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Investigation and management of hypocalcaemia
  1. Ruchi Nadar1,
  2. Nick Shaw1,2
  1. 1 Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
  2. 2 Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, West Midlands, UK
  1. Correspondence to Professor Nick Shaw, Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B4 6NH, UK;{at}


Hypocalcaemia is a common clinical scenario in children with a range of aetiological causes. It will often present with common symptoms but may occasionally be identified in an asymptomatic child. An understanding of the physiological regulation of plasma calcium is important in understanding the potential cause of hypocalcaemia and its appropriate management. The age of presentation will influence the likely differential diagnosis. We have presented a stepwise approach to the investigation of hypocalcaemia dependent on the circulating serum parathyroid hormone level at the time of presentation. The acute and long-term management of the underlying condition is also reviewed.

  • bone metabolism
  • endocrinology

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Hypocalcaemia is a commonly encountered clinical scenario in children. In this review, we highlight the evaluation of a child with hypocalcaemia based on the clinical setting, age of presentation and focused investigations, such as parathyroid hormone (PTH) assay and bone profile (serum magnesium, phosphate and alkaline phosphatase levels).


An understanding of physiological mechanisms of calcium homeostasis and the interplay between regulatory hormones and target organs is central to the interpretation of investigations. There are three key components in the regulation of plasma calcium, disturbances in which may lead to hypocalcaemia. These are the calcium-sensing receptor CaSR (an extracellular G protein coupled receptor), PTH and the active metabolite of vitamin D: 1,25 dihydroxyvitamin D3 (1,25(OH)2D3). In addition to hormonal mechanisms, adequate dietary intake and gastrointestinal absorption of calcium are both imperative in maintaining calcium homeostasis.

A fall in plasma calcium leads to a cascade of events terminating in the action of PTH on target organs leading to the restoration of plasma calcium to normal (figure 1).

Figure 1

Physiological response to hypocalcaemia. 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D3, 1,25 dihydroxyvitamin D3; PTH, parathyroid hormone.

The initial response occurs at the level of the CaSR present in the renal tubules and the chief cells of the parathyroid glands. In the kidney, CaSR is located in the basolateral membrane of the cortical and medullary thick ascending nephron.1 Here in response to low ambient calcium levels it stimulates increased tubular calcium reabsorption. At the same time, the chief cells of the parathyroid gland respond by rapid synthesis and release of PTH. Its action on osteoclasts in bone to increase resorption and the renal tubule to increase tubular reabsorption of calcium is mediated by PTH receptors. When PTH acts on bone, phosphate is also released along with calcium. This can bind with calcium, again preventing correction of hypocalcaemia. This is counteracted by PTH action on renal tubules to produce phosphaturia. The other indirect mechanism is to stimulate the renal 1-alpha hydroxylase enzyme to synthesise 1,25(OH)2D3 leading to increased intestinal absorption of calcium. Additionally 1,25(OH)2D3 also acts on the distal convoluted tubule (DCT) to enhance calcium reabsorption.2 Thus by these important physiological actions, plasma calcium returns to normal.

Magnesium metabolism is linked with calcium metabolism, at the level of the CaSR. Severe hypomagnesaemia impairs PTH secretion in response to hypocalcaemia by raising the threshold for PTH secretion. Genetic forms of hypomagnesaemia are associated with mutations in genes encoding TRPM6 and EGF which are involved in active reabsorption of magnesium in the DCTs.3 4 Hypomagnesaemia may be seen with the use of certain drugs (diuretics, gentamicin or cisplatin) in diabetic ketoacidosis, post-renal transplant and urinary tract obstruction. When low plasma magnesium is associated with hypocalcaemia, correction of hypomagnesaemia is essential to normalise plasma calcium.

Disorders causing hypocalcaemia

A classification of disorders based on the status of PTH function (table 1) is useful for the clinician.

Table 1

Examples of disorders which present with hypocalcaemia

Approach to a child with hypocalcaemia

A logical stepwise approach will lead to the right diagnosis in most cases. Important points to consider are the following: the clinical setting (critical illness, renal failure, sick neonate), age at presentation, pertinent points in the history and physical examination along with specific investigations (figure 2).

Figure 2

Hypocalcaemia with normal or inappropriately low parathyroid hormone (PTH). AIRE, autoimmune regulator gene; APECED, autoimmunepolyendocrinopathy with candidiasis and ectodermal dystrophy; Ca/Cr, calcium/creatinine; CaSR, calcium sensing receptor; GATA-3, GATA-binding protein 3; GCM-2, glial cell missing 2 gene.

Hypocalcaemia is common in acute critical illness. Its aetiology is multifactorial and includes abnormal PTH secretion, hypomagnesaemia, hypoalbuminaemia, sepsis, transfusions, acid–base imbalance and medications and dietary calcium intake.5 Both acute and chronic renal failure can manifest with hypocalcaemia so renal function must be assessed as a baseline in every child.

Occasionally, hypocalcaemia is incidentally discovered in children who are completely asymptomatic. Others present with subacute onset of symptoms such as muscle cramps, tingling numbness and carpopedal spasms. Acute symptomatic hypocalcaemia presents with seizures which are multifocal in neonates or generalised tonic clonic in older children. Neonates and infants may also present with stridor, apnoea or respiratory distress. Congestive cardiac failure due to hypocalcaemic cardiomyopathy may also be a presenting feature.

The age at presentation provides clues to the possible aetiologies (table 2). Vitamin D deficiency continues to be a common cause of symptomatic hypocalcaemia, especially during periods of rapid growth of infancy and adolescence.

Table 2

Examples of causes of hypocalcaemia depending on age of presentation

Features like frontal bossing, wide open anterior fontanelle, costochondral beading and knee deformities suggest rickets (group B; table 1). Short stocky habitus, obesity, brachydactyly or ectopic calcifications are characteristic of the Albright hereditary osteodystrophy (AHO) phenotype seen in pseudohypoparathyroidism (PHP) type IA. Chovstek’s sign (twitching of ipsilateral facial muscles by tapping of the facial nerve in the parotid region) and Trousseau’ sign (induction of carpal spasm by maintaining the pressure in a sphygmomanometer cuff to above systolic pressure for more than 3 min) are useful signs but are not specific.6

Approach to investigations

Once hypocalcaemia is detected, first-line investigations should be collected before any oral or intravenous correction. This includes blood samples for intact PTH, bone profile (corrected calcium, magnesium, phosphate and alkaline phosphatase (ALK)), renal function and 25-hydroxyvitamin D (25(OH)D) must be collected before any intravenous or oral correction (table 3). Sample should be collected in plain tubes as serum calcium is generally measured, and it is important to rule out EDTA contamination of the blood sample.

Table 3

Investigations in a case of hypocalcaemia

Based on serum PTH, the approach to diagnosis can be divided into three groups (figures 2 and 3): (1) low, (2) normal, or (3) high PTH. It is important to bear in mind that an elevated PTH in the presence of hypocalcaemia is the appropriate physiological response to low plasma calcium (figure 1).

Figure 3

Hypocalcaemia with a high PTH. 25(OH)D, 25-hydroxyvitamin D; alk phos, alkaline phosphatase; GNAS, guanine nucleotide binding protein alpha subunit; PTH, parathyroid hormone.

In hypoparathyroidism, PTH levels are low or ‘inappropriately normal’ for the low plasma calcium. As PTH is also essential for renal phosphate excretion, plasma phosphate levels are high in this situation. In vitamin D deficiency with hypocalcaemia, the serum phosphate levels are low due to renal phosphate loss mediated by elevated PTH and reduced phosphate absorption. Another characteristic of this group is elevated ALK levels. In PTH resistance syndromes (PHP), renal phosphate excretion is impaired, explaining the combination of low calcium, high phosphate and high PTH levels in this group.

The parent’s bone profile should be checked when hypocalcaemia presents in neonates and infants, as it may provide important diagnostic information.

Clinical scenario I: a neonate with hypocalcaemic seizures

History and investigations

A male neonate aged 10 days on formula milk feeds presented with hypocalcaemic seizures. He was born by full-term vaginal delivery and had an uneventful perinatal period. Investigations showed adjusted plasma calcium 1.49 mmol/L (2.2–2.7), PTH 2 ng/L (11–35 ng/L), phosphate 3.5 mmol/L (1.3–2.6) and ALK 230 IU/L (50–230).

Neonatal hypocalcaemia

Early (within 72 hours of birth) neonatal hypocalcaemia is a common occurrence in high-risk situations such as infants of diabetic mothers, prematurity and birth asphyxia.7 This is transient and the pathological basis is immaturity of the parathyroid gland. It is managed with calcium supplements given on a short-term basis. On the other hand, late neonatal hypocalcaemia (occurring after 72 hours) is caused by a high phosphate diet (such as cow’s milk), congenital hypoparathyroidism, maternal hyperparathyroidism and vitamin D deficiency (table 2).

Congenital hypoparathyroidism

Congenital hypoparathyroidism is caused by a group of genetically mediated defects in PTH synthesis, which lead to permanent hypocalcaemia. It typically presents as acute symptomatic hypocalcaemia in the neonatal period but may be delayed in onset up to later infancy. It may be an isolated entity or occur in association with other developmental defects. Familial isolated hypoparathyroidism involves several genes that can be inherited as autosomal dominant, recessive or X-linked recessive.8–10 The most common cause is due to mutations in the glial cell missing 2 gene (GCM2) which codes for a transcription factor responsible for parathyroid gland development—this can be dominantly or recessively inherited.11

The most well-known syndrome associated with congenital hypoparathyroidism is DiGeorge syndrome in which hypoplasia of the parathyroid glands occurs during development.12 Here, hypocalcaemia is often identified in infancy when the child presents with the associated cardiac defects. This may require treatment with calcium supplements and/or a vitamin D analogue but will often resolve in early childhood to recur during puberty or adulthood. Another condition is the hypoparathyroidism, deafness and renal anomalies (HDR) syndrome due to an autosomal dominantly inherited GATA3 mutation on chromosome 10.13 Sanjad-Sakati syndrome also known as the hypoparathyroidism, retardation and dysmorphism syndrome due to a mutation in the tubulin-specific chaperone E (TBCE) gene on chromosome 1 is inherited in an autosomal recessive manner and is common in the Middle East.14


Osteopetrosis can sometimes present in neonates with hypocalcaemia and elevated PTH levels.15

Diagnosis in case 1

Suppressed PTH and elevated plasma phosphate suggested hypoparathyroidism. His father had a normal bone profile, whereas mum had high PTH 240 ng/L (12–65), high plasma calcium (3.04 mmol/L) and low phosphate (0.57 mmol/L, normal range 0.8–1.5) suggesting primary hyperparathyroidism. He had transient neonatal hypoparathyroidism due to maternal hyperparathyroidism. This occurs due to increased transplacental calcium transfer, suppressing fetal parathyroid glands. Treatment with oral calcium supplements and 1-alpha hydroxyvitamin D3 (alfacalcidol) is required in the initial weeks but often will resolve after 3 to 6 months as the parathyroid glands recover and resume normal secretion of PTH.16

Clinical scenario II: an infant with a hypocalcaemic seizure and congestive cardiac failure

An Asian female infant of 5 months who was exclusively breast fed presented with hypocalcaemic seizures, failure to thrive and congestive cardiac failure. Her investigations revealed low adjusted plasma calcium 1.96 (2–2.7 mmol/L) and phosphate 0.69 (1.3–2.4) mmoL/L with elevated ALK 1391 (105–420 IU/L) and PTH 51.1 (<5 pmol/L) levels suggesting rickets. Two-dimensional echocardiography showed dilated cardiomyopathy due to chronic hypocalcaemia. Her 25(OH) vitamin D levels was 12.5 nmol/L (>50 nmol/L).

The differential diagnosis at this age is vitamin D deficiency, congenital hypoparathyroidism and autosomal dominant hypocalcaemia (ADH).

Disorders of vitamin D presenting as hypocalcaemia

Although vitamin D deficiency will most often present with rickets in children, it can present with symptomatic hypocalcaemia particularly during the rapid growth periods of infancy and puberty.17 This will be usually as hypocalcaemic convulsions or episodes of tetany. Another important presentation in infancy is with cardiomyopathy which can be life threatening.18 A phenomenon that can be seen in these age groups is the presence of a raised plasma phosphate despite a high PTH level which occasionally can cause confusion with PHP. Vitamin D levels should always be checked before making a diagnosis of PHP.

This PTH resistance in the renal tubules appears to be due to associated dietary calcium deficiency which will correct when adequate calcium intake is supplied.19

Any of the calcipenic forms of rickets due to defects in vitamin D metabolism or action may present with hypocalcaemia. Chronic renal or liver failure can also present with hypocalcaemia although rickets is a more common presenting feature. In the former, it is due to inadequate synthesis of 1,25(OH)2D3 and the failure to excrete phosphate while in liver failure is predominantly due to malabsorption of calcium and vitamin D.

Autosomal dominant hypocalcaemia

This condition is suspected when PTH levels are inappropriately normal during hypocalcaemia and is due to gain of function mutations of the CaSR. The most common form, ADH type 1 is due to a mutation in the CaSR gene, whereas a second form ADH type 2 is due to a mutation in the GNA11 (G protein subunit alpha 11) gene.20 In this condition, there is an altered set point in the parathyroid glands and kidneys such that a lower plasma calcium is required to trigger PTH release (figure 4). Such individuals have plasma calcium below the normal range often 1.8 to 2.0 mmol/L and increased renal calcium excretion (although urinary calcium excretion may be normal in ADH type 2). In at least 40% of affected individuals, the PTH is within the normal range whereas the rest will have a low PTH. Approximately 50% of individuals with ADH are asymptomatic, whereas the other 50% especially children will be symptomatic during febrile episodes or in the neonatal period.21 Treatment with a vitamin D analogue and/or calcium supplements should be reserved for symptomatic individuals due to the high risk of hypercalciuria and nephrocalcinosis. An alternative treatment option is the use of synthetic PTH by subcutaneous injection or infusion with a pump.

Figure 4

Relationship between ionised calcium and serum parathyroidhormone (PTH) with shift in relationship seen in autosomal dominant hypocalcaemia.34 Also note the effect of inactivating calcium sensing receptor (CaSR) mutations causing the pathophysiologically opposite condition, familial hypocalciuric hypercalcaemia.

Normally there is incremental PTH release in response to a decrease in plasma calcium levels. However in activating mutations of the CaSR, the set point for PTH release is altered such that the curve shifts to the left, reducing PTH output, resulting in ambient hypocalcaemia (figure 4).

Diagnosis in case II

This infant had severe vitamin D deficiency resulting in congestive cardiac failure due to hypocalcaemic cardiomyopathy. Mum and sibling also had severe vitamin D deficiency.

Clinical scenario III: a 6-year old with carpopedal spasms

A female child aged 6 years presented with carpopedal spasms during an episode of acute gastroenteritis. She reported similar episodes over the past few weeks. She was previously fit and well. Her plasma calcium level was 1.23 mmol/L (2.2–2.7), phosphate 2.75 mmol/L (0.90–1.80), PTH 5.0 ng/L (11–35), 25(OH) vitamin D 31 nmol/L (>50 nmol/L) and creatinine 46 μmol/L (18–51). The presence of low PTH levels during concomitant hypocalcaemia suggested hypoparathyroidism. She was started on a vitamin D analogue (alfacalcidol) and calcium supplementation. The differential diagnosis at this age is acquired hypoparathyroidism and ADH.

Acquired hypoparathyroidism

The most important cause of acquired hypoparathyroidism is the autoimmune polyendocrinopathy syndrome (autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED)) due to mutations in the autoimmune regulator gene (AIRE) inherited in an autosomal recessive manner.22 This condition often presents with hypoparathyroidism as the first endocrine manifestation with the subsequent potential development of adrenal insufficiency, hypogonadism, thyroid disease and diabetes mellitus over several decades.23 Non-endocrine manifestations include malabsorption, chronic active hepatitis and hyposplenism. It is important to consider this condition in any child presenting with hypoparathyoidism in early to mid-childhood (table 2) and once a gene defect is identified to ensure that any siblings are investigated. Any child with this condition should undergo annual screening for adrenal insufficiency with a Synacthen test and plasma renin. Some children with congenital hypoparathyroidism may also present at this age with a delayed presentation.

Acquired hypoparathyroidism may also be a consequence of surgery to the neck, for example, for thyroid disease or due to iron deposition in the parathyroid glands from repeated blood transfusions in children with thalassaemia major or rarely as a complication of Wilson’s disease.

Diagnosis in case III

An AIRE gene mutation confirmed APECED. Two years later, she became acutely unwell with dehydration and hypercalcaemia. Her urea 9.2 mmol/L and plasma calcium 2.9 mmol/L (2.2–2.7) were elevated, with normal creatinine and serum electrolytes, high plasma renin 35 nmol/L/hour (0.5–2.2) and plasma adrenocorticotrophic hormone 663 nmol/L (9-–52) indicating the development of primary adrenal insufficiency.

Clinical scenario IV: a 15-year old with muscle cramps

A boy aged 15 years presented with a 1 year history of muscle cramps and jaw locking. He had an uneventful previous medical history and normal intelligence. His plasma calcium was 1.4 mmol/L, phosphate 3.15 mmol/L (0.90–1.80), creatinine 68 μmol/L (43–75), 25(OH) vitamin D 49 nmol/L (>50 nmol/L), PTH 378 ng/L (11–35) and urine calcium/creatinine ratio 0.06 mmol/mmol (<0.7).

At this age, the differential diagnosis would be vitamin D deficiency, hypoparathyroidism or PHP.

The term PHP

PHP covers a number of related disorders in which resistance to PTH is the predominant feature. Those who present with hypocalcaemia resemble hypoparathyroidism with an elevated plasma phosphate but instead of a low PTH have a high PTH. Most of the disorders are due to a genetic or epigenetic defect in the GNAS (guanine nucleotide binding protein alpha subunit) gene on chromosome 20 and are an example of imprinting, that is, repression of gene expression from one parental allele.24 25 There are several types with distinctive features. The most well-known type is PHP type 1A in which affected individuals have features of AHO. Resistance to other hormones may also be found such as hypothyroidism and hypogonadism and growth hormone deficiency. Although this is a congenital disorder, hypocalcaemia does not usually present until mid-childhood due to the fact that paternal silencing of Gs alpha expression in the proximal renal tubule occurs postnatally.26

PHP type 1B does not have AHO features but may also have additional hormone resistance particularly hypothyroidism. PTH resistance develops over time and affected individuals often do not present with symptomatic hypocalcaemia until their teenage years. It is now recognised that there is considerable overlap in the different types of PHP which has led to a revised classification.27

Diagnosis in case IV

This boy has PHP type 1B. The late age of presentation is likely due to an increased demand for calcium at the time of increased linear growth from the pubertal growth spurt.

His thyroid function tests were normal. Genetic testing confirmed loss of maternal methylation pattern in GNAS (PHP1B). He was treated with long-term vitamin D analogue and calcium supplements.

Treatment of hypocalcaemia

This is dependent on two factors: (1) whether there are severe symptoms such as convulsions and the (2) the underlying cause. Intravenous calcium gluconate is used in acute symptomatic hypocalaemia. Various calcium salts are available for oral treatment. It is important to calculate the dose based on the elemental calcium content and not the calcium salt. (The equivalence of 1 mmol of elemental calcium is 40 mg.)

Urgent correction

It is given using an intravenous bolus of 10% calcium gluconate (1 mL of 10% calcium gluconate contains 0.22 mmol of elemental calcium) in a dose of 0.5 to 2 mL/kg over 5 to 10 min (with a maximum of 20 mL) followed by a continuous infusion of 1.0 mmol/kg under cardiac monitoring (maximum 8.8 mmol, occasionally higher doses may be needed) over 24 hours. A continuous intravenous infusion (preferably through a central line) must be started after a bolus to prevent recurrent symptoms. It is important to try and discontinue an intravenous infusion once the severe symptoms have settled, in favour of oral calcium supplements due to the risk of extravasation of calcium causing damage to skin and subcutaneous tissues.

Non-urgent correction

It is used in asymptomatic or mildly symptomatic children as oral calcium supplements given in a dose ranging from 0.2 to 10 mmol/kg per dose every 6 hours . The dose should be titrated based on response. When stopping high doses of oral calcium, it is important to do so gradually with intermittent monitoring of serum calcium levels.


Hypomagnesaemia can be treated with intramuscular or intravenous infusion of 50% magnesium sulfate 0.1–0.2 mL/kg (50–100 mg/kg). This should be followed by oral magnesium at the dose of 0.2 to 0.4 mmol/kg/day. Primary hypomagnesaemia requires long-term oral magnesium supplementation in a dose of 0.7 to 3.5 mmol/kg/day.

Long-term management of hypoparathyroidism and PHP

Though recombinant PTH preparations are available, their routine use in clinical practice is limited by cost and pharmacokinetic properties necessitating a subcutaneous route of administration. The cornerstone of treatment remains life-long treatment with vitamin D analogues, such as alfacalcidol or 1,25(OH)2D3 (calcitriol) in a dose of 25–50 ng/kg/day. These drugs primarily increase intestinal calcium absorption. Calcium supplements are usually required initially but can often be discontinued when the plasma calcium is normal if there is an adequate dietary calcium intake. The aim should be to maintain the plasma calcium at the lower end of the normal range (2.0 to 2.2 mmol/L) as renal calcium reabsorption remains low due to the lack of PTH activity with the risk of hypercalciuria. Monitoring should therefore include periodic assessment of the urine calcium/creatinine ratio and renal ultrasounds to detect nephrocalcinosis. During periods of intercurrent illness, these children tend to develop hypocalcaemia and may require increased doses of the vitamin D analogue.28 It is important that after recovery from intercurrent illnesses dose of medication is reduced to original doses or there would be risk of hypercalcaemia and nephrocalcinosis.

Recombinant full-length human PTH (1–84) has a short half life of 2.5 to 3 hours and it has to be administered as twice daily injections.29 It has not been used in children. Clinical trials in adults have shown good efficacy, however long term safety needs to be further studied.30 Continuous subcutaneous infusion of recombinant PTH1–34 has successfully been used in children with hypoparathyroidism who were difficult to manage on conventional therapy31 32; however, its use is not licensed in children and no randomised trials have been performed .

Vitamin D disorders

Vitamin D deficiency should be treated with ergocalciferol (D2) or cholecalciferol (D3) in doses ranging from 3000 to 10 000 units daily for 8 to 12 weeks or as a single large bolus dose of 150 000 to 3 00 000 units. Calcium supplements should also be given initially.33 Activated vitamin D (alfacalcidol) must not be used to treat vitamin D deficiency. Its role is limited to short-term use to correct severe, symptomatic hypocalcaemia. Stores of cholecalciferol are not replenished with analogue therapy, predisposing to recurrent vitamin D deficiency.

Vitamin D 1-alpha hydroxylase deficiency (vitamin D dependant rickets type 1) requires alfacalcidol or calcitriol in conjunction with calcium supplements. Hereditary 1,25(OH)2D3 resistant rickets (vitamin D dependant rickets type II) may respond to alfacalcidol or calcitriol in the milder forms but will often require intravenous calcium infusions via a central line to heal the rickets and correct the hypocalcaemia.



  • Contributors Both authors have contributed to the entire process of planning, review of literature and manuscript preparation for this article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Data availability statement Data sharing not applicable as no datasets generated and/or analysed for this study.