with glucocorticoids is particularly efficacious in patients with sarcoidosis and other granulomatous

diseases. Plicamycin has proved useful in patients with hypercalcemia of malignancy, but it causes a

cumulative toxicity (thrombocytopenia, hepatotoxicity, and nephrotoxicity). Bisphosphonates inhibit

osteoclast activity directly. These agents are administered orally or parenterally and are particularly

efficacious, although long-term use may be associated with significant osteomalacia.7 Prostaglandin

synthetase inhibitors were initially considered useful, but their efficacy has proved to be limited.

Intravenous phosphates and chelating agents have largely been abandoned because of their severe

toxicity; however, oral phosphates may be beneficial in patients requiring prolonged therapy.

HYPOCALCEMIA

Hypocalcemia can occur as a consequence of various acquired and hereditary diseases.13 Generally,

these disorders produce a deficiency or defect in the action of either PTH or vitamin D. It is most

commonly a significant clinical problem after neck operation for thyroid disease. Chronic vitamin D

deficiency is associated with compensatory PTH excess. The end result is rickets in children or

osteomalacia in adults.

TREATMENT

Table 76-4 Treatment of Hypercalcemia

Clinical Features

The major signs and symptoms of hypocalcemia are a direct consequence of the reduction in plasma

levels of ionized calcium, which increases neuromuscular excitability (Table 76-5). The earliest clinical

manifestations are numbness and tingling in the circumoral area, fingers, and toes. Mental symptoms

are also common. Patients become anxious, depressed, and occasionally confused. Tetany may develop,

characterized by carpopedal spasm, tonic–clonic convulsions, and laryngeal stridor. The magnitude of

symptoms at any given plasma concentration of ionized calcium varies from patient to patient. On

physical examination, contraction of the facial muscles is elicited by tapping anterior to the ear, over

the facial nerve (Chvostek sign), although this sign may be present in 10% of normocalcemic patients.

Trousseau sign is elicited by occluding blood flow to the forearm for 3 minutes. The development of

carpal spasm indicates hypocalcemia, although the test is unpleasant and clinically impractical.

Etiology

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Some of the causes of hypocalcemia are listed in Table 76-6. The most common cause of hypocalcemia

by far is excision of or damage to the parathyroid glands during thyroid surgery.

Postoperative Hypoparathyroidism

Postoperative hypoparathyroidism commonly develops after total thyroidectomy.13,14 Most patients

undergoing operation on the thyroid experience some alteration in serum calcium, although they often

are asymptomatic; the low calcium probably represents contusion or temporary alteration of the blood

supply to the parathyroid glands. The hypocalcemia is usually transient and is not treated unless

significant symptoms develop. Occasionally, in hyperparathyroid patients who have parathyroidectomy

and significant bone disease, a marked skeletal deposition of calcium and symptomatic hypocalcemia

occurs, the so-called bone hunger. The plasma calcium usually reaches its nadir at 48 to 72 hours after

surgery and then slowly returns to normal within several days. These patients may require calcium and

vitamin D therapy for weeks or months after parathyroidectomy.

DIAGNOSIS

Table 76-5 Clinical Features of Hypocalcemia

Idiopathic Hypoparathyroidism

A less common form of hypoparathyroidism is idiopathic lack of function. It occurs both sporadically

and in families. In some cases, it develops as part of a polyglandular disorder and is thought to have an

autoimmune basis. DiGeorge syndrome is a group of congenital disorders involving the branchial

pouches that produce partial or complete agenesis of the thymus and parathyroid glands.

Hypoparathyroidism can also develop in newborns as a result of prenatal suppression of the fetal

parathyroid glands as a consequence of maternal hypercalcemia.15 It is also common in otherwise

normal but premature infants.

ETIOLOGY

Table 76-6 Causes of Hypocalcemia

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Vitamin D Deficiency

Vitamin D deficiency can occur as a result of dietary deficiency or lack of sun exposure. Likewise, renal

disease produces a decrease in the 1-hydroxylase activity necessary for the formation of active vitamin

D. The result is a decrease in calcium absorption and an increased secretion of PTH by the stimulated

parathyroid glands. Osteomalacia, abnormal fractures, and the deformities of rickets may result.

Pseudohypoparathyroidism

Pseudohypoparathyroidism is a familial disease characterized by a rotund appearance, shortening of the

extremities, and sometimes mental deficiency. The defect is not in PTH secretion; in fact, most patients

have elevated plasma levels of PTH with evidence of increased bone resorption. Rather, the kidney is

unresponsive to the hormone, and as a consequence, hypocalcemia and hyperphosphatemia develop.

The deficit appears to be in the renal adenyl cyclase system.

Hypomagnesemia

This unusual deficit may result from chronic alcoholism, malabsorption, parenteral nutrition, or

increased renal clearance during therapy with aminoglycosides. The deficit appears to block the physical

response to PTH in addition to its release from the parathyroid gland.

Other Causes

In short-gut syndrome, after extensive small-bowel resection or bypass, or after some forms of bariatric

surgery, vitamin D and calcium may be absorbed in insufficient quantities. In pancreatitis, the massive

soft tissue destruction and saponification that occur with hemorrhagic disease may sequester significant

amounts of calcium in the retroperitoneum. Some undefined systemic factor also appears to contribute

to hypocalcemia in these patients. Hypoalbuminemia causes a reduction in the total plasma calcium

level, although the level of ionized calcium remains within the normal range and patients are

asymptomatic. Circulatory substances, such as the citrate used to anticoagulate banked blood and

radiographic contrast media, may bind to calcium. In patients with osteoblastic metastases, particularly

associated with prostate carcinoma, hypocalcemia has been attributed to increased calcium flux into the

lesions. Toxic shock syndrome is sometimes associated with hypocalcemia, but the mechanism has not

been defined. Acute hyperphosphatemia, as a consequence of exogenous administration of phosphate or

during the cytolytic chemotherapy of highly responsive tumors (e.g., Burkitt lymphoma and acute

lymphoblastic leukemia), may produce symptomatic hypocalcemia associated with soft tissue

calcification.

Treatment

The treatment of hypocalcemia is summarized in Table 76-7. For acute symptomatic hypocalcemia,

calcium should be administered intravenously. Calcium gluconate is less irritating to the veins than

calcium chloride, and the calcium release is slower, without a risk for overcorrection. Usually, 20 to 30

mL of 10% solution is infused over a 15- to 20-minute period, and then 50 to 100 mL is administered

over the next 12 hours in adults. A practical guide after an initial bolus dose includes 60 mL of 10%

calcium gluconate in a 500-mL bag of dextrose 5% in water, infused at 1 mL/kg/hr, and adjusted every

4 hours based on the serum level of calcium and patient symptoms. Bicarbonate precipitates any calcium

infused through the same intravenous line. Serum magnesium should always be measured, and

hypomagnesemia should be corrected if present. In patients with convulsions from advanced tetany,

diphenylhydantoin therapy is useful, but symptoms should never be allowed to progress to this point.

TREATMENT

Table 76-7 Treatment of Hypocalcemia

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Long-term therapy is gauged on the basis of symptoms. In the postoperative patient, the continued

stimulus of mild hypocalcemia to any remaining parathyroid gland tissue may prove useful.

Concomitant therapy with calcium and vitamin D is effective in a timely fashion. A starting dose of 2 g

of oral calcium carbonate per day in divided doses is usually well tolerated. Vitamin D can be

administered as calcitriol, an active synthetic vitamin D analog. Most adults respond to a dose of 0.5 to

1.0 mcg/day; reduced doses may be necessary for patients with renal dysfunction.

HYPERPARATHYROIDISM

Definitions

Parathyroid neoplasms are rarely identified by physical enlargement but rather are sought because of

the peripheral effects of excess hormone. Primary hyperparathyroidism develops spontaneously,

without apparent cause but possibly in response to exogenous stimuli. When the normal control of

serum calcium is disturbed and the autonomous production of PTH is increased, the state is referred to

as primary hyperparathyroidism. This category includes both benign single- and multiple-gland

enlargements and the much rarer parathyroid carcinoma. In some cases, the disease is familial. In

contrast, secondary hyperparathyroidism occurs when a defect in mineral homeostasis leads to a

compensatory increase in parathyroid function. This occurs most commonly in response to renal disease

but may also develop as a consequence of the hypocalcemia associated with some diseases of the

gastrointestinal tract, bones, or other endocrine organs. Occasionally, with prolonged secondary

stimulation, the hyperfunctioning glands are no longer physiologically responsive to an increase in

ionized calcium. This uncommon (affecting about 2% of patients after renal transplantation), relatively

autonomous state referred to as tertiary hyperparathyroidism, develops most commonly after renal

transplantation when the renal defect in calcium homeostasis is corrected.

Incidence

The advent in the 1970s of the widespread assessment of serum calcium as part of automated

multichannel analysis has considerably altered our understanding of hyperparathyroidism. Before that

time, primary hyperparathyroidism was thought to be a relatively rare condition. Most patients

presented with symptoms of disease, usually renal stones or bony manifestations. Currently, most

patients are asymptomatic or have only vague symptoms or signs that can be related to

hyperparathyroidism.16,17 Occasionally, patients recognize that they had symptoms only after their wellbeing improves following parathyroidectomy. Incidence varies with both age and gender (Table 76-8),

but hyperparathyroidism is believed to develop in about 50 to 100 people per 100,000 in the general

population, with approximately 50,000 new cases occurring annually in the United States.18 Marked

variations have been noted worldwide; the reasons for these differences remain unclear.

Table 76-8 Age-Specific and Gender-Specific Incidence of Primary

Hyperparathyroidism

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Etiology

The cause of primary hyperparathyroidism is not known. Although the sequence of progression from

secondary to tertiary disease in response to chronic stimulation has a logical appeal, it is difficult to

draw parallels with primary disease. Most patients with primary hyperparathyroidism have disease of a

single rather than of multiple glands, which is not what might be predicted if an external stimulus were

part of the pathophysiology. Hyperparathyroidism is most common in postmenopausal women, the

population group with the highest incidence of osteoporosis and the most significant alterations in

calcium and phosphate metabolism. Loss of renal function with aging is associated with elevations in

PTH and decreases in phosphate clearance. It has been suggested but not demonstrated that a renal

calcium leak, if sufficient, might result in a chronic calcium deficit stimulating the parathyroid glands.

Genetic studies of parathyroid adenomas have described an oncogene (PRAD1) that may be one step

in the path to neoplasia in these tumors. Overexpression of the normal PRAD1 gene, also known as

cyclin D1, allows progression of the cell cycle from the G1 phase to the S phase, thus promoting cellular

growth and division. PRAD1 is overexpressed in 20% to 40% of parathyroid adenomas; further research

may reveal other genetic alterations that contribute to the neoplastic growth. The MEN1 tumorsuppressor gene has also been implicated in the molecular pathogenesis of sporadic

hyperparathyroidism. About 15% to 20% of sporadic parathyroid adenomas have either somatic

mutation or biallelic deletion of the MEN1 gene.19,20

Hyperparathyroidism occurs in several familial forms. It is a major component of the multiple

endocrine neoplasia (MEN) syndromes types 1 and 2A. The parathyroid disease of MEN-1 syndrome is

multiple parathyroid adenomas that appear with increasing frequency over the patient’s lifetime.21 In

other families, hyperparathyroidism is inherited in an autosomal dominant fashion without other

manifestations of MEN-1 or MEN-2; some have osseous abnormalities (tumor–jaw syndrome) and some

apparently have isolated disease.

Figure 76-8. Parathyroid adenoma. The tumor consists of sheets of neoplastic chief cells and is separated from normal parenchyma

by a thin capsule.

Pathology

Single-Gland Versus Multiple-Gland Disease

Microscopically, the cell most commonly involved in primary hyperparathyroidism is the chief cell. Less

frequently, the oxyphil cell is the predominant cell type. Diseased glands typically have an increase in

the proportion of stromal cells and a reduction in the proportion of stromal fat. Single diseased glands,

or adenomas, have been classically described with a predominance of chief cells centering in a single

focus, with a compressed rim of surrounding normal tissue (Fig. 76-8). In contrast, parathyroid

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