The diagnosis and management of hypercalcaemia
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2723 (Published 02 June 2015) Cite this as: BMJ 2015;350:h2723
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Under the heading "Non-PTH mediated hypercalcaemia" and the subheading "Malignancy related hypercalcaemia", Should it not be hypocalciuria in preference to hypercalciuria, as PTH's action is the reabsorption of urine calcium?
Thank you for a great article.
Competing interests: No competing interests
Dear Editor,
We appreciate the comments and clarifications of colleagues, regarding our Clinical Review (1).
Sayer J. A. adds to the long list of possible causes of hypercalcemia, the molecular genetic defect in CYP24A1 that normally inactivates 1,25(OH)2D.
This is an accurate observation also supported by a recent finding in adults (2).
We agree with the first two points of dr. Laurent M. R., even though hypovitaminosis D may cause hypocalciuria, raising the doubt of familial hypocalciuria hypercalcemia. There is a lot of debate concerning the issue of vitamin D in patients with primary hyperparathyroidism (3,4); we believe that calcidiol levels should be determined since vitamin D insufficiency worsens, for example, skeletal involvement. Concerning the third point, we were referring to hypocalciuria and by no means to hypercalcemia. The thresholds reported are those set for the distinction between primary hyperparathyroidism and familial hypocalciuria hypercalcemia, an important step in order to avoid unnecessary operations. The role of magnesium is important, but for space limitations we did not mention (5).
We agree with the observation of dr. Bonsall A. M.; however, this is only a wording problem. The definition of hypercalcemia that has been used considers, as upper limit reference, the value of +2 SD above the mean of a population of apparently normal individuals.
Salvatore MINISOLA,
Jessica PEPE,
Cristiana CIPRIANI
Department of Internal Medicine and Medical Disciplines, “Sapienza” Rome University
References
1. Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ. 2015 Jun 2;350:h2723.
2. Jacobs TP, Kaufman M, Jones G, Kumar R, Schlingmann KP, Shapses S, Bilezikian JP. A lifetime of hypercalcemia and hypercalciuria, finally explained. J Clin Endocrinol Metab. 2014;99(3):708-12.
3. Minisola S, Romagnoli E, Scillitani A, Rao SD. Hypovitaminosis D in primary hyperparathyroidism: to treat or not to treat? That is the question. J Endocrinol Invest.2014 37(5):413-4.
4. SilverbergSJ, Clarke BL, Peacock M, Bandeira F, Boutroy S, Cusano NE, Dempster D, Lewiecki EM, Liu JM, Minisola S, Rejnmark L, Silva BC, Walker MD, Bilezikian JP. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3580-94
5. Eastell R, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-9.
Competing interests: No competing interests
Sir
In India and in probably many other countries the media and the Doctor community has managed to sell Vit.D very well and now patients get their share from fortified foods, OTC calcium preps which invariably contain Vit. D, self medication with exclusive Vit. D 60000 IU sachets, and imagine if all this is not disclosed to the treating doctor who might prescribe calcitriol !! (Ref.1) Vit. D toxicity cases will keep haunting the clinician in the near future.
Regards
Milind M Deshpande
Ref.1 Iatrogenic hypercalcaemia--a case report. J Indian Med Assoc 2009 Mar;107(3):173
Competing interests: No competing interests
An important cause of hypercalcaemia that must not be forgotten (again).
As is pointed out by Minisola et al. (1) vitamin D preparations can cause toxicity leading to hypercalcaemia. A British outbreak of infantile idiopathic hypercalcaemia secondary to vitamin D supplementation of infant formula and fortified milk products occurred in the early 1950’s. This suggested that some individuals have an intrinsic hypersensitivity to vitamin D.
In a landmark paper Schlingmann et al (2) the molecular basis for idiopathic infantile hypercalcaemia was discovered to be secondary to mutations in CYP24A1. This enzyme normally inactivates 1,25-dihydroxyvitaminD3 and patients have a biochemical picture of hypercalcaemia, hypercalciuria and suppressed PTH. Recently mutations in CYP24A1 have been identified in adult patients with hypercalcaemia and suppressed PTH presenting with renal stones (3). These findings emphasise the importance of determining a history of vitamin D supplements / tanning bed use in patients who have hypercalcaemia (4), as such exposures may be sufficient to reveal an underlying molecular genetic defect in CYP24A1.
References
(1) Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ 2015; 350:h2723
(2) Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011;365:410-21.
(3) Dinour D, Beckerman P, Ganon L, et al. Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis. J Urol. 2013;190:552-7
(4) Sayers J, Hynes AM, Srivastava S,Dowen F,Quinton R, Datta, HK, Sayer JA. Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole . Clinical Kidney Journal, 2015, 1-3.
Competing interests: No competing interests
Minisola et al. provide an excellent review for non-specialists on diagnosis and management of hypercalcaemia,1 but several points in their diagnostic algorithm can I think be debated.
First, they suggest confirming hypercalcaemia after discontinuation of vitamin D supplements, but excess vitamin D rarely contributes to hypercalcaemia if the patient is not taking exuberant doses. Directly proceeding to calcidiol measurements provides more certainty and avoids unnecessary delays.
Then, the authors suggest in hypercalcaemia with unsuppressed parathyroid hormone (PTH) to first supplement calcidiol if levels are <50 nmol/L. However, this bares no relevance to diagnosis since low vitamin D is quite common in the most likely cause i.e. primary hyperparathyroidism, which doesn't require normal vitamin D levels to establish the diagnosis in case of clear hypercalcaemia.
Thirdly, the authors suggest that hypercalcaemia in the presence of a glomerular filtration rate < 60 mL/min can be attributed to hypocalciuria in chronic kidney disease (CKD). However, hypercalcaemia usually occurs only after prolonged and much more severe CKD (<15 mL/min), and is usually due to adynamic bone disease, vitamin D analogues, excess calcium carbonate, tertiary hyperparathyroidism or transplantation. The cut-off suggested by the authors is far too high, and may lead to many elderly subjects with hypercalcaemia due to primary hyperparathyroidism in primary care inappropriately classified as having just CKD.
Finally, the authors mention hypermagnesemia in familial hypocalciuric hypercalcaemia, but they do not discuss hypomagnaesemia which may occur secondary to primary hyperparathyroidism and may aggravate some of the symptoms of hypercalcaemia. In my opinion, serum magnesium levels have diagnostic and therapeutic consequences in the setting of unsuppressed PTH and therefore constitute an integral part of the diagnostic and management approach at that point.
References
1. Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ. 2015 Jun 2;350:h2723. doi: 10.1136/bmj.h2723
Competing interests: No competing interests
In the definition of hypercalceamia given by the authors:
"Hypercalcaemia is diagnosed when the concentration of serum calcium is 2 standard deviations above the mean of values found in people with NORMAL calcium levels, in at least two samples at least one week apart over a period of three months.",
If not caused by a language translation issue, the use of the word NORMAL shows a fundemental lack of understanding of normal distributions. By definition in a normally distributed population there will values that lie more than 2 sd from the mean and therefore deigned to be outside a normal range for the level, hence you cannot say a normal range is derived from a population with only normal values.
Competing interests: No competing interests
Re: The diagnosis and management of hypercalcaemia
Dear Dr. Jordan,
Thanks for your question.
Hypercalciuria, in that particular context, is the result of increased intestinal calcium absorption, due to overproduction of calcitriol.
We agree that PTH action on renal tubules determines hypocalciuria, even though in hypercalcemic patients with primary hyperparathyroidism, the filtered load may be so high that hypercalciuria is the net result. Similarly, the anti-calciuric effect of PTHrP prevents or restricts effective renal calcium clearance.
Competing interests: No competing interests