How much is too much? Two contrasting cases of excessive vitamin D supplementation

Accepted Manuscript How much is too much? Two contrasting cases of excessive vitamin D supplementation

Sollip Kim, Laura D. Stephens, Robert L. Fitzgerald PII: DOI: Reference:

S0009-8981(17)30297-8 doi: 10.1016/j.cca.2017.08.004 CCA 14824

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Clinica Chimica Acta

Received date: Revised date: Accepted date:

16 June 2017 7 August 2017 7 August 2017

Please cite this article as: Sollip Kim, Laura D. Stephens, Robert L. Fitzgerald , How much is too much? Two contrasting cases of excessive vitamin D supplementation, Clinica Chimica Acta (2017), doi: 10.1016/j.cca.2017.08.004

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ACCEPTED MANUSCRIPT How much is too much? Two Contrasting Cases of Excessive Vitamin D supplementation Sollip Kim, MD1, Laura D. Stephens, MD2, and Robert L. Fitzgerald, PhD, DABCC2*

1

Department of Laboratory Medicine, Ilsan Paik Hospital, Inje University College of Medicine,

Department of Pathology, UC San Diego Health, San Diego, CA, United States

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2

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Goyang, Republic of Korea

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*Address correspondence to this author at: Center for Advanced Laboratory Medicine, UC San

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Diego Health, 9300 Campus Point Drive #7721, La Jolla, CA 92037-7721. E-mail:

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[email protected]

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Abbreviations:

1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; BMI, body mass

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electrocardiogram; IOM,

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index; DBP, D binding protein; EFSA, European Food Safety Authority; EKG,

Institute of Medicine; IU, international unit; LC-MS/MS, Liquid Chromatography-Tandem Mass

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Spectrometry; NMO, neuromyelitis optica; NSTEMI, non-ST-segment elevation myocardial infarction; PTH, Parathyroid hormone; PTHrP, Parathyroid hormone-related protein; UCSD, UC San Diego Health; US, United States; VDR, vitamin D receptor

ACCEPTED MANUSCRIPT

Abstract Background: In this report, we describe 2 contrasting cases of hypervitaminosis D. Case presentation: Patient 1 was a 75-y old man who developed symptomatic hypercalcemia

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(peak serum calcium concentration of 15.3 mg/dl; reference range: 8.5–10.6 mg/dl), cardiac

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injury, and a high total serum vitamin D concentration of 243 ng/ml (30-80 ng/ml) as a result of daily consumption of prescribed 50,000 IU ergocalciferol (vitamin D2) and 500 mg calcium-

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citrate for 1 y. Patient 2 was a 60-y old woman who consumed 40,000 IU of cholecalciferol (vitamin D3) daily for >10 months with a peak total serum vitamin D concentration of 479 ng/ml

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(30-80 ng/ml), but did not present with symptoms related to vitamin D toxicity.

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Conclusion: These cases demonstrate that individual responses to supraphysiologic concentrations of vitamin D for extended periods of time vary widely, and that defining a toxic

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concentration of this vitamin is difficult. The different outcomes in these two patients, despite

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months of high-dose vitamin D therapy, demonstrates that individual patient pharmacodynamics determine clinical sequelae.

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Key words: Vitamin D, Vitamin D associated toxicity, hypervitaminosis D, Hypercalcemia

ACCEPTED MANUSCRIPT 1. Introduction Vitamin D supplementation is increasing as a result of widespread recognition of vitamin D deficiency in the general population. In addition to the established role that vitamin D supplementation plays in correcting vitamin D deficiency [1,2] and promoting bone health [3],

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several studies have identified potential benefits of vitamin D supplementation on a variety of

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other conditions, including improving quality of life in patients with multiple sclerosis [4];

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reducing triglyceride levels in patients with metabolic syndrome [1]; and preventing asthma exacerbations [5]. A recent meta-analysis questioned the importance and therapeutic effects of

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vitamin D supplementation for many disease states [3].

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Due to the widespread practice of vitamin D supplementation, both under the guidance of

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physicians and by patients’ independent over-the-counter consumption, vitamin D toxicity is a clinical concern [6]. Often considered rare, vitamin D toxicity can be life-threatening or

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associated with substantial morbidity, if not identified promptly [7,8]. The exact mechanism of

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2.1 Case 1

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2. Case presentation

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vitamin D toxicity remains unclear.

A 75-y old man presented to UC San Diego Health (UCSD, San Diego, California) with non-ST-segment elevation myocardial infarction and altered mental status. The patient had a history of atrial fibrillation, coronary artery disease (status-post coronary artery bypass grafting), heart failure, thyroid cancer (status-post resection with subsequent hypothyroidism), and bladder cancer (status-post resection and chemotherapy). His BMI was 18.3 kg/m2. Upon admission, the patient was noted to have a total serum calcium 15.4 mg/dl (reference range: 8.5–10.6 mg/dl;

ACCEPTED MANUSCRIPT patient baseline: 8.9 mg/dl one month prior), ionized calcium 1.61 mmol/l (1.13–1.32 mmol/l), PTH 3 pg/ml (15–65 pg/ml), troponin T 0.74 ng/ml (<0.01 ng/ml), and ST-segment depressions on EKG. The patient was given intravenous fluids, calcitonin, and pamidronate for his hypercalcemia, and his calcium normalized within 24 hours. After an extended hospital stay, he

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was discharged to a skilled nursing facility for cardiac rehabilitation.

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Further review of the patient’s outside ambulatory notes indicated the patient had been

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prescribed 50,000 IU ergocalciferol (vitamin D2) daily and 500 mg calcium-citrate daily for at least the past year, presumably to treat iatrogenic hypoparathyroidism following thyroidectomy.

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Upon transfer to our hospital, the patient’s vitamin D testing by LC-MS/MS showed a total 25-

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laboratory results are presented in Table 1.

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hydroxyvitamin D (25(OH)D) of 243 ng/ml (reference range: 30 – 80 ng/ml). His relevant

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2.2 Case 260-y old woman with a BMI of 24.6 kg/m2 and no significant past medical history presented to the neurology clinic of UCSD Health with progressive left-sided weakness and foot

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drop. She was diagnosed with neuromyelitis optica (NMO) spectrum disorder based on her

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laboratory and radiographic findings and was treated with high-dose rituximab induction chemoimmunotherapy. She wished to use complementary medical therapies to reduce her NMO

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related symptoms and identified a protocol described on the internet that included high-dose biotin and cholecalciferol (vitamin D3). After discussing the potential toxicity of high-dose vitamin D3 supplements with her physician and being advised against self-treatment with supratherapeutic doses, she independently increased her vitamin D3 intake from 2,000 IU/day to 40,000 IU/day. Monitoring of her laboratory values revealed increased total 25-hydroxyvitamin D (25(OH)D) levels with a peak of 479 ng/ml (reference range: 30 – 80 ng/ml) after 10 months

ACCEPTED MANUSCRIPT of self-treatment. Her intact PTH demonstrated an appropriate decrease in relation to her ionized calcium levels, but after 10 months of supraphysiologic concentrations of vitamin D, her PTH, total calcium, and ionized calcium were within the reference range. Notably, she had no reported signs or symptoms of vitamin D related toxicity. Her relevant laboratory results are presented in

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Table 2.

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3. Discussion

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Like all vitamins and minerals, vitamin D has a therapeutic range. The recommended daily dietary intake is generally 200-600 IU with modifications for pediatric and pregnant

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populations [9]. Both the Institute of Medicine (IOM) and the European Food Safety Authority

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(EFSA) have established the tolerable upper limit of vitamin D intake at 100 µg/day (4000 IU) for adults [10, 11]. Consumption above this limit may lead to toxicity, specifically

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hypercalcemia, which can manifest as irreversible cardiovascular and renal injury, calcium

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deposition in soft tissues, and diffuse bone demineralization, among other sequelae [12]. Generally, the most common causes of hypercalcemia are primary hyperparathyroidism and

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cancer [13]. Measurement of parathyroid hormone (PTH) is the key to differentiating the two

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etiologies, as PTH is high in primary hyperparathyroidism and low in cancer due to negative feedback. In addition, select neoplastic cells are known to produce parathyroid related protein (PTHrP), which leads to hypercalcemia of malignancy and can be measured [13]. Hypercalcemia secondary to hypervitaminosis D may become more common as physician-prescribed and patient-initiated high-dose vitamin D supplementation is becoming more widespread [14]. Fortunately, the therapeutic index of vitamin D is large, and vitamin D related toxicity is considered rare. A recent retrospective study of over 25,000 patient samples that included a 25-

ACCEPTED MANUSCRIPT hydroxyvitamin D over a 6-y period identified less than 0.1% of tested samples with hypercalcemia-related hypervitaminosis D[15]. Case studies have illustrated how this hypercalcemia can arise from vitamin D supplement manufacturing errors [7, 16], as well as dosing mistakes [17].

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The toxicity from hypervitaminosis D is far from uniform. Some patients with long-term

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high-dose vitamin D supplementation have had no documented toxic effects. In one case report,

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for instance, an adult woman mistakenly took an incorrect dose of 60,000 IU of vitamin D daily for four months. Despite her supratherapeutic total vitamin D level of 746 ng/ml (reference

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range: 20-50 ng/ml), she had a normal serum calcium and no adverse symptoms [18]. A separate

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case report described an adult woman who had taken 150,000 IU vitamin D2 for 28 y without documented toxicity [19].

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Herein, we describe two cases of patients with long-term high-dose vitamin D

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supplementation who had differing clinical and laboratory outcomes. In the first case, an adult man was transferred to our hospital with symptomatic hypercalcemia and an NSTEMI. The

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differential diagnosis for his hypercalcemia included hyperparathyroidism (ruled out by a low

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PTH), paraneoplastic syndrome (ruled out by imaging studies and a normal PTHrP by LCMS/MS), multiple myeloma (not supported by immunofixation studies), and iatrogenic causes.

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Measurement of his elevated total vitamin D level (243 ng/ml; reference range: 30-80 ng/ml) and review of his outside medical records allowed the clinical team to conclude that the patient’s hypercalcemia was most likely due to long-term high-dose prescriptions of vitamin D2, in addition to calcium-citrate supplementation. In the second case, an adult woman independently consumed high-dose vitamin D3 as complementary therapy for her neurological disorder. Although her total vitamin D level was higher than that of the first patient (peak concentration of

ACCEPTED MANUSCRIPT 479 ng/ml; reference range: 30-80 ng/ml), her serum calcium was within the reference range after 10 months of supplementation, and she had no documented signs or symptoms of toxicity. In sum, both patients had total vitamin D levels greater than 200 ng/ml for 10-12 months, one patient developed toxicity and the other did not.

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The exact mechanism of toxicity for vitamin D remains elusive, but current concepts

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revolve around increased concentrations of the active metabolite of vitamin D, 1,25-

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dihydroxyvitamin D (1,25(OH)2D) reaching the vitamin D receptor (VDR) in the nucleus of target cells, resulting in gene over-expression [12]. Three specific hypotheses of this mechanism

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have been proposed: increased plasma concentrations of 1,25(OH)2D lead to increased

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intracellular concentrations of 1,25(OH)2D; increased plasma concentrations of 25(OH)D exceed the vitamin D binding protein (DBP) binding capacity, allowing free 25(OH)D to enter cells and

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directly affect gene expression; and increased concentrations of vitamin D, 25(OH)D, and other

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vitamin D metabolites exceed the DBP binding capacity, causing the release of free 1,25(OH)2D, which itself enters the target cell [12, 20]. Overactivity of the vitamin D signal transduction

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system in hypervitaminosis D as a result of an inability of the catabolic system involving

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CYP24A1 to keep up with the target cell levels of activated vitamin D metabolites could also another mechanism to vitamin D toxicity [20].

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The current mechanisms of toxicity do not provide an explanation of the differences in symptoms observed in our 2 patients with similarly high vitamin D levels. We hypothesize that pharmacodynamic differences in the patients’ metabolism of vitamin D may have contributed, and we propose several hypotheses to explain the differences. The first is that the 2 patients may have different vitamin D binding protein (DBP) binding capacities. Perhaps the first patient has a lower DBP binding capacity, such that the DBP transport proteins saturate at relatively lower

ACCEPTED MANUSCRIPT concentrations of vitamin D and its metabolites. This would increase the concentration of the free 25(OH)D3, which would then be available for renal uptake for hydroxylation to the active 1,25(OH)2D3 form. Excess 1,25(OH)2D3 might then enter the target cells and result in gene overexpression and hypercalcemia through a VDR-mediated mechanism [18,20]. To our

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knowledge, the effect of individual differences in DBP binding capacity have not been fully

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described except for several genotype studies [21,22]. Some investigators have suggested that

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measuring free or bioavailable vitamin D concentrations provide a more accurate picture of vitamin D status [23]. Unfortunately this measurement requires quantifying concentrations of

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DBP which are not widely available.

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The second hypothesis is that the patients may have different VDR statuses. In normal physiology, 1,25(OH)2D has a low affinity for the DBP transport protein and a high affinity for

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VDR, making it the only ligand with access to the transcriptional signal transduction machinery

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of vitamin D-responsive genes [18,20]. In vitamin D intoxication, 25(OH)D overload compromises the capacity of the DBP by allowing it to enter the cell nucleus, thereby possibly

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affecting transcription. Some target cells such as monocytes and macrophages express the

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membrane proteins megalin and cubulin to concentrate the 25(OH)D-DBP complex and convert into 1,25(OH)2D by the protein CYP27B1 [18,20]. The VDR gene regulates the expression of

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these proteins, thereby participating in the control in 1,25(OH)2D conversion and, ultimately, calcium and phosphate absorption, among other functions [24]. A potential mechanism to explain the differences in outcomes we observed is that our second patient has a polymorphism or inactivating mutation of the VDR gene resulting in decreased VDR expression or functionality, which would decrease the conversion of the 25(OH)D-DBP complex to 1,25(OH)2D and mitigate hypercalcemia. To date, the frequencies of VDR single nucleotide

ACCEPTED MANUSCRIPT polymorphisms have been studied [25,26], but the clinical impact of differences of the VDR protein remains unknown. A third hypothesis which could explain the observed differences in toxicity between the 2 patients is metabolism of vitamin D. As shown in Fig. 1 [Fig. 1], 25(OH)D3 has 2 pathways for

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metabolism. 1-hydroxylation by CPY27B1 leads to the active form 1,25(OH)2D3, whereas

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hydroxylation by CYP24A1 leads to an inactive metabolite. There is a complex feedback loop

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that depends on concentrations of calcium, PTH, and 1,25(OH)2D3 to control activity of the hydroxylase enzymes [27]. It is possible that patient 2 has a relative deficiency in CYP27B1, or

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overactivity of CYP24A1. Alterations in these 2 enzymes can have a profound effect on calcium

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homeostasis [28, 29]

Another distinction in our patients was the type of vitamin D they consumed; patient

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1was prescribed high-dose ergocalciferol (vitamin D2), and patient 2 self-treated with high-dose

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cholecalciferol (vitamin D3). Stephenson et al. [19] reported a case of daily megadoses of vitamin D2 with no evidence of vitamin D toxicity and suggested that vitamin D2 may be less

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potent than vitamin D3. A randomized, double-blind, placebo-controlled prospective trial also

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concluded that vitamin D3 slightly, but significantly, increased serum 25(OH)D more than

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vitamin D2 [30]. Our cases, however, demonstrated the opposite effect.

4. Conclusion

We present 2 contrasting cases of hypervitaminosis D where, despite long-term high-dose vitamin D supplementation, one patient developed clinically significant toxicity and hypercalcemia, and the other patient did not. We suggest pharmacodynamics differences in the patients’ vitamin D metabolism, variability in the vitamin D binding protein binding capacity,

ACCEPTED MANUSCRIPT and/or polymorphisms of the vitamin D receptor gene may explain the differences in our patients’ outcomes. Caution should be exercised when prescribing or self-treating with high-dose vitamin D supplementation, and monitoring of 25(OH)D and calcium is advised. Further studies are needed to evaluate physiological variations in vitamin DBP, VDR gene, and hydroxylase

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activity.

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Acknowledgement

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This work was supported by a grant from Research year of Inje University in 2016.

ACCEPTED MANUSCRIPT References [1]

Salekzamani S, Mehralizadeh H, Ghezel A, et al. Effect of high-dose vitamin D

supplementation on cardiometabolic risk factors in subjects with metabolic syndrome: a randomized controlled double-blind clinical trial. J Endocrinol Invest 2016; 39:1303-1313. Boas SR, Hageman JR, Ho LT, Liveris M. Very high-dose ergocalciferol is effective for

T

[2]

IP

correcting vitamin D deficiency in children and young adults with cystic fibrosis. J Cyst Fibros

[3]

CR

2009; 8:270-272.

Newberry S, Chung M, Shekelle PG, et al., Vitamin D and Calcium: A Systematic

US

Review of Health Outcomes (Update). Evidence Report/Technology Assessment No. 217.

AN

(Prepared by the Southern California Evidence-based Practice Center under Contract No. 2902012-00006-I.) AHRQ Publication No. 14-E004-EF. Rockville, MD: Agency for Healthcare

Ashtari F, Toghianifar N, Zarkesh-Esfahani SH, Mansourian M. High dose Vitamin D

ED

[4]

M

Research and Quality., 2014.

intake and quality of life in relapsing-remitting multiple sclerosis: a randomized, double-blind,

Pojsupap S, Iliriani K, Sampaio TZ, et al. Efficacy of high-dose vitamin D in pediatric

CE

[5]

PT

placebo-controlled clinical trial. Neurol Res 2016; 38:888-892.

asthma: a systematic review and meta-analysis. J Asthma 2015; 52:382-390. Kaptein S, Risselada AJ, Boerma EC, Egbers PH, Nieboer P. Life-threatening

AC

[6]

complications of vitamin D intoxication due to over-the-counter supplements. Clin Toxicol (Phila) 2010; 48:460-462. [7]

Araki T, Holick MF, Alfonso BD, et al. Vitamin D intoxication with severe

hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States. J Clin Endocrinol Metab 2011; 96:3603-3608.

ACCEPTED MANUSCRIPT [8]

Ozkan B, Hatun S, Bereket A. Vitamin D intoxication. Turk J Pediatr 2012; 54:93-98.

[9]

IOM (Institute of Medicine), Dietary reference intakes for calcium, phosphorus,

magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press, 1997. [10]

IOM (Institute of Medicine), Dietary Reference Intakes for Calcium and Vitamin D.

EFSA Panel on Dietetic Products. Nutrition and Allergies (NDA). Scientific opinion on

[12]

CR

dietary reference values for vitamin D. EFSA 2016; 14:4547.

IP

[11]

T

Washington, DC: The National Academies Press, 2011.

The Scientific Advisory Committee on Nutrition (SACN), SACN vitamin D and health

US

report. SACN: reports and position statements and Obesity and healthy eating: Public Health

[13]

AN

England, 2016.

Risteli J, Winter WE, Kleerekoper M, Risteli L, Bone and Mineral Metabolism. In: Burtis

M

CA, Ashwood ER, Bruns DE, editors. Tietz Textbook of Clinical Chemistry and Molecular

[14]

ED

Diagnostics. London: ClinicalKey eBook, 2012: 1733-1801. Tebben PJ, Singh RJ, Kumar R. Vitamin D-Mediated Hypercalcemia: Mechanisms,

Perez-Barrios C, Hernandez-Alvarez E, Blanco-Navarro I, Perez-Sacristan B, Granado-

CE

[15]

PT

Diagnosis, and Treatment. Endocr Rev 2016; 37:521-547.

Lorencio F. Prevalence of hypercalcemia related to hypervitaminosis D in clinical practice. Clin

[16]

AC

Nutr 2016; 35:1354-1358.

Anik A, Catli G, Abaci A, Dizdarer C, Bober E. Acute vitamin D intoxication possibly

due to faulty production of a multivitamin preparation. J Clin Res Pediatr Endocrinol 2013; 5:136-139.

ACCEPTED MANUSCRIPT [17]

Guerra V, Vieira Neto OM, Laurindo AF, Paula FJ, Moyses Neto M. Hypercalcemia and

renal function impairment associated with vitamin D toxicity: case report. J Bras Nefrol 2016; 38:466-469. [18]

Chakraborty S, Sarkar AK, Bhattacharya C, Krishnan P, Chakraborty S. A nontoxic case

Stephenson DW, Peiris AN. The lack of vitamin D toxicity with megadose of daily

IP

[19]

T

of vitamin D toxicity. Lab Med 2015; 46:146-149; quiz e131.

CR

ergocalciferol (D2) therapy: a case report and literature review. South Med J 2009; 102:765-768. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008; 88:582S-586S.

[21]

Fu L, Yun F, Oczak M, Wong BY, Vieth R, Cole DE. Common genetic variants of the

US

[20]

AN

vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation. Clin Biochem 2009; 42:1174-1177. Nimitphong H, Saetung S, Chanprasertyotin S, Chailurkit LO, Ongphiphadhanakul B.

M

[22]

ED

Changes in circulating 25-hydroxyvitamin D according to vitamin D binding protein genotypes after vitamin D(3) or D(2)supplementation. Nutr J 2013; 12:39. Denburg MR, Hoofnagle AN, Sayed S, et al. Comparison of Two ELISA Methods and

PT

[23]

CE

Mass Spectrometry for Measurement of Vitamin D-Binding Protein: Implications for the Assessment of Bioavailable Vitamin D Concentrations Across Genotypes. J Bone Miner Res

AC

2016; 31:1128-1136. [24]

VDR gene (vitamin D receptor). U.S. Department of Health & Human Services, 2017.

[25]

Landrum MJ, Lee JM, Benson M, et al. ClinVar: public archive of interpretations of

clinically relevant variants. Nucleic Acids Res 2016; 44:D862-868. [26]

Genomes Project C, Auton A, Brooks LD, et al. A global reference for human genetic

variation. Nature 2015; 526:68-74.

ACCEPTED MANUSCRIPT [27]

Jones G. Extrarenal vitamin D activation and interactions between vitamin D(2), vitamin

D(3), and vitamin D analogs. Annu Rev Nutr 2013; 33:23-44. [28]

Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of

hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving

T

defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med

Woods GN, Saitman A, Gao H, Clarke NJ, Fitzgerald RL, Chi NW. A Young Woman

CR

[29]

IP

1973; 289:817-822.

Deficiency. J Bone Miner Res 2016; 31:1841-1844.

Binkley N, Gemar D, Engelke J, et al. Evaluation of ergocalciferol or cholecalciferol

AN

[30]

US

With Recurrent Gestational Hypercalcemia and Acute Pancreatitis Caused by CYP24A1

dosing, 1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab 2011;

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CE

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96:981-988.

ACCEPTED MANUSCRIPT Table 1. Laboratory results of Patient 1 who consumed long-term high-dose vitamin D2. Laboratory

Reference

Parameter

range

Units

At

24 h after

admission

treatment for

20 days later

Total calcium

8.5 – 10.6

mg/dl

15.4

Ionized calcium

1.13 – 1.32

mmol/l

1.61

15-65

pg/ml

3

NA

ng/ml

NA

ng/ml

Vitamin D, 25-OH

8.5

1.33

NA

NA

3

NA

178

24

NA

20

ng/ml

243

NA

198

pg/ml

NA

NA

124

pg/ml

3

NA

NA

D3 30-80

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Vitamin D, 25-OH Total

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19.9 – 79.3

Vitamin D, 1,25-

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Dihydroxy

15 – 65

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PTHrP

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Vitamin D, 25-OH

219

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D2

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10.5

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PTH intact

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hypercalcemia

Abbreviation: NA, not available, PTH, parathyroid hormone; PTHrP, parathyroid hormonerelated protein

ACCEPTED MANUSCRIPT Table 2. Laboratory results of Patient 2 who consumed long-term high-dose vitamin D3.

range

Months after starting high-dose vitamin D supplementation

-2 mo

2 mo

5 mo

7 mo

9 mo

10 mo

mg/dl

NA

9.4

9.7

11.1

11.0

9.9

1.13 –

mmol/l

1.19

1.15

1.24

1.36

1.42

1.22

15-65

pg/ml

10

20

13

10

11

17

NA

ng/ml

<5

<5

<5

<5

<5

<5

NA

ng/ml

75

398

363

479

374

388

30-80

75

398

363

479

374

388

pg/ml

NA

117

149

NA

NA

181

NA

>2000

NA

NA

NA

NA

Ionized calcium

Vitamin D, 25-OH

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1.32 PTH intact

Vitamin D, 25-OH D3

79.3

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Dihydroxy

19.9 –

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Total Vitamin D, 1,25-

ng/ml

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Vitamin D, 25-OH

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D2

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8.5 – 10.6

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Total calcium

Baseline

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Parameter

Units

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Reference

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Laboratory

Vitamin B12

Abbreviation: mo, month; NA, not available; PTH, parathyroid hormone

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AN

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ACCEPTED MANUSCRIPT

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Fig. 1. Metabolism of vitamin D3. 25(OH)D3 is converted into the active hormone 1,25(OH)2D3 by CYP27B1 present in the kidney. Both 25(OH)D3 and 1,25(OH)2D3 are inactivated by

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25(OH)D2.

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CYP24A1 to form the 24 hydroxylated products respectively. Analogous pathways exist for

ACCEPTED MANUSCRIPT

Highlights

Vitamin D toxicity can lead to life-threating hypercalcemia, but does not necessarily occur in

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

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all patients with hypervitaminosis D following long-term high-dose vitamin D

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supplementation.

Proposed mechanisms are based on increased concentrations of the active metabolite of

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vitamin D reaching the vitamin D receptor (VDR) in the nucleus of the target cells and causing gene over-expression.

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Inter-patient differences in vitamin D metabolism, protein binding capacity, and receptor

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vitamin D consumption.

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status likely play an important role in predicting and mediating clinical effects of excess

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