Sporadic painless and subacute painful thyroiditis, along with postpartum thyroiditis, are a group of disorders also known as the destruction-induced thyroiditis (1,2,3,4). These are transient disorders, usually consisting of four phases (Fig. 22.1). The clinical hallmarks of the destruction-induced thyroiditis begin with the abrupt onset of thyrotoxic symptoms, which is associated with a low thyroid radioactive iodine uptake (Table 22.3, see Chapters 12 and 17) and elevated serum thyroid hormone and thyroglobulin concentrations, consistent with the leakage of pre-formed hormone from a damaged gland. This represents the major cause of non-hyperthyroid thyrotoxicosis. Following a brief euthyroid phase as the thyroid hormones fall back into the normal range, hypothyroidism ensues, which is a consequence of depleted thyroid hormone stores and, possibly, recent TSH suppression during the thyrotoxic phase. Because the destructive process is self-limited, however, recovery generally occurs.

Subacute thyroiditis is the most common cause of the painful thyroid and acute infectious thyroiditis is a potential life-threatening disease. Both of these disorders must be differentiated from the other causes of anterior neck pain in the acutely symptomatic patient (Table 22.4). Essentially all of the non-thyroidal causes of neck pain are infectious in origin and present as discrete painful masses (5). Acute hemorrhage into either a thyroid cyst or a nodule usually presents with the sudden onset of unilateral neck pain associated with a marked increase in the size of a preexisting nodule. The pain associated with a rapidly enlarging carcinoma, usually anaplastic, is often more chronic in nature (6), as is painful Hashimoto’s thyroiditis, which usually involves the entire gland and antibodies directed against thyroglobulin and thyroid peroxidase are usually present in high titer (7). Radiation thyroiditis occurs in the setting of radioactive iodine treatment for hyperthyroidism or following supravoltage external radiation of the anterior neck for thyroid cancer or lymphoma. Amiodarone, an iodine-rich antiarrhythmic drug, may cause iodine-induced thyrotoxicosis (Jod-Basedow disease) and, less commonly, thyroiditis, which may occasionally be painful (8,9). Globus hystericus, an anxiety reaction that is characterized by a constrictive feeling in the throat, is a diagnosis of exclusion.

Thyroid autoimmunity in sporadic painless thyroiditis is probably inherited (18), which would be consistent with the observations that postpartum thyroiditis is weakly associated with genes that regulate immune function (19). These include, in certain populations, HLA-DR4, DR5, and DR3 in combination with -A1 and -B8 (19,20).

As a form of destruction-induced thyroiditis, sporadic painless thyroiditis is usually a transient disorder consisting of four phases, similar to postpartum thyroiditis (Fig. 22.1), although not all phases are seen in all patients (4,20,21). Clinical presentation varies from overt thyrotoxicosis, to thyroid enlargement with minimal thyroid dysfunction or hypothyroidism, depending on the stage in which the diagnosis is made. A non-tender goiter is usually present.

Phase 1/toxic phase: The initial phase is one of thyrotoxicosis, due to the “leak” of thyroid hormone from the regions of lymphocytic infiltration within the thyroid gland. Tachycardia, palpitations, heat intolerance, and emotional disturbances are characteristic of the thyrotoxic phase of sporadic painless thyroiditis. The ratio of serum T₃ to serum T₄ is lower in sporadic painless thyroiditis and postpartum thyroiditis than it is in Graves’ disease (22); therefore patients are less symptomatic and features that develop with longstanding thyrotoxicosis, such as substantial weight loss or severe muscle weakness, are unusual. The toxic phase usually last from 1 to 3 months.

Phase 2/euthyroid phase: A brief period of euthyroidism follows the thyrotoxic phase and may last for a few months (23).

Phase III/hypothyroid phase: As the gland becomes depleted of hormone, hypothyroidism ensues and may last for up to 1 year. Fatigue, malaise, impaired concentration, carelessness, and symptoms related to depression are common in patients in the hypothyroid phase. In general, the duration of hypothyroidism in those patients who initially present with thyrotoxicosis is more likely to be brief. Hypothyroidism tends to be more severe and prolonged if it is the presenting disorder. While most patients return to a euthyroid state, some remain permanently hypothyroid (4,20,21). However, recent studies suggest a far higher incidence of permanent hypothyroidism, with up to 54% of women with postpartum thyroiditis remaining hypothyroid (24,25). The features associated with the development of permanent hypothyroidism in sporadic painless thyroiditis are high titers of antithyroid antibodies, the lack of a detected thyrotoxic phase, more severe degrees of hypothyroidism and persistent hypoechogenicity on ultrasound. While recurrences of sporadic painless thyroiditis are not unusual, they are nowhere near the recurrence rate of women with postpartum thyroiditis after a subsequent pregnancy, probably due to a lack of a clearly recognized inciting event (4,20,21). The risk of permanent hypothyroidism in patients with a recurrent episode is increased. Further, these patients are susceptible to iodine-induced hypothyroidism years later as may be seen in other disorders of the thyroid (see Chapter 11E).

While the major clinical feature that distinguishes sporadic painless thyroiditis from subacute thyroiditis (see later) is the presence of thyroid pain and tenderness, thyroidal pain has occasionally been reported in sporadic painless thyroiditis. Fine needle aspiration biopsies consistent with chronic lymphocytic thyroiditis were described in five of eight patients presenting with destruction-induced thyrotoxicosis and thyroidal pain (26). These patients also had high titers of antithyroid antibodies and many of them developed permanent hypothyroidism. Conversely, painless destruction-induced thyrotoxicosis with
pathologic changes characteristic of subacute thyroiditis has been reported in 10 of 12 patients in the Netherlands (27).

Indirect evidence suggests that subacute thyroiditis may be caused by a viral infection of the thyroid (41,42). The condition is often preceded by a prodromal phase of myalgias, malaise, low-grade fevers, fatigue, and frequently by an upper respiratory tract infection. It has been reported most frequently in the temperate zone, and only rarely from other parts of the world. It has been found to occur seasonally; the highest incidence is in the summer months (July through September), which coincide with the peak of enterovirus (Echovirus, Coxsackie virus A and B) infections (43). The incidence rate has been shown to vary directly with viral epidemics; during certain viral epidemics, specifically mumps, the incidence of subacute thyroiditis has been found to be higher. Interestingly, antibodies to the mumps virus have even been detected in individuals with subacute thyroiditis who do not have clinical evidence of mumps. Subacute thyroiditis has also been associated with other viral infections (2,44,45,46) including measles (47,48), influenza [both usual and H1N1 types (49)], the common cold, adenovirus, infectious mononucleosis, hand-foot-mouth disease (50), myocarditis (51), cat scratch fever, St Louis encephalitis (52), hepatitis (53), and the parvovirus B19 infection (54).

However, only mumps virus (55) and an unidentified cytopathic virus (45) have been directly isolated from affected thyroids while an electromagnetic imaging study demonstrated viral particles in thyroid tissue from a single patient with subacute thyroiditis (56).

In the most commonly quoted study regarding a viral etiology of subacute thyroiditis, Volpe et al. (57) reported rising antibody titers to mumps virus, echovirus, adenovirus, and enterovirus in convalescent sera of 32 patients with subacute thyroiditis (Fig. 22.3). However, an additional 26 patients had demonstrable serologic viral antibody titers that did not change (57). Coxsackie virus is most commonly associated with subacute thyroiditis. A single report has described a fourfold rise in serum Coxsackie antibody titers after a documented case of subacute thyroiditis (58) and Coxsackie virus antibody titers have been shown to directly follow the course of the thyroid disease (43). However, in another study, sera, stool, and fine needle thyroid aspirations in 27 consecutive patients with subacute thyroiditis failed to document evidence of either Coxsackie or enteroviral infection (59). A similar report failed to find evidence of Epstein–Barr or cytomegalovirus infections in fine needle aspiration biopsy specimens of patients with subacute thyroiditis (60). Finally, 10 patients presented with post-viral thyroiditis that followed a similar course to subacute thyroiditis but was painless (61).

Certain non-viral infections including Q fever and malaria have been associated with a clinical syndrome similar to subacute thyroiditis. In addition, a case of subacute thyroiditis occurring simultaneously with giant cell arteritis has been reported (62).

There is no clear association between subacute thyroiditis and autoimmune thyroid disease. Serum thyroid peroxidase and thyroglobulin antibody levels are usually normal. When described, the levels of thyroid peroxidase and thyroglobulin antibodies correlated with the phase of transient hypothyroidism. Antibodies to an unpurified thyroid preparation can be detected for up to 4 years after a bout of subacute thyroiditis.

Several reports have suggested that subacute thyroiditis may trigger the development of TSH receptor antibodies (63), contributing to a prolonged hypothyroid phase (64) and occasionally leading to the development of Graves’ disease
(65), although this was not observed in the most recent epidemiologic survey (37). In most studies, there was no correlation between the presence of thyrotropin-receptor–binding inhibitory immunoglobulin or of thyrotropin-receptor–stimulating immunoglobulin and the thyrotoxic phase of the thyroiditis (66). On the other hand, there has been some correlation between thyroid-blocking antibodies and the development of hypothyroidism. An explanation for this observation is that the appearance of the TSH-receptor antibodies results from an immune response that occurs after there is damage to the thyrocytes, specifically membrane desquamation (41,42). Following recovery from the inflammatory process of subacute thyroiditis, all immunologic phenomena disappear (66). Thus, the transitory immunologic markers that are observed during the course of subacute thyroiditis appear to occur in response to the release of antigenic material from the thyroid.

Manipulation of the immune system by vaccines and drugs has also led to the development of subacute thyroiditis. Reports have linked subacute thyroiditis with the hepatitis vaccine (67), influenza vaccine (68), the H1N1 vaccine (69), during interferon and interleukin-2 therapy (70,71,72,73) and combination interferon and ribavirin therapy (74,75). Other immune mechanisms have been suggested by an association between subacute thyroiditis and Sweets syndrome (76,77) and Takayasu’s arteritis (78). Subacute thyroiditis has also been reported in patients on long-term immunosuppression (79), suggesting a minimal effect of the immune system on development of the disease.