neuromuscular symptoms all respond well to surgical intervention. In contrast, surgery in patients with

renal failure, hypertension, and psychiatric symptoms is not so uniformly successful, although it benefits

some patients and is usually indicated in all except those at highest risk. The question of how to manage

the large group of patients with apparently asymptomatic disease requires particularly careful

consideration.

Management of Asymptomatic Hyperparathyroidism

4 A large proportion of patients with the diagnosis of hyperparathyroidism are minimally symptomatic

or asymptomatic. The appropriate treatment for these patients remains controversial. Although little

evidence indicates that irreversible complications, such as renal failure, eventually develop in patients

with asymptomatic mild disease, the natural history of the disease remains incompletely defined. Many

of the manifestations of this disease may go unrecognized until they are corrected surgically. Still

unanswered is the question of how much asymptomatic disease may contribute to generalized

osteopenia in this predominantly postmenopausal female population.

Figure 76-14. Ultrasound views of parathyroid adenomas. A: Sagittal image of the upper pole of the right lobe of the thyroid

gland, demonstrating a hypoechoic parathyroid adenoma posterior to the thyroid parenchyma. B: Sagittal image of the lower pole

of the left lobe of the thyroid gland with an adjacent hypoechoic parathyroid adenoma measuring 9 mm in greatest dimension.

Table 76-10 Indications/Contraindications

A recent report detailed the 15-year natural history of 116 patients with asymptomatic

hyperparathyroidism.18 Operation was recommended for those in whom symptoms or findings

developed, according to the guidelines of the National Institutes of Health Consensus Conference (see

later). During the monitoring period, 51% of the patients had operation, and biochemical normalization

and increased bone mass were observed in those who underwent surgery. However, the patients who

did not undergo operative correction continued to have biochemical abnormalities and the cortical bone

mass fell significantly. These data confirm the impression of most clinicians that mild

hyperparathyroidism rarely takes a precipitously worsening clinical course; however, the differential

bone effects that are evident by 15 years call into question how long such patients can be monitored

without correction.

In October 1990, a National Institutes of Health Consensus Development Conference reviewed the

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available evidence regarding the management of asymptomatic primary hyperparathyroidism.30 After

interval developments, a panel of experts reconvened in 2002, and revisited this issue.31 The panel

agreed that operation is the indicated treatment for all patients with symptoms; however, they

recognized a subgroup of patients who have no symptoms attributable to hyperparathyroidism, and

their conclusions included several indications for surgical intervention in these asymptomatic patients

(Table 76-10).

The panel mandated close (every 6 months) follow-up for those patients not treated by operation. In

addition, they recommended surgery for cases in which medical surveillance is neither desirable nor

suitable, such as when a patient requests surgery, consistent follow-up is unlikely, coexistent illness

complicates management, or a patient is younger than age 50 years.

This remains an area of considerable controversy, and subsequent reviews have supported similar

plans with only minor revisions.32,33 The complication rate of operation by an experienced surgeon is

very low. Within a short period, the financial cost of medical follow-up exceeds that of treatment by

operation. Based on these considerations, most patients should undergo operation, and those who do not

must be closely followed.

Principles of Surgical Correction

Although neck exploration for hyperparathyroidism may be straightforward, it sometimes becomes an

arduous procedure requiring considerable patience because of the variability in both the location and

the number of diseased glands. Persistent hyperparathyroidism and the necessity for reexploration can

usually be avoided by a meticulous initial procedure. Reoperation is predictably more difficult than the

initial operation, and the risks for damage to the recurrent laryngeal nerves and hypoparathyroidism are

greater during reoperation.

It is essential that the surgeon be confident of the preoperative diagnosis and prospectively discuss

the procedure with the patient. The potential complications of damage to either the recurrent laryngeal

nerve or the superior laryngeal nerve and the development of hypocalcemia require discussion.

Likewise, the possibility of an unsuccessful initial operation must be explained, and the patient should

recognize that reexploration, including median sternotomy, may be required. Although alternatives to

full-neck exploration are often now applied, no patient should be explored by a surgeon who is

unfamiliar with the principles and techniques of the conventional full-neck exploration.

For a full-neck exploration, the patient is placed under general anesthesia with a roll beneath the

shoulders and the neck extended. The neck is opened through a transverse incision overlying the thyroid

isthmus, and the platysma is similarly divided. Superior and inferior flaps are developed. The strap

muscles are separated in the midline and retracted laterally; division is unnecessary. One lobe of the

thyroid is chosen and rotated medially. Important landmarks include the tracheoesophageal groove, the

recurrent laryngeal nerve, the inferior and superior thyroid arteries, and the middle thyroid vein (Fig.

76-15). In most patients, the nerve lies in the tracheoesophageal groove or just laterally. Occasionally,

it may be situated more anteriorly. Uncommonly, it may originate directly from the vagus without

passing around the right subclavian artery. Both of these latter variations make the recurrent nerve

more susceptible to injury. The external branch of the superior laryngeal nerve, which innervates the

cricothyroid muscle, usually lies medial to the superior thyroid vessels and should be carefully

preserved.

Figure 76-15. Lateral view of the right side of the neck after rotation of the thyroid lobe. The important anatomic landmarks are

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emphasized.

For a full-neck exploration, all four glands should be identified at the initial exploration because of

the possibility of multiple-gland disease. Supernumerary glands may be present and should be sought at

the initial procedure. Although a frozen section has not been helpful in differentiating diseased from

normal glands, it is generally reliable for confirming the presence or absence of parathyroid tissue.

Small, thin biopsy specimens are sharply incised from the gland, with extreme care taken to avoid

damaging its delicate blood supply. Most surgeons use a frozen section selectively to confirm suspected

abnormal parathyroid tissue or to document difficult or confusing situations.34

The upper glands are usually located far dorsally on the surface of the thyroid lobe at the level of the

upper two-thirds of the gland. The lower glands are less constant and may be located anywhere from

well above the thyroid to the anterior mediastinum. The lower glands are most typically in the region

where the thyrothymic ligament attaches to the lower pole of the thyroid lobe. If the inferior glands

cannot be localized, the thymic pedicle should be carefully examined and mobilized. Because of their

common embryologic origin, the inferior gland is frequently associated with the thymic remnant.

Parathyroid glands within the mediastinum sometimes can be removed by mobilizing the thymus

through the cervical incision. If this technique is unsuccessful in identifying the parathyroid gland, the

thyroid lobe on the side of the missing gland is mobilized and palpated. Intraoperative ultrasonographic

examination may identify an intrathyroidal parathyroid gland. As a last resort, excision of the thyroid

lobe may be indicated.

If after meticulous exploration of all these areas three or four parathyroid glands have been

identified, none of which is enlarged, most surgeons favor terminating the operation.

Limited Surgical Exploration

5 With the availability of accurate preoperative localization methods, it has become routinely possible

to identify abnormal parathyroid glands prior to operation for most patients. This allows the surgeon to

know where to start the exploration. Then, intraoperative PTH measurement can be used to confirm

removal of all hyperfunctioning parathyroid tissue, that is, when to stop the operation. This strategy of

directed, limited neck exploration is applicable to about 75% of initial parathyroid explorations, and has

about the same success rate as full-neck exploration.35–37 The preoperative localization can be done by

either 99mtechnetium sestamibi nuclear medicine scan or by high-resolution ultrasound. The

intraoperative PTH measurement is first assessed at the outset of the procedure, and/or immediately

preceding parathyroid gland excision (the preexcision baseline). Blood samples are obtained at time

intervals after parathyroid gland resection. A decrease of the PTH level by 50% from the higher of the

incision or pre-excision baseline predicts long-term normocalcemia.38 Other investigators use more

sensitive criteria for the detection of multigland disease, including reduction of the PTH level into the

normal range and kinetic assessments of the rate of PTH decrease.39 This increase in sensitivity comes

with the cost of decreased specificity, however. Blood samples can be obtained either centrally or

peripherally.40

The limited nature of this operative approach also makes it easier to perform this operation under

regional or local anesthetic in an ambulatory setting. However, because of the possibility of multiple

gland disease or inaccurate preoperative localization, all surgeons undertaking this approach should also

be skilled in the full-neck exploration for hyperparathyroidism.41–43

Extent of Resection

The operative procedure performed has been based on the number of enlarged glands identified at fullneck exploration; however, with the use of intraoperative PTH monitoring, it has become clear that not

all enlarged parathyroid glands are hyperfunctioning.44 In contrast, nearly all hyperfunctioning glands

are enlarged and hypercellular. The full-neck exploration experience has demonstrated that removing all

enlarged glands is a highly successful approach to curing hyperparathyroidism. In the absence of PTH

monitoring, this remains an accepted approach. Typically, single-gland disease has been treated by

simple excision, whereas any combination of two- or three-gland enlargement is treated by resecting the

diseased tissue and leaving the normal glands in place. The question of whether two- or three-gland

enlargement implies the presence of disease in all glands (hyperplasia) has not been resolved. If one

gland is large and the remaining three are normal in size, resection of the single parathyroid cures

virtually all patients. Of 76 patients with two- or three-gland disease treated by excising the large

glands and leaving the normal glands, only eight (10.5%) had recurrent hypercalcemia, which tended to

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be mild (follow-up of 12 to 140 months postoperatively). This approach seems satisfactory in most

patients.45

Treating patients with four-gland disease has been more difficult. In many of these patients, the

disease occurs as a component of one of the familial syndromes, particularly MEN-1. Patients with fourgland parathyroid disease can be treated by subtotal parathyroidectomy (removing three and a half

glands) or by total parathyroidectomy with autotransplantation of some parathyroid tissue into the

nondominant forearm. Both operations depend on meticulous identification of all parathyroid tissue for

adequate results. The putative advantage of the subtotal parathyroidectomy is that it leaves the

remaining parathyroid tissue with its native blood supply. Total parathyroidectomy with autograft has

the advantage of removing all the abnormal parathyroid tissue from the neck and placing it in a site

where reoperation for recurrent hyperparathyroidism is simpler. Over time, subtotal parathyroidectomy

has become the more common approach.

The reported incidence of recurrent hypercalcemia after subtotal parathyroidectomy for nonfamilial

parathyroid hyperplasia is 0% to 16%; the incidence of permanent hypoparathyroidism is 4% to 5%.

Total parathyroidectomy with autograft is associated with a similar risk for permanent

hypoparathyroidism in the sporadic setting (5%) and a higher reported risk for recurrent hypercalcemia

(20%). Reoperation for recurrent hypercalcemia is simplified by the approach of total

parathyroidectomy with autotransplantation. Thus, given the current data, sporadic parathyroid

hyperplasia can be acceptably treated by either operation. In patients with MEN-1, the disease is not the

same as sporadic hyperplasia. Rather, defects in the MEN-1 gene cause multiple parathyroid adenomas

that arise independently over the life of the patient.21 The operative results reflect this independent

capability of all parathyroid tissue in these patients to become neoplastic. The hypercalcemia recurrence

rate is 26% to 36% with long-term follow-up after subtotal parathyroidectomy, and similar after total

parathyroidectomy with autograft. However, the incidence of permanent hypoparathyroidism after

autograft in MEN-1 is also significant (reported as high as 46%). While both approaches are currently

accepted, most experienced centers now advocate subtotal parathyroidectomy as the initial operation in

MEN-1 hyperparathyroidism, and anticipate that recurrent disease is likely, manageable, and less

problematic than permanent hypocalcemia.46,47

Technique of Parathyroid Autotransplantation

The parathyroid gland is sliced into 15 to 20 pieces and autografted into a forearm muscle bed. The sites

are marked with silk sutures. This location permits easy subsequent access under local anesthesia if

recurrent hypercalcemia develops. Function of the autograft is documented by (a) normocalcemia, with

the autograft as the only source of PTH, (b) by measuring higher concentrations of hormone in the

antecubital vein draining the graft bed than in the corresponding vein in the opposite arm, or (c)

“transient parathyroidectomy,” by placing a venous occlusive tourniquet on the arm above the graft,

and measuring changes over several minutes in the PTH levels drawn from the contralateral arm.48 Lack

of function is unusual outside of the MEN-1 patients; hypoparathyroidism develops in about 5% of

patients. Glands can also be cryopreserved in dimethyl sulfoxide and serum. If in the postoperative

period it becomes clear that the patient is aparathyroid, the cryopreserved tissue can be reimplanted

under local anesthesia.

Special Situations

Persistent or Recurrent Hyperparathyroidism

Persistent hyperparathyroidism occurs in fewer than 5% of patients after exploration by an experienced

surgeon. Most commonly, it is the result of a single diseased gland remaining in the neck or the

mediastinum. Recurrent disease develops after an interval of normocalcemia and may be the result of

regrowth of diseased tissue, implantation from a tumor broken at the initial procedure, or recurrent

parathyroid carcinoma.

In the evaluation of these patients, it is essential to document that the initial diagnosis was correct.

Familial hypocalciuric hypercalcemia should be excluded by measuring urinary calcium excretion.

Reviewing the original operative notes and pathology reports may provide clues to the position of

missed glands. The locations of parathyroid tumors not found at the initial operation but identified on

subsequent exploration in one large series are shown in Figure 76-16.

It is generally agreed that localization studies do have a place in the management of recurrent

disease. Noninvasive methods are used first, and if these are unsuccessful in identifying the diseased

gland, selective angiography and venous sampling for PTH are used. The utility of the techniques vary

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across institutions, dependent on local experience, expertise and preference. Selective angiography

localizes 50% to 80% of parathyroid glands that cannot be detected by any other modality. Venous

sampling may also be helpful in some patients, although interpretation can be complicated by the

collateralization that occurs postoperatively. Because it provides no direct image but indicates the side

and level of the neck where the hyperfunctioning tissue is located, it may help to direct the evaluation

of imaging studies and the exploration to one or the other side of the neck. Both these invasive

radiographic techniques require considerable expertise. Transient cortical blindness, transverse myelitis,

and cerebrovascular accidents have all been reported as complications of arteriography. Angiographic

ablation of mediastinal parathyroid tissue with large doses of ionic contrast has been successful in

selected patients. This technique may be used in some patients with mediastinal parathyroid adenomas

who are at increased surgical risk and who have other functional parathyroid tissue remaining.49

Figure 76-16. Location of parathyroid tumors missed on initial exploration but identified on subsequent operation.

Surgical reexploration can be a difficult procedure. The neck should almost always be reexplored first.

If the thymic remnant has not already been removed, it should be excised at this time. Two adjunctive

techniques, intraoperative ultrasonography to locate glands and intraoperative measurement of PTH to

document the adequacy of resection, may be useful in patients undergoing operation for persistent

disease.29

If the gland is not identified in the neck by means of the maneuvers described, the mediastinum is

examined; most surgeons do this only if there is imaging evidence of disease in the mediastinum, rather

than unguided exploration. Median sternotomy and exploration are necessary in only 1% to 2% of

patients with hyperparathyroidism. Successful transcervical mediastinal exploration is sometimes

possible with use of the Cooper thymectomy retractor, a substernal retractor that permits more

extensive mediastinal exploration and thymectomy through a cervical incision.50 Any remaining thymic

tissue is first isolated and examined. Inferior parathyroid glands most commonly migrate into the

anterior mediastinum. If the results of this exploration are negative, the area posterior and lateral to the

trachea is then explored. The location of superior parathyroid glands may be as far posterior as the

esophagus and as far superior as the pharynx.

Surgical reexploration is successful in experienced hands in about 80% of cases. The incidence of

complications is increased. Unilateral recurrent nerve injury occurs in 5% to 10% of patients

postoperatively, and permanent hypoparathyroidism in 10% to 20% of patients. Cryopreservation of

excised tissue may be included as a component of the management of these patients because it allows

later autotransplantation if the patient becomes hypoparathyroid postoperatively. However, the

demonstration of continued PTH production by intraoperative PTH measurement makes

cryopreservation unnecessary. The risks of these complications must be clearly outweighed by the

clinical improvement in patients with advanced disease. Reoperation in asymptomatic patients with

mild disease is controversial.

Hypercalcemic Crisis

Occasionally, patients with hyperparathyroidism become acutely hypercalcemic with severe symptoms.

The pathogenesis appears to involve a cycle of uncontrolled PTH secretion followed by hypercalcemia

and secondary polyuria, dehydration, and reduced renal function, which exacerbate the hypercalcemia.

Serum calcium concentrations may reach 16 to 20 mg/dL, and the syndrome is manifested by rapidly

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developing muscle weakness, nausea and vomiting, lethargy, fatigue, and even coma. Ultrasonography,

sestamibi scan, or CT scan may help to identify the enlarged gland to allow expedient correction.

Definitive treatment involves resecting the diseased parathyroid tissue, which is almost always

curative. Generally, however, it is safer to lower the serum calcium level before operation.

Hyperparathyroidism in Pregnancy

Hyperparathyroidism in pregnancy is a rare disorder that not only causes hypercalcemia in the mother

but also is associated with increased morbidity and mortality rates in the fetus. Even the newborn is at

risk for the development of tetany. The risk for fetal complications is higher if the hyperparathyroidism

is left untreated. The mother should undergo operation in the second trimester,51 though the outcome

for the pregnancy with modern management is good overall.52

Neonatal Hyperparathyroidism

Neonatal hyperparathyroidism occurs in infants who are homozygous for a mutation of the calciumsensing receptor and is characterized by hypotonia, poor feeding, constipation, and respiratory distress.

Each parent of these children is affected by familial hypocalciuric hypercalcemia. The 1-year survival

rate in children with symptoms is less than 50%, and patients without symptoms appear to have

significant bone disease. Total parathyroidectomy with autotransplantation is the treatment of choice.53

Secondary Hyperparathyroidism

Secondary hyperparathyroidism develops as a consequence of chronic renal failure. Phosphate retention

and hyperphosphatemia reduce the serum calcium levels. This effect is aggravated by the reduction in 1-

hydroxylase activity in the kidney, necessary for the activation of vitamin D3

. The secondary increase in

PTH levels to compensate for the hypocalcemic effects is exacerbated by aluminum accumulation in

bone. Aluminum, present both in the dialysate fluid and in phosphate-binding medications, contributes

to the osteomalacia (renal osteodystrophy) that develops in all these patients after several years of

dialysis. Therapy includes controlling the hyperphosphatemia with dietary restriction and phosphatebinding gels, calcium supplementation orally and in the dialysate bath, correction of acidosis,

administration of vitamin D sterol, and reduction in aluminum intake in both the dialysate and the diet.

Therapy should be initiated carefully because metastatic soft tissue calcification can occur. Indications

for surgical therapy include persistent, symptomatic hypercalcemia that cannot be controlled medically,

particularly in prospective renal transplant patients; bone pain and abnormal fractures; ectopic

calcification; and intractable pruritus. Subtotal parathyroidectomy and total parathyroidectomy with

heterotopic autotransplantation both appear to be acceptable options, although reexploration for

recurrent disease is less complicated after total parathyroidectomy with autotransplantation.

Parathyroidectomy can enhance aluminum deposition, so any excess should be corrected preoperatively

through chelation.

Parathyroid Carcinoma

Parathyroid carcinoma is a rare condition, accounting for less than 1% of all cases of

hyperparathyroidism. Histologic criteria remain controversial, and the diagnosis is securely made only

on the basis of local invasion or distant metastases. In comparison to patients with benign disease, these

patients tend to be somewhat younger and more symptomatic. In contrast to the marked female

predominance in benign disease, the male-to-female ratio in carcinoma is equal. Serum calcium, PTH,

and alkaline phosphatase levels are relatively more elevated, and patients often have an elevated level

of human chorionic gonadotropin. Patients may have manifestations of both renal and bone diseases.

The affected gland is palpable in almost half of patients.

Initial treatment should include radical resection of the involved gland, ipsilateral thyroid lobe, and

regional lymph nodes. Neither chemotherapy nor radiation therapy has shown any benefit. If the disease

recurs, resection should be attempted because without treatment these patients usually succumb to

uncontrolled hypercalcemia. The long-term prognosis is poor, and the opportunity for survival depends

on complete initial resection.24,54

MULTIPLE ENDOCRINE NEOPLASIA

Although these familial disorders are typically characterized by a predisposition to the development of

tumors of multiple endocrine organs, the parathyroid is characteristically involved in two of them. The

disorders are all inherited in an autosomal dominant fashion, and the tumors tend to be multicentric.

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