The symptoms and signs of overt thyrotoxicosis often provide a virtually pathognomonic clinical picture. Diagnostic indices based on these symptoms and signs accurately identify most patients with overt thyrotoxicosis (2), but these have not been prospectively applied to primary care populations and correlate poorly with biochemical severity (3). There is considerable variability among patients in particular clinical features and their severity. For example, although weight loss despite good appetite is a classic manifestation of thyrotoxicosis, some patients gain weight and others are anorectic (4). Furthermore, elderly patients may have few or none of the usual symptoms and signs of thyrotoxicosis (4), a syndrome termed apathetic thyrotoxicosis (5), and instead present with weight loss or cardiovascular manifestations. Certain other syndromes, such as atrial fibrillation and systolic hypertension; hypercalcemia, nephrolithiasis, and osteoporosis; new or exacerbated headaches; persistent nausea and vomiting; hyperdefecation; or muscle weakness should also suggest thyrotoxicosis. Severe thyrotoxicosis may mimic febrile illnesses, heart failure due to primary cardiac disease, or toxic delirium. Thus, the clinical manifestations of thyrotoxicosis can vary considerably, and of course, the diagnosis must be suspected clinically before it can be established or excluded by biochemical studies.

In the majority of thyrotoxic patients, the cause is Graves’ disease, which may have unique clinical manifestations of its own, including urticaria, pruritus, or enlargement of the thymus or spleen. Hyperthyroid Graves’ disease is often accompanied by ophthalmopathy; rare patients have localized myxedema or thyroid acropachy (see the sections on ophthalmopathy and localized myxedema and thyroid acropachy in Chapters 18B and 18C). The presence of exophthalmos, whether symmetric or not, or other extrathyroidal signs of Graves’ disease should prompt laboratory assessment for thyrotoxicosis. Furthermore, certain groups have an increased risk for developing Graves’ disease, including women in the third through sixth decades of life, patients with a family history of autoimmune thyroid disease, and those with certain other disorders with an autoimmune pathogenesis (e.g., pernicious anemia, autoimmune diabetes mellitus, and myasthenia gravis). Patients who smoke cigarettes (6), are receiving the immunomodulatory agents interferon-α and interleukin-2 (7), or have histories of previous high-dose cervical irradiation (8) or radioiodine treatment for nodular goiter (9) are also at increased risk for developing Graves’ disease.

Clinical features also may identify patients with less common forms of thyrotoxicosis. Patients with thyrotoxicosis caused by subacute (de Quervain’s) thyroiditis typically have thyroid pain and tenderness and constitutional complaints, including fever, night sweats, and malaise. Those with toxic nodular goiter are usually older, and their thyrotoxicosis may have been provoked by recent exposure to iodine-containing radiographic contrast agents or nutritional supplements. Detection of a thyroid nodule or multinodular goiter warrants screening for overt or subclinical thyrotoxicosis. The iodine-containing antiarrhythmic agent amiodarone can also provoke either iodine-induced hyperthyroidism (even in patients without thyroid nodules) or a painless form of thyroiditis causing transient thyrotoxicosis. Silent (painless or postpartum) thyroiditis most often affects women 2 to 10 months postpartum (see Chapter 56) or after abortion or miscarriage. Less often, it can occur in women who have not been pregnant or in men. Factitious thyrotoxicosis is most likely to occur in health-care workers or persons with access to thyroid hormone preparations, for example, those with a family member or pet taking thyroid hormone, or from ingesting nutritional supplements that contain thyroid hormones.

Certain abnormalities detected in the course of routine biochemical blood testing may suggest the presence of thyrotoxicosis. These include hypercalcemia, an elevated serum alkaline phosphatase concentration, and a serum cholesterol concentration that is either low or lower than previously determined. The concentrations of certain less commonly measured substances, including ferritin, angiotensin-converting enzyme, and sex hormone binding globulin can also be increased in thyrotoxicosis. The presence of thyrotoxicosis should be considered when atrial tachyarrhythmias are detected by electrocardiography.

Biochemical confirmation of thyrotoxicosis was traditionally based on detection of elevated serum total and free thyroxine (T₄) and triiodothyronine (T₃) concentrations (10). Most patients have high serum concentrations of both hormones, but some have isolated increases of either T₄ or T₃. Although serum thyroid hormone measurements are useful for detecting thyrotoxicosis and monitoring treatment of it, they have two limitations. First, there are other causes of high serum T₄ or T₃ concentrations. Second, some thyrotoxic patients have serum T₄ and T₃ concentrations within the upper portion of the normal range. The development of sensitive assays for serum TSH has simplified the diagnostic approach for common causes of thyrotoxicosis. Their use has also expanded the spectrum of thyrotoxicosis to include mild or subclinical thyrotoxicosis (see Chapter 47), in which suppression of the serum TSH occurs despite high- or even mid-normal serum T₄ and T₃ levels. It is important to remember, however, that the constellation of a low serum TSH with normal thyroid hormone levels can also be due to central hypothyroidism.

The serum total T₄ concentration can be measured accurately by competitive protein-binding assays using either anti-T₄ antibodies or serum thyroid hormone-binding proteins. Most of the T₄ in serum (99.97%) is bound to thyroxine-binding globulin (TBG), transthyretin (TTR, or thyroxine-binding prealbumin), or albumin. An increase in the concentration or thyroid hormone-binding of any of these serum proteins, especially TBG, can cause a high serum total T₄ concentration (hyperthyroxinemia), which could be misconstrued as thyrotoxicosis (Table 31.1). Conversely, decreased T₄ binding by serum proteins can mask excess thyroid hormone production.

Determining the serum free T₄ concentration resolves most potential pitfalls associated with increased serum protein binding of T₄. Although equilibrium dialysis and ultrafiltration are the most accurate techniques for serum free T₄ measurement, serum free T₄ immunoassays and the serum free T₄ index readily differentiate thyrotoxicosis from the most common cause of hyperthyroxinemia, which is TBG excess. Furthermore, free T₄ immunoassays and the serum free T₄ index are simpler, quicker, and less costly. Most serum free T₄ immunoassays employ an analogue of T₄ that does not bind to thyroid hormone-binding proteins. The free T₄ index is the product of the serum total T₄ and the thyroid hormone-binding ratio (THBR; also known as the T₃ or T₄ uptake) (11). These assays are discussed in detail in Chapter 13.

Other conditions that cause euthyroid hyperthyroxinemia can be more difficult to differentiate from thyrotoxicosis. Patients with familial dysalbuminemic hyperthyroxinemia have a mutated form of albumin that binds T₄ with increased affinity, increasing the serum total serum T₄ concentration (12,13). Serum free T₄ analogue immunoassay methods also may yield falsely elevated values in this condition. Because the mutated albumin usually binds T₃ poorly, the THBR value, which uses radiolabeled T₃ in vitro, is typically normal, and, therefore, the calculated free T₄ index value is deceptively high. Similarly, increased TTR binding of T₄, which can occur as either an inherited trait (14) or a paraneoplastic phenomenon in patients with carcinoma of the pancreas or liver (15) can cause an increased serum total T₄ concentration. Endogenous thyroid hormone-binding antibodies, which may be present in patients with chronic autoimmune thyroiditis or other autoimmune disorders, can cause spurious elevations of the measured serum T₄ or T₃ concentration (16).

Hyperthyroxinemia also may occur as a result of disorders that transiently increase the secretion of TSH (or chorionic gonadotropin). It can accompany systemic nonthyroidal disorders and medications that reduce T₄ clearance by deiodination. For example, in one study of patients admitted to an inpatient medical service, modest elevations in serum total T₄ and free T₄ index values were found in 4% and 12%, respectively (17). Two disorders—acute psychosis (18,19) and hyperemesis gravidarum (20)—have been associated with substantial prevalences of euthyroid hyperthyroxinemia. Propranolol, when given in high dosages [>160 mg/day (21)], and amiodarone (22) can impair T₄ clearance, causing euthyroid hyperthyroxinemia (see section on Effects of Pharmacologic Agents on Thyroid Hormone Metabolism in Chapter 11). Even though they have no clinical evidence of thyrotoxicosis, some patients receiving T₄ therapy have modest hyperthyroxinemia. Finally, patients with generalized thyroid hormone resistance typically have elevated serum total and free T₄ and T₃ concentrations with normal or slightly increased TSH concentrations (23) (see Chapter 58).