Diagnosis and management of hypocalcaemia
BMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39582.589433.BE (Published 05 June 2008) Cite this as: BMJ 2008;336:1298
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Dear Sir,
In relation to the recently published comprehensive clinical review on “Diagnosis and management of hypocalcaemia” [1] by M S Cooper & N J L Gittoes, we wish to emphasise the importance of obtaining a standard Electrocardiogram (ECG).
The effect of Hypocalcaemia on ECG has long been recognised [2]. The ECG hallmark of hypocalcaemia is QT interval prolongation secondary to a prolonged ST segment. This is a result of increase in the duration of phase two of the action potential of cardiac muscle. QTc interval prolongation is directly proportional to the degree of hypocalcaemia [3]. Other Electrocardiographic abnormalities reported include T wave changes, cardiac dysrrhythmias and ECG changes mimicking Acute Myocardial Infarction [4]. The associated Hypokalemia and Hypomagnesaemia make sole attribution of some of these changes to Hypocalcaemia somewhat controversial.
Electrocardiographic changes, therefore, can serve as an added marker of severity of Hypocalcaemia (& need for urgent intervention) along with symptoms, rapidity of onset and biochemical severity (Calcium level <1.9 mmol/l) [1] of hypocalcaemia.
[1].Cooper MS, Gittoes NJL. Diagnosis and management of hypocalcaemia BMJ 2008;336:1298-302
[2]. Wofford CP, Ernstene AC. Diagnostic significance of increased Q- T interval in Electrocardiogram. Cleveland Clinic Quarterly. 1941;8:12-16
[3].RuDusky BM. ECG abnormalities associated with hypocalcemia. Chest 2001;119:668-669
[4].Lehmann G, Deisenhofer I, Ndrepepa G, Schmitt C ECG changes in a 25-year-old woman with Hypocalcemia due to Hypoparathyroidism:Hypocalcemia mimicking acute Myocardial Infarction Chest 2000;118:260-262
Dr Muuhammad Muzaffar Mahmood SPR, Department of Diabetes and Endocrinology. Southmead Hospital. Bristol BS10 5NB.
Competing interests: None declared
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
Profound hypocalcaemia following intravenous bisphosphonate due to unmasking of subclinical vitamin D deficiency
Vitamin D deficiency is often unrecognised, particularly in the elderly. Cooper and Gottie’s recent review of hypocalcaemia noted that patients with pre-existing vitamin D deficiency who receive intravenous bisphosphonates may develop severe hypocalcaemia (1). This has been described in patients with underlying malignancy and hypercalcaemia/bone pain treated with intravenous bisphosphonates (2). The new, long acting bisphosphonates such are Zolendronic acid are increasingly used in patients with osteoporosis or Paget’s disease to improve acceptability and compliance.
We present a recent case which brings to light a number of important issues. A 82-year old lady with known widespread Paget’s disease, presented with a pathological fracture of the femur. Her calcium level was normal (2.26mmol/L) and she was treated with a single 30 mg Pamidronate infusion whilst on the orthopaedic ward. Her Paget’s disease remained active and 3 months later she was given a single 5mg Zolendronic acid infusion. A week later, she became unwell with flu-like symptoms, parasthesias and dyspnoea. She was found to have profound hypocalcaemia (corrected serum calcium: 1.46mmol/L). Her hypocalcaemia was corrected with calcium supplements and 1 alpha-hydoxycholecalciferol. Retrospectively, we found that she had been vitamin D deficient with 25 hydroxyvitamin D being 7.4 µgm /L (normal levels>30µgm/L)
This case highlights:
1. Subclinical vitamin D deficiency is common and more likely to occur in the elderly. As intravenous bisphosphonates are more likely to be used in this age group, vitamin D deficiency needs to be identified and treated prior to intravenous bisphoshonate use.
2. Paget’s disease and Vitamin D deficiency can coexist, especially in the elderly.
3. Vitamin D assays are not always readily available in a District General Hospital setting but we suggest this is measured at least before initiating treatment with long acting bisphosphonate.
4. It is important to recheck serum calcium during bisphoshonate infusion therapy.
References:
(1) Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. Brit Med J 2008; 336:1298-302.
(2) Peter R, Mishra V, Fraser WD. Severe hypocalcaemia after being given intravenous bisphosphonate. Brit Med J 2004; 328(7435): 335–336
Competing interests: None declared
Editorial note
The patient whose case is described has given her signed informed consent to publication.
Competing interests: No competing interests