Chapter 16: Thyroid & Parathyroid

EMBRYOLOGY & ANATOMY

The main anlage of the thyroid gland develops as a median endodermal downgrowth from the first and second pharyngeal pouches (Figure 16–1). During its migration caudally, it contacts the ultimobranchial bodies developing from the fourth pharyngeal pouches. When it reaches the position it occupies in the adult, with the isthmus situated just below the cricoid cartilage, the thyroid divides into two lobes. The site from which it originated persists as the foramen cecum at the base of the tongue. The path the gland follows may result in thyroglossal remnants (cysts) or ectopic thyroid tissue (lingual thyroid). A pyramidal lobe is frequently present. Agenesis of one thyroid lobe, almost always the left, may occur.

The normal thyroid weighs 15-25 g and is attached to the trachea by loose connective tissue. It is a highly vascularized organ that derives its blood supply principally from the superior and inferior thyroid arteries. A thyroid ima artery may also be present.

PHYSIOLOGY

The function of the thyroid gland is to synthesize, store, and secrete the hormones thyroxine (T₄) and triiodothyronine (T₃). Iodide is absorbed from the gastrointestinal tract and actively trapped by the acinar cells of the thyroid gland. It is then oxidized and combined with tyrosine in thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). These are coupled to form the active hormones T₄ and T₃, which initially are stored in the colloid of the gland. Following hydrolysis of the thyroglobulin, T₄ and T₃ are secreted into the plasma, becoming almost instantaneously bound to plasma proteins. Most T₃ in euthyroid individuals, however, is produced by extrathyroidal conversion of T₄ to T₃.

The function of the thyroid gland is regulated by a feedback mechanism that involves the hypothalamus and pituitary. Thyrotropin-releasing factor (TRF), a tripeptide amide, is formed in the hypothalamus and stimulates the release of the thyroid-stimulating hormone (TSH) thyrotropin, a glycoprotein, from the pituitary. Thyrotropin binds to TSH receptors on the thyroid plasma membrane, stimulating increased adenylyl cyclase activity; this increases cyclic adenosine monophosphate (cAMP) production and thyroid cellular function. Thyrotropin also stimulates the phosphoinositide pathway and—along with cAMP—stimulates thyroid growth.

EVALUATION OF THE THYROID

In a patient with enlargement of the thyroid (goiter), the history (including local and systemic systems and family history) and examination of the gland are most important and are complemented by the selective use of thyroid function tests. The surgeon must develop a systematic method of palpating the gland to determine its size, contour, consistency, nodularity, and fixation and to examine for displacement of the trachea and the presence of palpable cervical lymph nodes. Normal or abnormal structures that are attached to the larynx, such as the thyroid gland, move cephalad with deglutition, whereas adjacent lymph nodes typically do not. The isthmus of the thyroid gland crosses the front of the trachea immediately caudal to the cricoid cartilage.

Thyroid function is assessed by highly sensitive TSH assays that can differentiate among patients with hypothyroidism (increased TSH levels), euthyroidism, and hyperthyroidism (decreased TSH levels). In most cases, therefore, serum T₃, T₄, and other variables need not be measured. A free T₄ level is helpful in monitoring patients during treatment for Graves disease because the TSH level may remain suppressed despite the patient’s status improving. A serum T₃ level is useful for diagnosing T₃ toxicosis (high T₃ and low TSH), or the euthyroid sick, low T₃ syndrome (low T₃ and normal or slightly increased TSH).

Radioactive iodine (RAI) uptake is useful for differentiating between hyperthyroidism and increased secretion of thyroid hormone (low TSH and increased RAI uptake) on the one hand and subacute thyroiditis (low TSH and low RAI uptake) on the other. Patients with the latter “leak” thyroid hormone from the gland, which suppresses serum TSH levels and, consequently, iodine uptake by the thyroid. Patients with Graves disease have increased levels of thyroid-stimulating immunoglobulins that increase iodine uptake despite low TSH levels.

HYPERTHYROIDISM (THYROTOXICOSIS)

General Considerations

Hyperthyroidism is caused by the increased secretion of thyroid hormone (Graves disease, Plummer disease, iodine-induced [jodbasedow effect], amiodarone toxicity, TSH-secreting pituitary tumors, human chorionic gonadotropin [hCG]-secreting tumors), or by other disorders that increase thyroid hormone levels without increasing thyroid gland secretion (excess exogenous thyroid hormone intake, subacute thyroiditis, struma ovarii, and, rarely, metastatic thyroid cancers that secrete excess thyroid hormone). The most common causes of hyperthyroidism are diffusely hypersecretory goiter (Graves disease) and nodular toxic goiter (Plummer disease).

In all forms, the symptoms of hyperthyroidism are due to increased levels of thyroid hormone in the blood stream. The clinical manifestations of thyrotoxicosis may be subtle or marked and tend to go through periods of exacerbation and remission. Some patients ultimately develop hypothyroidism spontaneously (~ 15%) or as a result of treatment. Graves disease is an autoimmune disease—often with a familial predisposition—whereas the etiology of Plummer disease is unknown. Most cases of hyperthyroidism are easily diagnosed on the basis of the signs and symptoms; others (eg, mild or apathetic hyperthyroidism—which occurs most commonly in the elderly) may be recognized only with laboratory testing for a suppressed TSH level.

Thyrotoxicosis has been described with a normal T₄ concentration, normal or elevated radioiodine uptake, and normal protein binding but with increased serum T₃ by RIA (T₃ toxicosis). T₄ pseudothyrotoxicosis is occasionally seen in critically ill patients and is characterized by increased levels of T₄ and decreased levels of T₃ due to failure to convert T₄ to T₃. Thyrotoxicosis associated with toxic nodular goiter is usually less severe than that associated with Graves disease and is only rarely if ever associated with the extrathyroidal manifestations of Graves disease such as exophthalmos, pretibial myxedema, thyroid acropathy, or periodic hypocalcemic paralysis.

If left untreated, thyrotoxicosis causes progressive and profound catabolic disturbances and cardiac damage. Death may occur in thyroid storm or because of heart failure or severe cachexia.

Clinical Findings

A. Symptoms and Signs

The clinical findings are those of hyperthyroidism as well as those related to the underlying cause (Table 16–1). Nervousness, increased diaphoresis, heat intolerance, tachycardia, palpitations, fatigue, and weight loss in association with a nodular, multinodular, or diffuse goiter are the classic findings in hyperthyroidism. The patient may have a flushed and staring appearance. The skin is warm, thin, and moist, and the hair is fine.

In Graves disease, there may be exophthalmos, pretibial myxedema, or vitiligo, virtually never seen in single or multinodular toxic goiter. The Achilles reflex time is shortened in hyperthyroidism and prolonged in hypothyroidism. The patient on the verge of thyroid storm has accentuated symptoms and signs of thyrotoxicosis, with hyperpyrexia, tachycardia, cardiac failure, neuromuscular excitation, delirium, or jaundice.

B. Laboratory Findings

Laboratory tests reveal a suppressed TSH and an elevation of T₃, free T₄, and radioactive iodine. A history of medications is important, since certain drugs and organic iodinated compounds affect some thyroid function tests, and iodide excess may result in either iodide-induced hypothyroidism or iodine-induced hyperthyroidism (jodbasedow effect). In mild forms of hyperthyroidism, the usual diagnostic laboratory tests are likely to be only slightly abnormal. In these difficult-to-diagnose cases, two additional tests are helpful: the T₃ suppression test and the thyrotropin-releasing hormone (TRH) test. In the T₃ suppression test, hyperthyroid patients fail to suppress the thyroidal uptake of radioiodine when given exogenous T₃. In the TRH test, serum TSH levels fail to rise in response to administration of TRH in hyperthyroid patients.

Other findings include a high thyroid-stimulating immunoglobulin (TSI) level, low serum cholesterol, lymphocytosis, and occasionally hypercalcemia, hypercalciuria, or glycosuria.

Differential Diagnosis

Anxiety neurosis, heart disease, anemia, gastrointestinal disease, cirrhosis, tuberculosis, myasthenia and other muscular disorders, menopausal syndrome, pheochromocytoma, primary ophthalmopathy, and thyrotoxicosis factitia may be clinically difficult to differentiate from hyperthyroidism. Differentiation is especially difficult when the thyrotoxic patient presents with minimal or no thyroid enlargement. Patients may also have painless or spontaneously resolving thyroiditis and are hyperthyroid because of increased release of thyroid hormone from the thyroid gland. This condition, however, is self-limited, and treatment with antithyroid drugs, radioactive iodine, or surgery is rarely necessary.

Anxiety neurosis is perhaps the condition most frequently confused with hyperthyroidism. Anxiety is characterized by persistent fatigue usually unrelieved by rest, clammy palms, a normal sleeping pulse rate, and normal laboratory tests of thyroid function. The fatigue of hyperthyroidism is often relieved by rest, the palms are warm and moist, tachycardia persists during sleep, and thyroid function tests are abnormal.

Organic disease of nonthyroidal origin that may be confused with hyperthyroidism must be differentiated largely on the basis of evidence of specific organ system involvement and normal thyroid function tests.

Other causes of exophthalmos (eg, orbital tumors) or ophthalmoplegia (eg, myasthenia) must be ruled out by ophthalmologic, ultrasonographic, computed tomography (CT) or magnetic resonance imaging (MRI) scans, and neurologic examinations.

Treatment

Hyperthyroidism may be effectively treated by antithyroid drugs, radioactive iodine, or thyroidectomy. Treatment must be individualized and depends on the patient’s age and general state of health, the size of the goiter, the underlying pathologic process, and the patient’s ability to obtain follow-up care.

A. Antithyroid Drugs

The principal antithyroid drug used in the United States is methimazole, 30-100 mg orally daily; propylthiouracil (PTU), 300-1000 mg orally daily has become an infrequent choice due to side effects. These agents interfere with organic binding of iodine and prevent coupling of iodotyrosines in the thyroid gland. One advantage over thyroidectomy and radioiodine in the treatment of Graves disease is that drugs inhibit the function of the gland without destroying tissue; therefore, there is a lower incidence of subsequent hypothyroidism. This form of treatment is usually used in preparation for surgery or RAI treatment but may be used as definitive treatment. Reliable patients with small goiters are good candidates for this regimen. A prolonged remission after 18 months of treatment occurs in 30% of patients, some of whom eventually become hypothyroid. Side effects of PTU include rashes and fever (3%-4%), agranulocytosis (0.1%-0.4%), and, rarely, liver failure. Patients must be warned to immediately stop the drug, see a physician, and have a white blood cell count if sore throat or fever develops.

B. Radioiodine

Radioiodine (¹³¹I) may be given safely after the patient has been treated with antithyroid medications and has become euthyroid. Radioiodine is indicated for patients who are over 40 years or are poor risks for surgery and for patients with recurrent hyperthyroidism. It is less expensive than operative treatment and is effective. Radioiodine treatment at doses necessary to treat hyperthyroidism does not appear to increase the risk of leukemia or of congenital anomalies. However, an increased incidence of benign thyroid tumors and, rarely, thyroid cancer has been noted to follow treatment of hyperthyroidism with radioiodine. In young patients, the radiation hazard is certainly increased, and the chance of developing hypothyroidism is virtually 100%. After the first year of treatment with radioiodine, the incidence of hypothyroidism increases about 3% per year.

Hyperthyroid children and pregnant women should not be treated with radioiodine.

C. Surgery

1. Indications for Thyroidectomy

The main advantages of thyroidectomy is a more rapid and certain control of the disease than can be achieved with radioiodine treatment. Surgery is often the preferred treatment: (1) in the presence of a very large goiter or a multinodular goiter with relatively low RAI uptake, (2) if there is a suspicious or malignant thyroid nodule, (3) for patients with ophthalmopathy, (4) for the treatment of pregnant patients or children, (5) for the treatment of women who wish to become pregnant within 1 year after treatment, and (6) for patients with amiodarone-induced hyperthyroidism.

2. Preparation for Surgery

The risk of thyroidectomy for toxic goiter is small since the introduction of the combined preoperative use of iodides and antithyroid drugs. Methimazole or another antithyroid drug is administered until the patient becomes euthyroid and is continued until the time of operation. Three drops of potassium iodide solution or Lugol iodine solution are then given for about 10 days before surgery in conjunction with the propylthiouracil as this may decrease the friability and vascularity of the thyroid, thereby technically facilitating thyroidectomy.

An occasional untreated or inadequately treated hyperthyroid patient may require an emergency operation for some unrelated problem such as acute appendicitis and thus require immediate control of the hyperthyroidism. Such a patient should be treated in a manner similar to one in thyroid storm, since thyroid storm or hyperthyroid crises may be precipitated by surgical stress or trauma. Treatment of hyperthyroid patients requiring an emergency operation or those in thyroid storm is as follows: prevent release of preformed thyroid hormone by administration of Lugol iodine solution or with ipodate sodium; give β-adrenergic blocking agents to antagonize the peripheral manifestations of thyrotoxicosis; and decrease thyroid hormone production and extrathyroidal conversion of T₄ to T₃ by giving propylthiouracil.

The combined use of β-blocking agents and iodide lowers serum thyroid hormone levels. Other important considerations are to treat precipitating causes (eg, infection, drug reactions); to support vital functions by giving oxygen, sedatives, intravenous fluids, and corticosteroids; and to reduce fever. Benzodiazepines may be useful in the patient in whom nervousness is a prominent symptom, and a cooling blanket should be used in patients if needed fir temperature control.

3. Subtotal Thyroidectomy

The treatment of hyperthyroidism by subtotal, near-total, or total thyroidectomy eliminates both the hyperthyroidism and the goiter. As a rule, nearly all of the thyroid gland is removed, sparing the parathyroid glands and the recurrent laryngeal nerves. A very complete total thyroidectomy is generally indicated for patients with Graves ophthalmopathy.

The death rate associated with these procedures is extremely low—less than 0.1%. Thyroidectomy thus provides safe and rapid correction of the thyrotoxic state. The frequency of recurrent hyperthyroidism and hypothyroidism depends on the amount of thyroid remaining and on the natural history of the hyperthyroidism. Given an accomplished surgeon and good preoperative preparation, injuries to the recurrent laryngeal nerves and parathyroid glands occur in less than 2% of cases. Adequate exposure and avoidance of injury to the recurrent laryngeal nerves and parathyroid glands are essential.

Ocular Manifestations of Graves Disease

The pathogenesis of the ocular problems in Graves disease remains unclear. Evidence originally supporting the role of either long-acting thyroid stimulator (LATS) or exophthalmos-producing substance (EPS) has not been authenticated.

The eye complications of Graves disease may begin before there is any evidence of thyroid dysfunction or after the hyperthyroidism has been appropriately treated. Usually, however, the ocular manifestations develop concomitantly with the hyperthyroidism. Relief of the eye problems is often difficult to accomplish until coexisting hyperthyroidism or hypothyroidism is controlled.

The eye changes of Graves disease vary from no signs or symptoms to loss of sight. Mild cases are characterized by upper lid retraction and stare with or without lid lag or proptosis. These cases present only minor cosmetic problems and usually require no treatment unless the eyes are dry. When moderate to severe eye changes occur, there is retroorbital soft tissue involvement with proptosis, extraocular muscle involvement, and finally optic nerve involvement. Some cases may have marked chemosis, periorbital edema, conjunctivitis, keratitis, diplopia, ophthalmoplegia, and impaired vision. Ophthalmologic consultation is required.

Treatment of the ocular problems of Graves disease includes maintaining the patient in a euthyroid state without increase in TSH secretion, protecting the eyes from light and dust with dark glasses and eye shields, elevating the head of the bed, using diuretics to decrease periorbital and retrobulbar edema, and giving methylcellulose or guanethidine eye drops. High doses of glucocorticoids are beneficial in certain patients, but their effectiveness is variable and unpredictable. If exophthalmos progresses despite medical treatment, lateral tarsorrhaphy, retrobulbar irradiation, or surgical decompression of the orbit may be necessary. Total thyroidectomy is the treatment of choice when it can be done with a low risk of complications. Graves disease is more likely to worsen after radioiodine treatment than after thyroidectomy. It is important that patients with ophthalmopathy be made aware of the natural history of the disease and also that they be kept euthyroid, since hyperthyroidism and hypothyroidism may produce visual deterioration. Operations to correct diplopia should be deferred until after the ophthalmopathy has stabilized.

EVALUATION OF THYROID NODULES & GOITERS

Thyroid Nodules

The clinician should determine whether a nodular goiter or thyroid nodule is causing localized or systemic symptoms and whether it is benign or malignant. The differential diagnosis includes benign goiter, intrathyroidal cysts, thyroiditis, benign and malignant tumors, and, rarely, metastatic tumors to the thyroid. The history should specifically emphasize the duration of swelling, recent growth, local symptoms (dysphagia, pain, or voice changes), and systemic symptoms (hyperthyroidism, hypothyroidism, or those from possible tumors metastatic to the thyroid). The patient’s age, gender, place of birth, family history, and history of radiation to the neck are most important. Low-dose therapeutic radiation (6.5-2000 cGy) in infancy or childhood is associated with an increased incidence of benign goiter (~ 35%) or thyroid cancer (~ 13%) in later life. A thyroid nodule is more likely to be a cancer in a man than in a woman, and in younger (under 20 years) and older (over 60 years) patients rather than in others. In certain geographic areas, endemic goiter and benign nodules are common. Thyroid cancer is familial in about 25% of patients with medullary thyroid cancer (familial medullary thyroid cancer, multiple endocrine neoplasia [MEN] types 2A and 2B) and in about 7% of patients with papillary or Hürthle cell cancer. Papillary thyroid cancer occurs more often in patients with Cowden syndrome, Gardner syndrome, or Carney syndrome.

The clinician must systematically palpate the thyroid to determine whether there is a solitary thyroid nodule or if it is a multinodular gland and whether there are palpable lymph nodes. A solitary hard thyroid nodule is likely to be malignant, whereas most multinodular goiters are benign. Ultrasound evaluation helps document the number of nodules, whether a nodule is suspicious for cancer, and whether there are coexistent suspicious lymph nodes.

In many patients, the possibility of cancer is difficult to exclude without microscopic examination of the gland itself. Percutaneous needle biopsy is the most cost-effective diagnostic test and, along with ultrasound, has replaced radioiodine scanning for the evaluation of nodules. Cytologic results are classified by the Bethesda criteria (Table 16–2). False-positive diagnoses of cancer are rare, but about 20% of biopsy specimens reported as one of the indeterminate categories (follicular lesion of unknown significance or neoplasms) and there are more rare falsely benign results. If the specimen is reported as inadequate, biopsy should be repeated. Needle biopsy is not as helpful in patients with a history of irradiation to the neck because radiation-induced tumors are often multifocal, and a negative biopsy may therefore be unreliable. About 40% of these patients will have thyroid cancer. Radioiodine scanning can be used selectively to determine whether a follicular neoplasm by cytologic examination is functioning (warm or hot) or nonfunctioning (cold). Hot solitary thyroid nodules may cause hyperthyroidism but are rarely malignant, whereas cold solitary thyroid nodules have an incidence of cancer of 15%-20%. Thyroid carcinoma is uncommon (~ 3%) in multinodular goiters, but if there is a dominant nodule or one that enlarges, it should be biopsied or removed. Thyroid cancer occurs in nearly 40% of the children with solitary thyroid nodules; therefore, fine-needle biopsy or thyroidectomy is indicated. Ultrasound differentiates solid and cystic lesions and, as mentioned, may detect enlarged lymph nodes. About 15% of cold solitary lesions are cystic. CT or MRI scans are usually not necessary but are helpful when the limits of the tumor cannot be defined, such as in patients with large, invasive, or substernal goiters or tumors.

The principal indications for surgical removal of a nodular goiter are: (1) suspicion of or documented cancer, (2) symptoms of pressure, (3) hyperthyroidism, (4) substernal extension, and (5) cosmetic deformity. Incidentally discovered thyroid nodules by ultrasonography, CT, MRI, or positron emission tomography (PET) scans should be evaluated by ultrasound, then, if indicated, fine-needle aspiration biopsy. Nonoperative treatment is indicated in patients with small or moderately sized multinodular goiters and Hashimoto thyroiditis unless there is a clinically suspicious area, a nodule that is growing, a personal history of radiation exposure or a family history of thyroid carcinoma.

Simple or Nontoxic Goiter (Diffuse & Multinodular Goiter)

Simple goiter may be physiologic, occurring during puberty or pregnancy, or it may occur in patients from endemic (iodine-poor) regions or as a result of prolonged exposure to goitrogenic foods or drugs. As the goiter persists, there is a tendency to form nodules. Goiter may also occur early in life as a consequence of a congenital defect in thyroid hormone production or in patients with Hashimoto thyroiditis. It is generally assumed that nontoxic goiter represents a compensatory response to inadequate thyroid hormone production, although thyroid growth immunoglobulins may also be important. Nontoxic diffuse goiter usually responds favorably to thyroid hormone administration.

Symptoms are usually awareness of a neck mass and dyspnea, dysphagia, or symptoms caused by interference with venous obstruction. In diffuse goiter, the thyroid is symmetrically enlarged and has a smooth surface; however, most patients have multinodular glands by the time they seek medical care. Thyroid function is usually normal, though the sensitive TSH may be suppressed and the radioiodine uptake increased. Surgery is indicated to relieve the pressure symptoms of a large goiter for substernal goiter or to rule out cancer when there are localized areas of hardness or rapid growth. Aspiration biopsy cytology is helpful in these patients.

INFLAMMATORY THYROID DISEASE

The inflammatory diseases of the thyroid are termed acute, subacute, or chronic thyroiditis, which can be either suppurative or nonsuppurative.

Acute suppurative thyroiditis is uncommon and is characterized by the sudden onset of severe neck pain accompanied by dysphagia, fever, and chills. It usually follows an acute upper respiratory tract infection; can be diagnosed by percutaneous aspiration, smear, and culture; and is treated by surgical drainage. The organisms are most often streptococci, staphylococci, pneumococci, or coliforms. It may also be associated with a piriform sinus fistula. A barium swallow is therefore recommended in persistent or recurrent cases.

Subacute thyroiditis, a noninfectious disorder, is characterized by thyroid swelling, head and chest pain, fever, weakness, malaise, palpitations, and weight loss. Some patients with subacute thyroiditis have no pain (silent thyroiditis), in which case the condition must be distinguished from Graves disease. In subacute thyroiditis, the erythrocyte sedimentation rate and serum gamma globulin are almost always elevated, and radioiodine uptake is very low or absent with increased or normal thyroid hormone levels. The illness is usually self-limited, and aspirin and corticosteroids relieve symptoms. Most of these patients eventually become euthyroid.

Hashimoto thyroiditis, the most common form of thyroiditis, is usually characterized by enlargement of the thyroid with or without pain and tenderness. It is much more common in women (~ 15% of US women) and occasionally causes dysphagia or hypothyroidism.

Hashimoto thyroiditis is an autoimmune disease. Serum titers of antimicrosomal and antithyroglobulin antibodies are elevated. Appropriate treatment for most patients consists of giving small doses of thyroid hormone. Operation is indicated for marked pressure symptoms, for suspected malignant tumor, and for cosmetic reasons. If the thyroid is large or asymmetric, or if it contains a discrete nodule, or grows rapidly, percutaneous needle biopsy or thyroidectomy is recommended. Thyroid lymphoma can rarely occur in patients with Hashimoto thyroiditis.

Riedel thyroiditis is a rare condition that presents as a hard woody mass in the thyroid region with marked fibrosis and chronic inflammation in and around the gland. The inflammatory process infiltrates muscles and causes symptoms of tracheal compression. Hypothyroidism is usually present, and hypoparathyroid may develop. Surgical treatment is required to relieve tracheal or esophageal obstruction.

BENIGN TUMORS OF THE THYROID

Benign thyroid tumors are adenomas, involutionary nodules, cysts, or localized thyroiditis. Most adenomas are of the follicular type. Adenomas are usually solitary and encapsulated and compress the adjacent thyroid. The major reasons for removal are a suspicion of cancer, functional overactivity producing hyperthyroidism, and cosmetic disfigurement.

MALIGNANT TUMORS OF THE THYROID

General Considerations

An appreciation of the classification of malignant tumors of the thyroid is important, because thyroid tumors demonstrate a wide range of growth and malignant behavior. At one end of the spectrum is papillary carcinoma, which usually occurs in young adults, grows very slowly, metastasizes through lymphatics, and is compatible with long life even in the presence of metastases (Figure 16–2). At the other extreme is undifferentiated carcinoma, which appears late in life and is nonencapsulated and invasive, forming large infiltrating tumors composed of small or large anaplastic cells. Most patients with anaplastic thyroid carcinoma succumb as a consequence of local recurrence, pulmonary metastasis, or both within 9 months. Between these two extremes are follicular, Hürthle cell, and medullary carcinomas, sarcomas, lymphomas, and metastatic tumors. The prognosis depends on the histologic pattern, the age and gender of the patient, the extent of tumor spread at the time of diagnosis, whether the tumor takes up radioiodine, and other factors. On average, 5% of patients with papillary, 10% of those with follicular, 15% of those with Hürthle cell, and 20% of those with medullary thyroid cancer will die within 10 years from these tumors.

The cause of most cases of thyroid carcinoma is unknown, although persons who received low-dose (6.5-2000 cGy) therapeutic radiation to the thymus, tonsils, scalp, and skin in infancy, childhood, and adolescence have an increased risk of developing thyroid tumors. Children are most susceptible to radiation exposure such as occurred with the Chernobyl nuclear accident, but adults up to 50 years of age who were exposed to the atomic blast at Hiroshima had an increased incidence of benign and malignant thyroid tumors. The incidence of thyroid cancer increases for at least 30 years after irradiation. RET/PTC rearrangements occur in about 80% of radiation associated papillary thyroid cancers.

Types of Thyroid Cancer

A. Papillary Carcinoma

Papillary adenocarcinoma accounts for 85% of cancers of the thyroid gland. The tumor usually appears in early adult life and presents as a solitary nodule. It then spreads via intraglandular lymphatics within the thyroid gland and then to the subcapsular and pericapsular lymph nodes. Fifty percent of children and 20% of adults present with palpable lymph nodes. The tumor may metastasize to lungs or bone. Microscopically, it is composed of papillary projections of columnar epithelium. Psammoma bodies are present in about 60% of cases. Mixed papillary-follicular, follicular variants of papillary carcinoma, and poorly differentiated cancers including tall cell and columnar cell papillary thyroid cancers are sometimes found. The rate of growth may be stimulated by TSH. A BRAF mutation is the most common mutation in papillary thyroid cancer and is associated with lymph node metastases and a higher recurrence rate.

B. Follicular Adenocarcinoma

Follicular adenocarcinoma accounts for approximately 10% of malignant thyroid tumors. It appears later in life than the papillary form and may be rubbery or even soft on palpation. Follicular tumors are encapsulated. Microscopically, follicular carcinoma may be difficult to distinguish from normal thyroid tissue. Capsular (invasion through the capsule) and vascular invasion distinguish follicular carcinoma from follicular adenoma. Follicular thyroid cancers only occasionally (~5%) metastasize to the regional lymph nodes, but they have a greater tendency to spread by the hematogenous route to the lungs, the skeleton, and, rarely, the liver. Metastases from this tumor often demonstrate avidity for RAI after total thyroidectomy. Skeletal metastases may appear years after resection of the primary lesion. Hürthle cell carcinoma is considered a clinical variant of follicular carcinoma. It is more likely to be multifocal and involve lymph nodes than follicular carcinoma. Like follicular carcinoma, it makes thyroglobulin, however it does not usually take up radioiodine. The prognosis is not as good for either follicular or Hürthle cell cancers as with the papillary type (Figure 16–3).

C. Medullary Carcinoma

Medullary carcinoma accounts for approximately 7% of malignant tumors of the thyroid and 15% of thyroid cancer deaths. It contains amyloid and is a solid, hard, nodular tumor that does not take up radioiodine and secretes calcitonin. Medullary carcinomas arise from parafollicular cells of the ultimobranchial bodies or C cells. Familial medullary carcinoma occurs in about 25% of patients. It may be isolated or occur with pheochromocytomas (often bilateral), lichen planus amyloidosis, and hyperparathyroidism (MEN2A, Table 16–3). It may also occur with or without pheochromocytomas (usually bilateral), marfanoid habitus, multiple neuromas, and ganglioneuromatosis (MEN2B). Hirschsprung disease occurs more frequently in patients with familial medullary cancer. All patients with medullary thyroid cancer should be screened for an RET point mutation on chromosome 10 because 10% of patients without a positive family history have de novo mutations. For patients detected by family genetic screening, most experts recommend prophylactic total thyroidectomy at an age determine by the risk associated with the specific mutation. Isolated familial medullary thyroid cancer is the least aggressive form, whereas this cancer is most aggressive in MEN2B patients.

D. Undifferentiated Carcinoma

This rapidly growing tumor, also known as anaplastic carcinoma, occurs principally beyond middle life and accounts for 1% of all thyroid cancers. This tumor usually evolves from a papillary or follicular neoplasm. It is a solid, quickly enlarging, hard, irregular mass diffusely involving the gland and often invades the trachea, muscles, and neurovascular structures. The tumor may be painful and somewhat tender, may be fixed on swallowing, and may cause laryngeal or esophageal obstructive symptoms. Microscopically, there are three major types: giant cell, spindle cell, and small cell. Mitoses are frequent. Cervical lymphadenopathy and pulmonary metastases are common. Local recurrence after surgical treatment is the rule. Combination treatment with external radiation therapy, chemotherapy, and surgery offers palliation to some patients but is rarely curative (Figure 16–2).

Treatment

The treatment of differentiated thyroid carcinoma (which does not include anaplastic carcinoma or medullary thyroid cancer) is operative removal. For papillary carcinoma over 1 cm, acceptable operations are near-total or total thyroidectomy. For solitary papillary carcinomas less than 1 cm, thyroid lobectomy is adequate treatment. Subtotal or partial lobectomy is contraindicated because the incidence of tumor recurrence is greater and survival is shorter. Total thyroidectomy is recommended for papillary (> 1.0 cm), follicular, Hürthle cell, and medullary carcinomas if the operation can be done without producing permanent hypoparathyroidism or injury to the recurrent laryngeal nerves. Total thyroidectomy is preferred over other operations because of the high incidence of multifocal tumor within the gland, a clinical recurrence rate of about 7% in the contralateral lobe if it is spared, and the ease of assessment for recurrence by serum thyroglobulin assay and neck ultrasound examinations during follow-up examinations. This also allows one to use adjuvant or therapeutic radioiodine treatment. Preoperative ultrasound is essential in patients with papillary cancer, and all abnormal central and lateral neck lymph nodes should be removed. Whether an ipsilated prophylactic central neck dissection should be done is controversial.

A functional modified radical neck dissection preserving the jugular vein, sternocleidomastoid muscle, spinal accessory nerve, and sensory nerves is performed if lymph nodes in the lateral neck are clinically involved.

Medullary carcinoma is associated with such a high incidence of nodal involvement that a bilateral central neck node compartment dissection should be done in all patients. Concomitant ipsilateral and contralateral modified radical neck dissection may be indicated selectively for primary tumors more than 1.5 cm in diameter and when the central neck nodes are involved. When serum calcitonin or carcinoembryonic antigen (CEA) levels remain elevated after thyroidectomy, ultrasound or MRI examination of the neck and MRI of the mediastinum should be done. Laparoscopic evaluation of the liver for the common miliary metastases is recommended for patients with markedly elevated calcitonin levels. If there is no metastatic in the liver, then central neck dissection and bilateral functional neck dissections should be done, if not already done, including removal of nodes from the superior mediastinum.

Isolated distant metastatic deposits of differentiated thyroid carcinoma should be removed surgically if possible and treated with ¹³¹I after total thyroidectomy or thyroid ablation with radioactive iodine. All patients with thyroid cancer should be maintained indefinitely on suppressive doses of thyroid hormone (mild suppression for low-risk patients). For follow-up, it is helpful to measure basal and TSH-stimulated serum levels of thyroglobulin (a tumor marker for differentiated thyroid cancer), which are usually increased (> 2 ng/mL) in patients with residual tumor after total thyroidectomy.

For undifferentiated carcinoma, malignant lymphoma, or sarcoma, the tumor should be excised as completely as possible and then treated by radiation and chemotherapy. It is common that no operation beyond a diagnostic biopsy is useful for these patients, as they may be locally inoperable with a course dictated by the systemic disease.

EMBRYOLOGY & ANATOMY

Phylogenetically, the parathyroids appear rather late, being first seen in amphibia. They arise from pharyngeal pouches III and IV and may be arrested as high as the level of the hyoid bone during their descent to the posterior capsule of the thyroid gland. Four parathyroid glands are present in 85% of the population, and 85% are situated on the posterior lateral surface of the thyroid gland. About 15% of people have more than four glands. Occasionally, one or more may be incorporated into the thyroid gland or thymus and hence are intrathyroidal or intrathymic in location. Parathyroid III, which normally assumes the inferior position, may be found in the anterior mediastinum, usually in the thymus. The upper parathyroids (parathyroid IV) usually remain in close association with the upper portion of the lateral thyroid lobes at the level of the cricoid cartilage but may be loosely attached by a long vascular pedicle and migrate caudally in the tracheoesophageal groove into the posterior mediastinum. About 85% of parathyroid glands lie within 1 cm of where the inferior thyroid artery and recurrent laryngeal nerve cross.

The normal parathyroid gland has a distinct yellowish-brown color, is ovoid, tongue-shaped, polypoid, or spherical, and averages 2 × 3 × 7 mm. The total mean weight of four normal parathyroid glands is about 150 mg. These encapsulated glands are usually supplied by a branch of the inferior thyroid artery but may be supplied by the superior thyroid artery. The vessels can be seen entering a hilum-like structure, a feature that differentiates parathyroid glands from fat.

PHYSIOLOGY

Parathyroid hormone (PTH), vitamin D, and calcitonin play vital roles in calcium and phosphorus metabolism in bone, kidney, and gut. Specific radioimmunoassays are available to measure PTH, vitamin D, and calcitonin. Ionized calcium, the physiologically important fraction, can now be accurately measured. Total serum calcium concentration is composed of approximately 48% ionized calcium, 46% protein-bound calcium, and 6% calcium complexed to organic anions. Total serum calcium varies directly with plasma protein concentrations, but calcium ion concentrations are unaffected.

PTH and calcitonin work in concert to modulate fluctuations in plasma levels of ionized calcium. When the ionized calcium level falls, the parathyroid glands secrete more PTH, and the parafollicular cells within the thyroid secrete less calcitonin. The rise in PTH and fall in calcitonin produce increased bone resorption and increased resorption of calcium in the renal tubules. More calcium enters the blood, and ionized calcium levels return to normal.

In the circulation, immunoreactive PTH is heterogeneous, consisting of the intact hormone and several hormonal fragments. The amino terminal (N-terminal) fragment is biologically active, whereas the carboxyl terminal (C-terminal) fragment is biologically inert. Measurement of intact PTH by immunoassay is best for screening for hyperparathyroidism and for selective venous catheterization to localize the source of PTH production. PTH-related peptide (PTHrP) that is secreted by nonparathyroid malignant tumors does not cross-react with intact PTH assays.

Because PTH levels rise in normal subjects if ionized calcium levels are low, calcium and PTH must be determined from samples drawn simultaneously to diagnose hyperparathyroidism. The combination of increased PTH levels and hypercalcemia without hypocalciuria is almost always diagnostic of hyperparathyroidism.

PRIMARY HYPERPARATHYROIDISM

General Considerations

Primary hyperparathyroidism is due to excess or nonsuppressed PTH secretion from a single parathyroid adenoma (83%), multiple adenomas (6%), hyperplasia (10%), or carcinoma (1%). Once thought to be rare, primary hyperparathyroidism is now found in 0.1%-0.3% of the general population and is the most common cause of hypercalcemia in unselected patients. It is uncommon before puberty; its peak incidence is between the third and fifth decades, and it is two to three times more common in women than in men.

Overproduction of PTH in spite of upper normal or elevated serum levels of calcium results in mobilization of calcium from bone and inhibition of the renal reabsorption of phosphate, thereby producing hypercalcemia and hypophosphatemia. This causes a wasting of calcium and phosphorus, with osseous mineral loss and osteopenia or osteoporosis. Other associated or related conditions that offer clues to the diagnosis of hyperparathyroidism are nephrolithiasis, nephrocalcinosis, osteitis fibrosa cystica, peptic ulcer, pancreatitis, hypertension, and gout or pseudogout. Hyperparathyroidism also occurs in both MEN1, known as Wermer syndrome, and MEN2, known as Sipple syndrome (Table 16–3). The former is characterized by tumors of the parathyroid, pituitary, and pancreas (hyperparathyroidism, pituitary tumors, and functioning or nonfunctioning islet cell pancreatic tumors) that may cause Zollinger-Ellison syndrome (gastrinoma), hypoglycemia (insulinoma), glucagonoma, somatostatinoma, and pancreatic polypeptide tumors (PPomas). Other tumors in MEN1 syndrome include adrenocortical tumors, carcinoid tumors, multiple lipomas, and cutaneous angiomas. MEN2A consists of hyperparathyroidism (20%) in association with medullary carcinoma of the thyroid (98%), pheochromocytoma (50%), and lichen planus amyloidosis. MEN2B patients have a marfanoid habitus, multiple neuromas, and pheochromocytomas but rarely have hyperparathyroidism. Familial hyperparathyroidism can also occur alone or in the presence of jaw tumor syndrome.

Parathyroid adenomas range in weight from 65 mg to over 35 g, and the size usually parallels the degree of hypercalcemia. Microscopically, these tumors may be of chief cell, water cell, or, rarely, oxyphil cell type.

Primary parathyroid hyperplasia involves all of the parathyroid glands. Microscopically, there are two types: chief cell hyperplasia and water-clear cell (wasserhelle) hyperplasia. Hyperplastic glands vary considerably in size but are usually larger than normal (65 mg).

Parathyroid carcinoma is rare but is more common in patients with profound hypercalcemia and in patients with familial hyperparathyroidism and jaw tumor syndrome. Parathyroid cancers are palpable in half the patients and should be suspected in patients at operation when the parathyroid gland is hard, has a whitish or irregular capsule, or is invasive. Parathyromatosis is a rare condition causing hypercalcemia due to multiple embryologic rests or, more commonly, due to seeding when a parathyroid tumor has ruptured or the tumor capsule has been disrupted.

Clinical Findings

A. Symptoms and Signs

Historically, the clinical manifestations of hyperparathyroidism have changed. Forty years ago, the diagnosis was based on bone pain and deformity (osteitis fibrosa cystica), and in later years on the renal complications (nephrolithiasis and nephrocalcinosis). At present, over two-thirds of patients are detected by routine screening, or because of osteopenia or osteoporosis, and some are asymptomatic. Patients with even mild primary hyperparathyroidism are predisposed to cardiovascular events and fractures. After successful surgical treatment, many patients thought to be asymptomatic become aware of improvement in unrecognized preoperative symptoms such as fatigue, mild depression, weakness, constipation, polydipsia and polyuria, and bone and joint pain. Hyperparathyroidism should be suspected in all patients with hypercalcemia and the above symptoms, especially if associated with nephrolithiasis, nephrocalcinosis, hypertension, left ventricular hypertrophy, peptic ulcer, pancreatitis, or gout. Patients with primary hyperparathyroidism appear to have a shortened life expectancy that improves after successful parathyroidectomy. Younger patients and those with less severe hypercalcemia after parathyroidectomy have the best prognosis.

B. Laboratory Findings, Imaging Studies, and Differential Diagnosis (Approach to the Hypercalcemic Patient)

1. Laboratory Findings

Together, hyperparathyroidism and humoral hypercalcemia of malignancy (nonparathyroid cancer) are responsible for about 90% of all cases of hypercalcemia. Hyperparathyroidism is the most common cause of hypercalcemia detected by undirected methods such as routine screening, whereas cancer is the most common cause of hypercalcemia in hospitalized patients. Other causes of hypercalcemia are listed in Table 16–4. In many patients the diagnosis is obvious, while in others it may be difficult. At times, more than one reason for hypercalcemia may exist in the same patient, such as cancer or sarcoidosis plus hyperparathyroidism. A careful history must be obtained documenting: (1) the duration of any symptoms possibly related to hypercalcemia; (2) symptoms related to malignant disease; (3) conditions associated with hyperparathyroidism, such as renal colic, peptic ulcer disease, pancreatitis, hypertension, or gout; and (4) possible excess use of milk products, antacids, baking soda, or vitamins. In patients with a recent cough, wheeze, or hemoptysis, epidermoid carcinoma of the lung should be considered. Hematuria might suggest hypernephroma, bladder tumor, or renal lithiasis. A long history of renal stones or peptic ulcer disease suggests that hyperparathyroidism is likely.

The most important tests for the evaluation of hypercalcemia are, in order of importance, serum calcium, PTH, phosphate, chloride, alkaline phosphatase, creatinine; uric acid and urea nitrogen; urinary calcium; blood hematocrit and pH; serum magnesium; and erythrocyte sedimentation rate (Table 16–5). Measurement of 25-hydroxy and 1,25-hydroxy vitamin D levels, and serum protein electrophoresis are helpful in selected patients when other tests are equivocal.

A high serum calcium and a low serum phosphate suggest hyperparathyroidism, but about half of patients with hyperparathyroidism have normal serum phosphate concentrations. Patients with vitamin D intoxication, sarcoidosis, malignant disease without metastasis, and hyperthyroidism may also be hypophosphatemic, but patients with breast cancer and hypercalcemia are only rarely so. In fact, if hypophosphatemia and hypercalcemia are present in association with breast cancer, concomitant hyperparathyroidism is probable. Measurement of serum PTH has its greatest value in this situation, since the PTH level is low or nil in patients with hypercalcemia due to all causes other than primary hyperparathyroidism or familial hypocalciuric hypercalcemia. In general, serum PTH levels should be measured in all patients with persistent hypercalcemia without an obvious cause and in normocalcemic patients who are suspected of having hyperparathyroidism. Determination of intact serum PTH levels is sensitive and is not influenced by tumors that secrete parathyroid-related peptide. Nonparathyroid tumors that secrete pure PTH are extremely rare.

An elevated serum chloride concentration is a useful diagnostic clue found in about 40% of hyperparathyroid patients. PTH acts directly on the proximal renal tubule to decrease the resorption of bicarbonate, which leads to increased resorption of chloride and mild hyperchloremic renal tubular acidosis. An increased serum chloride is not found in other causes of hypercalcemia. Calculation of the serum chloride to phosphate ratio takes advantage of slight increases in serum chloride and slight decreases in serum phosphate concentrations. A ratio above 33 suggests hyperparathyroidism; this was a more clinically useful observation before the availability of rapid and accurate PTH measurement.

A 24-hour urine calcium level is helpful for diagnosing hypercalcemic patients who have low urinary calcium levels resulting from benign familial hypocalciuric hypercalcemia (BFHH) and for patients with marked hypercalciuria (> 400 mg/24 h). Patients with BFHH do not benefit from parathyroidectomy.

Serum protein electrophoretic patterns are helpful for diagnosis of multiple myeloma and sarcoidosis. Hypergammaglobulinemia is rare in hyperparathyroidism but is not uncommon in patients with multiple myeloma and sarcoidosis. Roentgenograms of the skull or site of bone pain in patients with elevated alkaline phosphatase levels will often reveal typical “punched-out” bony lesions, and the diagnosis of myeloma can be firmly established by bone marrow examination. Sarcoidosis can be difficult to diagnose, because it may exist for years with limited clinical findings. A chest x-ray revealing a diffuse fibronodular infiltrate and prominent hilar adenopathy is suggestive, and the demonstration of noncaseating granuloma in lymph nodes is diagnostic.

Serum alkaline phosphate levels are elevated in about 10% of patients with primary hyperparathyroidism and may also be increased in patients with Paget disease and cancer. When the serum alkaline phosphatase level is elevated, serum 5′-nucleotidase, which parallels liver alkaline phosphatase, should be measured to determine if the increase is from bone, which suggests parathyroid disease, or liver.

2. Bone Studies

Bone densitometry and radiographic examination of bone frequently reveals osteopenia (1 standard deviation below normal density) or osteoporosis (2.5 standard deviations below normal), but overt skeletal changes such as subperiosteal resorption or brown tumor are found in less than 10% of patients with hyperparathyroidism. Dual photon bone density studies of the femur, lumbar spine, and radius help document osteopenia that occurs in about 70% of women with hyperparathyroidism. Bone changes of osteitis fibrosa cystica are rare on x-ray unless the serum alkaline phosphatase concentration is increased. Primary and secondary hyperparathyroidism can produce subperiosteal resorption of the phalanges and bone cysts (Figure 16–3). A ground-glass appearance of the skull with loss of definition of the tables and demineralization of the outer aspects of the clavicles are less frequently seen. In patients with markedly elevated serum alkaline phosphatase levels without subperiosteal resorption on x-ray, Paget disease or cancer must be suspected. A 24-hour urine test for deoxypyridinoline cross-link assay or osteocalcin detects increased bone loss.

3. Differential Diagnosis

The differentiation between hyperparathyroidism because of primary parathyroid disease and that due to humoral hypercalcemia of malignancy can now almost always be determined by measuring intact PTH, which is increased in primary hyperparathyroidism but suppressed in humoral hypercalcemia of malignancy. The most common tumors causing humoral hypercalcemia of malignancy are squamous cell carcinoma of the lung, renal cell carcinoma, and bladder cancer. Less commonly it is due to hepatoma or to cancer of the ovary, stomach, pancreas, parotid gland, or colon. Recent onset of symptoms, increased sedimentation rate, anemia, serum calcium greater than 14 mg/dL, and increased alkaline phosphatase activity without osteitis fibrosa cystica suggest humoral hypercalcemia of malignancy; mild hypercalcemia with a long history of nephrolithiasis or peptic ulcer suggests primary hyperthyroidism. Documented hypercalcemia of 6 months or longer essentially rules out malignancy-associated hypercalcemia.

In milk-alkali syndrome, a history of excessive ingestion of milk products, calcium-containing antacids, and baking soda is often obtained. These patients become normocalcemic after discontinuing these habits. Patients with milk-alkali syndrome usually have renal insufficiency and low urinary calcium concentrations and are usually alkalotic rather than acidotic. Because of the high incidence of ulcer disease in hyperparathyroidism, milk-alkali syndrome may occasionally coexist with that disorder. This is very infrequent now that acid-suppressing medications, such as proton pump inhibitors, are available to manage peptic ulcer disease.

Hyperthyroidism, another cause of hypercalcemia and hypercalciuria, can usually be differentiated because manifestations of thyrotoxicosis rather than hypercalcemia bring the patient to the physician. Occasionally, an elderly patient with apathetic hyperthyroidism may be hypercalcemic. A sensitive TSH test should be evaluated in hypercalcemic patients whose PTH levels are not increased. Treatment of hyperthyroidism with antithyroid medications causes serum calcium to return to normal levels within 8 weeks.

Normal subjects taking thiazide diuretics may develop a transient increase in serum calcium levels, usually less than 1 mg/dL. Larger rises in serum calcium induced by thiazides have been reported in patients with primary hyperparathyroidism and idiopathic juvenile osteoporosis. Most patients who have hypercalcemia while taking thiazides have another reason for the increase. The best way to evaluate these patients is to switch them to a nonthiazide antihypertensive agent or diuretic and to measure the PTH level. Thiazide-induced hypercalcemia is not associated with increased serum PTH in patients without hyperparathyroidism.

Benign familial hypocalciuric hypercalcemia is one of the few conditions that causes chronic hypercalcemia and mildly elevated PTH levels. It can be difficult to distinguish from mild primary hyperparathyroidism. The best way to diagnose this disorder is to document a low urinary calcium and a family history of hypercalcemia, especially in children.

Other miscellaneous causes of hypercalcemia are Paget disease, immobilization (especially in Paget disease or in young patients), dysproteinemias, idiopathic hypercalcemia of infancy, aluminum intoxication, and rhabdomyolysis (Table 16–4).

C. Approach to the Normocalcemic Patient With Possible Hyperparathyroidism

Renal failure, hypoalbuminemia, pancreatitis, deficiency of vitamin D or magnesium, and excess phosphate intake may cause serum calcium levels to be normal in hyperparathyroidism. Correction of these disorders results in hypercalcemia if hyperparathyroidism is present. The incidence of normocalcemic hyperparathyroidism in patients with hypercalciuria and recurrent nephrolithiasis (idiopathic hypercalciuria) is not known. Because the serum calcium concentration may fluctuate, it should be measured on more than three separate occasions. Determination of serum ionized calcium is also sometimes revealing, since it may be increased in patients with normal total serum calcium levels.

If a patient has elevated serum levels of ionized calcium and PTH, the diagnosis of normocalcemic hyperparathyroidism has been confirmed. There are three major causes of hypercalciuria and nephrolithiasis: (1) increased absorption of calcium from the gastrointestinal tract (absorptive hypercalciuria), (2) increased renal leakage of calcium (renal hypercalciuria) and (3) primary hyperparathyroidism. Patients with absorptive hypercalcemia absorb too much calcium from the gastrointestinal tract and therefore have low serum PTH levels. Patients with renal hypercalciuria lose calcium from leaky renal tubules and have increased PTH levels. They can be distinguished from patients with normocalcemic hyperparathyroidism by their response to treatment with thiazides. In renal leak hypercalcemia, serum PTH levels become normal because thiazides correct the excessive loss of calcium, whereas in primary hyperparathyroidism increased serum PTH levels persist and the patient often becomes hypercalcemic.

Natural History of Untreated & Treated Hyperparathyroidism

Patients with untreated hyperparathyroidism have an increased risk of dying prematurely, mainly from cardiovascular and malignant disease. There is decreased respiratory muscular capacity and increased frequency of hypertrophic cardiomyopathy with left ventricular hypertrophy and decreased vascular compliance even in hyperparathyroid patients without hypertension. Hyperparathyroid patients have more hypertension, nephrolithiasis, osteopenia, peptic ulcer disease, gout, renal dysfunction, and pancreatitis. After successful parathyroidectomy, previously hyperparathyroid patients still have an increased risk of premature death, however, younger patients and those with less severe disease return to a normal survival curve sooner than do older patients or those with more severe hyperparathyroidism. Most patients with hyperparathyroidism—even those with normocalcemic hyperparathyroidism—have symptoms and associated conditions. In 80% of patients, these clinical manifestations improve or disappear after parathyroidectomy.

Treatment

The only curative treatment of primary hyperparathyroidism is parathyroidectomy. There are no convincing data to support a plan of medical observation, and considerable data support a surgical approach. Once associated conditions such as hypertension and renal dysfunction become well established, they seem to progress despite correction of the primary hyperparathyroidism. Thus, it appears to be better to intervene early while it is still possible to correct these problems. In all patients, however, the diagnosis should be established, and short delays to clarify the diagnosis are justified. The criteria for intervention in asymptomatic patients have been revised several times over two decades (Table 16–6), but have always also included the option for correction of the abnormality based on individual patient and physician judgments.

A. Marked Hypercalcemia (Hypercalcemic Crisis)

The initial treatment in patients with marked hypercalcemia and acute symptoms is hydration and correction of hypokalemia and hyponatremia. While the patient is being hydrated, assessment of the underlying problem is essential so that more specific therapy may be started. Milk and alkaline products, estrogens, thiazides, and vitamins A and D should be immediately discontinued. Furosemide is useful to increase calcium excretion in the rehydrated patient. Etidronate, plicamycin, and calcitonin are usually effective for short periods in treating hypercalcemia regardless of cause. Glucocorticoids are very effective in vitamin D intoxication, hyperthyroidism, and sarcoidosis and in many patients with cancer, including those with peptide-secreting tumors, but are less effective when there is extensive bone disease. As mentioned previously, hyperparathyroid patients only occasionally respond to glucocorticoid administration.

In patients with marked hypercalcemia, once the diagnosis of hyperparathyroidism is established, localization studies, cervical exploration, and parathyroidectomy should be performed in a vigorously hydrated patient, since this is the most rapid and effective method of normalizing the serum calcium.

B. Localization

Preoperative localization of parathyroid tumors can now be accomplished in about 80%-90% of patients with ultrasonography and sestamibi scans. These studies, however, are helpful in fewer patients with parathyroid hyperplasia (Figure 16–4). Localization studies are essential in patients with persistent or recurrent hyperparathyroidism and can direct a focused exploration in patients with primary hyperparathyroidism. An experienced surgeon can find the tumors in about 95% of patients who have not had previous parathyroid or thyroid surgery without preoperative tests, however preoperative knowledge of the location of the abnormal glands can simplify the operation.

For patients who have had prior neck operations, including thyroid and parathyroid procedures, preoperative localization is especially important. CT scan with specially timed contrast enhancement and selective venous catheterization with PTH immunoassay are often helpful. The surgeon must carefully evaluate these cases prior to exploration to optimize the opportunity for a successful operation. A frequently employed preference is that two concordant studies identify the site of the parathyroid abnormality prior to operating.

C. Operation

Three approaches are now acceptable for patients with sporadic primary hyperparathyroidism. A bilateral neck exploration (exposing all four parathyroid glands) is safe and does not depend upon preoperative tests or intraoperative PTH testing for success. A unilateral approach can be elected when one or more localization tests lateralize a solitary parathyroid tumor. At operation, a normal and abnormal parathyroid should be identified on the side of the localized tumor. A focal operation can be done in similar patients and the operation completed when the intraoperative PTH level decreases according to some planned criteria. When the sestamibi and ultrasound scans both independently identify the same tumor, a successful operation occurs in approximately 96% of patients. Videoscopic parathyroidectomy is recommended by a minority of surgeons.

In over 80% of cases, the parathyroid tumor is found attached to the posterior capsule of the thyroid gland. The parathyroid glands are usually symmetrically placed, and lower parathyroid glands are situated anterior to the recurrent laryngeal nerve, whereas the upper parathyroid glands lie posterior to the recurrent laryngeal nerve, where it enters the cricothyroid muscle. Parathyroid tumors may also lie cephalad to the superior pole of the thyroid gland, along the great vessels of the neck in the tracheoesophageal area, in thymic tissue, in the substance of the thyroid gland itself, or in the mediastinum. Care must be taken to avoid bleeding and not to traumatize the parathyroid gland or tumors, since color is useful in distinguishing them from surrounding thyroid, thymus, lymph node, and fat. Furthermore, rupture of the parathyroid gland may result in parathyromatosis (seeding of parathyroid tissue) and possible recurrent hyperparathyroidism. Two helpful maneuvers for localizing parathyroid tumors at operation are following the course of a branch of the inferior thyroid artery and looking for the fat that is usually associated with the parathyroid glands. One should attempt to identify four parathyroid glands when a bilateral approach is elected, though there may be more than four or fewer than four.

In a focused parathyroidectomy, if a probable parathyroid adenoma is found, it is removed and the diagnosis of adenoma confirmed by a decrease in PTH of greater than 50% from baseline and into the normal range. If the intraoperative PTH does not fall appropriately, then further exploration to identify additional abnormal parathyroid tissue should be undertaken during the same anesthetic. If normal glands are identified, they should be carefully documented. If two adenomas are found, both are removed, and both normal glands can be biopsied for confirmation but should not be removed.

The presence of a completely normal parathyroid gland at operation indicates that the tumor removed is adenomatous rather than hyperplastic, since in hyperplasia all the parathyroid glands are involved. However, the variation in the appearance of normal parathyroid glands, and the subtlety of hyperplastic glands can make this distinction complex.

When all parathyroid glands are hyperplastic, the most normal gland should be partially resected, leaving a 50 mg remnant, and confirmed to be well-vascularized prior to removal of the remaining glands. The upper thymus and perithymic tract should be removed in patients with hyperplasia, because a fifth parathyroid gland is present in 15% of cases.

If exploration fails to reveal a parathyroid tumor, a missing lower gland is often in the thymus (anterior mediastinum), whereas a missing upper gland is usually paraesophageal (or in the posterior mediastinum). One should therefore perform a careful and thorough exploration of the areas in which parathyroid tissue is likely to reside.

The recurrence rate of hyperparathyroidism after the removal of a single adenoma in patients with sporadic hyperparathyroidism is 2% or less. In patients with multiple endocrine neoplasia and familial hyperparathyroidism, recurrent hyperparathyroidism is expected as long as they have residual parathyroid tissue. Thus, the plan for management of these patients over their lifetime should be to limit both the complications from hyperparathyroidism, and the number and complexity of operations required to manage it.

D. Postoperative Care

Following removal of a parathyroid adenoma or hyperplastic glands, the serum calcium concentration falls to normal or below normal in 24-48 hours. Patients with severe skeletal depletion (“hungry bones”), long-standing hyperparathyroidism, vitamin D deficiency, or high preoperative serum calcium levels may develop profound hypocalcemia with paresthesias, carpopedal spasm, or even seizures. If the symptoms are mild and serum calcium falls slowly, oral supplementation with calcium is all that is required. When marked symptoms develop, it can be necessary to administer intravenous calcium gluconate. If the response is not rapid, the serum magnesium concentration should be determined and replenished. Treatment with calcitriol, 0.5 micrograms twice daily is sometimes required. (See section on Hypoparathyroidism.)

E. Reoperation

Treatment of persistent or recurrent hyperparathyroidism requires careful evaluation and planning. First the diagnosis must be reestablished, and the rationale for correcting the hyperparathyroidism must be specifically confirmed. If operation is planned, then preoperative localization is mandatory. Most surgeons perform noninvasive localization tests (ultrasound, sestamibi scan, CT scan) initially. If the localization is not clear, then invasive testing follows (selective venous catheterization with PTH measurement, rarely angiography). Most patients have a parathyroid tumor that can be removed through a cervical incision, making mediastinal exploration unnecessary. The success rate for patients requiring reoperation is about 90%, and the complication rate is higher depending upon the nature of the prior operation(s) and the location of the abnormal gland. The success rate is lower in patients with negative or equivocal localization tests and in patients with parathyromatosis and parathyroid cancer.

SECONDARY & TERTIARY HYPERPARATHYROIDISM

In secondary hyperparathyroidism, there is an increase in PTH secretion in response to low plasma concentrations of ionized calcium, usually due to renal disease or vitamin D deficiency, and malabsorption,. This results in chief cell hyperplasia. When secondary hyperparathyroidism occurs as a complication of renal disease, the serum phosphorus level is usually high, whereas in malabsorption, osteomalacia, or rickets it is frequently low or normal. Secondary hyperparathyroidism with renal osteodystrophy is a frequent complication of hemodialysis and peritoneal dialysis. Factors that play a role in renal osteodystrophy are: (1) phosphate retention secondary to a decrease in the number of nephrons; (2) failure of the diseased or absent kidneys to hydroxylate 25-dihydroxyvitamin D to the biologically active metabolite 1,25-dihydroxyvitamin D, with decreased intestinal absorption of calcium; (3) resistance of the bone to the action of PTH; and (4) increased serum calcitonin concentrations. The resulting skeletal changes are identical with those of primary hyperparathyroidism but are often more severe.

Most patients with secondary hyperparathyroidism are treated medically. Maintaining relatively normal serum concentrations of calcium and phosphorus during hemodialysis and treatment with calcitriol (orally or intravenously) have decreased the incidence of bone disease.

Indications for operation in patients with secondary hyperparathyroidism include: (1) a calcium × phosphate product > 70, (2) severe bone disease and pain, (3) pruritus, (4) extensive soft tissue calcification with tumoral calcinosis, and (5) calciphylaxis. Most patients with secondary hyperparathyroidism requiring parathyroidectomy have very high serum PTH levels. In the patient with secondary hyperparathyroidism in whom subtotal parathyroidectomy or total parathyroidectomy with autotransplantation is indicated, all but about 50 mg of the most normal parathyroid gland should be removed, or 15 (1-mm) slices of parathyroid tissue should be transplanted into individual muscle pockets in the forearm.

Following parathyroidectomy patients usually respond with dramatic relief of bone and joint pain and pruritus. Profound hypocalcemia frequently results following subtotal or total parathyroidectomy with autotransplantation for renal osteodystrophy, both because of “hungry bones” and because of decreased PTH secretion. Hypocalcemia due to hungry bones can be anticipated in patients with markedly elevated alkaline phosphatase levels and hand films documenting subperiosteal resorption.

Occasionally, a patient with secondary hyperparathyroidism develops relatively autonomous hyperplastic parathyroid glands. In most patients after successful renal transplantation, the serum calcium concentration returns to normal, and the hyperplastic parathyroid glands regress. In some patients, however, profound hypercalcemia develops (tertiary hyperparathyroidism). In general, surgical therapy for so-called tertiary hyperparathyroidism should be delayed until all medical approaches, including treatment with vitamin D, calcium supplementation, and phosphate binders, have been exhausted; if the condition persists beyond 1 year posttransplant, or if the hypercalcemia is severe, then operation for tertiary disease should be considered.

HYPOPARATHYROIDISM

General Considerations

Hypoparathyroidism, although uncommon, occurs most often as a complication of thyroidectomy, especially when performed for carcinoma or recurrent goiter. Idiopathic hypoparathyroidism, an autoimmune process associated with autoimmune adrenocortical insufficiency, is also unusual, and hypoparathyroidism after ¹³¹I therapy for Graves disease is rare. Neonatal tetany may be associated with maternal hyperparathyroidism. Hypothyroidism as well as hypoparathyroidism may occur in patients with Riedel struma.

Clinical Findings

A. Symptoms and Signs

The manifestations of acute hypoparathyroidism are due to hypocalcemia. Low serum calcium levels precipitate tetany. Latent tetany may be indicated by mild or moderate paresthesias with a positive Chvostek or Trousseau sign. The initial manifestations are paresthesias, circumoral numbness, muscle cramps, irritability, carpopedal spasm, convulsions, opisthotonos, and marked anxiety. Chronically, dry skin, brittleness of the nails, and spotty alopecia including loss of the eyebrows are common. Since primary hypoparathyroidism is rare, a history of thyroidectomy is almost always present. Generally speaking, the sooner the clinical manifestations appear postoperatively, the more serious the prognosis. After many years, some patients become adapted to a low serum calcium concentration, so that tetany is no longer evident.

B. Laboratory Findings

Hypocalcemia and hyperphosphatemia are demonstrable. The urine phosphate is low or absent, tubular resorption of phosphate is high, and the urine calcium is low.

C. Imaging Studies

In chronic hypoparathyroidism, x-rays may show calcification of the basal ganglia, arteries, and external ear.

Differential Diagnosis

A good history is most important in the differential diagnosis of hypocalcemic tetany. Occasionally, tetany occurs with alkalosis and hyperventilation. Symptomatic hypocalcemia occurring after thyroid or parathyroid surgery is due to parathyroid removal or injury, or is secondary to hungry bones. Other major causes of hypocalcemic tetany are intestinal malabsorption and renal insufficiency. These conditions may also be suggested by a history of diarrhea, pancreatitis, steatorrhea, or renal disease. Laboratory abnormalities include decreased concentrations of serum proteins, cholesterol, and carotene and increased concentrations of stool fat in malabsorption and an increased blood urea nitrogen and creatinine in renal failure.

Serum PTH concentrations are low in hypocalcemia secondary to idiopathic or iatrogenic hypoparathyroidism. In hypocalcemia secondary to malabsorption and renal failure, serum PTH concentrations are elevated and the serum alkaline phosphatase concentration is normal or increased.

Treatment

The aim of treatment is to raise the serum calcium concentration, to bring the patient out of tetany, and to lower the serum phosphate level so as to prevent metastatic calcification. Most postoperative hypocalcemia is transient; if it persists longer than 2-3 weeks or if treatment with calcitriol (1,25-dihydroxyvitamin D) is required, the hypoparathyroidism may be permanent.

A. Acute Hypoparathyroid Tetany

Acute hypoparathyroid tetany requires emergency treatment. Make certain an adequate airway exists. Reassure the anxious patient to avoid hyperventilation and resulting alkalosis, which exacerbates the hypocalcemia. Calcium gluconate IV, 10-20 mL of 10% solution administered slowly resolves the tetany. Fifty milliliters of 10% calcium gluconate may then be added to 500 mL of 5% dextrose solution and administered by intravenous drip at a rate of 1 mL/kg/h. Adjust the rate of infusion so that hourly determinations of serum calcium are normal.

To make the transition to oral supplements to support the serum calcium level, calcitriol (1,25-dihydroxyvitamin D), 0.25-0.5 μg twice daily, is very helpful and takes effect within 48-72 hours. This enables the GI tract to absorb increased amounts of calcium. Calcitriol has a rapid onset of action compared to other vitamin D preparations. Oral calcium supplements of up to 6 g/d can then generally resolve the hypocalcemia even in patients with permanent, severe hypoparathyroidism. Hypomagnesemia is present in some cases of tetany not responding to calcium treatment. In such cases, magnesium (as magnesium sulfate) should be given in a dosage of 4-8 g/d intramuscularly or 2-4 g/d intravenously.

B. Chronic Hypoparathyroidism

Once tetany has responded to intravenous calcium, change to oral calcium (citrate, gluconate, lactate, or carbonate) three times daily or as necessary. The management of the hypoparathyroid patient is difficult, because the difference between the controlling and intoxicating dose of vitamin D may be quite small. Episodes of hypercalcemia in treated patients are often unpredictable and may occur in the absence of symptoms. Vitamin D intoxication may develop after months or years of good control on a given therapeutic regimen. Dihydrotachysterol is useful in the exceptional case to supplement treatment with calcium and 1,25-dihydroxyvitamin D, when the usual measures fail to control the hypocalcemia. Frequent serum calcium determinations are necessary to regulate the proper dosage of vitamin D and to avoid vitamin D intoxication. The dose of vitamin D required to correct hypocalcemia may vary from 25,000 to 200,000 IU/d. Phosphorus should also be limited in the diet; in most patients, simple elimination of dairy products is sufficient. In some patients, aluminum hydroxide gel may be necessary to bind phosphorus in the gut to increase fecal losses.

Exogenous PTH analogs may be helpful in the long-term management of bone disease in patients with hypoparathyroidism. The optimal strategies are under development.