicity. The lower 25(OH)D lev- ity to the VDR, so at high concentrations 25(OH)D els (up to 100 ng/mL) are considered perfectly safe for itself may stimulate transcription. most children and adults, with the exception of indi- 3. Vitamin D intake raises the concentration of many vi- viduals who have a hypersensitivity to vitamin D, such tamin D metabolites especially vitamin D itself and as children and adults with idiopathic infantile hyper- 25(OH)D. In hypervitaminosis D, vitamin D metab- calcemia, Williams-Beuren syndrome, granulomatous olites such as vitamin D3, 25(OH)D3, 24,25(OH)2D3, disorders and some lymphomas (5). 25,26(OH)2D3 and 25(OH)D3-26,23-lactone increase The existing knowledge related to VDT is based significantly. These concentrations exceed the on case reports, series courses and animal experi- DBP binding capacity and cause release of free ments. The experimental analysis of VDT in humans 1-alpha 25(OH)2D3, the latter one enters target is impossible due to ethical problems. In the 1930s cells. The various studies and reports of vitamin D to the 1950s, public health officials in USA and Great intoxcation indicate that plasma 25(OH)D3 is a good Britain recommended the routine fortification of milk biomarker for toxicity. and other foods with vitamin D initially as prophylactic for rickets in children and later to improve the general CLINICAL FEATURES OF VITAMIN D TOXICITY condition of adults. In the 1940s, massive doses of vi- The clinical manifestation of hypervitaminosis D is tamin D (200,000 to 300,000 IU/D) were considered varied and mostly results from hypercalcemia and re- as an effective treatment strategy for many chronic flects the essential role of calcium in many tissues and illnesses from tuberculosis to rheumatoid arthritis. In targets, including bone, cardiovascular system, nerves 1950s, the incidence of hypercalcemia significantly and cellular enzymes. increased, mainly in Great Britain as well as in some Initial signs and symptoms of hypervitamino- other countries in Europe. This unexpected and unex- sis D may be similar to other hypercalcemic states plained (at that time) increase of incidence of hyper- and include generalized weakness and weight calcemia resulted in the discontinuation of the fortifi- loss (6, 8-11). cation of food with vitamin D. Because hypercalcemia Central nervous system features may include con- was observed at early stages of treatment, the therapy fusion, difficulty in concentration, drowsiness, apathy was discontinued and symptoms of vitamin D intoxica- and coma. Neuropsychiatric symptoms include de- tion disappeared after a few months. This experience pression and psychosis, both of which are resolved alerted physicians to the potential of vitamin D toxic- following improvement of the hypercalcemia. ity, and that concern persists to this day (5, 6). During Hypercalcemia can affect the gastrointestinal tract the 1930s to the 1950s, there was no reliable assay for and cause recurrent vomiting, abdominal pain, poly- vitamin D and its metabolite, so symptoms of hyper- dipsia, anorexia, and constipation. Hypercalcemia may 757 Ewa Marcinowska-Suchowierska, Paweł Płudowski also be observed due to induced hypergastrinemia re- With modern assays for calcitropic hormones, PTH, sults peptic ulcers and pancreatitis.