Serum Calcium
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Calcium concentration, both total and free, is characterized by a high physiological variation, depending on age, sex, physiological state (eg, pregnancy), and even season (owing to the seasonal variation of vitamin D, which is directly involved in the regulation of calcium concentration). Therefore, separate reference intervals have been established according to the age and sex of the individual being tested.
Total calcium reference ranges in males are as follows:
Younger than 12 months: Not established
Age 1-14 years: 9.6-10.6 mg/dL
Age 15-16 years: 9.5-10.5 mg/dL
Age 17-18 years: 9.5-10.4 mg/dL
Age 19-21 years: 9.3-10.3 mg/dL
Age 22 years and older: 8.9-10.1 mg/dL
Total calcium reference ranges in females are as follows:
Younger than 12 months: Not established
Age 1-11 years: 9.6-10.6 mg/dL
Age 12-14 years: 9.5-10.4 mg/dL
Age 15-18 years: 9.1-10.3 mg/dL
Age 19 years and older: 8.9-10.1 mg/dL
Free (ionized) calciumreference ranges in males are as follows:
Younger than 12 months: Not established
1-19 years: 5.1-5.9 mg/dL
Age 20 years and older: 4.8-5.7 mg/dL
Free (ionized) calciumreference ranges in females are as follows:
Younger than 12 months: Not established
1-17 years: 5.1-5.9 mg/dL
Age 18 years and older: 4.8-5.7 mg/dL
Calcium (urine) reference ranges are as follows*:
Males: 25-300 mg/24-hour urine collection
Females: 20-275 mg/24-hour urine collection
Hypercalciuria: >350 mg/specimen
*Values are for persons with average calcium intake (ie, 600-800 mg/day)
Measurement of the ionized calcium component is generally obtained in specialized laboratories and through a special procedure. In most laboratories, autoanalyzers are used to measure the total serum calcium level accurately and reproducibly, although atomic absorption spectrophotometers probably provide even greater accuracy.
Unless serum proteins contain abnormalities, total serum calcium concentration is normally between 8.5 and 10.2 mg/dL of serum. Because ionized calcium is the only component of the total serum calcium level that is regulated by calciotropic hormones, decisions on the total serum calcium concentration should not be made unless changes in concentrations of plasma proteins, particularly albumin, are considered.
Total serum calcium is less difficult to measure than the ionized calcium component is, and ionized calcium measurements are rarely needed if serum protein concentrations can be measured.
In patients multiple myeloma, the globulin concentration is often increased, leading to excessive binding of calcium to the monoclonal paraprotein and occasional elevation of the total serum calcium concentration, yet the ionized calcium level may be normal in these individuals. Assessment of ionized calcium would be useful in such patients. It should be emphasized that these patients frequently have bone lesions, which leads to release of calcium from the damaged bone tissue.
Although serum calcium levels above 11.5 mg/dL commonly cause symptoms, patients may be asymptomatic at this level. Critical levels are reached above 12 mg/dL, with levels above 15 mg/dL (severe hypercalcemia) being a medical emergency.
Preferred specimens are as follows:
Plasma, serum, whole blood
Urine specimens (random collection or 24-h timed collection)
Acceptable containers/tubes are as follows:
Green-top tube (sodium heparin, ammonium heparin, lithium heparin)
Red-top tube (clot activator)
Serum separator tube
Plasma separator tube
Electrolyte–balanced heparinized syringes (for whole blood sample testing)
Urine containers (may contain 6 mol/L HCl, 20-23 mL in 24-h urine collection, to prevent precipitation of calcium salts)
Specimen volumes are as follows:
0.5 mL plasma or serum (0.25 mL minimum volume)
0.5 mL whole blood
Entire urine collection
Whole blood specimens should be analyzed within 15-30 minutes of collection. If this is not possible, the specimen should be kept in ice. On ice, the specimen is stable for at least 2 hours; however, if concurrent potassium testing is requested on the same specimen, the low temperature leads to a spurious increase in potassium within 1 hour of collection.
If the specimen cannot be analyzed within 1 hour, the preferred specimen is serum. The specimen should be centrifuged, and the serum or plasma should be removed from the cells within 2 hours of collection.
Samples can be stored at room temperature for 8 hours or refrigerated at 2-8o C for up to 48 hours. If assays are not completed within 48 hours or the separated sample is to be stored beyond 48 hours, samples should be frozen at -15°C to -20°C. Frozen samples should be thawed only once. Analyte deterioration may occur in samples that are repeatedly frozen and thawed.
If drawing for more than total calcium, send the first tube drawn.
Collection considerations and sources of preanalytical errors [1]
Fist-clenching or forearm exercise can lead to falsely elevated ionized (free) calcium levels.
The sample should be drawn with the patient in a sitting position. Standing increases the total calcium concentration.
Hemolysis and delayed plasma/serum separation lead to a decreased calcium concentration.
Samples collected in tubes containing citrate, oxalate, or ethylenediaminetetraacetic acid (EDTA) are not suitable for calcium testing.
Ionized calcium can be measured in whole blood using the ion-specific electrode (ISE) potentiometric method. This was designated by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) as the reference method for ionized/free calcium evaluation.
Total calcium also can be measured using the ISE potentiometric method, but the sample must be preacidified to release all bound and complexed calcium to a free form. However, total calcium is commonly measured with spectrophotometric methods, such as the o-Cresolphthalein Complexone method, Arsenazo III method, atomic absorption spectrometry, or, rarely, isotope dilution mass spectrometry (ID-MS). The atomic absorption spectrometry method was designated by the IFCC as the reference method for total serum calcium evaluation, while the ID-MS is considered “the definitive method” for total calcium evaluation developed by the National Institute of Standards and Technology. [2]
Calcium is the fifth most abundant element in the body. Adults have a calcium content of over 1 kg, or approximately 2% of body weight. All but 1% is contained in the bones, where it exists as calcium hydroxyapatite. The extraosseous intracellular space and extracellular space contain a portion of the remaining 1%. A dynamic equilibrium is maintained between the extracellular space and the rapidly exchangeable fraction of bone calcium. In blood, virtually all calcium is present in the plasma.
About 50% of the calcium present in circulation is free (also known as ionized calcium); 40% of serum calcium is bound to proteins, especially albumin (80%) and, secondary, to globulins (20%); and about 10% exists as various small diffusible inorganic and organic anions (eg, bicarbonate, lactate, citrate).
Heart and skeletal muscle contractility are affected by calcium ions; in addition, calcium ions are vital to nervous system function and are associated with blood clotting and bone mineralization.
The concentration of serum calcium is tightly regulated by parathyroid hormone (PTH) and 1,25-hydroxy vitamin D.
For further reading, please see the Medscape Drugs and Diseases topics Hypocalcemia and Hypercalcemia.
Hypocalcemia
Serum total calcium concentrations below the reference interval for the appropriate age and sex reflect a hypocalcemic status. Nevertheless, results of total serum calcium should be interpreted with caution, as they might not follow the same pattern (decreased concentration) of free (ionized) calcium. This is because total calcium is influenced by multiple factors, such as concentration of albumin, serum pH, and concentration of immunoglobulins.
As 80% of the bound calcium present in the circulation is carried by albumin (albumin has multiple binding sites for calcium), changes in serum albumin concentration trigger significance changes in the concentration of total calcium. Hypoalbuminemia is the most common cause of pseudohypocalcemia. Therefore, serum albumin changes are generally corrected with the addition of 0.8 mg/dL for every gram that the serum albumin level falls below 4 g/dL. In patients with suspected hypercalcemia or hypocalcemia, this principle can be expressed as the following equation:
Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 – serum albumin [g/dL])
The corrected total serum calcium concentration is normally 8.5-10.2 mg/dL, but there is no sure means of predicting the serum calcium level, for either hypocalcemia or hypercalcemia, at which symptoms will occur. The rapidity of change, as well as the absolute serum calcium concentration, impacts symptom development. It has been found, however, that hypocalcemic symptoms rarely occur if the corrected serum calcium concentration is above 8 mg/dL, while hypercalcemic symptoms rarely develop in patients with a corrected serum calcium level under 11 mg/dL. [3, 4, 5]
Calcium binds to the negatively charged sites of proteins, especially albumin. Therefore, this binding is pH-dependent. Alkalosis (increased serum pH) leads to increased protein ionization, increased negative charge and calcium binding, and, consequently, increased bound calcium concentration and decreased in free calcium. Acidosis (decreased pH) has the opposite effects.
Serum calcium is decreased (hypocalcemia) in the following conditions:
Vitamin D deficiency (either from intake deficiency or decreased conversion/activation) or resistance (osteomalacia and rickets)
Chronic renal diseases (eg, renal acidosis, Fanconi syndrome)
Magnesium deficiency (PTH glandular release is magnesium-dependent)
Massive transfusion
Chronic liver disease and biliary obstructive diseases (from impaired absorption and conversion of vitamin D)
Overexpression of fibroblast growth factor 23 (oncogenic osteomalacia)
Severe calcium dietary deficiency
Severe pancreatitis (calcium saponification)
Hungry bone syndrome
Hypocalcemia results when the parathyroid glands are either absent or impaired. Impaired vitamin D synthesis can also cause the condition. Owing to an associated decrease in vitamin D synthesis and the presence of hyperphosphatemia and skeletal resistance to PTH, chronic renal failure is a frequent source of hypocalcemia. Latent or manifest tetany and osteomalacia are characteristic signs of hypocalcemia. [2]
Hypercalcemia
Serum total calcium concentrations above the reference interval for the appropriate age and sex reflect a hypercalcemic status.
Serum calcium is increased in the following:
Hyperparathyroidism (primary, such as multiple endocrine neoplasia (MEN) type 1, hyperplasia, adenoma, or carcinoma; or secondary, from chronic kidney injury and hyperphosphatemia or after PTH administration during treatment for osteoporosis)
Malignancies (humoral hypercalcemia of malignancy) that secrete PTH–related protein (PTHrP), especially squamous cell carcinoma of lung and renal cell carcinoma
Vitamin D excess
Multiple myeloma, owing to bone lesions
Paget disease of bone with prolonged immobilization
Other granulomatous disorders
Familial hypocalciuria hypercalcemia
Vitamin A intoxication
Hypothyroidism, owing to prolongation of vitamin D action as its metabolism is slowed down
Drug exposure: Some drugs that can increase serum calcium are as follows antacids (some), calcium salts, long-term thiazide therapy, lithium
Hypercalcemia results from increased mobilization of calcium from the skeletal system or increased intestinal absorption. The condition is usually caused by primary hyperparathyroidism or bone metastasis of carcinoma of the breast, prostate, thyroid gland, or lung.
In 10% of patients with malignancies, coexistent hyperparathyroidism is the source of hypercalcemia; this indicates that evaluation of serum PTH levels should be performed at initial presentation in all hypercalcemic patients. Surgical removal of one or more parathyroid glands is a consideration in patients with primary hyperparathyroidism and bone disease, renal stones or nephrocalcinosis, or other signs or symptoms. Severe hypercalcemia may cause cardiac arrhythmia. [2, 6, 7]
Urinary calcium
Urinary calcium laboratory results should be always normalized to the glomerular filtrate (GF) and take into account the serum and urine concentration of creatinine, using the following formula:
UCa [mg/100 mL GF] = (UCa [mg/dL] X SCr [mg/dL]) / UCr [mg/dL]
UCa = Urinary calcium concentration
SCr = Serum creatinine concentration
UCr = Urine creatinine concentration
Reference intervals for urinary calcium were established taking into account an unrestricted diet, as well as in fasting conditions.
In diet-unrestricted conditions, men and women can excrete up to 300 mg calcium/24 h; while in fasting, less than 200 mg/24 h calcium will be excreted in the urine.
Under fasting conditions, intestinal and renal calcium absorption are fixed, and the urinary excretion of calcium reflects the skeletal matrix resorption/release of calcium. A urinary calcium concentration of greater than 0.16 mg/ 100 mL GF is usually associated with osteoclastic bone resorption.
Evaluation of urinary calcium is a useful tool for assessing renal stones diseases and high-turnover osteoporosis. [2]
During pregnancy, the serum albumin concentration often can be decreased. However, an increase in serum free calcium is not observed. However, pregnancy-specific reference intervals should be used for correct patient evaluation.
Drugs (eg, phenytoin) and bilirubin are commonly competing with calcium for albumin binding. Therefore, laboratory results from icteric patients and patients undergoing treatments with highly albumin-bonded drugs should be interpreted with caution.
Since gadolinium can interfere with most metal tests, 48 hours must elapse between administration of gadolinium-containing contrast media and specimen collection.
[Guideline] Clinical and Laboratory Standards Institute. C31-A2 Ionized Calcium Determinations: Precollection Variables, Specimen Choice, Collection, and Handling; Approved Guideline – Second Edition. Vol.12, No.10:
Burtis CA, Ashwood ER, Bruns DE. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th. Philadelphia, Pa: Saunders; 2005.
Deng XR, Zhang YF, Wang TG, Xu BH, Sun JC, Zhao LB, et al. Serum calcium level is associated with brachial-ankle pulse wave velocity in middle-aged and elderly Chinese. Biomed Environ Sci. 2014 Aug. 27(8):594-600. [Medline].
Sanchis-Gomar F, Salvagno GL, Lippi G. Inhibition of xanthine oxidase and exercise on serum uric acid, 25(OH)D3, and calcium concentrations. Clin Lab. 2014. 60(8):1409-11. [Medline].
Kanagal DV, Rajesh A, Rao K, Devi UH, Shetty H, Kumari S, et al. Levels of Serum Calcium and Magnesium in Pre-eclamptic and Normal Pregnancy: A Study from Coastal India. J Clin Diagn Res. 2014 Jul. 8(7):OC01-4. [Medline]. [Full Text].
Jacobs TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab. 2005 Nov. 90(11):6316-22. [Medline].
Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003 May 1. 67(9):1959-66. [Medline].
Alina G Sofronescu, PhD, NRCC-CC, FACB Assistant Professor, Board Certified Clinical Chemist, Medical Director of Clinical Chemistry Laboratory, Department of Pathology and Microbiology, University of Nebraska Medical Center
Alina G Sofronescu, PhD, NRCC-CC, FACB is a member of the following medical societies: American Association for Clinical Chemistry, Canadian Society of Clinical Chemists
Disclosure: Nothing to disclose.
Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital
Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology
Disclosure: Nothing to disclose.
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