HORMONAL REGULATION OF CALCIUM HOMEOSTASIS^1,3

The concentration of ionised calcium in the plasma is subject to tight hormonal control, particularly parathyroid hormone (PTH). A G-protein-coupled calcium receptor plays a significant role in the maintenance of calcium homeostasis. This receptor, responsible for sensing extracellular calcium concentration, is present on the cell membrane of the chief cells of the parathyroid and in bone, gut and the kidney. In response to ionised hypocalcaemia, PTH secretion is stimulated, which in turns serves to restore serum calcium levels back to normal by increasing osteoclastic activity in the bone and renal reabsorption of calcium and stimulating renal synthesis of 1,25 OH-D₃ (calcitriol – the active metabolite of vitamin D), which increases gut absorption of calcium.

Calcitriol production is stimulated by hypocalcaemia, and vice versa. Calcitriol increases serum calcium by largely promoting gut reabsorption, and to a lesser extent renal reabsorption of calcium.

Calcitonin, a hypocalcaemic peptide hormone produced by the thyroid, acts as a physiological antagonist to PTH. Although calcitonin has been shown to reduce serum calcium levels in animals by increasing renal clearance of calcium and inhibiting bone resorption, its role in humans is less clear. Despite extreme variations in calcitonin levels, for example total lack in patients who have undergone total thyroidectomy, or excess plasma levels as seen in patients with medullary carcinoma of the thyroid gland, no significant changes in calcium and phosphate metabolism are seen. Calcitonin is useful as a pharmacological agent in the management of hypercalcaemia.

METABOLIC FACTORS INFLUENCING CALCIUM HOMEOSTASIS

Alterations in serum protein, pH, serum phosphate and magnesium closely impact on serum calcium concentrations. Total plasma calcium levels vary with alterations in plasma protein concentration. A correction is made for hypoalbuminaemia by adding 0.2 mmol/l to the measured serum calcium concentration for every 10 g/l decrease in serum albumin concentration below normal (40 g/l). The corresponding correction factor for globulins is –0.04 mmol/l of serum calcium for every 10 g/l rise in serum globulin.

Changes in pH alter calcium protein binding. An increase in pH by 0.1 pH units results in a decrease in ionised calcium by approximately 0.1 mmol/l.⁴

Calcium and phosphate are closely linked by the following reaction in the extracellular fluid: HPO₄²⁻ + Ca²⁺ = CaHPO₄. Increases in serum phosphate shift the reaction to the right. When the calcium phosphate solubility product exceeds the critical value of 5 mmol/l, calcium deposition occurs in the tissues, resulting in a fall in serum calcium concentration and a secondary increase in PTH secretion. Reductions in phosphate concentration lead to corresponding changes in the opposite direction.

As magnesium is required for PTH secretion and end-organ responsiveness, alterations in serum magnesium have an impact on serum calcium concentration.

Turnover of calcium in the bone is predominantly under the control of PTH and calcitriol, although prostaglandins and some of the cytokines also play a role in it. Bone resorption is mediated by osteoclasts, whereas osteoblasts are involved in bone formation. The daily calcium balance is summarised in Table 54.2.

Table 54.2 Daily calcium balance

MEASUREMENT OF SERUM CALCIUM

Most hospital laboratories measure total serum calcium. The normal plasma concentration is 2.2–2.6 mmol/l. However, the ionised form (1.1–1.3 mmol/l) is the active fraction and its measurement is not routine in many laboratories, although most state-of-the-art blood gas analysers can measure serum ionised calcium concentrations. Estimation of ionised calcium from total serum calcium concentration using mathematical algorithms is unreliable in critically ill patients.^5–7 Heparin forms complexes with calcium and decreases ionised calcium.⁸ A heparin concentration of < 15 units/ml of whole blood is therefore recommended for the measurement of ionised calcium.⁹ Anaerobic collection of the specimen is recommended, as CO₂ loss from the specimen may result in alkalosis and reduction in ionised calcium concentration. Calcium levels are also reduced by a concomitant lactic acidosis owing to chelation by lactate ion.¹⁰ Free fatty acids (FFAs) increase calcium binding to albumin and may form a portion of the calcium-binding site.¹¹ Increases in FFAs may be seen in relation to stress, use of steroids, catecholamines and heparin. The impact of pH on calcium measurements has been described above. The normal reference levels of serum calcium are reduced in pregnancy and in the early neonatal period.¹²

HYPERCALCAEMIA IN CRITICALLY ILL PATIENTS

The frequency of hypercalcaemia in critically ill patients is not well established, although it is not as common as hypocalcaemia. Depending on the patient population, the reported incidence ranges from 3–5% to as high as 32%.^13,14 Admission to the intensive care unit (ICU) with a primary diagnosis of a hypercalcaemic crisis is uncommon. Although a number of aetiologies has been described (Table 54.3), in the critical care setting it is usually due to malignancy-related hypercalcaemia, renal failure or posthypocalcaemic hypercalcaemia.¹⁵ Before undertaking a work-up for hypercalcaemia, it is important to exclude false-positive measurements. This is usually the result of inadvertent haemoconcentration during venepuncture and elevation in serum protein, although ionised calcium levels are not reported to be affected by haemoconcentration.¹⁶Pseudohypercalcaemia has also been described in the setting of essential thrombocythaemia. The erroneous result is thought to be due to in vitro release of calcium from platelets, analogous to the pseudohyperkalaemia seen in the same condition.¹⁷

Table 54.3 Causes of hypercalcaemia

From a pathophysiological standpoint, hypercalcaemia may be due to an elevation in PTH, in which case the homeostatic regulatory and feedback mechanisms are preserved, and this is termed equilibrium hypercalcaemia. Alternatively, it could be a non-parathyroid-mediated hypercalcaemia with associated breakdown of homeostatic mechanisms, and this situation is termed dysequilibrium hypercalcaemia.