hyperplasia has been characterized as a diffuse proliferation of clear cells in multiple glands, with little

remaining normal tissue (Fig. 76-9). These criteria have proved totally unreliable. Although pathologic

studies can usually distinguish parathyroid glands from other tissue, they may not prove useful beyond

this capacity. Intraoperative decisions frequently depend on recognizing disease of one or more

parathyroid glands, and in this regard, the histologic description of adenoma or hyperplasia is generally

unreliable in primary hyperparathyroidism.22

Patients with multiple-gland disease may have one gland that appears to be an adenoma and another

that appears diffusely involved or even histologically normal with gross enlargement. The most reliable

index of abnormality is the determination of glandular enlargement by visual inspection. The incidence

of single- and multiple-gland enlargement as judged by visual inspection in 66 consecutive patients with

hyperparathyroidism is shown in Table 76-9. The visual assessment and judgment of the experienced

surgeon have proved to be an effective basis for intraoperative decisions. This approach requires that all

four parathyroid glands be evaluated at the time of operation. However, the recent ability to rapidly

measure PTH during operation has provided a method to assess gland function rather than size. This

experience indicates that there may be more enlarged glands than there are hyperfunctioning glands.23

Figure 76-9. Primary parathyroid hyperplasia. The normal adipose tissue of the gland has been replaced by sheets and trabeculae

of hyperplastic chief cells.

Table 76-9 Gland Enlargement in 1,002 Consecutive Patients with Primary

Hyperparathyroidism

Carcinoma

Parathyroid carcinoma is a rare entity, and the histologic diagnosis can be exceedingly difficult. The

surgeon may suspect the diagnosis when dense invasion and scarring are encountered, although this

may also be secondary to some other inflammatory disease in the neck. Pathologic criteria include

marked mitotic activity, dense fibrous stroma, and evidence of local invasion into the capsule or

surrounding vessels.24 Malignant-appearing tumors, however, may pursue an apparently benign clinical

course; the converse is less frequently true. The only reliable criteria of malignancy are metastases,

most commonly to the lymph nodes, lung, or liver, and true local invasion.

Systemic Effects

The use of automated technology for determining serum calcium has changed not only the estimated

incidence of hyperparathyroidism but also the usual mode of presentation. Before screening, threefourths of patients presented with renal disease, particularly nephrolithiasis; one-third to one-half had

skeletal manifestations, and rare patients had both. Most recent series suggest that at least half of the

patients in whom hyperparathyroidism is diagnosed do not have renal or osseous disease and many are

minimally symptomatic or asymptomatic. Manifestations of the disease are protean but generally

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nonspecific, and they may be difficult to elicit in the history. A significant proportion of patients present

without a readily quantifiable index of disease severity. This finding has created some controversy

about the need for surgery in the asymptomatic patient and particularly for the elderly or high-risk

patient.18,25

The earliest complaints are often the vague symptoms of hypercalcemia. These vary with the

magnitude of plasma calcium elevation and can include muscle weakness, anorexia, nausea,

constipation, polyuria, and polydipsia. These nonspecific symptoms may or may not cause the patient to

seek medical attention. Some symptomatic patients have evidence of chronic disease involving the

kidney or skeleton. Usually, only one of these systems is significantly involved in any individual patient.

The treatment of hyperparathyroidism is designed to eliminate or halt the progression of the

complications of the disease. Symptomatic patients can be divided into two groups. Members of the first

group have renal manifestations, a slower onset of symptoms, and generally lower serum calcium

concentrations. Patients in the second group have a more rapid onset of symptoms, higher serum

calcium levels, and significant bone disease. No recognizable histologic or physiologic characteristics

distinguish patients with renal disease from those with bone disease.

Figure 76-10. Abdominal film demonstrating nephrocalcinosis, or diffuse calcification of the renal parenchyma (arrows).

Renal Manifestations

Renal complications develop because the hypercalcemia leads to an increase in urinary calcium

excretion and because PTH increases the excretion of phosphate and produces urinary alkalosis. Both

these events predispose to stone formation. Urinary stones can be treated surgically or with lithotripsy,

and subsequent definitive treatment of the hyperparathyroidism reduces the rate of reformation. Of

patients who present for the first time with renal colic, 5% to 10% are found to have primary

hyperparathyroidism. Nephrocalcinosis (Fig. 76-10) is calcification of the renal parenchyma and occurs

in 5% to 10% of patients with hyperparathyroidism. It causes more significant renal damage than

nephrolithiasis does. In general, the more severe the renal damage, the less likely it is that

nephrocalcinosis will regress after parathyroidectomy.

The incidence of hypertension in hyperparathyroidism increases with the degree of renal impairment.

Hypertension may be a significant cause of the morbidity associated with hyperparathyroidism, but

although a decrease in blood pressure has been demonstrated in some patients after parathyroidectomy,

the correlation between the two conditions is not clear.

Skeletal Manifestations

Parathyroid bone disease in its most classic and severe form, osteitis fibrosa cystica, is seldom

encountered; however, 5% to 15% of patients with parathyroid bone disease present with significant

symptoms of skeletal disease. Most commonly, these symptoms include bone pain and pathologic

fractures.

Bone changes are often demonstrable on detailed plain radiographs of the hands (Fig. 76-11).

Characteristically, subperiosteal resorption is evident on the radial aspect of the middle phalanx of the

second or third finger. Because of tufting of the distal phalanges, clubbing may be evident on physical

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examination. Other findings that typically involve the skull and long bones include bone cysts, “brown”

tumors (i.e., localized proliferations of osteoclasts), and diffuse demineralization or granularity. More

subtle bone loss can be detected by iliac crest bone biopsy or dual energy x-ray absorptiometry scan.

The risk of bone fracture increases with increasing severity of bone loss.

Figure 76-11. Magnification radiograph of the fingers in hyperparathyroidism. Subperiosteal cortical resorption (arrows) typically is

most visible on the radial aspect of the middle phalanges.

Gastrointestinal Manifestations

Hypercalcemia is clearly associated with nonspecific gastrointestinal complaints, including nausea,

vomiting, constipation, and anorexia, but attempts to demonstrate a definite relation between

hyperparathyroidism and either peptic ulcer disease or pancreatitis remain unconvincing. Hypercalcemia

stimulates gastric acid secretion experimentally and clinically, and has been associated with pancreatitis.

Therefore, a theoretic rationale for the complex of hyperparathyroidism and gastrointestinal symptoms

does exist.

Neuromuscular Manifestations

Neurologic and muscular complaints are those of hypercalcemia in general. Fatigability and proximal

muscle weakness are among the most debilitating manifestations. Atrophy of type II muscle fibers,

consistent with a neuropathic and not a myopathic cause, has been demonstrated. Sensory complaints

include dysesthesia, a reduced vibratory sense, and stocking–glove sensory deficits.

Psychological Manifestations

The emotional disturbances of hyperparathyroidism are often subtle and difficult to quantify. As with

other forms of hypercalcemia, they range from depression or anxiety to psychosis and coma. Patients

undergoing parathyroidectomy frequently experience a sense of well-being and relief from fatigue and

dullness postoperatively, even if they may have had no noticeable complaints preoperatively.

Other Manifestations

A variety of signs and symptoms of soft tissue calcification have been described. Nonspecific arthralgia,

particularly involving the proximal interphalangeal joints of the hands, is characteristic. The incidence

of chondrocalcinosis is increased. Pruritus, vascular and cardiac calcification, and band keratopathy of

the cornea have all been noted. Some reports have suggested an increased risk of malignancy and

coronary artery disease, but the effects remain unsubstantiated, and it is not clear if the mortality risk is

modifiable by correction of hyperparathyroidism.26–28

Physical Findings

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Except in patients with the classic deformities of advanced bone disease, the physical examination is

seldom helpful. Diseased parathyroid glands are infrequently palpable, except in patients with

parathyroid carcinoma. A mass in the anterior neck in a patient with primary hyperparathyroidism is

most commonly a thyroid nodule.

Laboratory Findings

Tests for calcium, PTH, phosphate, bicarbonate, and magnesium, in addition to other laboratory tests,

are useful to establish the diagnosis of hyperparathyroidism.

Calcium. Hypercalcemia is the single most important diagnostic finding; however, particularly in early

or mild cases, serial analysis may show fluctuations in and out of the normal range. Coexistent

hypoalbuminemia and acidosis may produce an apparently normal total serum level of calcium, even

though the ionized fraction is actually elevated. Serum concentrations of ionized calcium may be helpful

in the patient with intermittent or mild hypercalcemia.

3 Parathyroid Hormone. PTH measurement is an important method for establishing the diagnosis of

hyperparathyroidism. Because of the heterogeneity of the various circulating forms of PTH,

measurement of C-terminal or N-terminal fragments give conflicting and confusing results. Intact

hormone assays and whole molecule assays are the most dependable. The demonstration of an elevated

plasma PTH concentration alone does not establish the diagnosis of hyperparathyroidism. With a

simultaneous elevated serum calcium level, this finding is virtually diagnostic (Fig. 76-12).

Phosphate. PTH increases renal phosphate excretion and, in about half of patients, produces

hypophosphatemia. In the presence of renal disease, however, the serum phosphate levels may be

normal or significantly elevated.

Bicarbonate. PTH also increases bicarbonate excretion, so that a hyperchloremic metabolic acidosis

may develop. It has been suggested that the finding of an elevated serum chloride-to-phosphate ratio

may be helpful in the differential diagnosis of hypercalcemia. A ratio greater than 30 is considered

highly suggestive of hyperparathyroidism.

Magnesium. Hypomagnesemia develops in 5% to 10% of patients with hyperparathyroidism. After

parathyroidectomy, if both hypocalcemia and hypomagnesemia are present, it may be difficult to

correct the calcium until the serum magnesium has been corrected.

Other Diagnostic Tests. A variety of special diagnostic tests for hyperparathyroidism are available.

None is more specific than the measurement of serum concentrations of calcium and PTH, although they

may be useful in equivocal cases. For example, the 24-hour urinary calcium excretion is usually

elevated, but may be normal, in patients with hyperparathyroidism, although the finding is not specific

for this disease. This test is helpful in identifying patients with familial hypercalcemic hypocalciuria, in

whom the rate of urinary calcium excretion is low. Measurements of tubular reabsorption of phosphate

below 30% suggest primary hyperparathyroidism. Urinary cAMP is generated specifically as a

consequence of PTH activation of renal tubular adenyl cyclase. Increased urinary concentrations are

identified in most patients with primary hyperparathyroidism. These measurements are rarely necessary

because of the reliability of the intact PTH measurement.

Localization with Imaging Techniques

In order to try to simplify the operative approach to hyperparathyroidism, an attempt is usually made

to localize enlarged glands preoperatively. In the hands of an experienced surgeon, the cure rate for

hyperparathyroidism at the initial operation without preoperative localization exceeds 95% with the

conventional full-neck exploration. However, technologic developments have led surgeons to pursue

alternatives to the full-neck exploration. These innovations are increasingly accurate preoperative

localization with 99mtechnetium sestamibi scintigraphy, computed tomography scans with carefully

timed intravenous contrast administration, or high-resolution ultrasound, combined with intraoperative

intact PTH measurement that allows termination of the operation without visualization of all four

parathyroid glands. Surgeons have used these technologies in various combinations to limit the extent of

the neck exploration. All of the current alternative strategies, however, depend on a preoperative

parathyroid localization study to direct the exploration.

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Figure 76-12. Relation between serum immunoreactive parathyroid hormone and serum calcium in patients with

hypoparathyroidism, pseudohypoparathyroidism, ectopic hyperparathyroidism, and primary, secondary, and tertiary

hyperparathyroidism. GP1M, guinea pig antiserum 1M.

Figure 76-13. 99mTechnetium sestamibi scan of a patient with a parathyroid adenoma. The radionuclide is present in both thyroid

and parathyroid tissues on the 10-minute film; however, by 2 hours, the radionuclide has washed out of the thyroid and remains

only in the right-sided parathyroid gland. This scan shows a 794-mg right upper parathyroid adenoma (arrow).

The study most frequently used for imaging previously unoperated patients is

99mtechnetium

sestamibi scintigraphy (Fig. 76-13). Sestamibi scanning can identify the site of abnormal tissue in 75%

to 80% of patients but has limitations in patients with small adenomas or multiple-gland disease.

Sestamibi was originally developed for cardiac imaging. The use of a single nuclide with a short half-life

and a high-energy profile has advantages in lateral, oblique, and three-dimensional imaging that

technetium–thallium scanning, which was formerly used, does not provide.

High-resolution ultrasound examination of the neck is also used for localization of abnormal

parathyroid tissue, particularly when it is available for use by the clinician. The current machines scan

at high frequencies (10 to 13 MHz) that allow demonstration of small abnormalities in the neck (Fig.

76-14). The examination is best done by a clinician in real time, as that allows the most complete

assessment of the neck, rather than scans performed by a technician for later review of still pictures by

the physician. The sensitivity of cervical ultrasound for abnormal parathyroid glands is about the same

as for sestamibi scanning. Ultrasonography is an operator-dependent technique. It is rapid and relatively

inexpensive and can direct fine-needle aspiration for cytologic confirmation and immunoassay for PTH.

In patients with persistent or recurrent hyperparathyroidism, preoperative imaging is important to

guide the exploration. High-resolution real-time ultrasonography, computed tomography (CT), magnetic

resonance imaging (MRI), and sestamibi scanning all appear to have comparable sensitivities of 50% to

60%. The results of these examinations may be less successful at centers without significant experience

in their use.

Computed tomography is more expensive but less operator-dependent than ultrasonography. It clearly

is superior in identifying deeper structures and for examining the retrosternal mediastinum. MRI is

considerably more expensive than CT and has not been shown to be superior. Most surgeons prefer to

have results of two or more imaging tests that confirm an abnormality before exploration in the

reoperative setting.29

Treatment

Indications for Surgery

Generally, the only practical therapeutic option is surgery. Nephrolithiasis, bone disease, and

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