key: cord-0745928-t4bip468 authors: Batman, Adnan; Saygili, Emre Sedar; Yildiz, Duygu; Sen, Esra Cil; Erol, Rumeysa Selvinaz; Canat, Muhammed Masum; Ozturk, Feyza Yener; Altuntas, Yuksel title: Risk of hypercalcemia in patients with very high serum 25‐OH vitamin D levels date: 2021-04-29 journal: Int J Clin Pract DOI: 10.1111/ijcp.14181 sha: 0adf518291590a20e46e1a96cb6063eee2a24531 doc_id: 745928 cord_uid: t4bip468 OBJECTIVE: We aimed to evaluate the risk of hypercalcemia in patients with very high levels of 25‐hydroxy vitamin D (25(OH)D). METHODS: The distribution of patients who were screened for 25(OH)D in our hospital between January 2014 and December 2018 was evaluated and patients with serum concentrations of 25(OH)D >88 ng/mL were selected. Then, biochemical parameters of the cases with 25(OH)D >88 ng/mL were compared according to calcium status, vitamin D level (group 1, 88‐100 ng/mL; group 2, 100‐150 ng/mL, and group 3, >150 ng/mL), and gender. RESULTS: A total of 282 932 patients who underwent 25(OH)D tests in our hospital were evaluated. A total of 1311 (0.5%) patients had very high 25(OH)D levels (>88 ng/mL). Four hundred and ninety‐five patients who met our inclusion criteria and had complete data participated in the study. The median age was 58 years (interquartile range [IQR] = 41‐71 years) and the median level of 25(OH)D was 104.6 mg/mL (IQR = 94.9‐124.9 ng/mL). Most of the subjects (83.7%) with very high 25(OH)D levels were normocalcemic. A weak inverse correlation was observed between 25(OH)D level and intact parathyroid hormone (iPTH) level (r = −0.118, P = .01), but no correlation between 25(OH)D and calcium levels was observed. Alkaline phosphatase (ALP) levels were significantly higher in males (P = .032), and age and iPTH levels were higher in females (P < .001 and P = .004). ALP, phosphorus levels, and iPTH suppression rates were higher in hypercalcemic patients (P < .001, P < .001, and P < .001, respectively), while the iPTH level was significantly lower in hypercalcemic patients (P < .001) than in normocalcemic patients. Amongst the three groups with different 25(OH)D levels, no difference was found in levels of iPTH, calcium, phosphorus, ALP, or age. CONCLUSION: Most patients with very high vitamin D levels were normocalcemic, but severe hypercalcemia was also observed. Vitamin D replacement therapy and follow‐up should be performed according to clinical guideline recommendations. Vitamin D is an important steroid prohormone that maintains bone health. Its most important effect is on calcium, phosphorus metabolism, and bone mineralisation. 1 Vitamin D deficiency is recognised as a global epidemic. In addition to poor bone health, vitamin D deficiency is associated with autoimmune diseases, mental health problems, cardiovascular disease, insulin resistance, metabolic syndrome, immunodeficiency, neurocognitive dysfunction, and increased risk of extracellular complications such as cancer. [2] [3] [4] [5] It is also a lifestyle biomarker as vitamin D deficiency affects the quality of life. 6 During the coronavirus pandemic, the importance of vitamin D has reappeared. 7 As a result of the increasing awareness of health problems associated with vitamin D deficiency, there has been a growing trend in vitamin D screening and treatment around the world. 8 As a result, vitamin D has become a popular supplementary agent all over the world. In recent years, after careless and uncontrolled use of vitamin D therapy, there has been a significant increase in the number of cases of vitamin D hypervitaminosis and intoxication. While vitamin D intoxication can often be asymptomatic, causing hypercalcemia, it may also produce symptoms ranging from mild, such as thirst or polyuria, to severe, such as coma and death. 9 In this study, we aimed to investigate the distribution pattern of patients' serum concentrations of vitamin D during the last 5 years in our hospital in order to determine the burden of vitamin D hypervitaminosis and toxicity and compare these results with global trends. The information of patients who underwent 25-hydroxy vitamin D (25(OH)D) tests in our hospital between January 2014 and December 2018 was accessed from the database of our institute. The study protocol was approved by the ethics committee of our institute and the privacy of patients was preserved throughout the study. We determined the distribution of 25(OH)D concentrations and included those patients with 25(OH)D levels >88 ng/ mL (220 nmol/L), the upper limit of the normal range of vitamin D concentration in our hospital, in our study. For patients with multiple vitamin D assessments, only the initial test was taken into consideration for the study. Patients who met inclusion criteria and whose serum calcium, phosphorus, iPTH, and ALP levels were analysed at the same time as their 25(OH)D levels were included in our study ( Figure 1 • Vitamin D supplementation has increased awareness due to its many beneficial effects on health besides bone health. As a result of the increase in vitamin D awareness, hypervitaminosis D and intoxication cases due to excessive vitamin D supplementation have also increased. Cases of hypercalcemia due to Vitamin D over-intake have been reported in the case series. The variables in the study were evaluated in terms of the normal distribution with the one-sample Kolmogorov-Smirnov test and the data were presented as median (interquartile range (IQR)). Categorical variables were shown as counts and percentages. Categorical data were appropriately analysed by Chi-square (χ 2 ) test or Fisher's exact test. Discrepancies between the groups were analysed by Mann-Whitney U test and Kruskal-Wallis test because of the non-normal distribution. Correlation analyses were performed by calculating Spearman's and Pearson's correlation coefficients. The results were evaluated at a 95% confidence interval and P < .05 was considered statistically significant. All statistical analyses were performed using SPSS software, version 22.0 (SPSS Inc, Chicago, IL). Table 1) . Although there was no difference in age, gender, or 25(OH)D level between hypercalcemic and normocalcemic patients, ALP level, phosphorus level, and iPTH suppression rates were significantly higher in hypercalcemic patients (P < .001, P < .001, and P < .001, respectively), while the iPTH level was significantly lower in hypercalcemic patients (P < .001) than in normocalcemic patients (Table 1) Amongst the three groups defined by 25(OH)D levels, there was no significant difference in age, gender, calcium level, iPTH level, phosphorus level, ALP level, hypercalcemia rate or iPTH suppression rate, although the PTH suppression rate and hypercalcemia rate were both higher in group 3 ( Table 2) . Table 3 presents demographic and laboratory data of the patients by gender. ALP levels were significantly higher in males (P = .032), and age and iPTH levels were higher in females (P < .001 and P = .004, respectively). There was no difference in terms of 25(OH)D level, calcium, phosphorus level, iPTH suppression, or hypercalcemia rate. While bolus-and single-dose treatments were previously recommended to treat vitamin D deficiency in a rapid way, recent studies showed that bolus-dose use of vitamin D is associated with increased risk of fractures and falls, and this approach has been abandoned. 14 However, bolus-dose use is still widespread in developing countries and it was observed that prolonged supra-physiological use leads to vitamin D hypervitaminosis. 15 In our country, vitamin D hypovitaminosis and the use of vitamin D at a dose of 300 000 IU in osteoporosis, especially in the elderly, are common. 16 One of the reasons for common vitamin D excess in the elderly in our study may be the widespread and uncontrolled use of these preparations in this age group. In the literature, most patients with vitamin D hypervitaminosis are elderly and women. 17 Similarly, most patients who were tested for vitamin D in our study were female and elderly. The reason for this may be that elderly people are more often examined because of the symptoms of vitamin D deficiency, osteoarthritis, osteoporosis, and post-menopausal screening. In a meta-analysis of studies from our region, vitamin D deficiency was most frequently observed in elderly women. 18, 19 We thought that as a result of uncontrolled use of sup- Bold values indicate statistically significant (P < .05). Comparison of demographic and laboratory characteristics of patients with 25(OH)D levels >88 ng/mL by gender that ALP levels were lower but iPTH levels were higher in women than in men because of their advanced age and post-menopausal status. In addition, because of higher bone mass in men, the normal range of ALP is higher than in women. Because most of them were female (mostly post-menopausal), increases in calcium levels and iPTH suppression may not be evident in patients with very high vitamin D levels. The Therefore, long-term follow-up is required in vitamin D intoxication in terms of symptoms and findings associated with hypercalcemia. In addition to hypercalcemia, vitamin D intoxication can cause several symptoms such as depression, stupor, and coma psychiatrically; short QT, bradyarrhythmia, and hypertension in the cardiovascular system; nausea, vomiting, constipation, peptic ulcer, and pancreatitis in the gastrointestinal tract; and hypercalciuria, nephrocalcinosis, and renal failure in the kidneys. 28 In addition to 25 This study aims to emphasise that in recent years, there has been From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health Vitamin D and atherosclerotic cardiovascular disease Vitamin-D supplementation in prediabetes reduced progression to type 2 diabetes and was associated with decreased insulin resistance and systemic inflammation: an open label randomized prospective study from Eastern India Role of vitamin D in the immune system Vitamin D and diabetes mellitus The effect of vitamin D status on risk factors for cardiovascular disease Role of vitamin D in preventing of COVID-19 infection, progression and severity Increasing requests for vitamin D measurement: costly, confusing, and without credibility Vitamin D: deficiency, sufficiency and toxicity 10 years of 25-hydroxyvitamin-D testing by LC-MS/MS-trends in vitamin-D deficiency and sufficiency The rise and rise of vitamin D testing Vitamin D deficiency remains prevalent despite increased laboratory testing in New South Wales, Australia Comparative analysis of nutritional guidelines for vitamin D Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial Comparison of vitamin D replacement strategies with high-dose intramuscular or oral cholecalciferol: a prospective intervention study Vitamin D deficiency is a problem for adult out-patients? A university hospital sample in Istanbul, Turkey. Public Health Nutr Changing incidence of serum 25-hydroxyvitamin d values above 50 ng/mL: a 10-year population-based study Hypovitaminosis D in the Middle East and North Africa: prevalence, risk factors and impact on outcomes Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society Osteoporosis: gender differences and similarities Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety Self-administration of vitamin D supplements in the general public may be associated with high 25-hydroxyvitamin D concentrations A 21st century evaluation of the safety of oral vitamin D Seasonal variations in serum 25-hydroxy vitamin D levels in a Swedish cohort Solar ultraviolet B radiation and photoproduction of vitamin D3 in central and southern areas of Argentina Vitamin D toxicity-a clinical perspective Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment Disorders of the parathyroid gland and calcium homeostasis Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature The increasing problem of subclinical and overt hypervitaminosis D in India: an institutional experience and review Risk of hypercalcemia in patients with very high serum 25-OH vitamin D levels We thank the biochemistry department team, data scientist Nazım Topaç for his data arrangements and Dilek Gogas Yavuz for his consultancy support. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.This article does not contain any studies with animals performed by any of the authors. Institutional review board/Ethics Committee has approved the study. Informed consent was obtained from all individual participants included in the study. The article has not been presented at any conference or meeting. The authors declare that they have no conflict of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.