As part of routine testing, in persons with kidney , bone, or nerve disease, or when symptoms of significantly increased or decreased calcium concentrations are present.
A blood sample drawn from a vein in your arm; a timed urine collection may be used when blood calcium is abnormal; urine calcium may also be requested if you have kidney stones. Calcium is one of the most important minerals in the body. It is essential for the proper functioning of muscles, nerves and the heart and is required in blood clotting and in formation of bones. Roughly half of the calcium is referred to as 'free' and is active. The remaining half is 'bound' calcium.
It is attached to albumin and other compounds and is metabolically inactive. There are two tests to measure plasma calcium. The total calcium test measures both the free and bound forms. The ionised calcium test measures only the free, metabolically active form. Some calcium is lost from your body every day, filtered from the blood by the kidneys and excreted into the urine. The amount of calcium excreted is regulated by the body to keep the calcium in the blood within a narrow range. Measurement of the amount of calcium in the urine is used to determine how much calcium is being eliminated by the kidneys.
A blood sample is taken by needle from a vein in the arm. If a urine collection is required, a timed collection is best. Plasma calcium is tested to screen for, diagnosis, and monitor a range of conditions relating to the bones, heart, nerves, kidneys and teeth.
Plasma calcium levels do not directly tell how much calcium is in the bones, but rather, how much calcium is circulating in the blood. A total calcium level is often measured as part of health screening. When an abnormal total calcium result is obtained it is viewed as an indicator of some kind of underlying problem. To help diagnose the underlying problem, additional tests are often done to measure ionised calcium, urine calcium, phosphate , magnesium , vitamin D and parathyroid hormone PTH.
PTH and vitamin D are responsible for maintaining calcium concentrations in the blood within a narrow range of values. Measuring calcium and PTH together can help determine whether the parathyroid gland is functioning normally. Frequently the balance among these different substances, and the changes in them, are just as important as the concentrations. The total calcium test is the test most frequently ordered to evaluate calcium status. In most cases it is a good reflection of the amount of free calcium involved in metabolism since the balance between free and bound is usually stable and predictable.
Many laboratories report corrected calcium or Ca corr which is just total calcium adjusted to compensate for abnormally high or low levels of albumin in the blood which can cause the total calcium level to appear falsely high or low.
However in a few patients, the balance between bound and free calcium is disturbed and total calcium or even corrected calcium is not a good reflection of calcium status. In those circumstances, measurement of ionised calcium is necessary. Some conditions where ionised calcium should be the test of choice include: critically ill patients who are receiving transfusions or IV fluids, patients undergoing major surgery, and patients with blood protein abnormalities like low albumin.
Large fluctuations in ionised calcium can cause the heart to slow down or to beat too rapidly, can cause muscles to go into spasm tetany , and can cause confusion or even coma. In critically ill patients, it is extremely important to know the ionised calcium level to be able to intervene and prevent serious complications. Am J Kidney Dis ; 15 : — Am J Nephrol ; 16 : — Nephrol Dial Transplant ; 10 : — Ann Intern Med ; 88 : — Kidney Int ; 35 : — Morton AR, Hercz G.
Hypercalcaemia in dialysis patients: comparison of diagnostic methods. Dialysis Transplant ; 20 : — Calcium in patients on hemodialysis. Clin Nephrol ; 43 : — Am J Kidney Dis ; 21 : — Albumin analysis in serum of haemodialysis patients: discrepancies between bromocresol purple, bromocresol green and electroimmunoassay. Ann Clin Biochem ; 22 : — Mabuchi H, Nakahashi H.
Underestimation of serum albumin by the bromcresol purple method and a major endogenous ligand in uremia. Clin Chim Acta ; : 89 — Bromcresol purple method for serum albumin gives falsely low values in patients with renal insufficiency. Clin Chim Acta ; : 83 — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Subjects and methods. Clase , Catherine M. Oxford Academic. Google Scholar. Geoffrey L. Mary Louise Beecroft. David N. Revision received:. Cite Cite Catherine M. Select Format Select format. Permissions Icon Permissions. Abstract Background. Patient demographics.
Open in new tab. Laboratory values. A scatter plot of the difference between ionized and total calcium both expressed as z scores against serum albumin Fig. Open in new tab Download slide. Intraclass correlation coefficients. Multivariate regression. J Clin Endocrinol Metab. J Clin Invest. J Biol Chem.
Clin Chim Acta. Br Med J. Am J Kidney Dis. Am J Nephrol. Nephrol Dial Transplant. Ann Intern Med. Kidney Int. Dialysis Transplant. Clin Nephrol. Ann Clin Biochem. Issue Section:. Download all slides. Comments 0. Add comment Close comment form modal. I agree to the terms and conditions. You must accept the terms and conditions. Add comment Cancel. The principle target organs of PTH are bone and the kidneys.
By its action on osteoclasts, PTH promotes resorption of bone and thereby movement of calcium from bone to blood. In the renal tubules, PTH promotes calcium reabsorption to blood.
The net effect of PTH, then, is reduced calcium in bone, reduced excretion of calcium and increased plasma calcium concentration. Calcitriol alternative name 1,dihydroxycalciferol is produced in the kidneys from a vitamin D-derived substance, hydroxycholecalciferol. PTH stimulates the enzymatic conversion of hydroxycholecalciferol to calcitriol. In common with PTH, calcitriol secretion is promoted by reduced plasma ionized calcium concentration and inhibited by raised plasma ionized calcium concentration.
The principal target tissue of calcitriol is the gastrointestinal tract where it promotes absorption of dietary calcium. The effect, then, is to raise plasma calcium concentration. By the integrated action of PTH, calcitriol and the negative feedback effect of ionized calcium concentration on release of these hormones, ECF plasma calcium concentration is maintained within normal limits.
For well over 50 years the most common method of assessing calcium status has been to measure concentration of total calcium i. The colorimetric methods that continue to be used to measure total calcium are robust and available on all major clinical chemistry automated platforms.
There are few potential preanalytical errors associated with measurement of total calcium, and the blood sample used for routine biochemistry profiling can also be used for total calcium measurement. In addition to the great ease and convenience of measuring total calcium, the test has the advantage of familiarity; clinicians feel comfortable interpreting results [6].
For as long as calcium has been routinely measured in clinical laboratories, it has been appreciated that the physiological activity of calcium resides in the ionized fraction of total calcium and that this is the fraction that is clinically significant [7]. The clinical validity of total calcium measurement is based on the assumption that total calcium concentration accurately reflects ionized calcium activity.
Whilst that is the case in healthy individuals, it is not necessarily the case in some sick individuals. The two principal clinical situations in which total calcium concentration does not sufficiently accurately reflect ionized calcium activity are:. The significance of serum protein concentration lies in the observation that the amount of calcium bound by serum proteins is directly proportional to protein concentration.
If serum protein concentration increases, then the concentration of protein-bound calcium and therefore total calcium concentration increases. Conversely, if plasma protein concentrations decrease, total plasma calcium decreases.
The important point is that despite an increase or decrease in measured total calcium concentration, ionized calcium concentration, the physiologically and clinically important parameter, remains essentially unchanged. Since most of the protein-bound calcium in serum is bound to albumin, it is change in serum albumin concentration that is most significant in affecting total calcium concentration.
Interpretation of total calcium results should always include due consideration of serum albumin concentration. To mitigate the effect of abnormal serum protein concentration on total calcium measurement, a number of formulae have been devised for estimation of "corrected" total calcium concentration from measured total calcium and either serum albumin or protein concentration [].
One of the most widely used ones in the US is the so-called "modified" Orrell correction [1]:. Whichever formula is used, "corrected" calcium is an estimate of the total calcium concentration, had serum protein albumin concentration been normal. Although "corrected" total calcium reflects ionized calcium more accurately than uncorrected total calcium in patients with abnormal serum protein concentration, none of the correction formulae are entirely reliable for all patients.
This is because the formulae do not, nor could they, take account of all the many factors that can affect calcium binding in particular patients.
The limitations of the correction formulae have been exposed by a number of studies that have focused principally, although not exclusively, on the critically ill []. In common with other studies, "corrected" serum calcium was found to underestimate the prevalence of hypocalcemia and overestimate the prevalence of normocalcemia. Given that hypoalbuminemia is a common feature of critical illness and that none of the correction factors applied to total calcium results are reliable in predicting ionized calcium concentration in this patient group [15], measurement of total calcium is considered an inappropriate measure of calcium status among the critically ill.
For this patient population, at least, the only reliable means of assessing calcium status is to measure ionized calcium directly. Blood pH is a major determinant of the proportion of total calcium that is bound to protein, principally because hydrogen ions compete with calcium ions for protein binding sites [17]. A decreased pH acidosis is associated with decreased calcium binding and therefore increased proportion of total calcium in the ionized state.
To give some idea of the magnitude of this effect, each 0. By the same mechanism, raised blood pH alkalosis causes reduction in serum ionized calcium concentration. Since this phenomenon is merely a shift of calcium from one fraction to another, total calcium concentration is not affected. Despite what may well be a clinically significant change in calcium status, serum total calcium concentration remains unchanged.
The most reliable way of assessing calcium status among patients with concomitant acid-base disturbance is to measure ionized calcium directly.
Ionized calcium has been shown to be more reliable than total corrected calcium in some other patient groups, including those suffering mild hyperparathyroidism [19] and those with renal failure [20].
In health, plasma ionized calcium concentration is maintained between approximately 1. However, among certain patient groups, most notably the critically ill and neonates, hypocalcemia is the more common derangement. The two most common causes of hypercalcemia are primary hyperparathyroidism and malignant disease cancer.
In a tiny minority, excessive PTH is due to abnormal increase in size hyperplasia of all parathyroid glands or parathyroid cancer. The condition can occur at any age and in both sexes, but postmenopausal women are the most commonly affected. Excessive PTH secretion leads to bone demineralization osteoporosis and chronic hypercalcemia that predisposes to urine-stone formation and renal damage. In rare cases, the hypercalcemia is of sufficient severity to threaten life [22].
Surgical removal of the offending adenoma is curative. Hypercalcemia can be a complication of soft-tissue cancer, most commonly cancers of breast, lung and esophagus.
Hypercalcemia is also a common feature of multiple myeloma, a hematological malignancy of plasma cells in bone marrow. Taken together, malignant disease is the second most common cause of hypercalcemia. One of the principal causes of hypercalcemia in these cases is uncontrolled excessive production by tumor cells of a protein called parathyroid hormone-related peptide PTHrP [23].
This is, as its name implies, similar to PTH in both structure and action. Like PTH, it increases plasma calcium by resorbing bone and decreasing calcium excretion. The uncontrolled action of PTHrP inevitably results in abnormal loss of calcium from bone and consequent hypercalcemia. Direct destruction of bone tissue osteolysis by tumor cells that have metastasized to bone can also result in hypercalcemia; this is the principal mechanism of the hypercalcemia associated with multiple myeloma.
Generally speaking, hypercalcemia develops late in malignant disease and is a poor prognostic sign [24]. It is still important to detect because treatment aimed at normalizing calcium provides relief from symptoms of hypercalcemia, which in turn materially improves the quality of life of affected cancer patients [25]. Rare causes of hypercalcemia [26] include chronic renal failure, hyperthyroidism, sarcoidosis and tuberculosis.
Some drugs, including thiazide diuretics and lithium, can precipitate hypercalcemia, as can ingestion of excessive vitamin D. Hypocalcemia is much less common than hypercalcemia [27] except in two patient groups: the critically ill and neonates.
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