Chapter 71: Disorders of Calcium Metabolism

BACKGROUND

Calcium is the most abundant mineral in the body and is required for proper functioning of numerous intracellular and extracellular processes, including muscle contraction, nerve conduction, hormone release, and blood coagulation. Calcium also plays a unique role in intracellular signaling and is involved in the regulation of enzyme activity. Maintenance of calcium homeostasis is therefore critical. Ionized calcium, which is responsible for the physiologic effects, is maintained under normal conditions within a narrow normal range of approximately 4.5 to 5.3 ng/dL (1.12–1.32 mmol/L), with higher levels in neonates and infants.

The majority of total body calcium exists as bone mineral, with serum calcium representing less than 1% of total body calcium. Although total serum calcium levels are routinely measured, it is the ionized fraction that is biologically active. Total serum calcium levels include both ionized and bound calcium. The total calcium level reflects serum changes in albumin, pH, phosphate, magnesium, and bicarbonate. Ionized calcium may be reduced by exogenous factors such as citrate from transfused blood or free fatty acids from total parenteral nutrition. At physiologic pH, 40% of total serum calcium is bound to albumin, 10% can be bound to bicarbonate, phosphate, or citrate, and the remaining 50% exists in the ionized form.

Calcium absorption and regulation involves a complex interplay between multiple organ systems and regulatory hormones. This tight regulation of circulating calcium is controlled through constant adjustment of parathyroid hormone (PTH) secretion, 1,25-dihydroxyvitamin D (1,25(OH)₂D) production, and renal handling of calcium.

The three major targets for calcium regulation include bone, kidney, and intestine. In bone, PTH stimulates calcium resorption, thereby increasing total and ionized calcium levels. PTH increases intestinal absorption of calcium via activation of 1-α-hydroxylase in the kidney leading to conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)₂D. Increased levels of 1,25(OH)₂D will increase intestinal absorption of calcium and phosphorus. Without vitamin D-dependent calcium absorption, only 10% of ingested calcium will be absorbed through passive, concentration-dependent absorption. PTH increases renal calcium reabsorption and phosphorus excretion. The majority (60%–70%) of calcium is reabsorbed passively in the proximal tubule driven by a gradient that is generated by sodium and water reabsorption. Individuals with normal kidney function have protection against calcium overload by virtue of their ability to increase renal excretion of calcium and reduce intestinal absorption of calcium by actions of PTH and 1,25(OH)₂D.¹

Calcitonin plays a minor role in decreasing serum calcium levels via its effect on bone and the kidney. Serum calcium levels are detected by calcium-sensing receptors (CaSR) located on the parathyroid glands and renal tubule cells resulting in regulation of PTH secretion and renal reabsorption of calcium, respectively.²

CLINICAL PRESENTATION

HYPOCALCEMIA

Hypocalcemia is frequently observed in the inpatient setting, and incidentally noted biochemical hypocalcemia is often asymptomatic. Symptomatic hypocalcemia occurs in response ...