Susan A. Kecskes
USE THE FOLLOWING FOR HIGH YIELD FACTS:
• Less then one percent of the body’s calcium is in the circulation.
• Only the ionized form of circulating calcium is physiologically active.
• Parathyroid hormone (PTH), vitamin D, and calcitonin are the hormones that control calcium levels.
• IV calcium can be given as calcium chloride or calcium gluconate but the mg doses are different.
• IV calcium is very irritating to tissues and veins.
Calcium is one of the most abundant and important minerals in the body. It is essential for skeletal integrity and, in its physiologically active form, is responsible for cellular depolarization, muscle excitation/contraction, neurotransmitter release, hormonal secretion, and the function of both leukocytes and platelets.
Ninety-nine percent of body calcium is stored in bone. Of this, <1% present in the circulation, 40% is bound to proteins such as albumin, 12% is complexed with anions such as phosphate and citrate, and 48% is ionized.1 Serum calcium levels measure ionized, complexed, and protein-bound calcium. Ionized calcium is the physiologically active form. Since approximately half of serum calcium is bound to albumin, the serum calcium level may need to be adjusted for alterations in the albumin level. For every 1 g/dL decrease in serum albumin, “true” serum calcium may be estimated by adding 0.8 mg/dL.2
Corrected total calcium = measured total calcium + 0.8 (4 - serum albumin)
Alternatively, ionized calcium levels are widely available.
Parathyroid hormone (PTH), vitamin D, and calcitonin interact to regulate ionized calcium in a narrow range by controlling intestinal absorption, renal excretion, and skeletal distribution (Fig. 83-1). Ionized calcium levels are sensed by the calcium sensing receptor (CaSR) on the cell surface of parathyroid cells. When ionized calcium falls, PTH is secreted. If levels are elevated, PTH secretion is suppressed. PTH, in turn, promotes bone resorption and increases calcium reabsorption in the kidney. As bone resorption occurs, ionized calcium and phosphorus are released into the circulation. In the kidney, PTH stimulates renal reabsorption of calcium and excretion of phosphorus. It also facilitates conversion of 25-hydroxyvitamin D to the active form, 1,25(OH)2D, which promotes transepithelial transport of calcium and phosphorus in the intestine and the kidney.3
Figure 83-1. Calcium homeostasis: hypocalcemia.
Calcitonin is a hormone released by the thyroid gland which plays a more subdued role in calcium homeostasis. In response to hypercalcemia, calcitonin is released and inhibits osteoclast-mediated bone resorption, and renal and intestinal reabsorption of calcium.4
Hypocalcemia is defined as serum calcium <9 mg/dL. Major etiologies (Table 83-1) are hypoparathyroidism and vitamin D deficiency. Hypoparathyroidism leads to insufficient PTH release to stimulate release of calcium from bone and renal and intestinal preservation of calcium. It can be congenital or acquired. Magnesium is essential for PTH secretion and activation of PTH receptors. Low levels of magnesium may lead to functional hypoparathyroidism and hypocalcemia. Interestingly, high levels of magnesium (as in parenteral administration) may inhibit PTH release and also lead to hypocalcemia.3Vitamin D deficiency or resistance can lead to hypocalcemia, as well as difficulty converting vitamin D to the active form, 1,25(OH)2D. Pseudohypoparathyroidism, characterized by resistance to the effects of PTH, may also lead to hypocalcemia, along with elevated levels of PTH, and phosphorus. Additional etiologies are massive transfusion of citrated blood, phosphate enema toxicity, pancreatitis, and sepsis.
Causes of Hypocalcemia
• Radiation – induced
• Heavy Metal Toxicity
• Iron – thalassemia, hemochromatosis
• Copper – Wilson disease
• DiGeorge (velocardiofacial) syndrome
• Familial hypoparathyroidism
• Familial hypocalcemia with hypercalciuria
• X-linked hypoparathyroidism
Pseudohypoparathyroidism (resistance to PTH)
• Type Ia – Albright syndrome
• Type Ib
• Type II
Vitamin D dysfunction
• Vitamin D dependent rickets, Type II
• Inability to convert to active form
• Chronic renal failure
• Vitamin D dependent rickets, Type I
Loss of circulating calcium
• Phosphate enema toxicity
• Citrate toxicity
• Massive transfusion
• Hungry bone syndrome
Figure 83-2 Laboratory algorithm for hypocalcemia.
Nonspecific symptoms, including nausea, weakness, paresthesias, and irritability, are typical. Classic physical findings of neuromuscular irritability are Chvostek sign and Trousseau sign. Chvostek sign is positive when there is twitching of the upper lip following tapping of the cheek anterior to the earlobe over the facial nerve. Trousseau sign is positive when there is carpal spasm after inflating a BP cuff on the upper arm above the systolic blood pressure for 3 minutes.3 In more severe cases, tetany, seizures, laryngospasm, and psychiatric manifestations may be seen. The electrocardiogram (ECG) may show prolongation of the QT interval, bradycardia, and/or dysrhythmias. Depression of cardiac contractility and vasomotor dysfunction are seen with low levels of ionized calcium.
Laboratory testing should include ionized and total calcium, magnesium, phosphorus, serum albumin, creatinine, and alkaline phosphatase. Vitamin D and PTH levels may help elucidate the etiology (Fig. 83-2), as may urine calcium and phosphorus levels.
For significant or symptomatic hypocalcemia, intravenous calcium may be administered cautiously with continuous ECG monitoring. Calcium gluconate, 10% (50–100 mg/kg/dose), or calcium chloride, 10% (10–25 mg/kg/dose), may be administered over 2 to 5 minutes.5 Intravenous calcium is very irritating to tissues and veins. It should be diluted prior to administration to a maximum concentration of calcium gluconate, 50 mg/mL or calcium chloride, 20 mg/mL. It is preferably given through a central line or very secure peripheral venous access. It should never be given intramuscularly, subcutaneously, or via an endotracheal route, as tissue necrosis and sloughing will occur. Intravenous calcium predisposes to digitalis toxicity and precipitates when mixed with bicarbonate. Hyperphosphatemic patients are at risk of metastatic calcium deposition with calcium administration and require treatment aimed at lowering phosphorus levels. When hypomagnesemia is present, oral or intravenous correction should be undertaken. Magnesium sulfate may be administered intravenously at a dose of 25 to 50 mg/kg, diluted to a maximum concentration of 200 mg/mL, over 2 to 4 hours.5 Longer-term management may involve oral administration of calcium, vitamin D, and thiazide diuretics.
Hypercalcemia is defined as a serum calcium level >10.5 mg/dL. Although often asymptomatic, complaints may include constipation, anorexia, vomiting, abdominal pain, or pancreatitis. Rarely, lethargy, depression, psychosis, or coma may occur. ECG changes may include QT-segment shortening, bradycardia, heart block, and sinus arrest. Nephrolithiasis can be an important consequence of hypercalcemia.
The conditions in adults that are commonly associated with hypercalcemia (hyperparathyroidism and malignancies of the breast, lung, kidney, and head and neck) are rare in children. In children, hypercalcemia with malignancy is associated with bone metastases or tumor lysis syndrome. Other causes in children include primary or tertiary hyperparathyroidism, hyperthyroidism, vitamin D intoxication, immobilization, thiazide diuretics, milk-alkali syndrome, and sarcoidosis. There are a number of rare, inherited disorders associated with hypercalcemia including idiopathic hypercalcemia of infancy (Lightwood syndrome), Jansen disease, Williams-Beuren syndrome, primary oxalosis, congenital lactase deficiency, and Down syndrome.
Laboratory investigation should include total and/or ionized serum calcium, serum albumin, electrolytes (including magnesium and phosphorus), creatinine, PTH, vitamin D levels, ECG, and urinalysis (Fig. 83-3). Hyperchloremic metabolic acidosis suggests primary hyperparathyroidism.
FIGURE 83-3. Laboratory algorithm for hypercalcemia.
In symptomatic patients or those with levels >14 mg/dL, therapy is aimed at expansion of extracellular fluid, calcium excretion, increased bone storage, and definitive treatment of the underlying cause. Volume expansion begins with normal saline and is followed by diuresis with furosemide to promote calcium excretion. Hemodialysis may be required in the setting of renal insufficiency or life-threatening dysrhythmias. Calcitonin, glucocorticoids, mithramycin, and indomethacin have all been used to suppress bone resorption, although the onset of action is >24 hours.
1. Moore EW. Ionized calcium in normal serum, ulrafiltrates, and whole blood determined by ion-exchange electrodes. J Clin Invest. 1970;49:318.
2. Phillips P, Pain R. Correcting the calcium. Br Med J. 1977;1:1473.
3. Shoback D. Hypoparathyroidism. N Engl J Med. 2008;359:391.
4. Potts JT, Juppner H. Chapter 353. Disorders of the parathyroid gland and calcium homeostasis. In: longo DL, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw Hill; 2012.
5. Taketomo CK, Hodding JH, Kraus DM, eds Pediatric Dosage Handbook. 19th ed. Hudson, OH: Lexi-Comp; 2012.