Total and ionized calcium in the blood

Reference values (norm) for the concentration of total calcium in the blood serum are 2.15-2.5 mmol/l or 8.6-10 mg%; ionized calcium - 1.15-1.27 mmol/l.

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Determination of the level of ionized calcium

Ionized calcium can be measured by routine laboratory tests, usually with reasonable accuracy. Acidosis increases ionized calcium by decreasing protein binding, whereas alkalosis decreases ionized calcium. In hypoalbuminemia, detectable plasma calcium is usually low, reflecting low protein-bound calcium, whereas ionized calcium may be normal. Total plasma calcium decreases or increases by 0.8 mg/dL (0.2 mmol/L) for every 1 g/dL decrease or increase in albumin. Thus, an albumin level of 2 g/dL (normal 4.0 g/dL) decreases detectable plasma calcium by 1.6 mg/dL. Also, elevated plasma proteins, as occurs in multiple myeloma, may increase total plasma calcium.

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Physiological significance of calcium

Calcium is necessary for normal muscle contraction, nerve impulse conduction, hormone release, and blood clotting. Calcium also helps regulate many enzymes.

Maintenance of calcium stores in the body depends on dietary calcium intake, gastrointestinal absorption of calcium, and renal excretion of calcium. With a balanced diet, calcium intake is about 1,000 mg per day. About 200 mg per day is lost in bile and other gastrointestinal secretions. Depending on the concentration of circulating vitamin D, especially 1,25-dihydroxycholecalciferol, which is formed in the kidneys from the inactive form, about 200-400 mg of calcium is absorbed in the intestine each day. The remaining 800-1,000 mg appears in the feces. Calcium balance is maintained by renal calcium excretion, which averages 200 mg per day.

Extracellular and intracellular calcium concentrations are regulated by bidirectional calcium transport across cell membranes and intracellular organelles such as the endoplasmic reticulum, sarcoplasmic reticulum of muscle cells, and mitochondria. Cytosolic ionized calcium is maintained at micromolar levels (less than 1/1000 of the plasma concentration). Ionized calcium acts as an intracellular second messenger; it is involved in skeletal muscle contraction, cardiac and smooth muscle excitation and contraction, protein kinase activation, and enzyme phosphorylation. Calcium is also involved in the action of other intracellular messengers such as cyclic adenosine monophosphate (cAMP) and inositol 1,4,5 triphosphate, and thus is involved in the transmission of the cellular response to numerous hormones including epinephrine, glucagon, ADH (vasopressin), secretin, and cholecystokinin.

Despite its important intracellular role, nearly 99% of the total body calcium is located in bone, primarily as hydroxyapatite crystals. About 1% of bone calcium is freely exchangeable with the ECF and can therefore participate in buffering changes in calcium balance. Normal plasma calcium levels range from 8.8 to 10.4 mg/dL (2.2 to 2.6 mmol/L). About 40% of the total blood calcium is bound to plasma proteins, primarily albumin. The remaining 60% is ionized calcium plus calcium complexed with phosphate and citrate. Total calcium (i.e., protein-bound, complexed, and ionized) is usually measured clinically in the laboratory. Ideally, ionized or free calcium should be measured because it is the physiologically active form in plasma; however, due to technical difficulties, such determinations are usually limited to patients suspected of having a significant defect in protein calcium binding. Ionized calcium is generally considered to constitute approximately 50% of the total plasma calcium.

The physiological significance of calcium is to reduce the ability of tissue colloids to bind water, reduce the permeability of tissue membranes, participate in the construction of the skeleton and the hemostasis system, as well as in neuromuscular activity. It has the ability to accumulate in places of tissue damage by various pathological processes. Approximately 99% of calcium is found in bones, the rest is mainly in the extracellular fluid (almost exclusively in the blood serum). Approximately half of the serum calcium circulates in ionized (free) form, the other half is in a complex, mainly with albumin (40%) and in the form of salts - phosphates, citrate (9%). Changes in the content of albumin in the blood serum, especially hypoalbuminemia, affect the total concentration of calcium, without affecting the clinically more important indicator - the concentration of ionized calcium. The "corrected" total concentration of calcium in the serum in hypoalbuminemia can be calculated using the formula:

Ca (corrected) = Ca (measured) + 0.02×(40 - albumin).

Calcium fixed in bone tissue interacts with serum ions. Acting as a buffer system, deposited calcium prevents its serum content from fluctuating over large ranges.

Calcium metabolism

Calcium metabolism is regulated by parathyroid hormone (PTH), calcitonin and vitamin D derivatives. Parathyroid hormone increases serum calcium concentration by enhancing its leaching from bones, reabsorption in the kidneys and stimulating the conversion of vitamin D into the active metabolite calcitriol. Parathyroid hormone also enhances renal excretion of phosphate. Blood calcium levels regulate parathyroid hormone secretion via a negative feedback mechanism: hypocalcemia stimulates and hypercalcemia suppresses parathyroid hormone release. Calcitonin is a physiological antagonist of parathyroid hormone; it stimulates renal calcium excretion. Vitamin D metabolites stimulate intestinal absorption of calcium and phosphates.

The calcium content in the blood serum changes with dysfunction of the parathyroid and thyroid glands, neoplasms of various localizations, especially with metastasis to the bones, with renal failure. Secondary involvement of calcium in the pathological process occurs with gastrointestinal pathology. Often, hypo- and hypercalcemia can be the primary manifestation of the pathological process.

Regulation of calcium metabolism

Calcium and phosphate (PO) metabolism are interrelated. Regulation of calcium and phosphate balance is determined by circulating levels of parathyroid hormone (PTH), vitamin D, and to a lesser extent calcitonin. Calcium and inorganic PO concentrations are related by their ability to participate in a chemical reaction to form CaPO. The product of calcium and PO concentration (in mEq/L) is normally 60; when the product exceeds 70, precipitation of CaPO crystals in soft tissues is likely. Precipitation in vascular tissue contributes to the development of arteriosclerosis.

PTH is produced by the parathyroid glands. It has various functions, but perhaps the most important is the prevention of hypocalcemia. Parathyroid cells respond to a decrease in plasma calcium by releasing PTH into the circulation. PTH increases plasma calcium within minutes by increasing renal and intestinal absorption of calcium and by mobilizing calcium and PO from bone (bone resorption). Renal calcium excretion is generally similar to sodium excretion and is regulated by much the same factors that control sodium transport in the proximal tubule. However, PTH increases calcium reabsorption in the distal nephron independently of sodium. PTH also decreases renal reabsorption of PO and thus increases renal PO losses. Renal PO losses prevent an increase in plasma Ca2+PO2 binding product because calcium levels rise in response to PTH.

PTH also increases plasma calcium levels by converting vitamin D to its most active form (1,25-dihydroxycholecalciferol). This form of vitamin D increases the percentage of calcium absorbed from the intestine. Despite increased calcium absorption, increased PTH secretion typically leads to further bone resorption by suppressing osteoblastic function and stimulating osteoclast activity. PTH and vitamin D are important regulators of bone growth and remodeling.

Tests for parathyroid function include determination of circulating PTH levels by radioimmunoassay and measurement of total or nephrogenic urinary cAMP excretion. Urinary cAMP testing is rare, but accurate PTH assays are common. The best assays are for intact PTH molecules.

Calcitonin is secreted by the parafollicular cells of the thyroid gland (C cells). Calcitonin lowers plasma calcium concentrations by increasing cellular calcium uptake, renal excretion, and bone formation. The effects of calcitonin on bone metabolism are much weaker than those of PTH or vitamin D.