Thyroid Diseases
0025-7125/91 $0.00
+
.20
Thyroiditis Acute, Subacute, and Chronic
Peter A. Singer, MD*
The various types of thyroiditis encompass a heterogeneous group of disorders ranging from acute bacterial infections to chronic autoimmune disease. Taken together, inflammatory diseases of the thyroid may be the commonest thyroid abnormality encountered in clinical practice. Thyroiditis is generally classified according to the rapidity of onset, the severity of symptoms and signs, and its duration. A convenient classification, used by a number of authors, is depicted in Table l. The purpose of this article is to describe the pathogenic mechanisms of the different types of thyroiditis, as well as the clinical approach to their diagnosis and treatment.
ACUTE THYROIDITIS Acute thyroiditis (acute suppurative thyroiditis, bacterial thyroiditis, pyogenic thyroiditis) is an uncommon inflammatory disease, usually bacterial in origin, but may be caused by fungi, parasitic organisms, or even Pneumocystis carinii.24 The most common etiologic agents are Streptococcus pyogenes, Staphylococcus aureus, and Pneumococcus pneumoniae, although other bacteria, including Escherichia coli, Hemophilus injluenzae, and meningococcal organisms, as well as anaerobes, have been reported as causing infection. 62 Acute thyroiditis was much more common in the preantibiotic era. A literature review by Berger et aPO documented only 224 reported cases of acute thyroiditis. The apparent rarity of the disorder may be multifactorial: The thyroid gland's rich blood supply and generous lymphatic drainage may render it relatively resistant to setting up bacterial "housekeeping." Experiments in which bacteria were injected into the thyroid vasculature *Clinical Professor of Medicine, University of Southern California School of Medicine; and Director, Thyroid Disease Diagnostic Center, Section of Endocrinology and Metabolism, The Hospital of the Good Samaritan, Los Angeles, California
Medical Clinics of North America-Vo!' 75, No. 1, January 1991
61
62
PETER
A.
SINGER
of dogs failed to produce infection. 78 Also, the thyroid is encapsulated, which may make it somewhat impervious to infections from local structures. Lastly, the high iodine content of the thyroid may produce an unfavorable environment for bacterial growth. Infection may reach the thyroid via one of several routes, including hematogenous spread from distant sites, such as the urinary tract, or via the lymphatics as a result of local infections such as pharyngitis or mastoiditis. Persistent thyroglossal ducts, internal fistulae near the thyroid, infection of contiguous structures, and even penetrating injuries have been reported as sources of infection. 33 Interestingly, pre-existing thyroid disease, most commonly nodular goiter, has been reported to be present in more than 50% of cases. 2 Immunocompromised individuals may be particularly prone to developing infection. The disease is more common in women, usually between the ages of 20 and 40 years, although it does occur both in children and in the elderly. Clinical Manifestations
Symptoms of acute thyroiditis usually include an abrupt onset of unilateral anterior neck pain, fever, diaphoresis, and other symptoms of bacterial toxicity. The neck pain may radiate to the ear or mandible on the side of the infection. Symptoms of pharyngitis and dysphagia also may be present. Physical examination discloses an exquisitely tender swelling that may be fluctuant. The skin usually is erythematous over the affected area. Laboratory Diagnosis
The white blood cell count is generally elevated with a shift to the left. Patients are typically euthyroid, although transient elevations in serum thyroxine (T4) levels have been reported. It is thought that the elevated T4 concentrations are due to discharge of preformed hormone from the inflamed thyroid gland. I. 10 Hyperthyroidism per se does not occur. The thyroidal radioactive iodine uptake (RAID) is most often normal, although it may be low if inflammation is diffuse. 35 The thyroid scan shows a "cold" defect in the involved lobe. Differential Diagnosis and Treatment
The presentation of acute thyroiditis is dramatic, yet may be mimicked by other painful thyroid disorders, most notably subacute granulomatous thyroiditis or hemorrhage into a thyroid nodule, cyst, or a rapidly enlarging thyroid carcinoma with central necrosis. Subacute granulomatous thyroiditis Table 1. Classification of Thyroiditis Acute thyroiditis Subacute thyroiditis Subacute granulomatous thyroiditis Subacute lymphocytic thyroiditis Chronic thyroiditis Chronic lymphocytic (Hashimoto's) thyroiditis Invasive fibrous (Riedel's) thyroiditis
63
THYROIDITIS
is usually less severe than acute thyroiditis in its clinical presentation, and hemorrhage into a thyroid cyst or neoplasm is not accompanied by fever or other manifestations of bacterial toxicity. However, immunocompromised patients may lack fever. If acute thyroiditis is suspected, a fine-needle aspiration of the lesion should be done. The presence of purulent material, which should be gram-stained and cultured, is confirmatory. Treatment should consist of hospitalization with administration of parenteral antibiotics and, when there is fluctuance, drainage of the lesion. Excision of the affected area is necessary in some cases. A delay in the diagnosis or treatment may result in rupture of an abscess with worsening bacteremia and sepsis. Permanent sequelae of acute thyroiditis are rare. Severe and diffuse inflammation may cause destruction of the entire thyroid, with hypothyroidism the result. Recurrences of acute thyroiditis occur when there is an undiagnosed anatomic defect, such as persistence of a thyroglossal duct or an unrecognized internal fistula. 63 SUBACUTE THYROIDITIS Subacute thyroiditis may be subdivided into subacute granulomatous thyroiditis, which is characteristically painful, and subacute lymphocytic thyroiditis, which is painless. Both of these disorders, although distinct histologically and most likely etiologically, are strikingly similar in terms of clinical thyroid dysfunction and duration of disease and, hence, are included within the same general classification. Subacute Granulomatous (Painful) Thyroiditis This entity, first described by De Quervain 14 in 1904, when he showed granulomatous-type changes and giant cells in thyroid glands of affected individuals, has a number of eponyms, including granulomatous thyroiditis, subacute granulomatous thyroiditis, pseudogranulomatous thyroiditis, subacute thyroiditis, subacute painful thyroiditis, and, of course, De Quervain's thyroiditis. For the purposes of this discussion, the designation SAT will be used. This disorder is relatively common and may account for approximately 5% of all visits to physicians for thyroid abnormalities. 27 It is the commonest cause of the "painful thyroid," and heads the list of the differential diagnosis of anterior neck pain (Table 2). Etiology. Subacute granulomatous thyroiditis most likely is viral in origin. Evidence for a viral etiology includes the clinical observations that it frequently follows an antecedent respiratory infection, is associated with a viral prodrome, is self-limiting, and tends to have a seasonal distribution (summer and fall). Also, it has been associated with outbreaks of mumps, and the mumps virus has been cultured from the thyroid glands of affected individuals. 19 It has also been associated with other viral illnesses, including adenovirus, coxsackie, influenza, and infectious mononucleosis, and viral antibody titers in convalescent sera of patients with SAT have been demonstrated against a number of viruses, including the mumps virus, ECHO virus, adenovirus, and enteroviruses. 71
64
PETER
A. SINGER
Table 2. Differential Diagnosis of the Painful Anterior Neck Mass* Subacute granulomatous thyroiditis Acute hemorrhage into thyroid cyst, or adenomatoid nodule Acute hemorrhage into thyroid carcinoma Acute suppurative thyroiditis Rapidly enlarging thyroid carcinoma Painful Hashimoto's thyroiditis Infected thyroglossal duct cyst Infected branchial cleft cyst Cellulitis of anterior neck *Of all of the conditions in this table, subacute granulomatous thyroiditis and hemorrhage into a cyst or adenoma probably account for more than 90% of cases.
Recently, autoimmune abnormalities associated with SAT have been described. Antibodies directed against the TSH receptor have been demonstrated. 76 Also, sensitization of T lymphocytes against thyroid antigen have been shown, suggesting that cell-mediated immunity may play a role in the development of SAT. 75 It seems likely, however, that these phenomena are the result of antigen released during inflammation, rather than being related to the development of SAT per se. There appears to be evidence for a genetic predisposition to the development of SAT. An association between SAT and HLA-Bw 35 has been reported in approximately two thirds of both Caucasians and Chinese patientsY We have seen three siblings who developed SAT within a 2-year period of time, all of whom were positive for HLA-Bw 35. 55 Most likely, HLA-Bw 35 renders individuals genetically susceptible to the inciting agent, probably a virus, for the development of SAT. Very recently, an epidemic of what has been termed atypical subacute thyroiditis was described in 12 patients in a town of approximately 28,000 inhabitants in the Netherlands. The affected individuals had many clinical similarities to SAT, yet only one was positive for the HLA-Bw 35 phenotype (significantly less than expected), whereas 5 of 11 individuals tested were positive for HLA-BI5/62, a significantly greater than expected frequency. 13 This newly described disorder may represent a subtype of SAT, with a different genetic background and possibly a different etiology. Thus, rather than being a single disorder, SAT may consist of a group of heterogeneous disorders. Clinical Manifestations. Subacute granulomatous thyroiditis occurs most commonly in women (80% of cases) between the ages of 40 and 50 years. As mentioned previously, there is usually a viral prodrome, consisting of symptoms of myalgias, low-grade fever, lassitude, sore throat, and, not infrequently, dysphagia. Significant anterior neck pain is characteristic; it occurs with a fairly abrupt onset, is usually unilateral, and, in at least one third of the cases, radiates to the ear on the ipsilateral side. Pain may also radiate to the mandible, occiput, or even upper chest. During the course of the disease the pain may migrate to the contralateral side. Symptoms of hypermetabolism such as diaphoresis, tachycardia, palpitations, and weight loss occur where there is coexistent hyperthyroidism. 70 Physical examination typically shows a mildly febrile patient with an exquisitely tender, very hard, ill-defined nodular thyroid lesion. Most often it is difficult to delineate
THYROIDITIS
65
the borders of the lesion because pain and tenderness cause the patient to withdraw from the fingers of the examiner. The swelling is usually unilateral although thickening of the opposite lobe, with less tenderness than the dominant side may be present. If inflammation is significant erythema of the overlying skin may be present. Occasionally, the clinical presentation may be so dramatic as to cause high fever and severe toxic symptoms. In such cases, inflammation and edema may be so pronounced as to produce obstructive symptoms (Fig. 1). Diagnosis. The differential diagnosis of SAT is shown in Table 2. Although not all-inclusive, the list does include the principal disorders to be ruled out. Histologically confirmed SAT without pain has been reported, but such cases are probably uncommon. 51 Usual laboratory findings include a mild normochromic, normocytic anemia, and normal to slightly elevated total white blood cell count. The erythrocyte estimated sedimentation rate is nearly always significantly elevated, usually greater than 50 mmlhour. A normal sedimentation rate virtually excludes the diagnosis of active SAT. Hyperthyroidism occurs in approximately 50% of patients and results from "dumping" of preformed hormone into the circulation. The serum T4 level is disproportionately elevated relative to the serum triiodothyronine (T3), reflecting the intrathyroidal T4 and T3 content. 6 Also, impaired peripheral conversion of T4 to T3 due to the illness itself results in a lower T3 level. 54 In general, the hyperthyroidism is mild or, at most, modest in its severity. The RAW is always suppressed (less than 2% at 24 hours) during active inflammation and results from destruction of the thyroid's iodine-
Figure 1. A 52-year-old man with severe subacute granulomatous thyroiditis with threatened airway obstruction. Note the pronounced retropharyngeal edema (A) and its dramatic resolution following intravenous administration of methylprednisolone (B).
66
PETER
A. SINGER
trapping mechanism rather than from TSH suppression, because even euthyroid patients with SAT have a low RAIU. The RAIU test should be done when SAT is suspected in order to rule out other causes for anterior neck pain and tender swelling. If the RAIU is greater than 5% at 24 hours, SAT is very unlikely. All of the disorders listed in Table 2 (except for the rare case of acute pyogenic thyroiditis) have a normal RAIU. The serum thyroglobulin is significantly elevated in SAT, as it is with many other thyroid disorders.67 Because it is always elevated during active SAT, it may be a useful test in cases in which the diagnosis is not clear. A normal thyroglobulin level in a patient with anterior neck pain virtually excludes the diagnosis of SAT. Treatment and Clinical Course. Salicylates and nonsteroidal antiinflammatory drugs are considered by a number of authors as the "firstline" agents of choice, in order to decrease pain; however, they are rarely effective unless inflammation is mild. Oral glucocorticoids such as prednisone, 20 to 40 mg/day in divided doses, provide dramatic relief of pain and swelling, often within hours of first administration. Unless contraindicated, they are clearly the treatment of choice. The dose can be tapered after a week's administration, and discontinued within 2 to 4 weeks. Pain and swelling recur, often on the contralateral side, in approximately 20% of patients during tapering of glucocorticoids, or shortly after their withdrawal. Prednisone can then be restarted and the tapering process begun anew. When symptoms of hyperthyroidism are significant, beta-adrenergic blocking drugs such as propranolol are useful. The course of SAT typically consists of four phases. 74 The initial acute painful phase is associated with a tender thyroid mass and hyperthyroidism, and generally lasts three to six weeks. A several-week interval of euthyroidism then occurs, followed by a period of hypothyroidism, lasting anywhere from several weeks to a few months, during which thyroxine replacement may be necessary. An asymptomatic recovery phase follows, during which the thyroid is restored to normal function. Not all patients with SAT progress through all four phases of the disorder. Patients may go directly from the painful to the recovery phase, for example, bypassing hypothyroidism. The entire duration of SAT usually is no longer than 4 to 6 months, and persistent abnormalities have been considered to be uncommon, although permanent hypothyroidism has been reported by one author in 5% of patients. 39 That experience has not been shared by others, reports of permanent hypothyroidism being almost anecdotal. In other reports in which permanent hypothyroidism following SAT has occurred, persistent elevation of thyroid antibodies has been observed, suggesting coexistent autoimmune thyroid disease. 59. 64 Very recently, though, in long-term follow-up of patients who had SAT were shown to be particularly sensitive to the inhibitory effects of exogenously administered iodides, suggesting a persistent thyroid abnormality. 52 Thus, in contrast to the long-held notion that SAT is completely self-limiting, continued observation of patients who had SAT may be indicated.
a
Subacute Lymphocytic (Painless) Thyroiditis During the past 12 to 15 years, an entity characterized by transient hyperthyroidism, a suppressed RAIU, and painless goiter has been de-
THYHOIDlTIS
67
scribed. It has been variously termed lymphocytic thyroiditis with spontaneously resolving hyperthyroidism, subacute lymphocytic thyroiditis, painless lymphocytic thyroiditis, painless thyroiditis, or silent thyroiditis. 25, 43, 48, 79 The latter term was coined because of the absence of goiter in 50% of the cases reported by Woolp9 For the purposes of this discussion, the term painless thyroiditis (PT) will be used. Painless thyroiditis exists in two forms, either occurring sporadically or in the postpartum period. Nikolai 43 reported several years ago that approximately one third of his patients presenting with hyperthyroidism had PT. This strikingly high prevalence has not been noted by others, and it appears that the overall prevalence of PT as a cause of thyrotoxicosis may vary between 5% and 20%, although the latter figure seems high. 38 A geographic variation in the prevalence of PT has been observed, with those areas previously iodine deficient (but more recently exposed to sufficient iodide intake), such as the Great Lakes region, having a greater prevalence of the disorder. 69 Indeed, in the United States, approximately 90% of cases of PT have been reported from the Great Lakes area. The majority of the cases reported from outside the United States have been from Japan and Europe, although this may be more a manifestation of screening and detection, rather than a predilection of the disorder for those areas. An epidemic of PT was reported from southwestern Minnesota and adjacent areas of South Dakota and Iowa between 1984 and 1985. 34 It was later determined, however, that the hyperthyroidism was actually due to ingestion of ground beef prepared from neck trimmings rich in thyroid tissue. In retrospect, one wonders whether or not the very high incidence of PT reported by Nikolai some 10 years ago may not have been partly due to a similar phenomenon of factitial hyperthyroidism. The postpartum type of PT (PPPT) was initially reported by Amino et a14 when he described 14 patients who developed transient postpartum hypothyroidism. Later he showed that 5.5% of 507 women screened 3 months' postpartum had biochemical thyroid abnormalities, with 3.9% having transient hyperthyroidism and 1. 6% being hypothyroid. 5 J annson and co-workers,36 in Sweden, reported thyroid dysfunction in 6.5% of 400 women screened postpartum, and Nikolai46 showed that thyroid dysfunction was present in 27 (11.3%) of238 women screened 6 to 12 weeks' postpartum. By contrast, a study in Bronx, New York, of 212 women screened between 4 and 12 weeks' postpartum, yielded only 4 women (1. 9%) with thyroid dysfunction. 23 Other studies from the East Coast have reported similar results. It appears that a geographic distribution in the prevalence of PPPT occurs, as has been reported with the sporadic type. Etiology and Pathogenesis. Current evidence suggests an autoimmune basis for PT. 73 For example, there is a high prevalence of thyroid microsomal antibodies (AMA) present in sera of patients with the disorder, as well as histologic evidence of lymphocytic infiltration, both being characteristics seen with Hashimoto's thyroiditis. Also, an association between PT and other autoimmune diseases has been reported. Recently, a patient was described with Sjogren's syndrome who simultaneously developed PT and a lupus-type syndrome. 41 Painless thyroiditis has also been reported in association with autoimmune Addison's disease, as well as in patients who
68
PETER
A.
SINGER
have a previous history of other autoimmune thyroid disease, such as Graves' or Hashimoto's. What is unclear is why approximately 50% of patients with sporadic PT lack serologic evidence for thyroid autoantibodies and why there is usually complete resolution of histologic changes following recovery. Perhaps PT has different etiologies, one being autoimmune and the other possibly infectious. The latter hypothesis gains support from the report of a husband and wife, one of whom developed painful subacute granulomatous thyroiditis, and the other, concurrent PT.42 Postpartum PT is almost certainly autoimmune in origin. There is a higher prevalence of positive AMA than is seen with the sporadic type (80% versus 50%), and its onset 6 weeks or so postpartum suggests a rebound of the maternal immune system following its normal suppression during pregnancy.3 Also, PPPT frequently occurs following successive pregnancies and may be associated with other autoimmune thyroid diseases. Moreover, it may be familial. We reported a family of three women, including two sisters who had PPPT 13 years apart, and their mother, who had postpartum hyperthyroidism many years earlier. 58 A positive family history for autoimmune thyroid disease has been reported in 50% of patients with PPPT. 46 A common allele has been found in PT, especially with PPPT, in which there is an increased prevalence of HLA-DR3, DR4, and DR5 in Caucasians. 21 ,37 Thus, a genetic predisposition may be an important determinant in the pathogenesis of this disorder. Clinical Manifestations. Painless thyroiditis is characterized by a relatively abrupt onset of symptoms of hyperthyroidism, such as tachycardia, palpitations, heat intolerance, nervousness, and weight loss. Physical findings usually show a small, modestly firm, nontender goiter. As mentioned earlier, goiter may be absent in up to 50% of patients with sporadic PT. Patients with PPPT may present either with symptoms and biochemical findings of hyper- or hypothyroidism. Hypothyroidism may be diagnosed as the initial finding in some patients with PPPT in whom the hyperthyroid phase has been overlooked. Sporadic PT has a predilection for women (80% of cases) between the ages of 30 and 40 years. Laboratory Diagnosis. Serum T4 and T3 levels are increased (except with PPPT with hypothyroidism), and, as with SAT, there is a disproportionate elevation of T4 relative to T3 due to follicular disruption and release of preformed hormone into the circulation. Thyroid autoantibodies, especially the AMA, as mentioned, are frequently positive, In contrast to SAT, the estimated sedimentation rate is either normal or mildly elevated, The RAID is suppressed, and unless there is a contraindication to performing the test, it should be done in order to rule out the possibility of Graves' disease. It must be emphasized that it is essential to differentiate between Graves' and PT, because the former disorder requires specific therapy, whereas the latter does not. If infiltrative exophthalmos is absent in the patient with Graves' disease, the physician may not be able to differentiate between Graves' disease and PT on clinical grounds. Table 3 lists clinical and laboratory features that help distinguish Graves' disease from PT. Treatment and Clinical Course. Treatment of PT is directed towards relief of the symptoms of hyperthyroidism, by using beta-adrenergic block-
69
THYROIDITIS
Table 3. Differentiation Between Subacute Painless Thyroiditis and Graves' Disease CLINICAL FEATURE
PAINLESS THYROIDITIS
Onset Severity of symptoms (usual) Duration of symptoms Goiter
Abrupt Mild to moderate
0025-7125/91 $0.00
+
.20
Thyroiditis Acute, Subacute, and Chronic
Peter A. Singer, MD*
The various types of thyroiditis encompass a heterogeneous group of disorders ranging from acute bacterial infections to chronic autoimmune disease. Taken together, inflammatory diseases of the thyroid may be the commonest thyroid abnormality encountered in clinical practice. Thyroiditis is generally classified according to the rapidity of onset, the severity of symptoms and signs, and its duration. A convenient classification, used by a number of authors, is depicted in Table l. The purpose of this article is to describe the pathogenic mechanisms of the different types of thyroiditis, as well as the clinical approach to their diagnosis and treatment.
ACUTE THYROIDITIS Acute thyroiditis (acute suppurative thyroiditis, bacterial thyroiditis, pyogenic thyroiditis) is an uncommon inflammatory disease, usually bacterial in origin, but may be caused by fungi, parasitic organisms, or even Pneumocystis carinii.24 The most common etiologic agents are Streptococcus pyogenes, Staphylococcus aureus, and Pneumococcus pneumoniae, although other bacteria, including Escherichia coli, Hemophilus injluenzae, and meningococcal organisms, as well as anaerobes, have been reported as causing infection. 62 Acute thyroiditis was much more common in the preantibiotic era. A literature review by Berger et aPO documented only 224 reported cases of acute thyroiditis. The apparent rarity of the disorder may be multifactorial: The thyroid gland's rich blood supply and generous lymphatic drainage may render it relatively resistant to setting up bacterial "housekeeping." Experiments in which bacteria were injected into the thyroid vasculature *Clinical Professor of Medicine, University of Southern California School of Medicine; and Director, Thyroid Disease Diagnostic Center, Section of Endocrinology and Metabolism, The Hospital of the Good Samaritan, Los Angeles, California
Medical Clinics of North America-Vo!' 75, No. 1, January 1991
61
62
PETER
A.
SINGER
of dogs failed to produce infection. 78 Also, the thyroid is encapsulated, which may make it somewhat impervious to infections from local structures. Lastly, the high iodine content of the thyroid may produce an unfavorable environment for bacterial growth. Infection may reach the thyroid via one of several routes, including hematogenous spread from distant sites, such as the urinary tract, or via the lymphatics as a result of local infections such as pharyngitis or mastoiditis. Persistent thyroglossal ducts, internal fistulae near the thyroid, infection of contiguous structures, and even penetrating injuries have been reported as sources of infection. 33 Interestingly, pre-existing thyroid disease, most commonly nodular goiter, has been reported to be present in more than 50% of cases. 2 Immunocompromised individuals may be particularly prone to developing infection. The disease is more common in women, usually between the ages of 20 and 40 years, although it does occur both in children and in the elderly. Clinical Manifestations
Symptoms of acute thyroiditis usually include an abrupt onset of unilateral anterior neck pain, fever, diaphoresis, and other symptoms of bacterial toxicity. The neck pain may radiate to the ear or mandible on the side of the infection. Symptoms of pharyngitis and dysphagia also may be present. Physical examination discloses an exquisitely tender swelling that may be fluctuant. The skin usually is erythematous over the affected area. Laboratory Diagnosis
The white blood cell count is generally elevated with a shift to the left. Patients are typically euthyroid, although transient elevations in serum thyroxine (T4) levels have been reported. It is thought that the elevated T4 concentrations are due to discharge of preformed hormone from the inflamed thyroid gland. I. 10 Hyperthyroidism per se does not occur. The thyroidal radioactive iodine uptake (RAID) is most often normal, although it may be low if inflammation is diffuse. 35 The thyroid scan shows a "cold" defect in the involved lobe. Differential Diagnosis and Treatment
The presentation of acute thyroiditis is dramatic, yet may be mimicked by other painful thyroid disorders, most notably subacute granulomatous thyroiditis or hemorrhage into a thyroid nodule, cyst, or a rapidly enlarging thyroid carcinoma with central necrosis. Subacute granulomatous thyroiditis Table 1. Classification of Thyroiditis Acute thyroiditis Subacute thyroiditis Subacute granulomatous thyroiditis Subacute lymphocytic thyroiditis Chronic thyroiditis Chronic lymphocytic (Hashimoto's) thyroiditis Invasive fibrous (Riedel's) thyroiditis
63
THYROIDITIS
is usually less severe than acute thyroiditis in its clinical presentation, and hemorrhage into a thyroid cyst or neoplasm is not accompanied by fever or other manifestations of bacterial toxicity. However, immunocompromised patients may lack fever. If acute thyroiditis is suspected, a fine-needle aspiration of the lesion should be done. The presence of purulent material, which should be gram-stained and cultured, is confirmatory. Treatment should consist of hospitalization with administration of parenteral antibiotics and, when there is fluctuance, drainage of the lesion. Excision of the affected area is necessary in some cases. A delay in the diagnosis or treatment may result in rupture of an abscess with worsening bacteremia and sepsis. Permanent sequelae of acute thyroiditis are rare. Severe and diffuse inflammation may cause destruction of the entire thyroid, with hypothyroidism the result. Recurrences of acute thyroiditis occur when there is an undiagnosed anatomic defect, such as persistence of a thyroglossal duct or an unrecognized internal fistula. 63 SUBACUTE THYROIDITIS Subacute thyroiditis may be subdivided into subacute granulomatous thyroiditis, which is characteristically painful, and subacute lymphocytic thyroiditis, which is painless. Both of these disorders, although distinct histologically and most likely etiologically, are strikingly similar in terms of clinical thyroid dysfunction and duration of disease and, hence, are included within the same general classification. Subacute Granulomatous (Painful) Thyroiditis This entity, first described by De Quervain 14 in 1904, when he showed granulomatous-type changes and giant cells in thyroid glands of affected individuals, has a number of eponyms, including granulomatous thyroiditis, subacute granulomatous thyroiditis, pseudogranulomatous thyroiditis, subacute thyroiditis, subacute painful thyroiditis, and, of course, De Quervain's thyroiditis. For the purposes of this discussion, the designation SAT will be used. This disorder is relatively common and may account for approximately 5% of all visits to physicians for thyroid abnormalities. 27 It is the commonest cause of the "painful thyroid," and heads the list of the differential diagnosis of anterior neck pain (Table 2). Etiology. Subacute granulomatous thyroiditis most likely is viral in origin. Evidence for a viral etiology includes the clinical observations that it frequently follows an antecedent respiratory infection, is associated with a viral prodrome, is self-limiting, and tends to have a seasonal distribution (summer and fall). Also, it has been associated with outbreaks of mumps, and the mumps virus has been cultured from the thyroid glands of affected individuals. 19 It has also been associated with other viral illnesses, including adenovirus, coxsackie, influenza, and infectious mononucleosis, and viral antibody titers in convalescent sera of patients with SAT have been demonstrated against a number of viruses, including the mumps virus, ECHO virus, adenovirus, and enteroviruses. 71
64
PETER
A. SINGER
Table 2. Differential Diagnosis of the Painful Anterior Neck Mass* Subacute granulomatous thyroiditis Acute hemorrhage into thyroid cyst, or adenomatoid nodule Acute hemorrhage into thyroid carcinoma Acute suppurative thyroiditis Rapidly enlarging thyroid carcinoma Painful Hashimoto's thyroiditis Infected thyroglossal duct cyst Infected branchial cleft cyst Cellulitis of anterior neck *Of all of the conditions in this table, subacute granulomatous thyroiditis and hemorrhage into a cyst or adenoma probably account for more than 90% of cases.
Recently, autoimmune abnormalities associated with SAT have been described. Antibodies directed against the TSH receptor have been demonstrated. 76 Also, sensitization of T lymphocytes against thyroid antigen have been shown, suggesting that cell-mediated immunity may play a role in the development of SAT. 75 It seems likely, however, that these phenomena are the result of antigen released during inflammation, rather than being related to the development of SAT per se. There appears to be evidence for a genetic predisposition to the development of SAT. An association between SAT and HLA-Bw 35 has been reported in approximately two thirds of both Caucasians and Chinese patientsY We have seen three siblings who developed SAT within a 2-year period of time, all of whom were positive for HLA-Bw 35. 55 Most likely, HLA-Bw 35 renders individuals genetically susceptible to the inciting agent, probably a virus, for the development of SAT. Very recently, an epidemic of what has been termed atypical subacute thyroiditis was described in 12 patients in a town of approximately 28,000 inhabitants in the Netherlands. The affected individuals had many clinical similarities to SAT, yet only one was positive for the HLA-Bw 35 phenotype (significantly less than expected), whereas 5 of 11 individuals tested were positive for HLA-BI5/62, a significantly greater than expected frequency. 13 This newly described disorder may represent a subtype of SAT, with a different genetic background and possibly a different etiology. Thus, rather than being a single disorder, SAT may consist of a group of heterogeneous disorders. Clinical Manifestations. Subacute granulomatous thyroiditis occurs most commonly in women (80% of cases) between the ages of 40 and 50 years. As mentioned previously, there is usually a viral prodrome, consisting of symptoms of myalgias, low-grade fever, lassitude, sore throat, and, not infrequently, dysphagia. Significant anterior neck pain is characteristic; it occurs with a fairly abrupt onset, is usually unilateral, and, in at least one third of the cases, radiates to the ear on the ipsilateral side. Pain may also radiate to the mandible, occiput, or even upper chest. During the course of the disease the pain may migrate to the contralateral side. Symptoms of hypermetabolism such as diaphoresis, tachycardia, palpitations, and weight loss occur where there is coexistent hyperthyroidism. 70 Physical examination typically shows a mildly febrile patient with an exquisitely tender, very hard, ill-defined nodular thyroid lesion. Most often it is difficult to delineate
THYROIDITIS
65
the borders of the lesion because pain and tenderness cause the patient to withdraw from the fingers of the examiner. The swelling is usually unilateral although thickening of the opposite lobe, with less tenderness than the dominant side may be present. If inflammation is significant erythema of the overlying skin may be present. Occasionally, the clinical presentation may be so dramatic as to cause high fever and severe toxic symptoms. In such cases, inflammation and edema may be so pronounced as to produce obstructive symptoms (Fig. 1). Diagnosis. The differential diagnosis of SAT is shown in Table 2. Although not all-inclusive, the list does include the principal disorders to be ruled out. Histologically confirmed SAT without pain has been reported, but such cases are probably uncommon. 51 Usual laboratory findings include a mild normochromic, normocytic anemia, and normal to slightly elevated total white blood cell count. The erythrocyte estimated sedimentation rate is nearly always significantly elevated, usually greater than 50 mmlhour. A normal sedimentation rate virtually excludes the diagnosis of active SAT. Hyperthyroidism occurs in approximately 50% of patients and results from "dumping" of preformed hormone into the circulation. The serum T4 level is disproportionately elevated relative to the serum triiodothyronine (T3), reflecting the intrathyroidal T4 and T3 content. 6 Also, impaired peripheral conversion of T4 to T3 due to the illness itself results in a lower T3 level. 54 In general, the hyperthyroidism is mild or, at most, modest in its severity. The RAW is always suppressed (less than 2% at 24 hours) during active inflammation and results from destruction of the thyroid's iodine-
Figure 1. A 52-year-old man with severe subacute granulomatous thyroiditis with threatened airway obstruction. Note the pronounced retropharyngeal edema (A) and its dramatic resolution following intravenous administration of methylprednisolone (B).
66
PETER
A. SINGER
trapping mechanism rather than from TSH suppression, because even euthyroid patients with SAT have a low RAIU. The RAIU test should be done when SAT is suspected in order to rule out other causes for anterior neck pain and tender swelling. If the RAIU is greater than 5% at 24 hours, SAT is very unlikely. All of the disorders listed in Table 2 (except for the rare case of acute pyogenic thyroiditis) have a normal RAIU. The serum thyroglobulin is significantly elevated in SAT, as it is with many other thyroid disorders.67 Because it is always elevated during active SAT, it may be a useful test in cases in which the diagnosis is not clear. A normal thyroglobulin level in a patient with anterior neck pain virtually excludes the diagnosis of SAT. Treatment and Clinical Course. Salicylates and nonsteroidal antiinflammatory drugs are considered by a number of authors as the "firstline" agents of choice, in order to decrease pain; however, they are rarely effective unless inflammation is mild. Oral glucocorticoids such as prednisone, 20 to 40 mg/day in divided doses, provide dramatic relief of pain and swelling, often within hours of first administration. Unless contraindicated, they are clearly the treatment of choice. The dose can be tapered after a week's administration, and discontinued within 2 to 4 weeks. Pain and swelling recur, often on the contralateral side, in approximately 20% of patients during tapering of glucocorticoids, or shortly after their withdrawal. Prednisone can then be restarted and the tapering process begun anew. When symptoms of hyperthyroidism are significant, beta-adrenergic blocking drugs such as propranolol are useful. The course of SAT typically consists of four phases. 74 The initial acute painful phase is associated with a tender thyroid mass and hyperthyroidism, and generally lasts three to six weeks. A several-week interval of euthyroidism then occurs, followed by a period of hypothyroidism, lasting anywhere from several weeks to a few months, during which thyroxine replacement may be necessary. An asymptomatic recovery phase follows, during which the thyroid is restored to normal function. Not all patients with SAT progress through all four phases of the disorder. Patients may go directly from the painful to the recovery phase, for example, bypassing hypothyroidism. The entire duration of SAT usually is no longer than 4 to 6 months, and persistent abnormalities have been considered to be uncommon, although permanent hypothyroidism has been reported by one author in 5% of patients. 39 That experience has not been shared by others, reports of permanent hypothyroidism being almost anecdotal. In other reports in which permanent hypothyroidism following SAT has occurred, persistent elevation of thyroid antibodies has been observed, suggesting coexistent autoimmune thyroid disease. 59. 64 Very recently, though, in long-term follow-up of patients who had SAT were shown to be particularly sensitive to the inhibitory effects of exogenously administered iodides, suggesting a persistent thyroid abnormality. 52 Thus, in contrast to the long-held notion that SAT is completely self-limiting, continued observation of patients who had SAT may be indicated.
a
Subacute Lymphocytic (Painless) Thyroiditis During the past 12 to 15 years, an entity characterized by transient hyperthyroidism, a suppressed RAIU, and painless goiter has been de-
THYHOIDlTIS
67
scribed. It has been variously termed lymphocytic thyroiditis with spontaneously resolving hyperthyroidism, subacute lymphocytic thyroiditis, painless lymphocytic thyroiditis, painless thyroiditis, or silent thyroiditis. 25, 43, 48, 79 The latter term was coined because of the absence of goiter in 50% of the cases reported by Woolp9 For the purposes of this discussion, the term painless thyroiditis (PT) will be used. Painless thyroiditis exists in two forms, either occurring sporadically or in the postpartum period. Nikolai 43 reported several years ago that approximately one third of his patients presenting with hyperthyroidism had PT. This strikingly high prevalence has not been noted by others, and it appears that the overall prevalence of PT as a cause of thyrotoxicosis may vary between 5% and 20%, although the latter figure seems high. 38 A geographic variation in the prevalence of PT has been observed, with those areas previously iodine deficient (but more recently exposed to sufficient iodide intake), such as the Great Lakes region, having a greater prevalence of the disorder. 69 Indeed, in the United States, approximately 90% of cases of PT have been reported from the Great Lakes area. The majority of the cases reported from outside the United States have been from Japan and Europe, although this may be more a manifestation of screening and detection, rather than a predilection of the disorder for those areas. An epidemic of PT was reported from southwestern Minnesota and adjacent areas of South Dakota and Iowa between 1984 and 1985. 34 It was later determined, however, that the hyperthyroidism was actually due to ingestion of ground beef prepared from neck trimmings rich in thyroid tissue. In retrospect, one wonders whether or not the very high incidence of PT reported by Nikolai some 10 years ago may not have been partly due to a similar phenomenon of factitial hyperthyroidism. The postpartum type of PT (PPPT) was initially reported by Amino et a14 when he described 14 patients who developed transient postpartum hypothyroidism. Later he showed that 5.5% of 507 women screened 3 months' postpartum had biochemical thyroid abnormalities, with 3.9% having transient hyperthyroidism and 1. 6% being hypothyroid. 5 J annson and co-workers,36 in Sweden, reported thyroid dysfunction in 6.5% of 400 women screened postpartum, and Nikolai46 showed that thyroid dysfunction was present in 27 (11.3%) of238 women screened 6 to 12 weeks' postpartum. By contrast, a study in Bronx, New York, of 212 women screened between 4 and 12 weeks' postpartum, yielded only 4 women (1. 9%) with thyroid dysfunction. 23 Other studies from the East Coast have reported similar results. It appears that a geographic distribution in the prevalence of PPPT occurs, as has been reported with the sporadic type. Etiology and Pathogenesis. Current evidence suggests an autoimmune basis for PT. 73 For example, there is a high prevalence of thyroid microsomal antibodies (AMA) present in sera of patients with the disorder, as well as histologic evidence of lymphocytic infiltration, both being characteristics seen with Hashimoto's thyroiditis. Also, an association between PT and other autoimmune diseases has been reported. Recently, a patient was described with Sjogren's syndrome who simultaneously developed PT and a lupus-type syndrome. 41 Painless thyroiditis has also been reported in association with autoimmune Addison's disease, as well as in patients who
68
PETER
A.
SINGER
have a previous history of other autoimmune thyroid disease, such as Graves' or Hashimoto's. What is unclear is why approximately 50% of patients with sporadic PT lack serologic evidence for thyroid autoantibodies and why there is usually complete resolution of histologic changes following recovery. Perhaps PT has different etiologies, one being autoimmune and the other possibly infectious. The latter hypothesis gains support from the report of a husband and wife, one of whom developed painful subacute granulomatous thyroiditis, and the other, concurrent PT.42 Postpartum PT is almost certainly autoimmune in origin. There is a higher prevalence of positive AMA than is seen with the sporadic type (80% versus 50%), and its onset 6 weeks or so postpartum suggests a rebound of the maternal immune system following its normal suppression during pregnancy.3 Also, PPPT frequently occurs following successive pregnancies and may be associated with other autoimmune thyroid diseases. Moreover, it may be familial. We reported a family of three women, including two sisters who had PPPT 13 years apart, and their mother, who had postpartum hyperthyroidism many years earlier. 58 A positive family history for autoimmune thyroid disease has been reported in 50% of patients with PPPT. 46 A common allele has been found in PT, especially with PPPT, in which there is an increased prevalence of HLA-DR3, DR4, and DR5 in Caucasians. 21 ,37 Thus, a genetic predisposition may be an important determinant in the pathogenesis of this disorder. Clinical Manifestations. Painless thyroiditis is characterized by a relatively abrupt onset of symptoms of hyperthyroidism, such as tachycardia, palpitations, heat intolerance, nervousness, and weight loss. Physical findings usually show a small, modestly firm, nontender goiter. As mentioned earlier, goiter may be absent in up to 50% of patients with sporadic PT. Patients with PPPT may present either with symptoms and biochemical findings of hyper- or hypothyroidism. Hypothyroidism may be diagnosed as the initial finding in some patients with PPPT in whom the hyperthyroid phase has been overlooked. Sporadic PT has a predilection for women (80% of cases) between the ages of 30 and 40 years. Laboratory Diagnosis. Serum T4 and T3 levels are increased (except with PPPT with hypothyroidism), and, as with SAT, there is a disproportionate elevation of T4 relative to T3 due to follicular disruption and release of preformed hormone into the circulation. Thyroid autoantibodies, especially the AMA, as mentioned, are frequently positive, In contrast to SAT, the estimated sedimentation rate is either normal or mildly elevated, The RAID is suppressed, and unless there is a contraindication to performing the test, it should be done in order to rule out the possibility of Graves' disease. It must be emphasized that it is essential to differentiate between Graves' and PT, because the former disorder requires specific therapy, whereas the latter does not. If infiltrative exophthalmos is absent in the patient with Graves' disease, the physician may not be able to differentiate between Graves' disease and PT on clinical grounds. Table 3 lists clinical and laboratory features that help distinguish Graves' disease from PT. Treatment and Clinical Course. Treatment of PT is directed towards relief of the symptoms of hyperthyroidism, by using beta-adrenergic block-
69
THYROIDITIS
Table 3. Differentiation Between Subacute Painless Thyroiditis and Graves' Disease CLINICAL FEATURE
PAINLESS THYROIDITIS
Onset Severity of symptoms (usual) Duration of symptoms Goiter
Abrupt Mild to moderate
