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CLINICAL REVIEW: Mark S Cooper and Neil J L Gittoes Diagnosis and management of hypocalcaemia BMJ 2008; 336: 1298-1302 [Full text]

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The use of oral calcium to treat hypocalcaemia

Olivier Steichen   (9 June 2008)

Diagnosis of hypocalcaemia: additional causes should be considered

Federico Marchetti, Nagua Giurici, Alessandro Ventura   (9 June 2008)

Thiazide diuretics are efficient in the chronic management of hypoparathyroidism

Yair Liel   (11 June 2008)

Diagnosis of hypocalcemia- significant biochemical causes

Minnie Faith, Dr Gautham Pranesh, Lecturer, Department of Biochemistry, Christian Medical College, Bagayam, Vellore-632002, South India.   (12 June 2008)

The use of oral calcium to treat hypocalcaemia 9 June 2008
Olivier Steichen, Fellow AP-HP, Hôpital Tenon, Internal Medicine Department, 75020 Paris, France Send response to journal: Re: The use of oral calcium to treat hypocalcaemia	The review on hypocalcaemia by Drs Cooper and Gittoes is very clear and informative [1]. However, the therapeutic use of oral calcium is hardly mentioned. At least two points should be considered. First, hypoparathyroidism with mild and chronic hypocalcaemia can be treated with oral calcium alone [2]. Second, different calcium salts do not have the same bioavailability. Carbonate calcium is the cheapest and most supplied oral calcium salt. It is also used in most calcium plus vitamin D supplements. However, the absorption of calcium carbonate is markedly reduced in patients with achlorhydria, unless taken with meals [3]. Achlorhydric and older patients, who often suffer from hypochlorhydria, should be advised either to take calcium carbonate with meals, or to take calcium citrate (at any time of the day). The second option might be less cost-effective, since calcium citrate is on average 50% more expensive than calcium carbonate. The absorption of calcium carbonate is also impaired in fasting patients on proton-pump inhibitor (PPI) therapy [4]. To our knowledge, its absorption with meals has not been studied in these patients. Most experts therefore recommend that patients on PPI therapy take calcium citrate instead. References [1] Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008;336:1298-302. [2] Bushinsky DA, Monk RD. Electrolyte quintet: Calcium. Lancet 1998;352:306-11. Erratum in: Lancet 2002;359:266. [3] Recker RR. Calcium absorption and achlorhydria. N Engl J Med 1985;313:70-3. [4] O'Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 2005;118:778-81. Competing interests: None declared
Diagnosis of hypocalcaemia: additional causes should be considered 9 June 2008
Federico Marchetti, Attending physician Dept. of Pediatrics, IRCCS Burlo Garofolo, University of Trieste, via dell'Istria 65/1, 34100Trieste, Nagua Giurici, Alessandro Ventura Send response to journal: Re: Diagnosis of hypocalcaemia: additional causes should be considered	We appreciated the pragmatic setting and the clear and useful information provided by Cooper and Gittoes in this review (1). However, we would like to point out some additional aspects that we believe should have had been addressed. First of all, some important causes of severe hypocalcaemia pertaining particularly the critical patient have not been mentioned among the possible causes of hypocalcaemia. Specifically, alkalosis (2), acute pancreatitis (3) and repeated transfusions (4) have been omitted. Alkalosis can induce hypocalcaemia by increasing the protein binding of calcium. It is unknown how severe acute pancreatitis induces hypocalcaemia, but several possible mechanisms have been hypothesized. Among these, a possible autodigestion of mesenteric fat due to pancreatic fluid leakage, a transient hypoparathyroidism or hypomagnesemia. Blood transfusion is another common potential etiology for hypocalcaemia and is due to complexing of calcium ions by the citrate that is added to the red blood cell product to prevent clotting. In addition, the Authors mention autoimmune polyglandular syndrome type 1 (APECED) among the idiopathic causes of impaired function of the parathyroid gland. In regards to this condition, we would like to further stress that these patients can suffer from persistent, severe hypocalcaemia despite an appropriate supplementation with calcitriole and calcium. It is important to keep in mind that, in addition to hypoparathyroidism, other conditions typical of APECED can be associated and further impair the calcaemia of these patients. Specifically, severe malabsorption due to autoimmune enteropathy or lymphangiectasia or pancreatic insufficiency can coexist. These conditions should be kept in mind in cases of severe hypocalcaemia in an APECED unresponsive to standard therapy since they might benefit from immunosuppressive treatment (5). References 1) Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336:1298-302 2) Wang S, McDonnell EH, Sedor FA, Toffaletti JG. pH effects on measurements of ionized calcium and ionized magnesium in blood. Arch Pathol Lab Med 2002;126:947-50 3) McMahon MJ, Woodhead JS, Hayward RD. The nature of hypocalcaemia in acute pancreatitis.Br J Surg 1978;65:216-8 4) Wilson RF, Binkley LE, Sabo FM Jr, et al. Electrolyte and acid- base changes in massive blood transfusions. Am Surg 1992;58:535-45 5) Padeh S, Theodor R, Jonas A, Passwell JH. Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression. Arch Dis Child 1997;76:532-34 Nagua Giurici, Federico Marchetti, Alessandro Ventura Department of Pediatrics, Institute of Child Health, IRCCS Burlo Garofolo, University of Trieste, via dell’Istria 65/1. 34100 Trieste, Italy Corresponding Author: Federico Marchetti, marchetti@burlo.trieste.it Competing interests: None declared
Thiazide diuretics are efficient in the chronic management of hypoparathyroidism 11 June 2008
Yair Liel, Acting head, Endocrinology Service Soroka University Medical Center, Beer-Sheva, Israel Send response to journal: Re: Thiazide diuretics are efficient in the chronic management of hypoparathyroidism	As mentioned in Cooper and Gittoes' review (1), while oral calcium and active vitamin D analogs (calcitriol or 1-alpha vitamin D) are undoubtely the mainstay of hypocalcemia management in patients with hypoparathyroidism or pseudohypoparathyroidism, this treatment can result in considerable hypercalciuria and urinary caluli formation. An efficient method to overcome the hypercalciuria related to calcium -active vitamin D analog treatment includes the supplementation of low dose of a thiazide diuretic, which considerably decreases the rate of urinary calcium excretion. This is particularly important in patients with hypercalciuric hypocalcemia due to activating mutations of the calcium sensor-receptor (2). Not less important, the use of a cheap thiazide diuretic allows to achieve target calcium concentration with lower doses of calcium and the more expensive active vitamin D analog and thus reduce the cost of management of a lasting condition. References: 1. Cooper MS and Gittoes NJL. Diagnosis and management of hypocalcaemia. BMJ 2008; 336: 1298-302. 2. Sato K, Hasegawa Y, Nakae J, et al. Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. J Clin Endocrinol Metab 2002; 87:3068-73. Competing interests: None declared
Diagnosis of hypocalcemia- significant biochemical causes 12 June 2008
Minnie Faith, Senior Lecturer Department of Biochemistry, Christian Medical College, Bagayam, Vellore-632002, South India., Dr Gautham Pranesh, Lecturer, Department of Biochemistry, Christian Medical College, Bagayam, Vellore-632002, South India. Send response to journal: Re: Diagnosis of hypocalcemia- significant biochemical causes	Cooper and Gittoes have elucidated the clinical review on “diagnosis and treatment of hypocalcemia” in a clear and succinct manner (1). The authors have pointed out a number of etiological causes for hypocalcemia. We would like to add the following biochemical causes for hypocalcemia due to low vitamin D levels, which have not been emphasized in the article. Patients undergoing parathyroidectomy for primary hyperparathyroidism with low levels of 25 hydroxy vitamin D deficiencies have been shown to be predisposed for hypocalcemia post-operatively (2). Similarly patients with vitamin D dependent rickets type I characterized by deficiency of vitamin D 1 alpha hydroxylase deficiency have hypocalcemia as one of the clinical features (3). Another rare but significant cause of hypocalcemia is mutation in the vitamin D receptor causing vitamin D resistant rickets which is associated with hypocalcemia, severe rickets, secondary hyperparathyroidism and increased levels of 1,25 dihydroxy vitamin D3 levels (4). An important, noteworthy cause of hypocalcemia that is not mentioned by the authors is the hypocalcemia seen in neonates of diabetic mothers (5,6). It is speculated that secondary hypoparathyroidism and hypomagnesemia may have a role to play in the development of hypocalcemia in these infants (7,8). References 1. Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008;336:1298-302. 2. Stewart ZA, Blackford A, Somervell H, Friedman K, Garrett-Mayer E, Dackiw AP, Zeiger MA. 25-hydroxyvitamin D deficiency is a risk factor for symptoms of postoperative hypocalcemia and secondary hyperparathyroidism after minimally invasive parathyroidectomy. Surgery. 2005 Dec;138(6):1018-25; discussion 1025-6 3. Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, Miller WL, Portale AA. Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha- hydroxylase deficiency. J Clin Endocrinol Metab. 2007 Aug;92(8):3177-82. 4. Nicolaidou P, Papadopoulou A, Matsinos YG, Georgouli H, Fretzayas A, Papadimitriou A, Priftis K, Douros K, Chrousos GP. Vitamin D receptor polymorphisms in hypocalcemic vitamin D-resistant rickets carriers.Horm Res. 2007;67(4):179-83. 5. Barnes-Powell LL. Infants of diabetic mothers: the effects of hyperglycemia on the fetus and neonate. Neonatal Netw. 2007 Sep-Oct;26(5):283-90. 6. Gyselaers W, Indrato R, Westerhuis M, Visser G, Rosén K. STAN-recorded intrapartum loss of beat-to-beat variation associated with prolonged QT-interval: indicative for fetal hypocalcemia? J Matern Fetal Neonatal Med. 2007 Jan;20(1):69-73. 7. Mehta KC, Kalkwarf HJ, Mimouni F, Khoury J, Tsang RC. Randomized trial of magnesium administration to prevent hypocalcemia in infants of diabetic mothers. J Perinatol. 1998 Sep-Oct;18(5):352-6. 8. Banerjee S, Mimouni FB, Mehta R, Llanos A, Bainbridge R, Varada K, Sheffer G. Lower whole blood ionized magnesium concentrations in hypocalcemic infants of gestational diabetic mothers. Magnes Res. 2003 Jun;16(2):127-30. Competing interests: None declared