Hypocalcemia is a common feature of vitamin D deficiency. The common causes of vitamin D deficiency are listed in Box 112-1. Lack of sunlight exposure impairs endogenous vitamin D synthesis. Because vitamin D is a fat-soluble vitamin, nutritional osteomalacia usually is associated with a deficient intake of food products containing fatty substances. Gastrectomy may lead either to dietary deficiency due to avoiding fatty products and/or due to malabsorption of vitamin D, as noted with Billroth type II surgery, in which a vitamin D–absorbing bowel segment is bypassed. Deficiency of bile salts impairs vitamin D absorption. Small-bowel diseases, laxative abuse, and certain anticonvulsants (phenytoin) interfere with absorption. Urinary losses of vitamin D were linked to Fanconi’s syndrome and nephrotic syndrome.⁷ Because hepatic formation of 25(OH) vitamin D from vitamin D is not tightly controlled and depends primarily on the availability of vitamin D, the serum level of 25(OH) vitamin D₃ is utilized as a measurement of body stores of vitamin D; low levels of 25(OH) vitamin D indicate vitamin D deficiency.¹

Impaired Metabolism of Vitamin D

Hypocalcemia in patients ingesting phenobarbital is associated with low levels of circulating 25(OH) vitamin D. Half-life of vitamin D and 25(OH) vitamin D are shortened by barbiturates, owing to induction of microsomal enzymes in the liver. Low circulating levels of 25(OH) vitamin D also have been observed in patients with hepatic failure due to reduced transformation of vitamin D to 25(OH) vitamin D in the liver.⁸

Dietary calcium deprivation increases the clearance and inactivation of 25(OH) vitamin D and causes vitamin D deficiency. This variety of vitamin D deficiency may be caused by secondary hyperparathyroidism, which augments renal synthesis of 1,25(OH)₂ vitamin D and in turn enhances the degradation of 25(OH) vitamin D to inactive metabolites.

Hypothetically, this mechanism may account for vitamin D deficiency in clinical states of calcium malabsorption, including gastrointestinal (GI) diseases, anticonvulsant therapy (e.g., phenytoin), and certain drugs such as colchicine, fluoride, and theophylline. Likewise, increased intake of foods rich in phytate, oxalate, and citrate that chelate calcium in the GI tract and render it nonabsorbable may cause vitamin D deficiency.^1,⁹

Vitamin D–dependent rickets type I (VDDR-1), also designated as pseudovitamin D deficiency, is inherited as an autosomal recessive disorder in which 25(OH) vitamin D_1α-hydroxylase in the proximal tubules is deficient due to defects in the 1α-hydroxylase gene. It is manifested by early hypocalcemia, hypophosphatemia, severe secondary hyperparathyroidism, and severe rickets. The serum 1,25(OH)₂ vitamin D is undetectable or very low, whereas 25(OH) vitamin D levels are normal. The clinical abnormality can be reversed completely by the administration of pharmacologic doses of vitamin D or physiologic doses of 1,25(OH)₂ vitamin D. Linkage analysis in families with VDDR-1 mapped the disease locus to chromosome 12q13-14.¹⁰

End-Organ Resistance to 1,25(OH)₂ Vitamin D

Hypocalcemia refractory to 1,25(OH)₂ vitamin D₃ was described as type II vitamin D–dependent rickets, also known as hereditary 1,25(OH)₂ vitamin D₃–resistant rickets. This familial disorder is inherited by autosomal recessive transmission and is characterized by hypocalcemia, impaired intestinal absorption of calcium, rickets, and alopecia, which reflects a defect in the physiologic action of 1,25(OH) vitamin D in the skin. In contrast to vitamin D–dependent rickets type I, in type II the serum 1,25(OH)₂ vitamin D level is elevated, and patients either respond to pharmacologic doses of 1,25(OH)₂ vitamin D₃ or do not respond at all. In some patients with this disorder, an abnormal nuclear uptake, abnormal cytosol receptor binding of 1,25(OH) vitamin D, or both are present. These findings suggest that the mechanism of the end-organ resistance is a defect in the receptor. Mutations of vitamin D receptor genes have been identified.

Disorders Related To Parathyroid Hormone

Reduced Production of PTH

Hypoparathyroidism

Hypoparathyroidism is a disorder characterized by hypocalcemia and hyperphosphatemia due to a deficient or absent secretion of PTH.

Hypoparathyroidism is a common cause of hypocalcemia. It commonly presents as paresthesias, muscle spasms (i.e., tetany), and seizures. However, mild chronic hypoparathyroidism may cause hypocalcemia so gradually that the only symptoms may be visual impairment from cataracts after years of hypoparathyroidism.

Hypoparathyroidism may be either an acquired abnormality designated as secondary hypoparathyroidism, or primary hypoparathyroidism, also known as idiopathic hypoparathyroidism.

Secondary Hypoparathyroidism

Hypoparathyroidism may be caused by surgery. This variety of hypoparathyroidism may result from accidental removal of parathyroids or traumatic interruption of their blood supply. Hypocalcemia that appears after excision of parathyroid adenoma results from functional suppression and hypofunctioning of the remaining normal glands and is frequently transient. “Hungry bone syndrome” can develop following parathyroidectomy in patients with markedly elevated preoperative PTH levels. Decreased postoperative levels of PTH cause a “rebound” recalcification of bones secondary to unbalanced osteoblast and osteoclast activity. This results in profound hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase. Similarly, hypocalcemia has been reported to occur in 15% of patients after thyroidectomy.¹¹

Hypoparathyroidism may be a component of multiple endocrine dysfunctions, including adrenal insufficiency, pernicious anemia, thalassemia, and Wilson’s disease. In the last two disorders, the deposition of iron and copper, respectively, in the parathyroid glands is the likely underlying mechanism.¹²

Hypocalcemia may occur in magnesium depletion.¹³ It has been shown that the chronic state of low serum magnesium diminishes the release of PTH.¹³ Hypomagnesemia has been reported to induce skeletal resistance to PTH.¹⁴ Magnesium level should always be checked during the workup of profound refractory hypocalcemia. The mechanisms that underlie the effects of hypomagnesemia on serum calcium are poorly understood. It may be speculated, however, that magnesium depletion may impair the activity of the calcium pump and thus alter the distribution of calcium between the extracellular and intracellular spaces.

Hypocalcemia in association with hypomagnesemia has been reported in 60% of patients with severe acute respiratory syndrome.¹⁵ Hypocalcemia may follow therapeutic use of magnesium sulfate (e.g., in preeclampsia) secondary to magnesium-induced suppression of PTH. Aminoglycosides and cytotoxic agents may exert a toxic effect on parathyroid glands, leading to hypocalcemia.^1,¹³ Symptomatic hypoparathyroidism has been observed in association with HIV infection.¹

Primary (Idiopathic) Hypoparathyroidism

Primary hypoparathyroidism may occur in association with other endocrine disorders or as an isolated entity. The latter is termed isolated hypoparathyroidism, and it may occur as a sporadic or familial disorder, inherited as both an autosomal dominant and recessive form.¹⁴

Aplasia or hypoplasia of the parathyroids is most commonly caused by the DiGeorge velocardiofacial syndrome, associated with deletions of chromosome 22q11.2. Most cases are sporadic, but familial cases with autosomal dominant inheritance have been reported. Affected patients have abnormalities in organs derived from the third and fourth branchial arches including the parathyroid glands, thymus, and outflow tract of the heart. These patients typically present in the first week after birth with signs of hypocalcemia such as tetany and seizures. They have characteristic facial features, an upturned nose, and a widened distance between the inner canthi (telecanthus), with short palpebral fissures. Cardiac defects include truncus arteriosus, tetralogy of Fallot, or interrupted aortic arch. Thymic hypoplasia leads to immune deficiencies. CATCH 22 syndrome is an acronym for cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia caused by chromosome 22q11 deletions.¹⁶

Autoimmune hypoparathyroidism is commonly a part of polyglandular autoimmune syndrome type I, which is a familial syndrome. It occurs during childhood, is inherited as an autosomal recessive trait, and is associated with mucocutaneous candidiasis and adrenal insufficiency. It can present as hypoparathyroidism in the absence of the two other disorders. Adrenal insufficiency is a late phenomenon in this syndrome. The acronym APECED stands for autoimmune polyglandular endocrinopathy with candidiasis and ectodermal dystrophy, including vitiligo, alopecia, nail dystrophy, enamel hypoplasia of teeth, and corneal opacities.¹⁷

Hypoparathyroidism was also reported in association with two mitochondrial cytopathies with mitochondrial DNA mutations: Kearns-Sayre syndrome and Kenny-Caffey syndrome.¹⁸

Impaired Action of PTH Due to Peripheral Resistance

Pseudohypoparathyroidism

Pseudohypoparathyroidism is a rare inheritable disorder characterized by mental retardation, moderate obesity, short stature, brachydactyly with short metacarpal and metatarsal bones, exostoses, radius curvus, and an expressionless face.¹⁹ The biochemical abnormalities are hypocalcemia and hyperphosphatemia. Some patients exhibit only the biochemical abnormalities. Thus, the disorder may be subdivided into pseudohypoparathyroidism type IA, which is also known as Albright’s hereditary osteodystrophy, and type IB. Pseudohypoparathyroidism type IA is associated with both the somatic and biochemical abnormalities, and type IB presents as the biochemical defect without the somatic abnormalities. Because of the hypocalcemic stimulus, secondary hyperparathyroidism may develop in some patients, leading to osteitis fibrosa cystica. Failure of the kidney to form 1,25(OH)₂ vitamin D₃ in response to PTH results in a low circulating level of this metabolite.

Calcitonin

Calcitonin binds to specific cell membrane receptors on bone-resorbing osteoclasts and depresses their activity. In this regard, it antagonizes the effect of PTH on bone.

Medullary carcinoma of the thyroid is derived from parafollicular cells of ultimobranchial organ, which secrete calcitonin. It may present as a familial and autosomal dominant or sporadic disorder. Patients with this tumor have high circulating levels of calcitonin, and hypocalcemia has been reported in some patients.²⁰

Hypocalcemia has been described in critically ill patients admitted to intensive care units (ICUs).²¹ The degree of hypocalcemia correlated with the severity of the disease and was most commonly detected in patients who were septic. The mechanism of this abnormality is unknown. Circulating levels of calcitonin precursors (CTpr) increase up to several thousandfold in response to microbial infections, and this increase correlates with the severity of the infection and mortality. The relationship of elevated CTpr to the emergence of hypocalcemia needs to be investigated.²²

Bisphosphonates

Hypocalcemia has been reported in patients with bone metastases of solid tumors who were treated with pamidronate ²³ and in a patient treated with alendronate for osteoporosis. In both cases, bisphosphonate induced skeletal resistance, and PTH was proposed as a possible mechanism. Hypomagnesemia may cause hypocalcemia by a similar mechanism.²⁴

Rapid Removal of Calcium from the Circulation

Malignant Neoplasms

Hypocalcemia may develop in patients with malignant neoplasms in association with osteoblastic bone-forming metastases, most commonly cancer of the prostate and breast. These lesions may lead to rapid deposition of mineral in the newly formed matrix, thus causing hypocalcemia.

Hyperphosphatemia

The various causes of hyperphosphatemia that may lead to hypocalcemia are listed in Box 112-2. The oral or intravenous (IV) administration of phosphate lowers serum calcium concentration in normal animals and hypercalcemic human subjects, which formed the basis for the clinical use of phosphate administration in states of hypercalcemia. The association of hyperphosphatemia and hypocalcemia has been reported to occur in a variety of circumstances. Hyperphosphatemia has been observed in persons ingesting large quantities of phosphate-containing laxatives or receiving enemas with phosphate. Hyperphosphatemia and hypocalcemia with tetany may develop in infants fed cow’s milk, which contains 1220 mg of calcium and 940 mg of phosphorus per liter (human milk contains 340 mg of calcium and 150 mg of phosphorus per liter).^25,²⁶ The mechanism responsible for lowering serum calcium concentration by the administration of phosphate is not entirely understood. One possibility is that the decrease in serum calcium concentration is caused by deposition of calcium phosphate in the bone, soft tissues, or both.

In chronic renal failure, a constant increase in serum phosphorus concentration is observed when the glomerular filtration rate is 30 mL/min or less, and hyperphosphatemia is a common accompaniment of acute renal failure.

In patients undergoing chemotherapy for neoplastic diseases, particularly of lymphatic origin, large quantities of phosphates may be released into the circulation as a result of the cytolysis. Spontaneous tumor lysis may cause hyperphosphatemia and, consequently, hypocalcemia.

Acute Pancreatitis

The hypocalcemia associated with acute pancreatitis is not well understood. The precipitation of calcium soaps in the abdominal cavity, which results from the release of lipolytic enzymes and fat necrosis, has been suggested as the mechanism of hypocalcemia. Recently, endotoxemia has been implicated.²⁷

Citrate, Lactate, Bicarbonate, Na-EDTA, Foscarnet, and Poisoning with Ethylene Glycol

Citrate is present in stored blood products (such as plasma and platelets) as an anticoagulant that exerts its action through the binding of ionized calcium. Patients receiving a massive transfusion frequently experience hypocalcemia; however, this is usually transient secondary to the rapid hepatic metabolism of citrate.²⁸ The ionized hypocalcemia (with a normal total calcium concentration) can lead to tetany, myocardial dysfunction, or hypotension. The same applies to IV lactate and Na-EDTA, which causes ionized hypocalcemia. Bicarbonate may directly complex calcium or may increase protein binding of calcium from the resulting alkalosis. Low serum ionized calcium may be a complication of ethylene glycol (antifreeze) poisoning because of calcium binding by oxalic acid, which is the metabolite of the poison. An analog of the pyrophosphate, foscarnet, used to treat cytomegalovirus infection in HIV-infected patients causes ionized hypocalcemia secondary to chelation of calcium by foscarnet.¹

Clinical Consequences of Hypocalcemia

The clinical presentation of hypocalcemia depends on its severity, rapidity of the fall in serum calcium concentration, age of the patient, chronicity of hypocalcemia, and comorbid conditions.

Most infants with hypocalcemia are asymptomatic. Among those who become symptomatic, the characteristic sign is increased neuromuscular irritability. Generalized or focal clonic seizures may be the first indication of hypocalcemia. Other manifestations may include stridor caused by laryngospasms and wheezing caused by bronchospasms. Vomiting may be caused by pylorospasm.

Neuromuscular manifestations in adults with hypocalcemia are variable (Table 112-1). The characteristic symptom is tetany, which includes perioral numbness and tingling, paresthesias in the extremities, carpopedal spasm, laryngospasm, and focal and generalized seizures. The spasms of the diaphragm and of intercostal muscles may cause respiratory arrest and asphyxia.

TABLE 112-1 Clinical Manifestations of Abnormalities in Magnesium and Calcium

Increased Serum Levels
System	Magnesium	Calcium
Gastrointestinal	Nausea/vomiting	Anorexia, nausea/vomiting, abdominal pain, constipation
Neuromuscular	Weakness, lethargy, ↓ reflexes	Depression, confusion, coma, muscle weakness, back and extremity pain
Cardiovascular	Hypotension, cardiac arrest	Hypotension, arrhythmias
Renal	—	Polydipsia, polyuria
Decreased Serum Levels
System	Magnesium	Calcium
Gastrointestinal	—	—
Neuromuscular	Hyperactive reflexes, muscle tremors, tetany, delirium, seizures	Hyperactive reflexes, paresthesias, weakness, paralysis, tetany, seizures, carpopedal spasm, seizures
Cardiovascular	Arrhythmia	Heart failure

The characteristic physical findings in patients with hypocalcemia that are indicative of latent tetany are Trousseau’s sign (carpal spasm) and Chvostek’s sign (facial muscle contraction). Visual impairment may by caused acutely by papilledema, whereas usually chronic hypocalcemia, when due to hypoparathyroidism, causes cataracts. Myocardial functional and anatomic abnormalities have been associated with hypocalcemia. Acute hypocalcemia may be associated with hypotension. Very often the absence of the compensatory reflex tachycardia aggravates the condition. The typical ECG change consists of prolongation of the QT interval. Hypocalcemia prolongs phase 2 of the action potential and thus prolongs repolarization time, because inward calcium currents are one of the factors determining the plateau configuration of the action potential. QT prolongation is associated with a variety of ventricular arrhythmias, most characteristically torsades de pointes. These abnormalities can be reversed with calcium replacement. Calcium therapy significantly shortens the repolarization intervals and decreases the frequency of ventricular premature contractions.²⁹ Chronic hypocalcemia may infrequently cause hypocalcemic cardiomyopathy, which is a dilated cardiomyopathy. Partial recovery of cardiac function has been reported after restoration of normocalcemia.³⁰

Treatment of Hypocalcemia

Symptomatic hypocalcemia generally responds promptly to IV administration of calcium. The commonly used preparations are 10% calcium gluconate (10-mL ampules containing 90 mg of elemental calcium) and 10% calcium chloride (10-mL ampules containing 360 mg of elemental calcium). The treatment should be instituted immediately, because delay may be associated with further aggravation of tetany and lead to generalized seizures and even cardiac arrest.

The IV administration of 100 to 200 mg elemental calcium (5-10 mEq) should be slow to avoid complications. Then the administration of calcium can be continued as a slow drip of 100 to 200 mg of elemental calcium, diluted in 250 to 500 mL of 0.45% NaCl or D₅W, given over several hours until oral calcium takes over. Calcium extravasation should be avoided because it causes local irritation and thrombophlebitis.

Chronic treatment with oral calcium should follow the IV therapy in patients with chronic hypocalcemia due to irreversible causes such as hypoparathyroidism. Oral calcium administration constitutes the best initial therapy in mild cases. The commonly used preparations are in tablet form: calcium lactate, 300 mg (60 mg of elemental calcium); chewable calcium gluconate, 1 g (90 mg of elemental calcium); calcium carbonate (Os-Cal), 250 mg of elemental calcium; calcium carbonate, 650 mg (250 mg of elemental calcium); and calcium citrate, 950 mg (200 mg of elemental calcium).

Oral calcium also may be used for patients for whom the diagnosis of irreversible hypoparathyroidism has not been established with absolute certainty. In patients who fail to respond to oral calcium, vitamin D in large doses is the only available treatment. The commonly used preparations are capsules containing 1.25 mg (50,000 units) of vitamin D₂ (ergocalciferol). The average dose ranges between 1.25 and 3.75 mg/d. DHT3 is three times as potent as vitamin D₂ in raising serum calcium concentration. Each capsule contains 0.125 mg of DHT3. The average daily dose ranges between 0.25 and 1 mg of DHT3. Both vitamins are available in liquid oil solutions as well. Both hypoparathyroidism and pseudohypoparathyroidism respond to physiologic doses of 1,25(OH)₂ vitamin D₃ and 1α(OH) vitamin D₃ with restoration of serum calcium concentration to normal. Calcitriol is marketed as Rocaltrol and is dispensed in capsules containing 0.25 and 1 µg. Chlorothiazides may enhance the calcemic action of vitamin D and its analogs, whereas furosemide may aggravate the hypocalcemia through its hypercalciuric action.

Patients in whom hypocalcemia is associated with hypomagnesemia respond poorly to IV calcium, but the serum calcium concentration is restored to normal levels with correction of the hypomagnesemia.

Symptoms rarely develop in patients with chronic renal failure and hypocalcemia. However, very often reduction of elevated serum phosphorus with phosphate-binding antacids causes an increase in serum calcium concentrations.

Hypocalcemia associated with osteomalacia resulting from vitamin D deficiency is rarely symptomatic. It usually responds to physiologic doses of vitamin D and increased oral calcium intake.

Hypercalcemia

Primary hyperparathyroidism and malignancy account for 80% to 90% of all cases of hypercalcemia.³¹ Primary hyperparathyroidism is the leading cause of hypercalcemia in the outpatient setting. Its incidence is 1% in the normal population.³² Hypercalcemia is most often detected in routinely tested blood specimens. Malignancy is the prevalent cause of hypercalcemia in hospitalized patients. The most common iatrogenic hypercalcemia is milk-alkali syndrome, which ranks third after malignancy and hyperparathyroidism and accounts for 10% to 15% of cases with hypercalcemia. The free over-the-counter access to the generic brands of calcium carbonate and their widespread use for heartburn, osteoporosis, and as an alleged prevention of colon cancer may be the underlying cause for the rise in the incidence of milk-alkali syndrome.³³

Hypercalcemia presents a challenge to every clinician. In some instances, the cause of hypercalcemia is self-evident on the basis of the circumstantial clinical findings, whereas extensive efforts are required to establish the etiology in other situations. The important causes of hypercalcemia are listed in Box 112-3.

Box 112-3

Disorders Associated with Hypercalcemia

Primary hyperparathyroidism

Adenoma and carcinoma:

Hyperplasia

Multiple endocrine adenomatosis

Ectopic secretion of parathyroid hormone by neoplasms (rare)

Secondary hyperparathyroidism:

Malabsorption and vitamin D deficiency

Chronic renal failure

Following kidney transplantation

Familial hypocalciuric hypercalcemia

Hypercalcemia associated with malignancy:

Lytic bone metastases

Circulating tumor-secreted factors:

Parathyroid hormone–related protein

1,25-Dihydroxyvitamin D₃–induced hypercalcemia

Locally acting, noncirculating, tumor-secreted cytokines:

Interleukin (IL)-1 and IL-6

Tumor necrosis factor beta (TNF-β)

Granulocyte-macrophage colony-stimulating factor

Transforming growth factor alpha (TGF-α)

Prostaglandins

Hypercalcemia in patients with hyperabsorptive hypercalciuria

Hypervitaminosis D

Hypervitaminosis A

Granulomatous diseases:

Foreign body granuloma

Hyperthyroidism

Adrenocortical insufficiency

Infantile hypercalcemia

Hypercalcemia associated with acute renal failure

Calcium ion exchange resins

Hyperparathyroidism

Primary hyperparathyroidism is present in 10% to 20% of all patients with hypercalcemia.¹ Making the diagnosis of hyperparathyroidism is important because of its amenability of surgical cure. The disease is more common in females than in males; the incidence increases in women after menopause but is less frequent in older men. Primary hyperparathyroidism is caused by a solitary adenoma in 80% to 85% of patients, multigland hyperplasia in 15% to 20%, and parathyroid carcinoma in less than 1% of patients.³⁴

The morphologic differentiation between adenomas and hyperplasia sometimes is very difficult. The presence of a capsule and a rim of compressed normal gland tissue around the periphery of an adenoma may be helpful in making a definitive diagnosis. The persistence or recurrence of hypercalcemia after surgery for a purported adenoma should raise the suspicion of parathyroid hyperplasia. If more than one gland shows histologic features of hyperplasia, a subtotal or total parathyroidectomy is recommended. Some patients with primary hyperparathyroidism have especially pronounced hypercalciuria despite a very mild degree of hypercalcemia and minimal or no bone disease. In patients with primary hyperparathyroidism, a very strong positive correlation was found between 1,25(OH)₂ vitamin D₃ in the serum and the urinary calcium excretion. Patients with nephrolithiasis and hypercalcemia had circulating levels of 1,25(OH)₂ vitamin D₃ higher than those present in hyperparathyroid patients without renal stones. The reason for this difference in the 1,25(OH)₂ vitamin D₃ levels is unknown, but it stresses the importance of vitamin D metabolism in the clinical presentation of primary hyperparathyroidism.¹

Hyperparathyroidism is also associated with multiple endocrine neoplasia (MEN) type 1 and 2, both of which are inherited in an autosomal dominant fashion. MEN 1 syndrome is characterized by parathyroid hyperplasia, neuroendocrine tumors of the pancreas and duodenum, and pituitary adenomas. Hyperparathyroidism occurs in over 95% of patients with MEN 1. MEN 2 syndrome includes MEN 2A and MEN 2B. MEN 2A syndrome is characterized by pheochromocytoma, parathyroid hyperplasia, and medullary thyroid cancer. MEN 2B syndrome includes medullary thyroid cancer, pheochromocytoma, mucosal neuromas, and a distinct physical appearance but does not involve hyperparathyroidism. Establishing the diagnosis of hyperparathyroidism associated with MEN syndrome has important surgical implications.^35,³⁶ The diagnosis of primary hyperparathyroidism requires the findings of elevated serum calcium and intact PTH (iPTH) levels, normal renal function, and normal or increased urinary calcium excretion. Patients presenting with bone, renal, GI, or neuromuscular symptoms are considered symptomatic and are best treated with surgical excision. Asymptomatic patients with primary hyperparathyroidism are surgical candidates if they meet the criteria established by the National Institutes of Health (NIH Criteria for Parathyroidectomy).^37,³⁸ These criteria include markedly elevated serum calcium (>12 mg/dL), history of life-threatening hypercalcemia, creatinine clearance reduced by 30%, markedly elevated 24-hour urine calcium (>400 mg/d), nephrolithiasis, age younger than 50, osteitis fibrosa cystica, and substantially reduced bone mass (>2 SD below control).

Recent advances in technology have allowed the surgeon to localize the parathyroid adenoma preoperatively or intraoperatively, thus allowing a minimally invasive surgical approach. Options include the ^99mTc-sestamibi scan with or without single photon emission computed tomography (SPECT), computed tomography (CT), ultrasonography, magnetic resonance imaging (MRI), and thallium-201/technetium pertechnetate scanning. The most promising perioperative adjunct, however, seems to be intraoperative PTH monitoring.³⁹

Familial hypocalciuric hypercalcemia is an unusual form of parathyroid hyperplasia with autosomal dominant transmission. It is usually asymptomatic and incidentally diagnosed by an elevated serum calcium level and confirmed by a low urinary calcium level. The clinical course is relatively benign with an absence of nephrolithiasis and an infrequent occurrence of pancreatitis and chondrocalcinosis and usually requires no specific therapy.

Malignancy Associated with Hypercalcemia

Hypercalcemia is most commonly produced by tumors of lung, breast, kidney, and ovary and by hematologic malignancies. Two main mechanisms are known to mediate the hypercalcemia of malignancy: local and humoral.⁴⁰ The local mechanism is manifested by the presence of osteolytic lesions in the skeleton. The malignant cells may act to destroy the bone directly; however, even local osteolysis is mediated by activated osteoclasts in most instances. The humoral factor most commonly associated with hypercalcemia of malignancy is parathyroid hormone–related protein (PTHrP).⁴¹ PTHrP induces osteoclastic resorption of bone, increases tubular reabsorption of calcium in the kidneys, and inhibits osteoblast activity through the action of cytokines such as IL-6.⁴² These factors explain why serum calcium rises rapidly in cancer patients in contrast to the gradual rise in hyperparathyroidism.

Multiple Myeloma and Hypercalcemia

Hypercalcemia occurs in about a third of patients with myeloma. Osteolytic bone lesions are the most common skeletal radiographic findings. The bone destruction in myeloma is mediated by osteoclasts that accumulate adjacent to the collections of myeloma cells. This association of myeloma cells with osteoclasts is most likely related to the osteoclast-activating effect of cytokines that are locally secreted by the malignant cells. Myeloma cells produce in vitro several osteoclast-activating factors, including TGF-β, IL-1, and IL-6. The increase in bone resorption in most cases is associated with a suppressed osteoblastic bone-forming activity. This explains the depressed skeletal uptake of bone-seeking radiolabeled elements in myeloma, resulting in negative bone scans in the majority of the affected patients. Myeloma cells exhibit a unique capability to grow rapidly in the bone. Myeloma cells secrete osteoclast-mobilizing and osteoclast-stimulating cytokines, whereas osteoclasts secrete IL-6, which is a major growth factor of the myeloma cells. This relationship between myeloma cells and osteoclasts explains the rapid destruction of bone in this malignancy.^43,⁴⁴

Vitamin D Intoxication and Hypercalcemia

All patients receiving vitamin D, other than in small doses, for the treatment of hypoparathyroidism may develop hypercalcemia, with the attendant risk of renal failure. The appearance of hypercalcemia in hypoparathyroid patients receiving pharmacologic doses of either ergocalciferol (vitamin D₂) or DHT3 is almost unpredictable, because the margin between normocalcemic and hypercalcemic doses of the vitamin is very narrow. Some episodes of hypercalcemia may pass unnoticed and yet may be the underlying cause of reduced renal function in these patients. Hypercalcemia associated with vitamin D intoxication may be present from 1 to 6 weeks after discontinuation of the treatment, and normocalcemia may persist for an additional 4 months without any treatment. The toxic effect of vitamin D excess is associated with a high circulating level of 25(OH) vitamin D₃, which is continuously produced by the liver from the adipose tissue stores of vitamin D. The serum level of 1,25(OH)₂ vitamin D₃ generally is not elevated and even may be reduced; however, the free non-protein-bound 1,25(OH)₂ vitamin D₃ levels may be elevated. The hypercalcemia associated with 1,25(OH)₂ vitamin D₃ administration, however, is much more short lived (3-7 days).⁴⁵

Various factors may alter the response to vitamin D. The inhibitory effect of estrogens on bone resorption may be absent after menopause, which allows more calcium to be released from the bone for any given dose of vitamin D. The administration of corticosteroids may reduce the effect of vitamin D; in fact, corticosteroids may be used to treat vitamin D intoxication. The most important precaution in preventing the complications of vitamin D intoxication is to measure serum calcium concentrations frequently in these patients. Likewise, the presence of excessive hypercalciuria, even in the absence of hypercalcemia, is a risk factor for nephrocalcinosis and renal failure. Thus, monitoring of urinary calcium excretion in these circumstances is recommended as well.

Vitamin A Intoxication and Hypercalcemia

Hypercalcemia is also associated with excessive intake of vitamin A,⁴⁶ which is readily available in various pharmaceutical preparations. Isotretinoin, a derivative of vitamin A that is effective in the treatment of severe acne, has been reported as a cause of hypercalcemia. The main symptom of vitamin A intoxication is painful swelling over the extremities. Prolonged hypercalcemia in this condition also has been associated with nephrocalcinosis and impairment of renal function. In experimental animals, excessive amounts of vitamin A cause fractures, increased number of osteoclasts, and calcification of soft tissues. In human subjects, periosteal bone deposition constitutes the typical radiographic feature.

Sarcoidosis and Hypercalcemia

Sarcoidosis is a systemic granulomatous inflammatory disease characterized by noncaseating granulomas in multiple organ systems. Hypercalciuria is the most common defect in calcium metabolism; however, hypercalcemia occurs in approximately 5% of patients.⁴⁷ In a small proportion of patients, very high serum calcium concentration leads to metastatic calcifications and eventual death from uremia.

Seasonal incidence of hypercalcemia in sarcoidosis is directly related to the amount of sunlight exposure. Plasma levels of 1,25(OH)₂ vitamin D₃ have been found to be increased in patients with sarcoidosis and hypercalcemia, a finding that accounts for the abnormal calcium metabolism in this disease. In most of the patients, glucocorticoids can normalize the level of calcium and 1,25(OH)₂ vitamin D₃ in the serum. Serum immunoreactive PTH has been found to be low in patients with sarcoidosis, regardless of the presence or absence of hypercalcemia.⁴⁷

Hyperthyroidism, Hypothyroidism, and Hypercalcemia

Hyperthyroidism is associated with accelerated bone turnover, which is caused by direct stimulation of bone cells by the high thyroid hormone concentrations.⁴⁸ Biochemical markers of bone formation and resorption (osteocalcin, alkaline phosphatase, bone-specific alkaline phosphatase, and urinary collagen pyridinoline) are elevated in hyperthyroid patients, indicating increased bone turnover in favor of osteoclastic bone resorption.⁴⁹ The resultant hypercalcemia may be reversed by antithyroid therapy.⁵⁰

Serum calcium and phosphate levels are normal and alkaline phosphatase is low in the vast majority of patients with hypothyroidism; however, some patients may manifest hypercalcemia. Calcium balance in patients with hypothyroidism tends to be positive as a result of increased intestinal absorption and reduced urinary excretion. Both changes predispose to the development of hypercalcemia. The bone turnover in hypothyroid patients is reduced.

Adrenal Insufficiency and Hypercalcemia

Hypercalcemia is a common abnormality in adrenal insufficiency. The mechanism of hypercalcemia in this clinical setting is not well understood. One study indicates that the increase in serum calcium concentration is due to an increase in the protein-bound fraction of serum calcium that results from accompanying volume depletion. The volume depletion also may cause an increase in the renal tubular reabsorption of calcium, and vitamin D’s enhancement of calcium absorption from the intestine may be greater in the absence of glucocorticoid hormone.⁵¹

Idiopathic Infantile Hypercalcemia

Idiopathic infantile hypercalcemia (IIH) is a rare cause of hypercalcemia in the first year of life and is a diagnosis of exclusion. It usually presents between the ages of 3 and 7 months, with clinical features including vomiting, irritability, constipation, increased thirst, and failure to thrive.⁵² The pathophysiology of IIH remains unclear, but some authors attribute the hypercalcemia to intestinal vitamin D sensitivity that leads to increased calcium absorption and contributes to persistent hypercalciuria.⁵³ Treatment options for IIH include corticosteroids, low-calcium diet, calcitonin, and cellulose phosphate. The natural history of this disease remains elusive, but patients usually experience spontaneous resolution of hypercalcemia (usually before age 3), persistent hypercalciuria, and increased risk of nephrocalcinosis.

Jansen’s Metaphyseal Chondrodysplasia

Jansen’s metaphyseal chondrodysplasia is characterized by short limbs, mild hypercalcemia, and low serum PTH levels. It is caused by activating mutations of the PTH/PTHrP receptor and is inherited as an autosomal dominant trait. It is associated with increased proliferation and delayed maturation of chondrocytes.

Immobilization and Hypercalcemia

Immobilization may be associated with excessive loss of bone minerals, hypercalcemia, and rapidly developing osteoporosis. The lack of postural mechanical stimuli to the skeleton disturbs the balance between bone formation and resorption, thus leading to loss of bone mass and its minerals. Usually the amount of calcium released from bone is excreted in the urine and does not increase serum calcium concentrations. Owing to reduced ability to excrete calcium in the urine, patients with preexisting renal impairment are prone to develop immobilization hypercalcemia.⁵⁴

Milk-Alkali Syndrome

Milk-alkali syndrome (MAS) may occur in patients who ingest large amounts of milk and alkali as a therapy to relieve the symptoms of peptic ulcers. The syndrome is characterized by hypercalcemia, hyperphosphatemia, alkalosis, metastatic calcifications, and progressive renal failure. It has been shown that these abnormalities may be reversed by discontinuation of the therapy. Ingestion of large amounts of calcium carbonate (at least 4-5 grams daily) and absorbable alkali is a prerequisite for establishing the diagnosis.³³ For hypercalcemia to develop, calcium intake must be excessive, but inability to excrete this excessive calcium may also be important. Preexisting renal insufficiency has been implicated in the pathogenesis of MAS, as well as medications that affect renal calcium excretion, such as thiazide diuretics.

Thiazide Diuretics and Hypercalcemia

Chronic administration of thiazide diuretics may lead to hypercalcemia in patients treated with large doses of vitamin D (hypoparathyroid patients and patients with osteoporosis) and in patients with hyperparathyroidism. The mechanism of action may involve: (1) reduced urinary excretion of calcium due to a direct tubular effect, or extracellular fluid depletion with secondary increase in tubular reabsorption of sodium and calcium, or both; and (2) increased bone responsiveness to the resorptive actions of vitamin D and PTH.

Lithium and Theophylline Toxicity

Patients treated chronically with lithium may develop hypercalcemia with elevated PTH levels. The incidence of primary hyperparathyroidism in patients with bipolar affective disorders treated with lithium is 47-fold higher than in the general population. To date, 50 cases of parathyroid adenomas and hyperplasia that were associated with chronic lithium therapy have been reported.^55,⁵⁶ Theophylline toxicity may be associated with hypercalcemia, probably due to stimulation of β-adrenergic receptors in bone.

Clinical Manifestations of Hypercalcemia

The symptoms of hypercalcemia depend on its rate of onset, magnitude, duration, the underlying disorder, and comorbid conditions. Acute hypercalcemia may induce acute renal failure due to extracellular volume contraction and direct renal vasoconstriction. This abnormality is reversible, whereas chronic hypercalcemia may cause nephrolithiasis and nephrocalcinosis with tubulointerstitial scarring and chronic renal failure. Hypercalcemia may cause constipation, nausea and vomiting, and peptic ulcer disease. Polyuria is caused both by its natriuretic effect and impaired urinary concentration, with features of nephrogenic diabetes insipidus.

Hypercalcemia leads to membrane hyperpolarization with shortened QT interval on an ECG. Cardiac arrhythmias are rare. Neuromuscular effects include impaired concentration and memory, muscle weakness and fatigue, confusion, lethargy, stupor, and coma (see Box 112-3). Bone pain can occur in patients with hyperparathyroidism or malignancy. Osteoporosis of the cortical bone is associated with hyperparathyroidism. Compression fractures of the vertebral bodies, sometimes with sudden onset of paralysis, may be the first manifestation of multiple myeloma. Familial hypocalciuric hypercalcemia is rarely associated with the bone disease, but chondrocalcinosis and pseudogout have been reported to occur in high frequency. Hypercalcemic crisis is a life-threatening emergency that warrants aggressive treatment. It may be a complication of primary hyperparathyroidism, malignancy, and other hypercalcemic disorders. It is characterized by very high serum calcium levels exceeding 15 mg/dL. The treatment is aimed at restoring extracellular volume to normal and lowering serum calcium levels. Acute hemodialysis with calcium-free dialysate may become a necessity.

Treatment of Hypercalcemia

Lowering of serum calcium concentration can be produced by (1) inhibiting calcium release from the bone, increasing its deposition in the bone and other tissues, or both; (2) increasing removal of calcium from the extracellular fluid or inhibiting its absorption in the bowel; and (3) decreasing the ionized fraction by complex formation with chelating substances.

Hypercalcemia augments urinary losses of sodium and water, resulting in the contraction of extracellular volume and reduced glomerular filtration rate. The latter leads to diminished urinary excretion of calcium and further aggravation of hypercalcemia. Therefore, the first therapeutic goal is to restore the extracellular volume to normal by IV administration of normal saline. This usually requires 3 to 4 L of saline. This therapeutic action per se lowers the serum calcium concentration, partly by the dilutional effect and partly by increased urinary excretion of calcium. There is a risk of extracellular volume overload during rapid IV administration of saline, which is particularly hazardous in elderly patients. Therefore, monitoring of central venous pressure in this situation may be very helpful. Likewise, addition of loop diuretics as an adjunct therapy not only may minimize the risk of fluid overload but also may substantially increase the urinary excretion of calcium. The effect of loop diuretics as calciuretic agents requires prompt replacement of urinary losses of sodium and water. The use of loop diuretics may be particularly beneficial in patients who develop hypercalcemia as a result of excessive secretion and high serum levels of PTH, PTHrP, or both. Hormone-induced excessive tubular reabsorption of calcium plays a major role in the development and maintenance of hypercalcemia in these circumstances.

Disorders of Magnesium Metabolism

Magnesium is the second most abundant intracellular cation. The intracellular concentration of magnesium ranges between 10 and 20 mEq/L; however, most of it is bound to organic compounds, including adenosine triphosphate (ATP). Of the fraction found in the extracellular space, one-third is bound to serum albumin. Therefore the plasma level of magnesium may be a poor indicator of total body stores in the presence of hypoalbuminemia. The exchange between the extracellular and intracellular compartments appears to be slow, and changes in intake and intestinal absorption are tightly balanced by parallel changes in urinary excretion.^57,⁵⁸

The renal tubular handling of magnesium displays a Tm (tubular maximum) with serum levels being close to the Tm threshold values. Thus, any rise in serum level and in the filtered load is counterbalanced by urinary spillover, and vice versa, a fall in filtered load leads to a sharp decline in urinary excretion almost down to zero. Therefore, in the presence of normal kidney function, serum levels are maintained at nearly constant values ranging form 1.4 to 1.7 mEq/L (1.7-2.1 mg/dL). Hypermagnesemia can be encountered primarily with impaired kidney function and excessive oral or parenteral load. Hypomagnesemia results from decreased dietary intake, intestinal malabsorption, or renal losses.⁵⁷

Magnesium plays an important role in the function of many key enzymes including ATP, Na⁺/K⁺-ATPase, creatine kinase, and adenylate cyclase. Intracellular magnesium is key to protein synthesis, oxidative phosphorylation, nucleic acid stability, storing and utilization of energy, and enzymatic reactions. Extracellular magnesium is essential to nerve conduction, neuromuscular transmission, cardiac conduction and contractility, and vascular tone.

Though total serum magnesium concentration is commonly utilized to measure magnesium, it may not be the best test.⁵⁹ Changes in serum protein concentrations may affect total concentration but are not reflective of total body magnesium. A magnesium tolerance test can be used to determine magnesium status but requires calculating the amount of retained parenteral magnesium. Finally, ionized magnesium measurement devices are available but not yet readily available.

Hypomagnesemia and Magnesium Depletion

Hypomagnesaemia is a common problem in hospitalized patients, particularly in the ICU. The kidney is primarily responsible for magnesium homeostasis through regulation by calcium/magnesium receptors on renal tubular cells that sense serum magnesium levels.⁶⁰ Hypomagnesemia results from a variety of etiologies ranging from poor intake, increased renal excretion, GI losses, malabsorption, and a variety of endocrine dysfunctions. The causes of hypomagnesemia can be divided into two major categories: (1) extrarenal magnesium losses, including deficient intake, and (2) renal losses.

Extrarenal Losses

Dietary deprivation, prolonged malnutrition, tube feedings, and parenteral nutrition deficient in magnesium may induce cumulative magnesium depletion and hypomagnesemia. GI losses may be caused by steatorrhea, severe diarrhea, or acute pancreatitis. Hypomagnesemia may also follow surgery for morbid obesity with short bowel syndrome and diarrhea.⁵⁷

Endocrine causes include hyperthyroidism, hypercalcemia associated with malignancy, and hyperaldosteronism.⁶¹ Hungry bone syndrome after parathyroidectomy may lead to both hypocalcemia and hypomagnesemia owing to increased deposition of both divalent ions in the newly deposited bone mineral.

Chronic alcoholism is one of the leading causes of magnesium depletion. Poor nutrition, diarrhea, chronic pancreatitis, and possibly a renal tubular defect may contribute to hypomagnesemia.⁶² Severe burns may lead to sequestration of magnesium in the necrotic tissue, including necrotic fat, leading to magnesium depletion. Finally, acute dialysis for severe refractory hypercalcemia without addition of magnesium to the dialysate may cause hypomagnesemia.

Renal Losses

Osmotic diuresis induced by IV salt loads, diabetic ketoacidosis, and mannitol administration all increase urinary excretion of many electrolytes, including magnesium. During recovery from ketoacidosis, especially after phosphate replacement, a precipitous fall in serum magnesium may occur.

Hypercalcemia as seen with primary hyperparathyroidism, hyperthyroidism, and IV administration of calcium causes renal losses of magnesium as both divalent cations compete for the same reabsorption mechanism in Henle’s loop. Similarly, loop diuretics cause renal magnesium and calcium wasting, whereas thiazides enhance urinary excretion of magnesium but cause tubular retention of calcium. Primary hyperaldosteronism and the syndrome of inappropriate antidiuretic hormone (SIADH) are associated with modest increases in urinary magnesium excretion.

Renal magnesium wasting has been observed in patients treated with aminoglycosides, amphotericin B, and cisplatin.⁶³^–⁶⁵ These agents may lead to potassium wasting and renal tubular acidosis. Cyclosporine and tacrolimus cause magnesium wasting with potassium retention. Loop diuretics can also lead to magnesium wasting. The diuretic phase of acute renal failure also may lead to magnesium loss.