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.
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:
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:
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:
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).
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)
Isolated or part of a complex developmental anomaly (e.g. Di George syndrome)
Reduced parathyroid function (i.e. parathyroid hormone secretion)
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)
Most common causes
2 Hypocalcaemic clinical features of neuromuscular irritability
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)