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Hypocalcaemic Disorders

Rajesh V Thakker

The clinical presentation of hypocalcaemia ranges from an asymptomatic biochemical abnormality to a severe, life-threatening condition. There are many causes (Figure 1), which can be classified according to whether serum parathyroid hormone (PTH) concentrations are low (hypopara-thyroid disorders) or high (disorders associated with secondary hyperparathyroidism). The most common causes are hypoparathyroidism, deficiency or abnormal metabolism of vitamin D, acute or chronic renal failure, and hypomagnes-aemia. Normal total serum calcium is 2.15-2.65 mmol/litre.


Clinical features and investigations

Mild hypocalcaemia (serum calcium 2.0-< 2.15 mmol/litre), may be asymptomatic. Those with more severe (serum calcium < 1.90 mmol/litre) and long-term hypocalcaemia may develop acute symptoms of neuromuscular irritability (Figure 2), ectopic calcification (e.g. in the basal ganglia, which may be associated with extrapyramidal neurological symptoms), subcapsular cataract, papilloedema and abnormal dentition. Investigations should be directed at confirming the presence of hypocalcaemia and establishing the cause.

  • In hypoparathyroidism, serum calcium is low, phosphate is high and PTH is undetectable. Renal function and concentrations of the 25-hydroxy and 1,25-dihydroxy metabolites of vitamin D are normal.

  • The features of pseudohypoparathyroidism (PHP) are similar to those of hypoparathyroidism except for PTH levels, which are markedly increased.

  • In chronic renal failure, serum calcium is low, phosphate  is high and alkaline phosphatase, creatinine and PTH are elevated. 25-hydroxy vitamin D3 is normal and 1,25-dihydroxy-vitamin D3 is low.

  • In vitamin D-deficiency osteomalacia, serum calcium and phosphate are low, alkaline phosphatase and PTH are raised, renal function is normal and 25-hydroxy vitamin D3 is low.


Management of acute hypocalcaemia

Management depends on the severity of the hypocalcaemia, the rapidity with which it developed and the degree of neuromuscular irritability. Treatment should be given to:

  • symptomatic patients (e.g. with tetany)

  • asymptomatic patients with serum calcium < 1.90 mmol/litre, who may be at high risk of developing complications.

The preferred treatment for acute symptomatic hypocalcaemia is calcium gluconate, 10 ml 10% w/v (2.20 mmol of calcium) i.v., diluted in 50 ml of 5% dextrose or 0.9% sodium chloride and given by slow injection (> 5 minutes); this can be repeated as required to control symptoms. Serum calcium should be assessed regularly.

Continuing hypocalcaemia may be managed acutely by administration of a calcium gluconate infusion; for example, dilute 10 ampoules of calcium gluconate, 10 ml 10% w/v (22.0 mmol of calcium), in litre of 5% dextrose or 0.9% sodium chloride, start infusion at 50 ml/hour and titrate to maintain serum calcium in the low-normal range. Generally, 0.30—0.40 mmol/kg of elemental calcium infused over 4—6 hours increases serum calcium by 0.5—0.75 mmol/litre. If hypocalcaemia is likely to persist, oral vitamin D therapy should also be commenced.

It is important to note that, in hypocalcaemic patients who are also hypomagnesaemic, the hypomagnesaemia must be corrected before the hypocalcaemia will resolve. This may occur in the post-parathyroidectomy period or in those with severe intestinal malabsorption.


Management of persistent hypocalcaemia

The two major drug groups available for treatment of hypocalcaemia are supplemental calcium, about 10—20 mmol calcium 6—12 hourly, and vitamin D preparations (see page 76). Patients with hypoparathyroidism seldom need calcium supplements after the early stages of stabilization on vitamin D. Various vitamin D preparations have been used, including:

  • vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol), 25,000-100,000 units (1.25-5 mg/day)

  • dihydrotachysterol (now seldom used), 0.25-1.25 mg/day

  • alfacalcidol (la-hydroxycholecalciferol), 0.25—1.0 |Lig/day

  • calcitriol (1,25-dihydroxycholecalciferol), 0.25-2.0 jig/day. In children, these preparations are prescribed in doses based on body weight.

Cholecalciferol and ergocalciferol are the least expensive preparations, but have the longest durations of action and may cause prolonged toxicity. The other preparations, which do not require renal loc-hydroxylation (see page 74), have the advantage of shorter half-lives and thereby minimize the risk of prolonged toxicity. Calcitriol is probably the drug of choice because it is the active metabolite and, unlike alfacalcidol, does not require hepatic 25-hydroxylation.

Close monitoring (at about 1-2-week intervals) of the patient's serum and urine calcium are required initially, and at 3—6-monthly intervals once stabilization is achieved; the aimis to avoid hypercalcaemia, hypercalciuria, nephrolithiasis and renal failure. It should be noted that hypercalciuria may occur in the absence of hypercalcaemia.



Hypocalcaemia is the hallmark of hypoparathyroidism, which may result from agenesis (e.g. Di George syndrome) or destruction of the parathyroid glands (e.g. following neck surgery, in autoimmune diseases), reduced secretion of PTH (e.g. neonatal hypocalcaemia, hypomagnesaemia) or resistance to PTH (which may occur as a primary disorder such as PHP, or secondary to hypomagnesaemia).

Di George syndrome arises from a developmental failure of the derivatives of the third and fourth pharyngeal pouches, causing agenesis or hypoplasia of the thymus (immuno-deficiency) and parathyroids (hypocalcaemia), cleft lip and palate, and congenital heart defects.

Surgical damage to the parathyroids occurs most commonly after radical neck dissection (e.g. for laryngeal or oesophageal carcinoma), total thyroid resection, or repeated parathyroidectomy for multigland disease (e.g. in multiple endocrine neoplasia type 1 or 2, see page 45). Hypocalcaemic symptoms begin 12-24 hours postoperatively and may need treatment with oral or intravenous calcium. Parathyroid function often returns; persistent hypocalcaemia requires treatment with vitamin D preparations.

Autoimmune hypoparathyroidism  may occur as an isolated endocrinopathy, or as part of the polyglandular autoimmune type 1 syndrome. This syndrome comprises hypoparathyroidism, Addison's disease, candidiasis (Figure 3) and two or three of the following:

  • type 1 diabetes mellitus

  • primary hypogonadism

  • autoimmune thyroid disease

  • pernicious anaemia

  • chronic active hepatitis

  • steatorrhoea (malabsorption)

  • alopecia (totalis or areata)

  • vitiligo.

Neonatal hypocalcaemia may occur in the baby of a mother with hypercalcaemia caused by primary hyperpara-thyroidism. Maternal hypercalcaemia results in increased calcium delivery to the fetus, and this fetal hypercalcaemia suppresses fetal PTH secretion. Post-partum, the infant's suppressed parathyroids are unable to maintain normocalcaemia. Therapy may be required; however, the disorder is usually self-limiting.

Severe hypomagnesaemia (< 0.40 mmol/litre) may occur in any severe intestinal malabsorptive disorder (e.g. Crohn's disease) or renal tubular disorder. It is associated with hypoparathyroidism because magnesium is required for the release of PTH from the parathyroid gland and also for PTH action via adenyl cyclase. Magnesium chloride, 35-50 mmol i.v. in 1 litre of 5% glucose or other isotonic solution given over 12-24 hours, may be required; this is repeated to restore normomagnesaemia.

Pseudohypoparathyroidism is characterized by hypocalcaemia caused by PTH resistance. Three major variants are recognized on the basis of biochemical and somatic features - PHP type la (PHPIa), PHP type Ib (PHPIb) and pseudo-pseudohypoparathyroidism (PPHP).

  • Patients with PHPIa exhibit PTH resistance (hypocalcae-mia, hyperphosphataemia, elevated serum PTH, absence of an increase in serum and urinary cyclic AMP and urinary phosphate following intravenous human PTH infusion) associated with the features of Albright's hereditary osteo-dystrophy (AHO), which include short stature, obesity, sub­cutaneous calcification, mental retardation, round facies and brachydactyly (shortening of the metacarpals, particularly the third, fourth and fifth, Figure 4).

  • The term 'PHPIb' is used to describe PTH resistance in the absence of any somatic features of AHO.

  • The term TPHP' is used to describe the somatic features of AHO in the absence of any evidence of PTH resistance.

PHPIa patients may also exhibit resistance to other hormones (e.g. thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone) that act via guanine nucleo-tide protein (G-protein-coupled receptors). Reduced activity of the a subunit of the stimulatory form of the GTP-binding protein (GSαl) has been demonstrated in most patients with PHPIa and PPHP, and mutations of the gene encoding GSαl have also been observed in such patients.


1 Causes of hypocalcaemia

Low parathyroid hormone levels (hypoparathyroidism)

 Parathyroid agenesis

Isolated or part of a complex developmental anomaly (e.g. Di George syndrome)

Parathyroid destruction

  • Surgery

  • Radiation

  • Infiltration by metastases or systemic disease (e.g. haemochromatosis, amyloidosis, sarcoidosis, Wilson's disease, thalassaemia)


  • Isolated

  • Polyglandular (type 1)

Reduced parathyroid function  (i.e. parathyroid hormone secretion)

  • Parathyroid hormone gene defects

  • Hypomagnesaemia

  • Neonatal hypocalcaemia (may be associated with maternal hypercalcaemia)

  • Hungry bone disease (post-parathyroidectomy)

  • Calcium-sensing receptor mutations

High parathyroid hormone levels (secondary hyperparathyroidism)

Vitamin D deficiency

As a result of nutritional lack, malabsorption, liver disease, or acute or chronic renal failure

Vitamin D resistance (rickets)

As a result of renal tubular dysfunction (Fanconi's syndrome), or vitamin D receptor defects

Parathyroid hormone resistance

(e.g. pseudohypoparathyroidism, hypomagnesaemia)


  • Calcium chelators (e.g. citrated blood transfusions, phosphate)

  • Inhibitors of bone resorption (e.g. bisphosphonate, calcitonin, plicamycin)

  • Altered vitamin D metabolism (e.g. phenytoin, ketaconazole)


  • Acute pancreatitis

  • Acute rhabdomyolysis

  • Massive tumour lysis

  • Osteoblastic metastases (e.g. from prostate or breast carcinoma)

  • Toxic shock syndrome

  • Hyperventilation

Most common causes


2 Hypocalcaemic clinical features of neuromuscular irritability

  • Paraesthesia, usually of fingers, toes and circumoral regions

  • Tetany, carpopedal spasm, muscle cramps

  • Chvostek's sign1

  • Trousseau's sign2

  • Seizures of all types (focal or petit mal, grand mal or syncope)

  • Prolonged QT interval on EGG

  • Laryngospasm

  • Bronchospasm

  1. Chvostek's sign is twitching of the circumoral muscles in response to gentle tapping of the facial nerve just anterior to the ear; it may be present in 10% of normal individuals.

  2. Trousseau's sign is carpal spasm elicited by inflation of a blood pressure to 20 mm Hg above the patient's systolic blood pressure for 3 minutes.

  3. Moniliasis and hyperpigmentation of the hands, particularly over the knuckles, in an 8-year-old with hypoparathyroidism and Addison's disease. The patient also had vitiligo, and thus had some of the features of polyglandular autoimmune syndrome type 1.

  4. Radiograph of the hands in pseudohypoparathyroidism type la. The patient has a normal right hand, but there is shortening of the left fourth metacarpal (brachydactyly). The metatarsals may be similarly shortened.

Rajesh V Thakker is May Professor of Medicine and Head of the Molecular Endocrinology Group at the University of Oxford, UK.

Reprinted with permission from Elsevier LTD from Medicine, Vol 29, 2001, pp 57-59, Thakker: "Hypocalcaemic Disorders (from the Calcium and Bone section)

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