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Overview of Disorders of Calcium Concentration

by James L. Lewis, III, MD

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

Maintenance of body Ca stores depends on

  • Dietary Ca intake

  • Absorption of Ca from the GI tract

  • Renal Ca excretion

In a balanced diet, roughly 1000 mg of Ca is ingested each day and about another 200 mg/day is secreted into the GI tract in the bile and other GI secretions. Depending on the concentration of circulating vitamin D, particularly 1,25(OH) 2 D (1,25-dihydroxycholecalciferol, calcitriol , or active vitamin D, which is converted in the kidney from 25(OH)D, the inactive form), roughly 200 to 400 mg of Ca is absorbed from the intestine each day. The remaining 800 to 1000 mg appears in the stool. Ca balance is maintained through renal Ca excretion averaging 200 mg/day.

Both extracellular and intracellular Ca concentrations are tightly regulated by bidirectional Ca transport across the plasma membrane of cells and intracellular organelles, such as the endoplasmic reticulum, the sarcoplasmic reticulum of muscle cells, and the mitochondria. Cytosolic ionized Ca is maintained within the micromolar range (< 1/1000 of the serum concentration). Ionized Ca 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. Ca 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, ADH ( vasopressin ), secretin, and cholecystokinin. Parathyroid hormone (PTH) increases urinary cAMP.

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

Normal total serum Ca concentration ranges from 8.8 to 10.4 mg/dL (2.20 to 2.60 mmol/L). About 40% of the total blood Ca is bound to plasma proteins, primarily albumin. The remaining 60% includes ionized Ca plus Ca complexed with phosphate (PO 4 ) and citrate. Total Ca (ie, protein-bound, complexed, and ionized Ca) is usually what is determined by clinical laboratory measurement. Ideally, ionized or free Ca should be determined because it is the physiologically active form of Ca in plasma; this determination, because of its technical difficulty, is usually restricted to patients in whom significant alteration of protein binding of serum Ca is suspected. Ionized Ca is generally assumed to be about 50% of the total serum Ca.

Regulation of Calcium Metabolism

The metabolism of Ca and of PO 4 (see Overview of Disorders of Phosphate Concentration) is intimately related. The regulation of both Ca and PO 4 balance is greatly influenced by concentrations of circulating PTH, vitamin D, and, to a lesser extent, calcitonin . Ca and inorganic PO 4 concentrations are also linked by their ability to chemically react to form CaPO 4 . The product of concentrations of Ca and PO 4 (in mEq/L) is estimated to be 60 normally; when the product exceeds 70, precipitation of CaPO 4 crystals in soft tissue is much more likely. Calcification of vascular tissue accelerates arteriosclerotic vascular disease and may occur when the Ca × PO 4 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 Ca and, in response, release preformed PTH into the circulation. PTH increases serum Ca within minutes by increasing renal and intestinal absorption of Ca and by rapidly mobilizing Ca and PO 4 from bone (bone resorption). Renal Ca excretion generally parallels Na excretion and is influenced by many of the same factors that govern Na transport in the proximal tubule. However, PTH enhances distal tubular Ca reabsorption independently of Na. PTH also decreases renal PO 4 reabsorption and thus increases renal PO 4 losses. Renal PO 4 loss prevents the solubility product of Ca and PO 4 from being exceeded in plasma as Ca concentrations rise in response to PTH. PTH also increases serum Ca by stimulating conversion of vitamin D (see Vitamin D) to its most active form, calcitriol . This form of vitamin D increases the percentage of dietary Ca absorbed by the intestine. Despite increased Ca 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. 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 Ca 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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