HYPERTHYROIDISM

Hyperthyroidism

Disease processes associated with increased thyroid secretion result in a predictable hypermetabolic state. Increased thyroid secretion can be caused by primary alterations within the gland (Graves' disease, toxic nodular goiter, toxic thyroid adenoma) or central nervous system disorders and increased TSH-produced stimulation of the thyroid. Most hyperthyroid states occur because of primary malfunction. Even more unusual hyperthyroid states can result from mismanaged exogenous thyroid ingestion, molar pregnancy with increased release of human chorionic gonadotropin, and unusually, thyroid malignancy with overproduction of thyroid hormone.

Graves' Disease

Grave's disease is the most common cause of hyperthyroidism (diffuse toxic goiter). This disease entity was originally described by an Irish physician, Dr. Robert Graves, in 1835. Women between the ages of 20 and 40 years are most commonly affected. The hyperthyroidism in Grave's disease is caused by stimulatory autoantibodies to TSH-R. Although several theories about the stimulus that initiates production of these antibodies have been proposed, there is no universal agreement about the etiology of the process. Genetic susceptibility to this disease is possible as evidenced by the increased probability of Grave's disease in monozygotic twins.

Pathology

On microscopic examination, the follicles are small with hyperplastic columnar epithelium. Hyperplasia of these cells is exhibited by rapidly dividing nuclei and papillary projections of the follicular epithelium within the central follicles. Increased deposition of lymphoid tissue is also demonstrable in many patients with Graves' disease.

Clinical Features

A patient with classic Graves' disease usually has a visibly enlarged neck mass consistent with a goiter that may demonstrate an audible bruit secondary to increased vascular flow. Clinical thyrotoxicosis and exophthalmos complete the classic triad of the disease. Hair loss, myxedema, gynecomastia, and splenomegaly can accompany the clinical findings. Tracheal compression can result in symptoms of airway obstruction, although acute compression with respiratory distress is exceedingly rare.

The ocular consequences of prolonged and untreated thyrotoxicosis, such as proptosis, supraorbital and infraorbital swelling, and conjunctival swelling and edema, can be severe. The ophthalmopathy is thought to be due to stimulation of the overexpressed TSH-R in the retro-orbital tissues of Grave's patients. In its most severe form, spasm of the upper eyelid resulting in retraction and visualization of a larger amount of sclera than normal can lead to lid lag and exacerbation of the already swollen conjunctiva. All these pressure-related phenomena can progress to decreased oculomuscular movements, ophthalmoplegia, and diplopia. Optic nerve damage and blindness can be a long-term consequence if the underlying condition is not corrected. However, this is rarely seen currently with improved screening assays that detect Grave's disease at early stages. Sustained hyperthyroidism is treated aggressively to remove the stimulus to the retro-orbital tissues.

The hypermetabolic state of hyperthyroidism is clinically manifested as sweating, weight loss, heat intolerance, and thirst. Cardiovascular stress can be demonstrated by high-output cardiac failure, congestive heart failure with peripheral edema, and arrhythmias such as ventricular tachycardia or atrial fibrillation. Gastrointestinal signs may include diarrhea and electrolyte wasting. The menstrual cycle can be altered to the point of amenorrhea. Psychiatric signs may include altered sleep patterns, emotional mood swings, fatigue, excitability, and agitation.

Diagnosis

An enlarged smooth thyroid mass and signs and symptoms of thyrotoxicosis suggest the diagnosis. A cost-effective workup can include an extensive history, physical examination, and thyroid function tests. In addition to elevated levels of T₃ and T₄, a decreased or undetectable level of TSH is demonstrated. Thyroid antibodies are usually detected in elevated quantities. An ¹²³I radionuclide scan demonstrates diffuse uptake throughout an enlarged gland. Ultrasound or computed tomography (CT) of the neck can be used to evaluate clinical landmarks . However, the absolute requirement of CT and ultrasound for preoperative assessment is not universally agreed on.

Treatment

When a diagnosis of Graves' disease has been made, therapy is initiated rapidly to ameliorate symptoms and decrease thyroid hormone synthesis. This is particularly crucial for patients with vision-threatening exophthalmos. The former is accomplished with β-blocker therapy, which is started immediately, and the latter with thionamide, radioactive iodine ablation, or surgery, each of which is equally effective in normalizing serum thyroid hormone levels within 6 weeks. Clearly, patients with Grave's disease need to be educated regarding appropriate choices, the risks associated with each treatment, and the expectation of complete success.

Radionuclide Therapy

Radioiodide ablation with ¹³¹I is the therapy of choice in the United States. It ablates the thyroid within 6 to 18 weeks. Patients with mild, well-tolerated hyperthyroidism can safely proceed to radioactive iodine ablation immediately. However, those who are elderly or severely thyrotoxic may require pretreatment with a thionamide. The overall cure rate with radioactive iodine is 90%. Hypothyroidism will develop in cured individuals, hence the need for careful measurement of thyroid hormone and TSH levels at regular intervals after therapy. Most patients are candidates for radioactive iodine; exceptions include women who are pregnant or lactating or those with a suspicious nodule.

Advantages of ¹³¹I therapy include avoidance of surgery and the associated risks of recurrent laryngeal nerve damage, hypothyroidism, or postsurgical recurrence. It may be that ¹³¹I therapy is more cost-effective in the long run; however, the financial advantage is not as clear if repeated ¹³¹I therapy is needed. Additional disadvantages include exacerbation of cardiac arrhythmias, particularly in elderly patients, possible fetal damage in pregnant women, worsening ophthalmic problems, and rare, but possibly life-threatening thyroid storm.

Antithyroid Medication

PTU and methimazole inhibit the organification of intrathyroid iodine, as well as the coupling of iodotyrosine molecules to form T₃ and T₄. PTU has the additive effect of blocking peripheral conversion of T₄ to T₃. This is important because peripheral access to T₃ and T₄ has multiple hyperdynamic and hypermetabolic effects. Additionally, the peripheral adrenergic effects of thyrotoxicosis can be modulated by the use of β-blocking agents such as propranolol. Corticosteroids in combination with β-blockers can help gain rapid control of the hypermetabolic effects of increased peripheral T₄ and T₃. Patients may choose a trial of antithyroid medication over radioactive iodine therapy. The goal of this therapy is to attain euthyroidism; however, hypothyroidism may result and necessitate thyroid hormone replacement. Antithyroid medication is effective in gaining rapid control of thyrotoxicosis, but the relapse rate after discontinuation of medication may approach 50% 12 to 18 months after cessation. Additionally, patients need to be monitored for side effects of the drugs, which may include granulocytopenia and, in rare instances, aplastic anemia. Other side effects include fever, polyarteritis, and rash.

Thyroid Resection

Surgery is advocated by a minority of thyroid specialists in the United States. It is primarily indicated for patients who have an obstructive goiter, have a fear of radioactivity, are noncompliant, or have had an adverse effect with thionamide drugs. Additional candidates are pregnant patients or those with a suspicious nodule. Advantages of surgical ablation of the thyroid include rapid, effective treatment of thyrotoxicosis without the necessity for medications and their accompanying side effects. The amount of residual tissue is a subject of debate. Complete ablation of thyroid tissue requires total thyroidectomy, which is associated with the highest rates of hypoparathyroidism and recurrent laryngeal nerve damage. Some groups have reported that total thyroidectomy is the most effective way to treat patients with severe Graves' disease because it offers the lowest rate of relapse. It may be that patients, particularly those with ophthalmopathy, are stabilized most successfully by total thyroidectomy. Removal of the entire antigenic focus may be the most likely explanation for this observation. Other subtotal resections include near-total thyroidectomy or subtotal thyroidectomy.

Careful documentation of euthyroid status before surgery in all hyperthyroid patients is mandatory. If the patient is not properly treated preoperatively, thyroid storm can be life threatening. Fortunately, this complication is rarely encountered if appropriately anticipated. Thyroid storm is manifested by severe tachycardia, fever, confusion, vomiting to the point of dehydration, and adrenergic overstimulation to the point of mania and coma after thyroid resection in an uncontrolled hyperthyroid patient. The best way to treat thyroid storm is preoperative anticipation and preparation. Additionally, all patients undergoing general anesthesia are checked for undiagnosed hyperthyroidism, if clinically suspected. Treatment of a patient with overt thyroid storm includes rapid fluid replacement and institution of antithyroid drugs, β-blockers, iodine solutions, and steroids. In life-threatening circumstances, peritoneal dialysis or hemodialysis may be effective in lowering T₄ and T₃ levels.

Toxic Nodular Goiter/Toxic Adenoma

Toxic nodular goiter, also known as Plummer's disease, refers to a nodule contained within an otherwise goitrous thyroid gland that has autonomous function. It usually occurs in the setting of a patient with endemic goiter. Increased thyroid hormone production occurs independent of TSH control. Such patients generally have a milder course and are older than those with Graves' disease. The thyroid in these patients may be diffusely enlarged or associated with retrosternal goiters. Initial symptoms are mild, peripheral thyroid hormone levels are elevated, and TSH levels are suppressed. Antithyroid antibody levels are usually decreased. The diagnosis is generally confirmed after clinical suspicion, and an ¹³¹I radionuclide scan is performed that localizes one or two autonomous areas of function while the rest of the gland is suppressed ( Fig. 36-6 ). Toxic nodular goiter can be treated with thionamides, radioiodine therapy, or surgery; however, the latter two are preferred because these nodules rarely resolve with prolonged thionamide therapy. Radioiodine is widely used for patients with toxic adenomas, although it is not as effective as in Grave's disease. Most patients are euthyroid after radioiodine therapy because the radioiodine preferentially accumulates in hyperfunctioning nodules. The surgical approach is lobectomy or near-total thyroidectomy, particularly when clinical symptoms are pronounced. In the case of a single, hyperfunctioning adenoma, lobectomy is generally curative.

Nontoxic Goiter

Multinodular Goiter

Multinodular goiter describes an enlarged, diffusely heterogeneous thyroid gland. Initial findings may include diffuse enlargement, but asymmetric nodularity of the mass often develops. The cause of this mass is usually iodine deficiency. Initially the mass is euthyroid, but with increasing size, elevations in T₃ and T₄ can occur and gradually progress to clinical hyperthyroidism. Workup and diagnosis involve evaluation of thyroid function tests. Ultrasound and radioisotopic scanning demonstrate heterogeneous thyroid substance. Nodules with poor uptake can appear as lesions suggestive of malignancy. The incidence of carcinoma in multinodular goiter has been reported to be 5% to 10%. Therefore, FNA for diagnosis and resection for suspicious lesions is considered.

Substernal Goiter

A substernal goiter is an unusual manifestation of intrathoracic extension of an enlarged thyroid that generally occurs as a result of multinodular goiter. Most intrathoracic or substernal goiters are labeled secondary because they are enlargements or extensions of multinodular goiters based on the inferior thyroid vasculature. They expand downward into the anterior mediastinum. The extremely rare (∼1%) primary substernal goiter arises as aberrant thyroid tissue within the anterior or posterior mediastinum and is based on the intrathoracic vasculature and not supplied by the inferior thyroid artery.

Special Considerations for Patients With Goiter

Patients with an enlarged thyroid mass (>5 cm) can have a spectrum of symptoms ranging from none to severe dysphagia, choking, and pain. Occasionally, the diagnosis is suggested by the presence of an anterior mediastinal mass on chest radiography. In 10% to 20% of cases, an asymptomatic patient may have no palpable abnormality in the cervical area and a completely intrathoracic lesion.

CT is the preferred imaging study, and all regions from the mandible to the upper part of the abdomen are included in the scan. The lesion itself is scrutinized. Benign goiters have rounded, smooth borders. Thyroid malignancies generally have more ill-defined borders. CT also allows evaluation of regional lymph nodes and metastasis. If the patient has a history of cervical pain and night sweats, a diagnosis of lymphoma is considered. The use of FNA with CT guidance is important to secure a tissue diagnosis. Magnetic resonance imaging (MRI) does not usually add significant information to a well-performed CT scan. For patients with an intrathoracic lesion and a history of coughing, preoperative bronchoscopy can give important information about vocal cord status and possible luminal invasion by a malignancy.

Almost all goiters and other thyroid masses are initially approached surgically through a cervical incision. Goiters are usually mobilized easily, even when they are substernal. The blood supply is generally based on the inferior thyroid artery, which is in its normal position and allows even large substernal masses to be gently mobilized into the neck. Careful attention must be directed to the location of the esophagus, trachea, and recurrent laryngeal nerve. The esophagus can be injured by overaggressive manipulation of the thyroid mass. The recurrent laryngeal nerve is usually displaced posteriorly and inferiorly; however, it can be draped anteriorly over the mass and damaged in that position. Great care must be exercised in mobilization of the mass until the nerve is identified. The cervical incision is extended to a median sternotomy if there is significant bleeding from the anterior mediastinum, if the anatomy and location of the recurrent laryngeal nerve are in doubt, or if the mass cannot be mobilized through the surgical field.