1. GENERAL INFORMATION
1.1 Definition, incidence, risk factors and pathophysiology
Hypocalcaemia is defined as a serum calcium level less than 8.5 mg/dL. Hypocalcaemia is probably more common than hypercalcaemia. While in the past symptomatic hypocalcaemia was mainly a complication of thyroid surgery with accidental removal of the parathyroid glands, it has recently also been described due to bisphosphonates use. It is observed in 39% (grade 3-4: 1.2%) of patients treated with zoledronic acid and causes more complications in patients with a pre-existing vitamin D deficiency. It might also be a complication of osteoblastic metastases (e.g. breast cancer, prostate cancer) or tumour lysis syndrome .
Other causes of hypocalcaemia in cancer patients are hypoalbuminaemia (most common cause), hypomagnesaemia due to cisplatin treatment, hyperphosphataemia, multifactorial enhanced protein-binding, PTH deficiency or resistance, and vitamin D deficiency due to decreased oral intake.
Hypocalcaemia may also be a complication due to hypomagnesaemia (due to pancreatitis, aminoglycoside treatment, amphotericin B, loop diuretics, alcoholism, and malnutrition) which causes end-organ resistance to PTH; acute pancreatitis (due to chelation of calcium by free fatty acids); rhabdomyolysis with increase of phosphates from creatine phosphokinase and other anions (e.g. lactate, bicarbonate) leading to chelation of calcium; sepsis or toxic shock syndrome; hepatic or renal insufficiency; dysfunction of the parathyroid gland due to infiltration by sarcoidosis, tuberculosis or haemochromatosis; medication (e.g. phenobarbital and phenytoin enhancing vitamin D catabolism and decreasing calcium absorption in the gut; foscarnet complexing with calcium; fluoride chelating calcium; estrogens inhibiting bone resorption; cimetidine decreasing gastric pH and slowing fat breakdown; and aluminium or alcohol suppressing PTH.
Calcium is critical for normal cell function, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signalling. Intracellular calcium regulates cyclic adenosine monophosphate (cAMP)-mediated messenger systems and most cellular functions. The intracellular calcium level is controlled by pumps. Of the total body calcium, 99% is found in bone while 1% is present in extracellular fluids.
2.1 Clinical presentation
Acute hypocalcaemia may lead to syncope, congestive heart failure and angina pectoris due to its multiple cardiovascular effects. Other symptoms are muscle cramping, shortness of breath secondary to bronchospasm, tetanic contractions, distal extremity numbness and tingling sensations.
Chronic hypocalcaemia may lead to cataract, dry skin, coarse hair, brittle nails, psoriasis, chronic itching, and poor dentition.
Clinical examination may reveal dry skin and psoriasis, perioral anesthaesia, cataract, papillar oedema, laryngeal stridor, wheezing, dysphagia, stridor, bradycardia, rales, S3 gallop, tetany, focal numbness, and muscle spasms (Chvostek sign, Trousseau sign, main d’acoucheur), irritability, confusion, hallucinations, dementia, extra-pyramidal manifestations and seizures.
Acute hypocalcaemia causes prolongation of the QT interval, which may lead to ventricular dysrhythmias.
Diagnosis is made by determining serum calcium and albumin. Magnesium, phosphate, and other electrolyte levels; BUN and creatinine; liver function tests, coagulation parameters; and the PTH level should also be determined.
Severe, symptomatic hypocalcaemia may result in cardiovascular collapse, hypotension unresponsive to fluids and vasopressors, and dysrhythmias. When recognized and with an appropriate treatment hypocalcaemia has a good prognosis and death occurs seldomly but has been reported. Cancer has a greater impact on morbidity and mortality than hypocalcaemia itself.
All patients treated chronically with bisphosphonates should receive prophylactically 500 mg oral calcium and 400 IU vitamin D daily, as a standard option, on a type C basis.
Symptomatic patients with classic clinical findings of acute hypocalcaemia require immediate treatment with IV calcium (100-300 mg calcium in 5-10 minutes followed by a continuous infusion of calcium at 0.5 mg/kg/h and increased to 2 mg/kg/h) until repletion, as a standard option, on a type C basis.
Most patients with chronic hypocalcaemia are diagnosed by clinical suspicion and laboratory testing. They are treated with oral calcium replacement (1-3 g/d), as a standard option, on a type C basis.
Dr. Dirk Schrijvers (Reviewer)
University Hospital Antwerp – Antwerp, Belgium
Dr. Silvia Spinazzé (Associate Editor)