Figure 76-1. Schematic illustration of the location of the superior (A) and inferior (B) parathyroid glands from 503 autopsy

studies. The more common locations are indicated by the shaded areas. The numbers represent the percentage of glands found at

each location. Typically, the glands were posterolateral to the thyroid and above or below the junction of the inferior thyroid

artery with the recurrent laryngeal nerve.

Calcium is absorbed in its inorganic form from the duodenum and proximal jejunum. The rate of

absorption is precisely regulated according to body calcium status. The calcium in the extracellular fluid

is constantly being exchanged with that in the intracellular fluid, the exchangeable bone, and the

glomerular filtrate. Calcium reabsorption by the kidney is closely related to that of sodium, and about

99% of the filtered load is reabsorbed under normal conditions.

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Figure 76-2. A: Pharyngeal arches in a 5-week embryo. The corresponding pouches extend from within the pharynx into each

arch. B: Schematic representation of the differentiating epithelium of the respective pharyngeal pouches.

Figure 76-3. A normal adult parathyroid is composed of about half parenchyma and half fat (×150).

Phosphate

Phosphate anion is also an integral component of most biologic systems. It is critical to the pathways of

glycolysis and is the functional group for a number of high-energy transfer compounds, including

adenosine triphosphate. It is also the major anion in crystalline bone. Normal levels of plasma

phosphate range from 2.5 to 4.3 mg/dL, and the level varies inversely with the serum level of calcium.

The relation is such that the product of plasma calcium and phosphate is relatively constant ranging

between 30 and 40 (with calcium and phosphate both expressed in mg/dL). When the product is above

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this level, the potential for the precipitation of calcium phosphate in body tissues increases.

In contrast to the percentage of calcium absorbed, the percentage of phosphate absorbed from the

diet is relatively constant, and excretion usually provides the major mechanisms for regulating

phosphate balance (Fig. 76-4). Unlike stores of calcium, the readily exchangeable soft tissue stores of

phosphate, such as those in muscle, are large.

Figure 76-4. Average daily calcium and phosphate turnover in humans.

Regulation of Calcium and Phosphate Metabolism

The maintenance of calcium and phosphate homeostasis depends on major contributions from three

organ systems – the gastrointestinal tract, the skeleton, and the kidneys – with minor contributions from

the skin and liver.2 The primary hormonal regulators of this metabolism are PTH, vitamin D, and

calcitonin. The actions of each of these hormones in the organs are summarized in Table 76-1.

Parathyroid Hormone

2 PTH is the single most important hormonal regulator of calcium and phosphate metabolism in

humans. It has direct effects on the skeleton and kidney and indirect effects on the intestine, mediated

through vitamin D. In target tissues, PTH binds first to membrane receptors, activating adenyl cyclase

to generate cyclic adenosine monophosphate (cAMP), which regulates other intracellular enzymes.

In bone, the effects of PTH are complex, stimulating both resorption and the formation of new bone.

However, sustained elevations of PTH stimulate osteoclasts and inhibit osteoblasts. Osteocytes, in the

matrix of cortical bone, may also act to reabsorb matrix in response to PTH, a process referred to as

osteocytic osteolysis. Calcium and phosphate mobilization in response to PTH occurs in two phases.

Initially, mineral is mobilized from areas of rapid equilibrium. This phase is followed by a more

sustained release mediated by newly synthesized lysosomal and hydrolytic enzymes. In the kidney, PTH

increases the reabsorption of extracellular fluid calcium at any given concentration, although excess

secretion, because of hypercalcemia, increases the net daily amount of urinary calcium excretion.

Reabsorption in the proximal tubule and loop of Henle is linked with sodium transport such that factors

that alter sodium transport concomitantly alter calcium reabsorption. In contrast, reabsorption in the

distal nephron is independent of sodium and directly influenced by PTH. PTH also increases phosphate

excretion. This action is accompanied by enhanced bicarbonate secretion. PTH probably has only

indirect effects on the gastrointestinal tract, by stimulating the hydroxylation of 25-hydroxyvitamin D to

1,25-dihydroxyvitamin D in the kidney.

Table 76-1 Hormonal Regulation of Calcium and Phosphate Metabolism

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Figure 76-5. The parathyroid gland produces a precursor of PTH, prepro-PTH, that is sequentially cleaved to pro-PTH and PTH.

PTH secretion is controlled by the extracellular fluid calcium concentration.

PTH is synthesized initially as a precursor, preproPTH, which is sequentially cleaved in the

parathyroid gland to proPTH and then to PTH (Fig. 76-5). Secretion of this 84-amino-acid molecule is

controlled by a negative feedback loop with extracellular fluid calcium. Most PTH is secreted in this

form and then cleaved in the liver into N- and C-terminal fragments. The N-terminus contains most of

the biologic activity and is rapidly degraded by the liver, whereas the inactive C-terminus is slowly

metabolized by the kidney.

Vitamin D

Vitamin D acts at two major sites. It increases intestinal absorption of calcium and phosphate. In

addition, in the skeleton, it promotes mineralization and enhances PTH-mediated mobilization of

calcium and phosphate. It has no known direct effect on the kidney.

Vitamin D3

, or cholecalciferol, is produced normally by the action of sunlight on 7-dehydrocholesterol

in the skin (Fig. 76-6). It is then hydroxylated in the liver (25 position) and kidney (1 position) to form

the active 1,25-dihydroxyvitamin D3

(calcitriol). Vitamin D2

is normally present in yeast and fungi but

not in humans. It is the major pharmacologic source of vitamin D. Pharmaceutical preparations include

vitamin D2

(ergocalciferol), 25-hydroxycholecalciferol (calcifediol), and 1,25-dihydroxycholecalciferol

(calcitriol). 1-Hydroxycholecalciferol and dihydrotachysterol are synthetic preparations that require

only 25-hydroxylation for activity and so are useful for supplementation in patients with renal failure,

who lack the 1-hydroxylase.

Calcitonin

Calcitonin is a 32-amino-acid protein produced by the parafollicular C (calcitonin) cells of the thyroid.

The C cells are embryologically derived from the neural crest and, in lower animals, are found in the

ultimobranchial bodies, which are glandular structures derived from the lowest branchial pouch. In

humans, these structures are incorporated into the superior and lateral aspects of the thyroid lobes.

Total thyroidectomy, with removal of all the C cells, is well tolerated. Calcitonin is not essential for

the normal control of calcium metabolism in adult humans. It does inhibit bone resorption and can

produce hypocalcemia in experimental animals. It also increases urinary calcium and phosphate

excretion. These effects are mediated primarily through cAMP. Several secretagogues for calcitonin

have been identified, including catecholamines, gastrin, and cholecystokinin, but the most potent appear

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to be calcium and pentagastrin. Exogenously administered calcitonin can be useful pharmacologically to

reduce serum calcium levels.

Mineral Homeostasis

Under normal conditions, serum calcium and phosphate levels vary minimally during the course of the

day. Regulation occurs primarily through PTH but also through a series of feedback loops involving

vitamin D and calcitonin (Fig. 76-7). A fall in serum-ionized calcium increases PTH secretion and

stimulates the production of 1,25-dihydroxyvitamin D3

. Conversely, increases in serum calcium inhibit

PTH secretion and the formation of active calciferol.

Pathophysiology

Diseases of the parathyroid glands present almost exclusively as disorders of calcium metabolism.

Hypercalcemia is the most common manifestation, and in the patient who presents with an elevated

serum calcium level, the differential diagnosis can be complex. A thorough understanding of both

hypercalcemia and hypocalcemia is essential for the successful treatment of patients undergoing

parathyroid surgery. Primary disorders of plasma phosphate are not usually related to surgical disease

and are not discussed in detail here.

HYPERCALCEMIA

Hypercalcemia is a relatively common clinical problem.3,4 In the general population and in hospital

outpatients, the incidence is between 0.1% and 0.5%. Most patients in this group have primary

hyperparathyroidism. In contrast, hypercalcemia is identified in almost 5% of hospitalized patients, and

nearly two-thirds of them have a malignancy.

Clinical Manifestations

The symptoms of hypercalcemia are varied and nonspecific (Table 76-2). Severity is a function of both

the magnitude and rapidity of onset of the hypercalcemia. Many of the manifestations are subtle and are

evident only in retrospect, after the patient has been successfully treated for the cause of the elevated

calcium. Specific symptoms and diagnostic tests are addressed in more detail in the section on

hyperparathyroidism.

Figure 76-6. Schematic illustration of the synthesis of vitamin D3

. Ergosterol, 1-alpha-hydroxyvitamin D3

, and dihydrotachysterol

are synthetic preparations of vitamin D.

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Differential Diagnosis

Although the diagnosis of primary hyperparathyroidism can, after appropriate investigation, be

established with confidence in most patients, all causes of hypercalcemia must be considered and

excluded. The multiple causes of hypercalcemia are listed in Table 76-3.

Etiology

Hyperparathyroidism

The diagnosis of hyperparathyroidism is discussed in detail later. Patients typically have elevated

plasma concentrations of calcium and PTH, increased urinary excretion of calcium, and a low plasma

concentration of phosphate.

Malignancy

Generally, patients with hypercalcemia and malignancy (humoral hypercalcemia of malignancy) can be

classified into two groups.5–7 Patients with solid tumors, such as lung carcinoma (25% of all cases of

humoral hypercalcemia of malignancy); breast carcinoma (20%); squamous cell carcinoma of the head,

neck, esophagus, or female genital tract (19%); or renal cell cancer (8%), account for three-fourths of

all cases. Humoral hypercalcemia of malignancy in this setting generally appears late in the disease,

with nearly all patients having known, or readily evident, malignancy. These patients have elevated

levels of serum calcium, low levels of serum phosphorus, and elevated levels of urinary cAMP,

consistent with increased PTH activity but normal or low-serum PTH levels. The hypercalcemia is now

known to be caused by PTH-related protein secreted by the tumor, rather than by the bony metastases

that many of these patients have because of the advanced nature of their cancers. In the second group,

accounting for one-fourth of cases, are patients with hematologic malignancies, such as multiple

myeloma, certain lymphomas and leukemias, and a subset of the patients with breast cancer. These

patients have elevated levels of serum calcium, but in contrast to most patients with solid tumors and

humoral hypercalcemia of malignancy, they have elevated levels of serum phosphate and low levels of

urinary cAMP. These patients always have lytic bony lesions and histologically demonstrate increased

osteoclast bone resorption adjacent to tumor cells. This osteoclast-activating activity is an effect of

cytokines, mainly interleukin-1 beta and tumor necrosis factor-beta (lymphotoxin). These cytokines

promote local net bone resorption and thus produce hypercalcemia and hyperphosphatemia.

Figure 76-7. Feedback loops involved in the regulation of serum calcium and phosphorus. PTH, parathyroid hormone; CT,

calcitonin.

DIAGNOSIS

Table 76-2 Clinical Features of Hypercalcemia

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Vitamin D and Vitamin A Intoxication

When administered in excess, vitamins A and D can produce hypercalcemia. Affected patients tend to

have normal or elevated serum phosphate levels associated with a low PTH level. Metastatic

calcification may occur.

Thiazide Diuretics

Thiazides may increase serum calcium levels to a mild degree, primarily through hemoconcentration

and decreased renal excretion. Serum phosphate may also be depressed. It often takes several weeks for

the hypercalcemia to resolve after the medication is discontinued.

Hyperthyroidism

Hyperthyroidism is associated with increased bone resorption. Often, the plasma PTH is low, and a

history of other thyrotoxic symptoms can be elicited. The hypercalcemia usually resolves as the patient

becomes euthyroid.

Milk–Alkali Syndrome

Typically, the milk–alkali syndrome occurs in patients with peptic ulcers who consume large quantities

of milk and absorbable antacids. Usually, some degree of renal failure is present. PTH levels are low.

This syndrome has become much less common with the increased use of nonabsorbable antacids,

histamine 2-receptor antagonists, and proton pump inhibitors as therapy for peptic ulcer disease.

ETIOLOGY

Table 76-3 Causes of Hypercalcemia

Sarcoidosis and Other Granulomatous Diseases

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These syndromes are associated with hypersensitivity to vitamin D. The granulomas can convert

inactive vitamin D to its active form. Patients have elevated plasma globulins and low PTH levels. The

administration of large doses of corticosteroids for 10 days usually reduces the hypercalcemia. Biopsy of

lymph nodes or the liver may confirm the diagnosis.

Familial Hypocalciuric Hypercalcemia

This disease is an asymptomatic, autosomal dominant condition characterized by mild to moderate

hypercalcemia, hypocalciuria, and normal or only slightly elevated PTH levels. It develops in people

heterozygous for a mutation in the calcium-sensing receptor.8–10 The mutation causes an increase in the

set point for extracellular calcium concentration, so that the “normal” calcium level is higher in these

people than in the normal population. No treatment is necessary, although people with this disease

should receive genetic counseling. Neonatal severe hyperparathyroidism, which can be fatal, develops in

children homozygous for mutations in this receptor. Treatment for neonates with this disease is

controversial, but they appear to benefit from early surgical management.

Immobilization

Immobilization produces hypercalcemia by increasing the ratio of bone resorption to bone formation.

These patients can usually be distinguished by history, although on laboratory evaluation they have

elevated serum levels of calcium and phosphate and a decreased serum concentration of PTH. Often,

hypercalciuria is present, which may lead to the development of renal stones. Treatment is early

mobilization and forced diuresis.

Other Causes

A variety of other diseases may produce hypercalcemia. For example, Paget disease (osteitis deformans)

typically causes mild elevations in serum calcium. Paget disease can be diagnosed on the basis of the

characteristic radiographic lesion. Adrenal insufficiency may be associated with hypercalcemia, although

the symptoms are typically those of the primary abnormality. Lithium therapy appears to produce

hypercalcemia by altering the parathyroid set point for inhibition by calcium, and, over long courses of

therapy, may also be associated with hyperparathyroidism. Idiopathic hypercalcemia of infancy is a rare

disorder that is probably the result of hypersensitivity to vitamin D. It occurs in infants with mental

retardation and is satisfactorily treated with glucocorticoids. Other causes include aluminum-induced

renal osteomalacia and a host of analytic errors related to improper specimen collection with prolonged

tourniquet times, tube contamination, and instrument drift.

Medical Treatment

Although the choice of therapy is tailored to the cause of the hypercalcemia, several general measures

can prove effective.11,12

For the patient with mild hypercalcemia, a trial of a decrease in dietary calcium is indicated. A

reduction in intake of milk and other dairy products is suggested, along with discontinuation of thiazide

diuretics and vitamin D preparations. Mobilization prevents bone demineralization.

Patients with more marked hypercalcemia or severe symptoms should be admitted to the hospital for

treatment, with careful observation and monitoring. In the patient with severe hyperparathyroidism,

although the definitive therapy is surgical, it is unwise to proceed with neck exploration until the

calcium has been reduced to near-normal levels. The mainstay of therapy is intravenous hydration,

preferably with normal saline solution in sufficient quantities to maintain the urine output above 100

mL/hr. These patients are often dehydrated before therapy, and fluid can be administered intravenously

at a rate of 200 mL/hr. Caution must be exercised in older patients, whose cardiac reserve may be

marginal. This therapy exploits the parallel handling of calcium and sodium by the kidneys. The diuretic

furosemide also increases sodium and calcium excretion but should not be used until the patient is well

hydrated.

The end points of therapy are a decrease in the serum calcium level and a reduction of symptoms.

Diuresis with saline solution is usually effective when the hypercalcemia results from

hyperparathyroidism or a benign cause. In contrast, the hypercalcemia of malignancy may produce

severe symptoms associated with extremely high serum calcium levels that are difficult to control. In

this setting, a variety of other measures may be considered (Table 76-4). Some of the agents used to

treat hypercalcemia cause significant toxicity, and close patient monitoring is required during

treatment. Calcitonin is a fairly weak hypocalcemic agent, but it acts rapidly and is associated with less

toxicity than many of the other drugs.12 Salmon calcitonin is the most potent preparation. Treatment

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