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Calcium, Total

Plasma calcium exists in the blood in three forms; 50% is ionized, 40% is protein bound, and 10% is complexed to anions such as bicarbonate, citrate, sulfate, phosphate, and lactate. Plasma ionized calcium is the biologically active moiety.  Total calcium levels are maintained between 8.8 and 10.2 mg/dL. Parathyroid hormone and vitamin D regulate normal plasma calcium levels by their actions on kidney, intestine, and bone ion transport. Because calcium concentration is so tightly regulated, persistent hypercalcemia should almost always be investigated.

The main causes of hypercalcemia are primary hyperparathyroidism, malignant disease, and chronic renal failure. The differential diagnosis of hypercalcemia depends on the clinical setting. Overall, primary hyperparathyroidism and malignancy account for 80 – 90% of hypercalcemia cases. However, primary hyperparathyroidism is the cause of ~60% of ambulatory cases and of ~25% of inpatient cases, whereas malignancy causes ~35% of ambulatory cases and 65% of inpatient cases.

Malignancies can raise serum calcium levels by either direct bone destruction or secretion of calcemic factors. Patients with squamous cell carcinoma of the lung, metastatic breast cancer, multiple myeloma, and renal cell carcinoma are most prone to hypercalcemia. These tumors may produce PTH related protein (PTH-rp) which binds to PTH receptors, but is not detected by standard intact PTH immunoassays. Specific assays for PTH-rp are available.

The prevalence of hyperparathyroidism in the general population is 1 to 2 cases per 1000 people, but is more frequent in the elderly and in women. The most common pathological lesion is a single parathyroid adenoma (85% of cases) or chief cell hyperplasia (10%). Parathyroid carcinoma occurs in 1 to 3% of cases. Hyperparathyroidism also occurs in multiple endocrine neoplasia type 1 and 2A. Patients identified by laboratory screening are commonly asymptomatic. Presentation with kidney stones is unusual today, but 5% of patients with kidney stone disease have primary hyperparathyroidism. Finding an elevated PTH level in a patient with hypercalcemia makes the diagnosis.

The signs and symptoms of hypercalcemia are summarized in the following table.

Evaluation of hypercalcemia usually begins with measurement of total calcium. If total calcium is markedly elevated, an ionized calcium level is usually not needed. Slightly to moderately elevated total calcium should be confirmed by measurement of ionized calcium. The patient’s history may indicate the cause, such as; immobilization for more than a week, drug therapy, hyperthyroidism, adrenal insufficiency, or familial hypocalciuric hypercalcemia. If time permits, total calcium levels should be repeated two more times to rule out a transient cause of hypercalcemia before undertaking a complete work-up. If hypercalcemia is still evident, serum albumin and total protein should be determined. Calcium levels should be corrected for elevated albumin levels (see below). If total protein is high, but albumin is normal or low, a monoclonal gammopathy should be ruled out by serum protein electrophoresis. Serum chloride, phosphorus and intact PTH are also useful in diagnosing the most frequent causes of hypercalcemia; malignancy and hyperparathyroidism. Serum chloride is mildly elevated in primary hyperparathyroidism.

Hypocalcemia most commonly results from PTH deficiency or failure to produce 1,25 dihydroxy vitamin D. The most common causes of hypoparathyroidism are parathyroid or thyroid surgery and parathyroid infiltration by cancer, sarcoid, amyloid or hemochromatosis. Acute illnesses such as pancreatitis, hepatic failure, sepsis, and various medications can also cause hypocalcemia. The normal response to a fall in the plasma ionized calcium level is increased PTH secretion and 1,25 dihyroxy vitamin D synthesis, leading to increased calcium absorption from the intestine and increased resorption from bone and kidneys.

Some drugs are associated with hypocalcemia. Gentamicin and cisplatin cause renal magnesium loss, which leads to hypocalcemia. Heparin therapy releases fatty acids that bind calcium ions and cause transient hypocalcemia. Anticonvulsants such as dilantin and phenobarbital induce the microsomal oxidase pathway which accelerates inactivation of vitamin D. Loop diuretics such as furosemide enhance renal calcium excretion. Phosphate salts bind up calcium ions causing hypocalcemia.

The laboratory evaluation of a low total plasma calcium level should include measurement of ionized calcium, magnesium, and phosphorus levels. Low ionized calcium rules out artefactual causes of hypocalcemia, such as hypoalbuminemia. Abnormally high or low magnesium levels should be excluded because they can inhibit PTH secretion. A low serum phosphorus level is consistent with vitamin D deficiency, while a high level suggests chronic renal failure or pseudohypoparathyroidism. Measurement of intact PTH levels helps to differentiate between conditions caused by PTH and vitamin D defects. The demonstration of an inappropriately low intact PTH level in the presence of hypocalcemia is consistent with the diagnosis of hypoparathyroidism. Serum 25-hydroxyvitamin D levels can be measured to confirm vitamin D deficiency.

Total calcium levels are affected by changes in plasma protein concentrations. Most of the protein bound fraction of calcium is bound to albumin; each 1 g/dL of albumin binds 0.8 mg/dL of calcium. Three formulas have been used to correct calcium for decreased serum albumin levels:

%Calcium bound = 8 (albumin) + 2(globulin) + 3

Corrected calcium = measured Calcium /0.6 + [total protein/8.5]

Corrected calcium = Calcium – albumin + 4

Each formula will give a slightly different value for corrected calcium. A better approach is to directly measure ionized calcium levels.

Two of the four approved gadolinium based magnetic resonance (MR) imaging contrast agents, gadodiamide (Omniscan) and gadoversetamide (OptiMARK), have recently been shown to interfere with calcium measurements on some chemistry analyzers, resulting in falsely low values. Patients with normal renal function may have spuriously low calcium measurements up to 24 hours after administration of these contrast agents, but patients with renal insufficiency may be affected for up to 4.5 days. 

Preanalytical factors can cause erroneous calcium results. A common source of preanalytical error is the prolonged use of a tourniquet during blood collection which mas falsely increase calcium concentration. Collection of blood in a vacutainer tube containing citrate, oxalate or EDTA may falsely decrease values, because these additives chelate calcium.

In the hospital, many critically ill patients receive calcium infusions or intravenous medications containing calcium. This is one of the most common causes of spurious hypercalcemia involving inpatients. To avoid this error, phlebotomy should be delayed for at least 2 hours after the intravenous calcium infusion is completed. 

Reference range is 8.8 - 10.2 mg/dL. Calcium levels less than 6.0 mg/dL or greater than 13.0 mg/dL are considered critical values.

Specimen requirement is one SST tube or one green top (heparin) tube of blood. Prolonged venous stasis should be avoided because it can produce artefactual hypercalcemia.