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RE: RE: Misconception for the cause of vitamin D toxicity

  • Bourne L Auguste, MD, FRCPC, Nephrologist & Clinical Fellow in Home Dialysis, Toronto General Hospital, University Health Network; Department of Medicine, University of Toronto
  • Other Contributors:
    • Joanne Bargman, MD, FRCPC, Professor of Medicine, Staff Nephrologist, Toronto General Hospital, University Health Network; Department of Medicine, University of Toronto
14 April 2019

We thank Charoenngam and colleagues for their prompt feedback on the conclusions from our case study (1). In light of this, it is important provide the readers and the authors further clarity given their stated misperceptions.
Firstly, the observational studies and opinion pieces referenced by the authors examined acute vitamin D toxicity. Patients received relatively high doses for short periods of time (usually < 6 months) (2-4). Our case study highlights a patient who took vitamin D that exceeded the recommended daily dose for at least 30 months (1,5). The authors of the cited editorial failed to highlight a key statement from the Institute of Medicine, “serum 25 hydroxyvitamin D levels above 125 nmol/L should raise concerns among clinicians about potential adverse effects” (5). Furthermore, the population studies cited by Charoenngam and colleagues did not include patients exposed to large (>10,000 IU) daily doses of vitamin D for 30 consecutive months. One randomized controlled trial highlighted in the cited reviews gave 100,000 IU boluses once every 4 months for 5 years (6). In a 5-year period these patients would have received the equivalent of 1.5 million IU of vitamin D. Our patient’s cumulative dose of vitamin D over a 4-month interval ranged from 960,000 - 1.44 million IU. In a 30-month period, this would equate to 10.8 million IU. Evidently, our patient received nearly 10 times the dose in half the duration of time that was given in comparison to that RCT, where serum calcium levels were not measured (6). Additionally, it has been reported that chronic vitamin D toxicity should be considered when values exceed >200 nmoL/L (4,7,8). Further to this point, other published case reports and case series have demonstrated vitamin D toxicity associated with hypercalcemia in patients exposed to smaller doses and over a shorter duration compared to our case study (9,10).
Secondly, Charoenngam and colleagues cite a case report of a patient with a large upper urinary tract carcinoma, specifically metastatic clear cell renal carcinoma (11). Our patient had a lower urinary tract urothelial non-invasive carcinoma of the bladder with no metastatic disease. Furthermore, non-metastatic bladder cancer associated with humoral hypercalcemia is exceedingly rare; normally requiring excision of the carcinoma to treat elevated 1,25 dihydroxyvitamin D levels and hypercalcemia as medical treatment is usually refractory (12, 13). In our case study, the patient’s 1,25 dihydroxyvitamin D levels started to decrease with medical treatment and before the resection of his non-invasive carcinoma arguing against it as being the driver for his vitamin D toxicity. Furthermore, our patient had evidence of chronic calcium deposition as reinforced by the renal biopsy findings, supporting that the toxicity was long standing. It is difficult to accept that a locally non-invasive bladder carcinoma resulted in the burden of hypercalcemia that our patient experienced which left him with permanent kidney damage.
Finally, Charoenngam and colleagues contend that 25 hydroxyvitamin D cannot result in elevated 1,25 dihydroxyvitamin D levels. However, it has been reported that chronically elevated 25 hydroxyvitamin D levels can lead to oversaturation of the vitamin D binding protein, increasing the levels of free active 1,25 dihydroxyvitamin D (8,14,15).
The authors propose esoteric differential diagnoses for our patient’s hypercalcemia, failing to acknowledge the potential risks of vitamin D toxicity associated with chronic misuse. The purpose of our case study was not to minimize the importance of vitamin D, but rather raise awareness that chronic misuse can result in permanent renal damage.

References:

1. Auguste BL, Avila-Casado C, Bargman JM. Use of vitamin D drops leading to kidney failure in a 54-year-old man. Canadian Medical Association Journal. 2019;191(14):E390-E394.

2. Holick MF. Vitamin D Is Not as Toxic as Was Once Thought: A Historical and an Up-to-Date Perspective. Mayo Clinic Proceedings. 2015;90(5):561-4.

3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-30.

4. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D, Amer J Clin Nutr.. 1, 2007;85 (1): 6–18.

5. Ross C, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Ramon A. Durazo-Arvizu RA, et ak. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know, Journal Clin Endocri & Metabol. 2011; 96(1): 53–58.

6. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double-blind controlled trial. BMJ 2003; 326: 469–75.

7. Rizzoli R., Stoermann C., Ammann P., Bonjour J.P. Hypercalcemia and hyperosteolysis in vitamin D intoxication: Effects of clodronate therapy. Bone. 1994;15:193–198

8. Alshahrani F, Aljohani N. Vitamin D: deficiency, sufficiency and toxicity. Nutrients. 2013;5(9):3605–3616. Published 2013 Sep 13. doi:10.3390/nu5093605

9. Jansen TL, Janssen M, de Jong AJ. Severe hypercalcaemia syndrome with daily low-dose vitamin D supplementation. Br J Rheumatol 1997; 36: 712–3.

10. Schwartzman MS, Franck WA. Vitamin D toxicity complicating the treatment of senile, postmenopausal, and glucocorticoid-induced osteoporosis. Am J Med 1987;82:224–30

11. Asao K, McHugh JB, Miller DC, Esfandiari NH. Hypercalcemia in upper urinary tract urothelial carcinoma: a case report and literature review. Case reports in endocrinology. 2013;2013:470890-.

12. Bennett, JK, Wheatley, J. K., Walton, K. N., Watts, N. B., McNair, O., & O’Brien, D. P. (1986). Nonmetastatic bladder cancer associated with hypercalcemia, thrombocytosis and leukemoid reaction. J Urol. 1986; 35(1): 47-48.

13. La Rosa AH, Ali A, Swain S, Manoharan M. Resolution of hypercalcemia of malignancy following radical cystectomy in a patient with paraneoplastic syndrome associated with urothelial carcinoma of the bladder. Urol Ann. 2015;7(1):86–87. doi:10.4103/0974-7796.148627

14. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88: 582S-6S.

15. Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, Jones G. Vitamin D Toxicity-A Clinical Perspective. Front Endocrinol (Lausanne). 2018;9:550

Competing Interests: None declared.
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