Virtually any bacterium can infect the thyroid. Streptococcus, staphylococcus, pneumococcus, salmonella (17-19), bacteroides, t. pallidum, pasteurella spp (20), multocida (21) and m. tuberculosis (22-25) have all been described.) The subject has been extensively reviewed (13,26,27). In addition, certain fungi, including coccidioides immitis, aspergillus, actinomycosis (28, 29, 30), candida albicans, nocardia (31), actinobacter baumanii (32) and cryptococcus (33) have also been associated with thyroiditis. In the latter cases, the hosts have often been immuno-compromised, either due to malignancy or to AIDS (34, 35). Rarely acute suppurative thyroiditis is due to thyroid abscess with deep neck infection. (35) Malignancy may also be associated with thyroid abscess due to a fistulous connection (37) and a thyroid abscess due to clostridium septicum is almost always associated with carcinoma of the colon (38). Metastatic breast cancer has been described as presenting clinically with acute thyroiditis (39). Recently, the role of diagnostic fine needle thyroid aspiration has been emphasised, firstly as a factor in the cause of acute suppurative thyroiditis with associated thyrotoxicosis in a patient with atopic dermatitis (40) and also being causative in a case of secondary infection with necrosis in a patient with papillary thyroid carcinoma (41) and an intrathyroid abscess in a multinodular goiter which grew E. coli (42) care should be taken when performing FNAC in patients who may be susceptible to tracking of infection into the thyroid.

Most commonly, however, especially in children, infection of the thyroid gland is a result of direct extension from an internal fistula from the pyriform sinus (4-6, 27, 43, 44). This tract is thought to represent the course of migration of the ultimo branchial body from the site of its embryonic origin in the fifth pharyngeal pouch (7). Careful histopathological studies of these fistulae have demonstrated that they are lined by squamous columnar or ciliated epithelium and occasionally form branches in the thyroid lobe (4, 6). In addition, occasional cells positive for calcitonin have been found in the fistulae and increased numbers of C-cells were noted in the thyroid lobe at the point of termination of the tract. The predominance of acute thyroiditis in the left lobe of the thyroid gland, particularly in infants and children, is explained by the fact that the right ultimo branchial body is often atrophic and does not develop in the human (as well as in other species such as reptiles). The reason for this phenomenon is not known. Acute thyroiditis may involve a normal gland, or arise in a multinodular goiter. At times, no source of infection can be demonstrated. The possibility of a persistent thyroglossal duct should be considered for patients with midline infections (45).

Pathological examination reveals characteristic changes of acute inflammation. With bacterial infections, heavy polymorphonuclear and lymphocytic cellular infiltrate is found in the initial phase, often with necrosis and abscess formation. Fibrosis is prominent as healing occurs. In material obtained by fine needle aspiration, the infectious agent may be seen on a gram, acid fast or appropriate fungal stains. Fungal thyroiditis was clearly demonstrated in a patient with candida albicans (5).

Acute thyroiditis is quite rare with no more than one to two patients per year observed in a large tertiary care hospital. As the number of immunocompromised patients increase, cases of suppurative thyroiditis are increasing. It may be somewhat more common in the pediatric age group, although it is still quite unusual. The proper treatment of an acute thyroiditis in children generally requires the surgical removal of the fistula (4-6). This almost always leads to a permanent cure of the condition.

The dominant clinical symptom is pain in the region of the thyroid gland which may subsequently enlarge and become hot and tender. The patient is unable to extend the neck and often sits with the neck flexed in order to avoid pressure on the thyroid gland. Swallowing is painful. There are usually signs of infection in structures adjacent to the thyroid, local lymphadenopathy as well as temperature elevation and, if bacteremia occurs, chills. Gas formation with suppurative thyroiditis has been noted (46). Symptoms are generally more obvious in children than in adults. Adults may present with a vague slightly painful mass in the thyroid region without fever, which may raise the possibility of a malignancy. Suppurative thyroiditis may even spread to the produce necrotizing mediastinitis and pericarditis in the absence of a pyriform sinus fistula (36). It may occur more commonly in the fall and winter following upper respiratory tract infections.

In general, there are no signs or symptoms of hyper- or hypothyroidism. However, exceptions to both have been reported particularly if the thyroiditis is generalized, such as occurs with fungal processes (33) or mycobacterial infections. At times, even in patients with bacterial thyroiditis, destruction of the thyroid gland is sufficient to release thyroid hormone in amounts sufficient to cause symptomatic hyperthyroidism (21, 22). The adult thyroid gland contains approximately 600 ug of T4/g (47). Given a typical 15 to 20 g gland, sufficient hormone can be released to cause transient thyrotoxicosis.

Pain in the anterior neck will usually lead to a consideration of the possibility of thyroiditis. Since the major differential diagnosis will lie between acute suppurative thyroiditis and subacute thyroiditis, it is critical to compare the history, physical, and particularly laboratory data in these two conditions (see Table 1). In general, the patient with acute thyroiditis appears septic, has greater and more localized pain in the thyroid gland, may have an associated upper respiratory infection, has lymphadenopathy and may be immuno-compromised. Localization of the tenderness to the left lobe should suggest the possibility of an infection as should any erythema or apparent abscess formation. The presence of an elevated white blood count with a shift to the left would argue for infection, however, elevations in sedimentation rate are common in both acute and subacute thyroiditis. As mentioned, patients with bacterial thyroiditis are not hyperthyroid, but exceptions do occur. This is more common, but, by no means universal in patients with subacute thyroiditis.

Depending on the age and clinical circumstances, one may wish to proceed with invasive or non-invasive studies. The most discriminating tests for recognizing a difference between the two conditions are either an iodine uptake or scan showing a very low value in subacute thyroiditis with a normal value found in the patient with localized bacterial thyroiditis (27). If a thyroid ultrasound shows a localized process, a needle aspiration can be performed. This will be definitive. A CT scan may be useful in identifying the location of the abscess, but this is required only in unusual situations (48). Gallium scans are sometimes performed in the course of an evaluation for a fever of unknown origin. Localization of gallium to the thyroid gland would be a very useful finding confirming thyroid inflammation as the source of the problem. If an infectious process is identified, particularly of the left lobe of a younger individual, then a barium swallow should be performed with attention to the possibility of a fistulous tract located on the left side between the pyriform sinus and the thyroid gland. During a CT scan procedure the patient can be asked to blow into a syringe which may help to identify a piriform sinus fistula (49). In general bacterial infections tend to be localized whereas the post viral subacute thyroiditis is more often generalized, although intermediate conditions can certainly exist.

Occasionally, pain from an infectious process elsewhere in the neck will present as anterior neck tenderness. For example, a retropharyngeal abscess may present with typical symptoms of acute thyroiditis. The thyroid gland, however, will have a normal uptake, be normal on scan, and only on CT scan will the retropharyngeal abscess be recognized. The tendency for the pain of thyroid inflammation to be referred to the throat or ears should be kept in mind, although recognition of the anatomic source of the problem is usually not such a difficult issue in patients with acute thyroiditis due to their localized symptoms. While patients with tuberculosis or parasitic infections tend to have a more indolent course, these infections can present with acute symptoms and this possibility should be considered if the epidemiology is consistent. For example, thyroidal echinococcosis occurs in countries in which this parasite is endemic (50). Trypanosomiasis of the thyroid has also been reported (27).

The diagnosis and choice of antibiotic therapy are often aided by microscopic examination and appropriate staining of a fine needle aspirate. The procedure is best done under ultrasound guidance so that the source of the specimen is identified. It may also serve as a mechanism for drainage of an abscess and can be repeated to facilitate healing. Some abscesses will require surgical exploration and drainage. The choice of therapy will also depend on the immune status of the patient. Systemic antibiotics are required for severe infections. Candida albicans thyroiditis can be treated with amphotericin B and 5 fluconazol 100 mg daily.

In some patients with thyroiditis, the destruction may be sufficiently severe that hypothyroidism results. Thus, patients with a particularly diffuse thyroiditis should have follow-up thyroid function studies performed to determine that this has not occurred. Surgical removal of a fistula or branchial pouch sinus (51) is required to prevent recurrence when this is present.

A cause can rarely be established. A tendency for the disease to follow upper respiratory tract infections or sore throats has suggested a viral infection. Earlier suggestions that the disease may represent a bacterial infection have been disproven. An autoimmune reaction is also unlikely. The development during the illness of cell-mediated immunity against various thyroid cell particulate fractions or crude antigens appears to be related to the release of these materials during tissue destruction (54, 55).

Although the search for a viral cause has usually been unrewarding, a few cases seem to be due to the virus that causes mumps (52, 56). The disease has occurred in epidemic form. High titers of mumps antibodies have been found in some patients with subacute thyroiditis, and occasionally parotitis or orchitis is associated with thyroiditis. The mumps virus has been cultured directly from thyroid tissue involved by subacute thyroiditis. Although the mumps virus seems to be one discrete etiologic factor, the disease has been reported in association with other viral conditions including measles, influenza, adenovirus infection, infectious mononucleosis (57), myocarditis, cat scratch fever, and coxsackie virus (Figure 1) (58). Two comprehensive studies (59, 60) failed to find evidence of enteroviruses in 27 patients and Epstein-Barr virus or cytomegalo virus in 10 patients, respectively but a single case report has implicated EB virus in a case of subacute thyroiditis with typical clinical features (61).

Numerous attempts to culture viruses from cases not associated with mumps have failed. Virus-like particles have been demonstrated in the follicular epithelium of a single patient suffering form subacute thyroiditis (58). However, viral antibody titers to common respiratory tract viruses are often elevated in these patients. Since the titers fall promptly, and multiple viral antibodies may appear in the same patient, the elevation probably is an anamnestic response to the inflammatory condition. (Figure 1, above) Histo-compatibility studies show that 72% of patients with subacute thyroiditis manifest HLA-Bw35 (63). Familial occurrence of subacute thyroiditis associated with HLA-B35 has been reported (64, 65, 66, 67). Thus, the susceptibility to subacute thyroiditis is genetically influenced and it has also been suggested that subacute thyroiditis might occur by transmission of viral infection in genetically predisposed individuals (61). A reported association between subacute thyroiditis and acute febrile neutrophilic dermatosis (Sweet's syndrome) (68) may imply a common role for cytokines in both these conditions.

New treatments, particularly those in which there is manipulation of the immune system, have led to the development of subacute thyroiditis (69). Infusion of interleukin 2 caused hyperthyroxinemia with a low radioiodine uptake in six patients who received this in combination with TNF  or  interferon (70). The patients proceeded to pass through the pattern of hyperthyroidism and transient hypothyroidism, with a re-establishment of normal thyroid function typical of the patient with autoimmune painless thyroiditis. However, none of the patients had detectable antithyroid antibodies. This condition is thus intermediate between subacute lymphocytic (painless) thyroiditis (Chapter 13) and subacute thyroiditis which is typically painful. A patient who developed subacute thyroiditis after influenza vacccination (71) suggests immune alteration as a contributary factor. In patients with chronic hepatitis C studies following interferon therapy (IFN) showed that a minority (15%) developed a destructive thyroiditis while others had a mild elevation of TSH (70). IFN can exacerbate previous thyroid autoimmunity and cause destructive thyroidal changes de novo. Subacute thyroiditis has recently been noted in patients treated with combination therapy of IFN plus ribavirin for this disease (72, 73), as well as during treatment of hepatitis B with Interferon (74). Peginterferon alpha-2a has also been reported to cause subacute thyroiditis (75) and the condition is seen in Takayasu's arteritis suggesting an immune abnormality (76). On the other hand, subacute thyroiditis has been reported in patients receiving long term immunosuppressive therapy suggesting a minimal role for autoimmunity in the condition (77, 78). Other reports of subacute thyroiditis for example with renal cell carcinoma (79) or after gastric bypass (80) do not contribute to its etiology.

The thyroid gland may be adherent to its capsule or to the strap muscles but it can usually be dissected free, a feature distinguishing subacute thyroiditis from Riedel's thyroiditis. The involved tissue appears yellowish or white and is more firm than normal.

The gland is enlarged, and the enlargement is usually bilateral and uniform, but it may be asymmetrical, with predominant involvement of one lobe. Although the lesion may extend to the capsular surface, it can also be confined to the thyroid parenchyma and merely be palpable as a suspiciously hard area.

The macroscopic pathologic picture of subacute thyroiditis frequently bears a striking resemblance to cancer. The lesion is firm to dense in consistency, pale white in color, and has poorly defined margins that encroach irregularly on the adjacent normal thyroid. Microscopically, one sees a mixture of subacute, chronic, and granulomatous inflammatory changes associated with zones of parenchymal destruction and scar tissue. Early infiltration with polymorphonuclear leukocytes is replaced by lymphocytes and macrophages. The normal follicles may be largely replaced by an inflammatory reaction, but a few small follicles containing colloid remain (Fig. 2, below). Three dimensional cytomorphological analysis of fine needle aspiration biopsy samples from patients with subacute thyroiditis examined with scanning and transmission electron microscopy has shown a loss of a uniform, honeycomb cellular arrangement; variation in size and decrease or shortening of microvilli in follicular cells together with the appearance of round or ovoid giant cells (81). The most distinctive feature is the granuloma, consisting of giant cells clustered about foci of degenerating thyroid follicles (Fig. 2). The early literature contains accounts of tuberculous thyroiditis, a diagnosis largely based on the granulomatous tissue reaction, from which the descriptive but unfortunate term pseudotuberculous thyroiditis arose (82). Data on the mechanism of inflammation and the pathogenesis of subacute thyroiditis at the cellular level are sparse. However a study of apoptosis and expression of Bcl 1-2 family proteins in 11 patients with SAT has suggested that apoptotic mechanisms may be involved in the development of SAT (83). A detailed immunohistochemical study of growth factors in SAT (84) has shown that growth factor rich monocytes/macrophages (containing VEGF, beta FGF, PDGF and TGF beta 1) mediate the granulomatous stage. EGF is important in the regenerative stage as it has mitogenic effects on the thyrocyte. VEGF and betaFGF contribute to the angiogenesis at both these stages of the disease. Analysis of factors influencing the severity of the acute phase response during the course of SAT, it was found that serum interleukin -1 receptor antagonist may have a significant anti-inflammatory role in the condition (85); also, a decrease in TNF alpha results in earlier resolution of experimentally induced granulomatous thyroiditis (86)

Mast cells play an important part in the repair process of thyroid tissue affected by the disease via production of growth factors and biomolecules which modulate thyroid folliculogenesis and angiogenesis (69).

Subacute thyroiditis is encountered infrequently, but each year a handful of cases will be identified in a busy thyroid clinic. Woolner et al (82) collected 162 cases diagnosed on clinical grounds at the Mayo Clinic over a 5-year period; during the same time, 1,250 patients with Graves' disease were seen. Thus, the disease had approximately one-eighth the incidence of Graves' disease in this clinic population. During an evaluation of subtypes of hypothyroidism over a 4 year period in Denmark an incidence of subacute thyroiditiis of 1.8% was found in a cohort of 685 patients with hypothyroidism (88, 89). Although the disease has been described at all ages, it is rare in children (89, 90). Female patients outnumbered male patients in a ratio of 1.9,-6:1, with a preponderance of cases in the third to fifth decades (26, 52, 82, 91, 92) and it has been noted as a rare cause of hyperthyroidism in pregnancy (93). In 160 patients studied during 37 years at the Mayo Clinic an age and sex adjusted incidence of 4.9 cases/100,000/yr was noted (91).

Characteristically, the patient has severe pain and extreme tenderness in the thyroid region. A small minority of patients have been noted to present with painless or minimally painful subacute thyroiditis following viral symptomatology (94). These may be regarded as atypical subacute thyroiditis patients but their natural history of the disease is not known. When the symptom is difficulty in swallowing, the disorder may be initially mistaken for pharyngitis. Transient vocal cord paresis may occur (95) At times, the pain begins in one pole and then spreads rapidly to involve the rest of the gland ("creeping thyroiditis"). It may radiate to the jaw or the ears. Malaise, fatigue, myalgia and arthralgia are common. A mild to moderate fever is expected, and at times a high, swinging fever causes temperatures to rise daily above 104°F (40.0°C). The disease may reach its peak within 3 to 4 days and subside and disappear within a week, but more typically, a gradual onset extends over 1 to 2 weeks and continues with a fluctuating intensity for 3 to 6 weeks. Several recurrences of diminishing intensity extending over many months may be the unhappy fate of the patient.

The thyroid gland is typically enlarged two or three times the normal size or larger and is tender to palpation, sometimes exquisitely so. It is smooth and firm. Occasionally the condition may be confined to one lobe (96, 97).

Approximately one-half of the patients present during the first weeks of the illness, with symptoms of thyrotoxicosis, including nervousness, heat intolerance, palpitations, - even ventricular tachycardia (98), tremulousness, and increased sweating. These symptoms are caused by excessive release of thyroid hormone from the thyroid gland during the acute phase of the inflammatory process. At least 2 cases of thyroid storm due to subacute thyroiditis have been described (99, 100). As the disease process subsides, transient hypothyroidism occurs in about one-quarter of the patients. Ultimately thyroid function returns to normal and permanent hypothyroidism occurs in less than 10 percent of the cases (26, 27, 52). Occasionally the condition may be painless and present as fever of unknown origin (101).

Table 2 provides a comparison between the clinical and laboratory findings of patients with subacute and acute thyroiditis (27, 102-107). Laboratory examination may disclose a moderate leukocytosis. A curious and striking elevation of the erythrocyte sedimentation rate, at times above 100 mm/hr, or serum C-reactive protein (108) is a useful diagnostic clue. Short of tissue diagnosis, most helpful is the characteristic combination of elevated erythrocyte sedimentation rate, high serum T4, T3, and TG concentrations in the presence of low thyroidal RAIU, and an absent or low titer of circulating TG antibodies. While the estimation of thyrotropin receptor antibodies (TRAb) in a thyrotoxic patient may be clinically useful in Graves' disease there have been reports of positive TRAb in patients with subacute thyroiditis although the frequency of positivity is low (109-112). Mild anemia and hyperglobulinemia may be present. The value of a 99m-Tc-pertechnetate scintigraphy as a marker of disease actviity and severity has been noted (113). Further imaging studies have shown diffuse increased uptake of Tc-99m sestamibi in the thyroid region of patients in the acute phase (thyrotoxic) of subacute thyroiditis suggesting increased perfusion; at the same time Tc-99m pertechnetate uptake was markedly reduced. It is possible that Tc-99m sestamibi uptake in the early phase may reflect the inflammatory process associated with the disease (114). In the same patients color Doppler ultrasonography showed an absence of vascularization in the acute phase and its use in the differential diagnosis of unclear cases has been emphasised (115, 116) Subacute thyroiditis with thyrotoxicosis may also be distinguished from Graves' hyperthyroidism by using T1- and T2- diffusion weighted magnetic resonance imaging (117) although this investigation may not be available or even desirable in all centres. Fine needle aspiration biopsy is often diagnostic although patients are often alarmed at the prospect of this test due to the pain in the thyroid. However FNA may be helpful in ruling out malignancy (116).

A.S., a 46-year old woman, noted the onset of a tender, slowly enlarging swelling in the low anterior neck in December. There was no antecedent infection or virus-like syndrome. She was aware of associated increased nervousness, mild tremor, increased sweating, and anorexia, without alteration in weight. In January, increasing pain that radiated to the back of her head and orbits necessitated medical consultation. A family history of thyroid disease was not elicited.

On physical examination she appeared to be in pain, BP was 155/80, and pulse 112/min and regular. Clinically, she appeared to be euthyroid. The thyroid gland was estimated to be 40 grams in weight and was tender, firm, and slightly irregular. The remainder of the examination was non-contributory.

Laboratory data included an erythrocyte sedimentation rate of 58 mm/min, FT4I of 16.1 m g/dl (normal, 3.6 to 9.3 m g/dl), TT4 level of 14.9 m g/dl (normal 4.2 to 9.4), and a Tg antibody titer of 1/40.

Figure 3 (below) shows a sequence of 125I and 241Am scans obtained throughout the course of her illness. On presentation, there was no 125I uptake seen on thyroid scintiscan, with an RAIU of 1 percent. At the same time, the 241Am scan showed virtually no stable iodine in the thyroid. A 241Am scan repeated in March showed continuing low 127I levels in the thyroid, at which time the serum TT4 level was 1.7 m g/dl and the FT4I was 0.8 m g/dl. The 241Am scans on these two dates demonstrate mainly background radiation scatter. With the resolution of her clinical syndrome over the next few months, the results of the thyroid scans were seen to return to normal. The result of the 125I scintiscan in June was completely normal, with an RAIU of 20 percent, at which time her TT4 level and FT4I had returned to the normal range. The 241Am scan 3 months later showed some reaccumulation of 127I, but the stable iodine store was still reduced. The last 241Am scan 14 months after onset demonstrated total repletion of her thyroidal 127I stores. At this time, the gland was normal in size (weight 20 g) and consistency.

If subacute thyroiditis affects only one part of the thyroid gland, the serum T4 concentration and thyroidal RAIU may be entirely normal. A thyroid scan will demonstrate failure of the involved areas of the gland to concentrate iodide. When the thyroid is diffusely involved, which is more typical, a dramatic disturbance in iodine metabolism is observed.

During the initial phase of the disease, the RAIU is depressed or entirely absent and the concentrations of serum T4 and T3 are often elevated. Due to the concomitant release of nonhydrolyzed iodoproteins from the inflamed tissue, the serum T3 level is also high. During this phase the serum TSH level is low, and the TSH response to TRH is suppressed (103) due to the high levels of circulating thyroid hormone. Iodide that is collected and metabolized by the gland is rapidly secreted because of the decreased ability to store colloid (105). At this time, the involved tissue shows decreased but not necessarily depleted stores of iodine, as determined by x-ray fluorescence (102, 105). Administration of TSH usually fails to produce a normal increase in RAIU. Evidently, thyroid cell damage reduces the ability of the gland to respond to TSH. As the process subsides, the serum T4, T3, and TG levels decline, but the serum TSH level remains suppressed. The normal concentrations of SHBG in the hyperthyroid phase probably reflect the short duration of exposure to increased thyroid hormone (120).

Later, during the recovery phase, the RAIU becomes elevated with the resumption of the ability of the thyroid gland to concentrate iodide. The serum T4 concentration may fall below normal; the TSH level may become elevated. Usually after several weeks or months, all the parameters of thyroid function return to normal (Fig.4). Restoration of iodine stores appears to be much slower and may take more than a year after the complete clinical remission (102, 105). In about 2% of patients subacute thyroiditis may trigger auto-reactive B cells to produce TSH receptor antibodies, resulting in TSH antibody associated thyroid dysfunction in some patients (112).

Diagnosis is usually not difficult. With an acutely enlarged, tender thyroid, an RAIU near zero, and elevated serum T4 and Tg concentrations and ESR, the diagnosis is almost certain. Circulating thyroid autoantibodies are absent or the titer is low. Among the diagnostic alternatives, infectious thyroiditis must be considered and the possibility of invading bacteria excluded (see Table 2). The thyroid in Hashimoto's thyroiditis may be slightly tender and painful, but this event is rare, and the typical disturbances in iodine metabolism and erythrocyte sedimentation rate are not found. Hemorrhage into a cyst in a nodular thyroid gland may be confused with subacute thyroiditis although the condition may be associated with an autonomously functioning nodule (119). Hemorrhage is usually more sudden and transient, a fluctuant mass may be found in the involved region, and the erythrocyte sedimentation rate is normal. Occasionally, subacute thyroiditis mimics hyperthyroidism in a patient whose RAIU is suppressed by iodine. This event occurs particularly in transient thyrotoxicosis induced by iodine (106). The sudden onset of subacute thyroiditis, the presence of toxic symptoms without the typical signs of long-term hyperthyroidism, the tender gland, the constitutional symptoms, and the high erythrocyte sedimentation rate are helpful in making the differentiation. In some instances, measurement of antibodies and thyroid-stimulating immunoglobulins, and observation of the course of the illness may be required to confirm the diagnosis.

The single disease entity that is probably most difficult to differentiate from subacute thyroiditis is a variant of lymphocytic thyroiditis (107). This condition is unrelated to iodine ingestion and most likely is a variant of autoimmune thyroiditis. The patient presents with goiter, mild thyrotoxicosis, and a low RAIU. The course of the disease is indistinguishable from that of subacute thyroiditis and proceeds from a thyrotoxic phase through a hypothyroid phase to spontaneous remission with normalization of thyroid function. The goiter is typically painless, and there are no associated systemic symptoms. This condition has been formerly confused with subacute (de Quervain's) thyroiditis, whence come the misleading terms silent, painless, or atypical subacute thyroiditis. The most helpful distinguishing features, short of histologic examination of biopsy material, are the absence of pain and a normal erythrocyte sedimentation rate. (See also Chapter 13.) Localized subacute thyroiditis, with induration, mild tenderness, and depressed iodine binding visualized on scan, can be very suggestive of thyroid cancer. Usually the degree of pain and tenderness, elevated erythrocyte sedimentation rate and leukocytosis, and remission or spread to other parts of the gland make clinical differentiation possible. Gray-scale and color Doppler sonography may be helpful in this situation (115, 121) or even magnetic resonance imaging (117) but a fine needle aspiration is required for a definitive differentation between these two processes (119).

In some patients, no treatment is required. However, for many, some form of analgesic therapy is required to treat the symptoms of the disease until it resolves. At times, this relief of symptoms can be achieved with non-steroidal anti-inflammatory agents or aspirin. However, if this fails, as it often does when the symptoms are severe, prednisone administration should be employed (26, 52). Large doses promptly relieve the symptoms through non-specific anti-inflammatory effects. Treatment is generally begun with a single daily dose of 40 mg prednisone. After one week of this treatment, the dosage is tapered over a period of 6 weeks or so. The relief of the tenderness in the neck is so dramatic as to be virtually diagnostic of the problem as being due to subacute thyroiditis. As the dose is tapered, most patients have no recrudescence of symptoms, but occasionally this does occur and the dose must be increased again. Alternatively oral cholecystographic agents (such as sodium ipodate or sodium iopanoate) may be used safely and effectively for the management of hyperthyroidism in these patients even when they have relapsed after corticosteroid therapy (122). The recurrent rate of subacute thyroiditis after cessation of prednisolone therapy is about 20% but no difference has been found in routine laboratory data between recurrent and non-recurrent groups of patients (123). Levothyroxine administration may be useful in situations where the patient is not already hyperthyroid due to the release of thyroidal contents into the circulation. It is thought that TSH suppression will reduce the thyroid stimulation which might otherwise prolong the inflammatory process. It is also necessary to administer thyroid hormones, at least transiently, if the patient enters a phase of hypothyroidism subsequent to the acute inflammation. TSH-suppressive doses of levothyroxine should only be administered when there is evidence that exacerbation of the condition occurs when TSH is present. Otherwise, the return of thyroid function to normal, which presumably is facilitated by TSH, can be prevented or delayed. During the recovery process, there may be a marked but transient increase in the 24 hour radioactive iodine uptake which can reach levels typical of Graves' Disease. This occurs prior to re-establishment of normal thyroid function and should not be confused with hyperthyroidism due to Graves' Disease. Surgical intervention is not the primary treatment for subacute thyroiditis. Experience from the Mayo clinic (124) has shown that if surgery is performed for a clinically indeterminate thyroid nodule resection is safe and with low morbidity.

In 90% or more of patients, there is a complete and spontaneous recovery and a return to normal thyroid function. However, the thyroid glands of patients with subacute thyroiditis may exhibit irregular scarring between islands of residual functioning parenchyma, although the patient has no symptoms. Up to 10% of the patients may become hypothyroid and require permanent replacement with levothyroxine. However, permanent hypothyroidism is significantly less common in SAT compared to the outcome noted in amiodarone induced thyrotoxicosis type 2 (the destructive thyroiditis) (125). It is of interest that elevated levels of serum Tg may persist well over a year after the initial diagnosis, indicating that disordered follicular architecture and/or low grade inflammation can persist for a relatively long period (126).

Although there is no specific therapy for Riedel's thyroiditis, several management strategies are available dependent on the clinical features of the disease in the individual patient. Corticosteroid therapy has been found to be effective in some cases (141,152-156), probably those with active inflammation. Initial doses of up to 100mg per day of prednisolone have been used but sustained improvement has been reported with lower doses of 15-60 mg per day (141). There are no controlled trials of steroid therapy in Riedel's and although some patients obtain long term benefit after steroid withdrawal (157) others may relapse (158). The reasons for this variation are unclear but inflammatory activity and duration of disease may be relevant factors. In those who fail to respond to steroid therapy or relapse after withdrawal tamoxifen therapy should be tried. Three reports have described an encouraging response with this agent, admittedly in only a small number of patients (159-161). It is possible that tamoxifen acts in Riedel's by inhibition of fibroblast proliferation through the stimulation of TGF beta. Combination therapy with prednisolone and tamoxifen is also effective (162).

As hypothyroidism is rare in Riedel's, thyroxine therapy is usually not required and is not thought to influence the course of the disease. Surgical intervention may be necessary to release the trachea or perform tracheotomy in the case of severe stridor. Unilateral lobectomy has been performed for unilateral disease (163) and larger resections should be considered in some instances (164). It is recommended that surgical exploration and biopsy are usually required to exclude malignancy which may be suspected at presentation.