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Overview of Disorders of Calcium Concentration

By James L. Lewis, III, MD

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Calcium is required for the proper functioning of muscle contraction, nerve conduction, hormone release, and blood coagulation. In addition, proper calcium concentration is required for various other metabolic processes.

Maintenance of body calcium stores (to avoid hypocalcemia or hypercalcemia) depends on

  • Dietary calcium intake

  • Absorption of calcium from the GI tract

  • Renal calcium excretion

In a balanced diet, roughly 1000 mg of calcium is ingested each day and about 200 mg/day is secreted into the GI tract in the bile and other GI secretions. Depending on the concentration of circulating parathyroid hormone (PTH) and active vitamin D, 1,25(OH)2D (1,25-dihydroxycholecalciferol, calcitriol ), roughly 200 to 400 mg of this calcium is absorbed from the intestine each day. The remaining 800 to 1000 mg appears in the stool. Calcium balance is maintained through renal calcium excretion averaging 200 mg/day, which also depends on circulating PTH and calcitonin levels.

Both extracellular and intracellular calcium concentrations are tightly regulated by bidirectional calcium transport across the plasma membrane of cells and intracellular organelles, such as the endoplasmic reticulum, the sarcoplasmic reticulum of muscle cells, and the mitochondria.

Ionized calcium is the physiologically active form. Cytosolic ionized calcium is maintained within the micromolar range (< 1/1000 of the serum concentration). Ionized calcium acts as an intracellular 2nd messenger; it is involved in skeletal muscle contraction, excitation-contraction coupling in cardiac and smooth muscle, and activation of protein kinases and enzyme phosphorylation. Calcium is also involved in the action of other intracellular messengers, such as cAMP and inositol 1,4,5-triphosphate, and thus mediates the cellular response to numerous hormones, including epinephrine , glucagon, vasopressin (ADH), secretin, and cholecystokinin.

Despite its important intracellular roles, about 99% of body calcium is in bone, mainly as hydroxyapatite crystals. About 1% of bone calcium is freely exchangeable with the ECF and, therefore, is available for buffering changes in calcium balance.

Normal total serum calcium concentration ranges from 8.8 to 10.4 mg/dL (2.20 to 2.60 mmol/L). About 40% of the total blood calcium is bound to plasma proteins, primarily albumin. The remaining 60% includes ionized calcium plus calcium complexed with phosphate and citrate. Total calcium (ie, protein-bound, complexed, and ionized calcium) is usually what is determined by clinical laboratory measurement.

However, ideally, ionized (or free) calcium should be estimated or measured because it is the physiologically active form of calcium in plasma and because its blood level does not always correlate with total serum calcium.

  • Ionized calcium is generally assumed to be about 50% of the total serum calcium.

  • Ionized calcium can be estimated, based on total serum calcium and serum albumin levels (see Estimation of Ionized Calcium Concentration).

  • Direct determination of ionized calcium, because of its technical difficulty, is usually restricted to patients in whom significant alteration of protein binding of serum calcium is suspected.

Normal ionized serum calcium concentration range varies somewhat between laboratories, but is typically 4.7 to 5.2 mg/dL (1.17 to 1.30 mmol/L).

Regulation of Calcium Metabolism

The metabolism of calcium and of phosphate (see Overview of Disorders of Phosphate Concentration) is intimately related. The regulation of both calcium and phosphate balance is greatly influenced by concentrations of circulating PTH, vitamin D, and, to a lesser extent, calcitonin . Calcium and phosphate concentrations are also linked by their ability to chemically react to form calcium phosphate. The product of concentrations of calcium and phosphate (in mEq/L) is estimated to be < 60 normally; when the product exceeds 70, precipitation of calcium phosphate crystals in soft tissue is much more likely. Calcification of vascular tissue accelerates arteriosclerotic vascular disease and may occur when the calcium and phosphate product is even lower (> 55), especially in patients with chronic kidney disease.

PTH is secreted by the parathyroid glands. It has several actions, but perhaps the most important is to defend against hypocalcemia. Parathyroid cells sense decreases in serum calcium and, in response, release preformed PTH into the circulation. PTH increases serum calcium within minutes by increasing renal and intestinal absorption of calcium and by rapidly mobilizing calcium and phosphate from bone (bone resorption). Renal calcium excretion generally parallels sodium excretion and is influenced by many of the same factors that govern sodium transport in the proximal tubule. However, PTH enhances distal tubular calcium reabsorption independently of sodium.

PTH also decreases renal phosphate reabsorption and thus increases renal phosphate losses. Renal phosphate loss prevents the solubility product of calcium and phosphate from being exceeded in plasma as calcium concentrations rise in response to PTH.

PTH also increases serum calcium by stimulating conversion of vitamin D to its most active form, calcitriol . This form of vitamin D increases the percentage of dietary calcium absorbed by the intestine. Despite increased calcium absorption, long-term increases in PTH secretion generally result in further bone resorption by inhibiting osteoblastic function and promoting osteoclastic activity. PTH and vitamin D both function as important regulators of bone growth and bone remodeling (see Vitamin D Deficiency and Dependency).

Radioimmunoassays for the intact PTH molecule are still the recommended way to test for PTH. Second-generation assays for intact PTH are available. These tests measure bioavailable PTH or complete PTH. They give values equal to 50 to 60% of those obtained with the older assay. Both types of assays can be used for diagnosing primary hyperparathyroidism or monitoring hyperparathyroidism secondary to renal disease, as long as normal ranges are noted.

PTH increases urinary cAMP. Sometimes total or nephrogenous cAMP excretion is measured in diagnosis of pseudohypoparathyroidism.

Calcitonin is secreted by the thyroid parafollicular cells (C cells). Calcitonin tends to lower serum calcium concentration by enhancing cellular uptake, renal excretion, and bone formation. The effects of calcitonin on bone metabolism are much weaker than those of either PTH or vitamin D.

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