ABSTRACT: Consider hyperthyroidism in patients who complain of anxiety or nervousness and palpitations. The diagnosis can be confirmed by measurement of thyroid-stimulating hormone, free thyroxine, and free triiodothyronine levels. Graves' disease is the most common cause of hyperthyroidism; more women are affected than men. A radioiodine uptake test and thyroid scan can distinguish among the various causes of hyperthyroidism. Reserve fine-needle aspiration and biopsy for patients with palpable thyroid nodules. Radioiodine ablation is the treatment of choice for most patients. Some patients, such as children, pregnant women, and patients with large goiters, may be candidates for total or partial thyroidectomy. Antithyroid medications-propylthiouracil and methimazole-are appropriate for patients with mild hyperthyroidism, pregnant women, and children and adolescents with Graves' disease.
Hyperthyroidism is frequently seen in primary care. Among American adults, 0.5% have hyperthyroidism, and an additional 0.7% to 0.8% have subclinical disease.1-3 In one study, the prevalence of subclinical hyperthyroidism in those older than 60 years was 1% in men and 1.5% in women.4
Overt hyperthyroidism is defined as a serum thyroid-stimulating hormone (TSH) level of less than 0.1 µU/mL and a serum free thyroxine (FT4), triiodothyronine (T3), or free triiodothyronine (FT3) level above the reference range. Subclinical hyperthyroidism is defined as a serum TSH level below the lower limit of the reference range, with serum FT4, FT3, and T3 concentrations within the reference range.
Technically, hyperthyroidism and thyrotoxicosis are not the same, even though the terms are often used interchangeably. Hyperthyroidism refers to the sustained increase in biosynthesis and secretion of thyroid hormones by the thyroid gland, such as occurs in Graves' disease. Thyrotoxicosis refers to the clinical syndrome of hypermetabolism that results when the serum concentrations of FT4, FT3, or both are increased, whether the cause is endogenous or exogenous.5 For example, iatrogenic thyrotoxicosis caused by excessive ingestion of levothyroxine is not hyperthyroidism by this definition. However, the term "hyperthyroidism" will be used throughout this article to refer to both entities.
Here I provide a practical approach to the evaluation and treatment of hyperthyroidism-with a special focus on Graves' disease. Cases that begin on page 1091 illustrate this approach in practice. "Pearls" that summarize key points in the management of hyperthyroidism are listed in Box I.
Normal thyroid function begins with the production of thyrotropin-releasing hormone in the hypothalamus. This stimulates the release of TSH (also called thyrotropin) by the anterior pituitary. TSH then circulates to the thyroid gland, where it promotes the formation and release of the thyroid hormones-T4 (also called tetraiodothyronine) and T3-into the systemic circulation. Only T3 is metabolically active. Of the total thyroid hormone production, 90% is T4 and 9% is T3. The remaining 1% is reverse-triiodothyronine, an inactive compound. Approximately 80% of circulating T3 derives from the removal of 1 iodine molecule from T4 by a deiodinase enzyme found in almost all tissues. T3 and T4 regulate further TSH secretion by forming a negative feedback loop.
Common causes of hyperthyroidism are listed in Table 1. Specific diseases occur in particular age groups with distinct presentations.
The most common cause of hyperthyroidism is Graves' disease (toxic diffuse goiter), which typically affects women in the third and fourth decades.1,6 As the alternate name for the condition implies, affected persons have a diffusely enlarged thyroid gland that is synthesizing and releasing excess thyroid hormones into the systemic circulation.
Graves' disease is an autoimmune phenomenon characterized by the presence of B- and T-lymphocytes that are sensitized to the TSH receptor sites in the thyroid gland. Antibodies attach to the TSH receptor sites on the cell wall and stimulate production and release of thyroid hormones.7 Antibodies directed against the key intrathyroidal enzyme, thyroid peroxidase, are often present in patients with Graves' disease; less frequently, antibodies are directed against thyroglobulin.
SIGNS AND SYMPTOMS
The release of excess thyroid hormones produces the common symptoms and signs of hyperthyroidism listed in Table 2.Patients often complain of either anxiety and nervousness or palpitations. Clinical signs are cardiac (tachycardia, atrial fibrillation, angina, congestive heart failure, systolic hypertension)8; neurologic (tremor, hyperactivity); ophthalmic (exophthalmos [Graves' disease only], lid lag, lid retraction, stare); and dermatologic (pretibial myxedema and acropachy [Graves' disease only], warm, moist skin).9
Laboratory studies. Findings consistent with hyperthyroidism include a low or undetectable serum TSH level and an elevated FT4 level.9 Levels that indicate subclinical hyperthyroidism are given in Box II. The sensitivity and specificity of TSH measurement are 95% to 98%; this test can be used to:
Exclude thyroid disease states.
Monitor antithyroid therapy in hyperthyroid patients.
Monitor replacement therapy in hypothyroid patients.
FT4 is now measured by direct analysis (the "direct free" T4 assay). The combination of a serum TSH level and FT4 level is 98% specific and 99.5% sensitive for the diagnosis of thyroid disease states. Total T3, which is 99.5% protein-bound, has a half-life of 24 hours. The T3 test is used to diagnose T3 thyrotoxicosis (which accounts for 10% of hyperthyroid states) and to detect early rebound hyperthyroidism after antithyroid medications have been discontinued in the treatment of thyrotoxic states.10
In addition, blood tests for antibodies may be used in the workup of hyperthyroidism. Thyroid-stimulating immunoglobulins, thyroid-stimulating antibodies, or thyroid receptor antibodies confirm the diagnosis of Graves' disease; these antibodies are present in more than 90% of adults with this disease. However, many experts feel the clinical usefulness of tests for these antibodies is limited.11
Imaging studies. Two types of nuclear studies assist in confirming and differentiating causes of hyperthyroidism (Table 3). Often, these studies are used together.
A thyroid scan demonstrates the anatomic structure and volume of the gland and the location of thyroid tissue. The scan can determine whether a nodule is "cold" or "hot." While most thyroid cancers appear as cold areas on the scan, evaluation of tissue samples is required to confirm the diagnosis.
Measurement of radioactive iodine (RAI) uptake demonstrates the metabolic (physiologic) functioning of the thyroid gland based on fractional rates of activity. Early measurements (during the first hour) reflect iodide transport. Intermediate measurements (up to 6 to 8 hours) reflect iodide transport and organification. Late measurements (up to 24 hours) reflect the net balance between iodide oxidation/organification and the subsequent release of iodine by the gland. Graves' disease is characterized by diffuse, increased RAI uptake at 24 hours. In contrast, some of the other clinical causes of hyperthyroidism produce minimal or no uptake on the thyroid scan. For example, factitious or iatrogenic hyperthyroidism is caused by the inappropriate or excessive ingestion of exogenous thyroid hormone that physiologically "turns off" the thyroid gland. In subacute or postpartum thyroiditis, the preformed thyroid hormone actually "leaks" into the circulation, and the thyroid gland is not stimulated by TSH to biosynthesize excessive hormone.
Ultrasonographic evaluation of the thyroid gland is also used in some settings. This procedure may confirm or rule out the presence of nodules or cysts, although tissue analysis is required to make a diagnosis.
Biopsy. Fine-needle aspiration and biopsy (FNAB) of thyroid tissue is helpful in confirming a diagnosis and ruling out malignancy. Some centers perform FNAB only on hypofunctioning nodules, while other experts recommend FNAB for all nodules. Have the procedure done by an experienced clinician and the results interpreted by a skilled cytologist.12 Ultrasonographic guidance may be useful for nodules of less than 1 cm.
OVERVIEW OF TREATMENT CHOICES
Treatment choices for patients with hyperthyroidism include RAI ablation, surgery, and antithyroid medications-propylthiouracil (PTU) or methimazole.13
RAI ablation. This is the treatment of choice for most patients. RAI ablation is safe; it does not adversely affect fertility and it does not increase the risk of congenital malformations or of cancer in the patient or his or her children. Nevertheless, many physicians are still hesitant to consider RAI ablation in patients of childbearing age.
This treatment is not recommended for pregnant women, because RAI may ablate the fetal thyroid. Advise women to postpone pregnancy for 6 months following RAI ablation. RAI is also contraindicated in breast-feeding mothers, because it transfers to breast milk.
Because hypothyroidism develops in many patients within 3 months of RAI treatment, patients require follow-up every 4 to 6 weeks. Alternatively, some authorities recommend beginning thyroid replacement at 8 weeks following RAI ablation, with dosage adjustment over time. In patients whose hyperthyroidism was severe, the TSH level may not "recover" for several months from the preceding depressed state. Follow up these treated patients every 3 months for 1 year, then yearly thereafter.
Surgery. Once popular, total or partial thyroidectomy is now uncommon. Table 4 lists the settings in which thyroidectomy may be appropriate. The commonly listed complications of hypoparathyroidism and vocal cord paralysis are rare when the procedure is performed by an experienced surgeon (with rates of 0% to 13% and less than 1%, respectively).14
Drug therapy. Medications used in the management of symptomatic hyperthyroidism include:
Agents that decrease thyroid hormone secretion (PTU, methimazole, super-saturated potassium iodide [SSKI], and glucocorticoids).
Agents that inhibit conversion of T4 to T3 (PTU, β-blockers, glucocorticoids).
Agents that antagonize the end effects of T3 (glucocorticoids, β-blockers).
The antithyroid medications-PTU and methimazole-were developed in the 1940s and are currently used in a minority of patients. The highest success rates are seen in those patients with small goiters and mild disease. Patient noncompliance, lack of therapeutic response, and side effects-agranulocytosis, hepatitis, and skin reactions-can limit their use. Antithyroid medications are used in pregnant women, patients who require "pretreatment" before RAI therapy (those with cardiac disease or the elderly), and children and adolescents with Graves' disease.
PTU and methimazole have intrathyroidal activity on the synthesis of thyroid hormone.15 They block intrathyroidal action by inhibiting iodine oxidation and organification, iodotyrosine coupling, and thyroglobulin synthesis.16 Both antithyroid agents possess these actions. Common side effects are found with both agents.
PTU inhibits the production of thyroid hormone and, unlike methimazole, inhibits the peripheral conversion of T4 to T3. Patients usually require 100 to 150 mg 3 times per day. After the hyperthyroid state is controlled, dosage can often be reduced for maintenance therapy. Before initiating therapy, order a complete blood cell count. Repeat as needed, particularly if the patient has fever or sore throat. Onset of agranulocytosis can be sudden. Neutropenia occurs in about 10% of patients and is often mild. PTU can be discontinued if the polymorphonuclear leukocytes are fewer than 1500/µL. After 12 to 24 months, the dose can be tapered if the patient's FT4 level remains normal.17 After 1 year of treatment, half of patients will continue to be euthyroid.16 However, up to 80% of patients will relapse eventually. Alternative modalities-RAI or surgery-will be required in those who remain hyperthyroid or in those in whom hyperthyroidism recurs after drug withdrawal.
Methimazole has a longer half-life than PTU. It is 10 to 50 times more potent than PTU, and most hyperthyroid states can be controlled with 10 to 15 mg daily. Methimazole is not protein-bound and is lipid-soluble. Consequently, it freely crosses placental membranes and breast tissue. While PTU is preferred by most physicians, methimazole can be given once daily in most patients (which can increase compliance), is less expensive, can effect a euthyroid state sooner, and has a better side-effect profile. The side effect of agranulocytosis appears to be dose-dependent with methimazole and idiosyncratic with PTU, while hepatitis and vasculitis are more prevalent with PTU. However, during pregnancy and lactation, PTU is preferred.
Nonselective β-blockers (eg, propranolol) inhibit extrathyroidal conversion of T4 to T3. These agents also decrease heart rate and temperature and control symptoms of anxiety, tremors, and palpitations. Propranolol can be used to control symptoms in any hyperthyroid patient.
Glucocorticoids (eg, prednisone) can be used in Graves' disease (or thyroid storm) to inhibit thyroid secretion and inhibit peripheral conversion of T4 to T3; they may also prevent hypotension. Often, daily doses of 60 to 80 mg are necessary.
SSKI blocks release of T4 and T3 from the thyroid gland. SSKI and glucocorticoids are used only in patients with thyroid storm or with severe symptoms.
TREATMENT OF GRAVES' DISEASE
In the management of Graves' disease, most patients are converted from hyperthyroidism to hypothyroidism via RAI ablation or surgery; patients then receive individualized dosages of thyroid replacement hormone.18 The mean replacement dosage of levothyroxine in adults is 1.7 µg/kg/d,19 with dosages adjusted based on TSH values. Excessive amounts can cause iatrogenic thyrotoxicosis and promote osteoporosis and cardiac disease.20-22 The average replacement dosage in the geriatric patient is 1 µg/kg/d. This dosage is also adjusted based on the serum TSH level.
β-Blockers, glucocorticoids, and SSKI are also used in the management of Graves' disease, as discussed above.
Consultation with an endocrinologist is recommended in the following settings:
When the diagnosis is uncertain.
When a patient has comorbidities that require prompt treatment (eg, atrial fibrillation, heart failure).
In a medical emergency, such as thyroid storm.
When specific agents produce adverse effects or do not produce the expected response. n
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