Lewis E. Braverman
Robert D. Utiger
This chapter introduces the section on thyrotoxicosis, a common and important thyroid disorder. It has multiple causes, and its recognition and treatment are important components of endocrine practice.
We use the term thyrotoxicosis to mean the clinical syndrome of hypermetabolism and hyperactivity that results when the serum concentrations of free thyroxine (T4), free triiodothyronine (T3), or both, are high. The term hyperthyroidism is used to mean sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland. Thus, the terms thyrotoxicosis and hyperthyroidism are not synonymous. While many patients with thyrotoxicosis have hyperthyroidism, others—for example, those in whom thyrotoxicosis is caused by thyroiditis or exogenous thyroid hormone administration—do not.
The clinical manifestations of thyrotoxicosis are, for the most part, independent of its cause. However, certain features of the illness often provide clues about the cause of thyrotoxicosis in an individual patient. These features include the duration of thyrotoxicosis, the size and shape of the thyroid gland, and the presence or absence of the extrathyroidal manifestations of Graves' disease. For example, at the time of diagnosis, patients with thyrotoxicosis caused by thyroiditis rarely have had symptoms for more than a few weeks, whereas those with Graves' disease have usually had symptoms for at least several months. An attempt should be made to determine the cause of thyrotoxicosis in all patients, because knowledge of the cause determines prognosis and guides therapy.
The causes of thyrotoxicosis can be subdivided into those disorders that are associated with hyperthyroidism and those that are not (Table 22.1). All these disorders are discussed in detail in the following chapters. Among the causes of spontaneously occurring thyrotoxicosis, Graves' disease is the most common; its frequency as the cause of thyrotoxicosis ranges from approximately 60% to 90% in different regions of the world. Most of the remaining cases are caused by toxic nodular goiter, autonomously functioning thyroid adenomas (toxic adenomas), or the several types of thyroiditis (1,2,3). Except for exogenous thyrotoxicosis, all the other causes of thyrotoxicosis are rare.
TABLE 22.1. CAUSES OF THYROTOXICOSIS
Common Causes
Type of Thyrotoxicosis
Pathogenic Mechanism
Thyrotoxicosis associated with hyperthyroidisma
Production of abnormal thyroid stimulator (Graves' disease)
TSH receptor-stimulating antibody
Intrinsic thyroid autonomy
Toxic adenoma
Benign tumor
Toxic multinodular goiter
Foci of functional autonomy
Thyrotoxicosis not associated with hyperthyroidismb
Inflammatory disease
Silent (painless) thyroiditisb
Release of stored hormones
Subacute thyroiditis
Release of stored hormones
Extrathyroidal source of hormone
Exogenous thyroid hormone
Hormone in medication or rarely, food or nutritional supplements
Uncommon Causes
Type of Thyrotoxicosis
Pathogenic Mechanism
Thyrotoxicosis associated with hyperthyroidisma
Production of thyroid-stimulating hormones
TSH hypersecretion
Thyrotroph adenoma
Thyrotroph resistance to thyroid hormone
Trophoblastic tumor
Chorionic gonadotropin
Hyperemesis gravidarum
Chorionic gonadotropin
Gestational thyrotoxicosis
TSH-receptor mutation resulting in increased sensitivity to chorionic gonadotropin
Intrinsic thyroid autonomy
Thyroid carcinoma
Foci of functional autonomy
Nonautoimmune autosomal-dominant hyperthyroidism
Constitutive activation of TSH receptors
Struma ovari
Toxic adenoma in a dermoid tumor of ovary
Drug-induced hyperthyroidism
Iodine and iodine-containing drugs and radiographic contrast agentsc
Iodine excess plus thyroid autonomy
Thyrotoxicosis not associated with hyperthyroidismb
Inflammatory disease
Drug-induced thyroiditis (amiodarone, interferon-α)
Release of stored thyroid hormone
Infarction of thyroid adenoma
Release of stored thyroid hormone
Radiation thyroiditis
Release of stored thyroid hormone
aRadioiodine uptake by thyroid gland (or abnormal or abnormally located thyroid tissue) high.
bThyroid radioiodine uptake low.
cThyroid radioiodine uptake usually low, but may be normal.
dIncluding postpartum thyroiditis.
TSH, thyrotropin.
While many patients with thyrotoxicosis have overt clinical and biochemical disease, thyrotoxicosis may be subclinical. Subclinical thyrotoxicosis is defined as normal serum free T4 and T3 concentrations and low serum thyrotropin (TSH) concentrations; the patients may or may not have symptoms of thyrotoxicosis, but if present the symptoms are usually mild and nonspecific. The causes of overt and subclinical thyrotoxicosis are similar, but the most common cause of subclinical thyrotoxicosis is exogenous thyroid hormone administration rather than Graves' disease (4). Whether and how patients with endogenous subclinical thyrotoxicosis should be treated is controversial (see Chapter 79).
The underlying problem in patients with thyrotoxicosis is acceleration of many physiologic processes, and the clinical manifestations reflect that acceleration. The more common clinical manifestations are listed in Table 22.2, and they are discussed in detail in the following chapters. None of the clinical manifestations are specific; it is usually the combination of several of them that brings to mind the possibility of the disorder in a patient. The frequency and severity of these symptoms and signs vary considerably among patients; some patients have only a few symptoms or signs and others many, and their severity varies widely; rarely thyrotoxicosis is life threatening (see Chapter 43).
TABLE 22.2. COMMON CLINICAL MANIFESTATIONS OF THYROTOXICOSIS
Symptoms
Nervousness
Fatigue
Weakness
Increased perspiration
Heat intolerance
Tremor
Hyperactivity
Palpitation
Appetite change (usually increase)
Weight change (usually weight loss)
Menstrual disturbances
Signs
Hyperactivity
Tachycardia or atrial arrhythmia
Systolic hypertension
Warm, moist, smooth skin
Stare and eyelid retraction
Tremor
Hyperreflexia
Muscle weakness
Among the factors that determine the manifestations of thyrotoxicosis are the age of the patient (5,6) and the presence of concomitant disturbances in the function of one or another organ system, so that the impact of thyrotoxicosis is either exaggerated or diminished. For example, as compared with younger patients, older patients have fewer symptoms and signs of sympathetic activation, such as anxiety, hyperactivity, and tremor, and more symptoms and signs of cardiovascular dysfunction, such as dyspnea and atrial fibrillation, and they are more likely to lose weight. The extent and severity of the clinical manifestations of thyrotoxicosis are not strongly correlated with its biochemical severity (7).
It is now easy to obtain biochemical confirmation of thyrotoxicosis by measurements of serum TSH and direct or indirect measurements of the serum free T4, free T3, or both (see Chapter 13). Other tests, such as measurements of radioiodine uptake, radioiodine and other imaging tests, and measurements of TSH-receptor antibodies, may be done to determine the cause of thyrotoxicosis. Fortunately, however, the cause can usually be determined by history and physical examination, and tests to determine the cause are not routinely necessary. Among these tests, measurement of thyroid radioiodine is the most useful, because it distinguishes between thyrotoxicosis caused by hyperthyroidism and that caused by thyroiditis or exogenous thyroid hormone administration.
Finally, the various antithyroid treatments available—antithyroid drugs, radioactive iodine, and thyroidectomy—effectively ameliorate hyperthyroidism and therefore thyrotoxicosis (see Chapter 45). However, none is ideal, because they do not address the fundamental abnormality that causes thyrotoxicosis in most patients, and preferences for them vary widely throughout the world (8,9).
TABLE 22.3. CLINICAL MANIFESTATIONS OF SPECIFIC CAUSES OF THYROTOXICOSIS
Clinical Finding
Cause
Diffuse goiter
Graves' disease, silent thyroiditis
Uninodular goiter
Thyroid autonomy
Multinodular goiter
Thyroid autonomy
Impalpable thyroid gland
Exogenous thyroid hormone
Thyroid pain and tenderness
Subacute thyroiditis
Ophthalmopathy
Graves' disease
Localized dermopathy
Graves' disease
Thyroid acropachy
Graves' disease
REFERENCES
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3. Williams I, Ankrett VO, Lazarus JH, et al. Aetiology of hyperthyroidism in Canada and Wales. J Epidemiol Community Health 1983;37:245.
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