Chapter 19. Acute and Subacute Thyroiditis John H. Lazarus, M.D., Professor of Medicine, Llandough Hospital, Cardiff, Wales Revised September 2009 CLASSIFICATION The diagnostic term thyroiditis includes a group of inflammatory or inflammatory-like conditions. The terminology that has been employed is confusing, and no classification is ideal. We prefer the following nomenclature, which takes into account the cause when known. 1. Infectious thyroiditis, also referred to as either acute or chronic, and which in fact may be either, along with the qualifying term suppurative, nonsuppurative, or septic thyroiditis. It includes all forms of infection, other than viral, and is caused by invasion of the thyroid by bacteria, mycobacteria, fungi, protozoa, or flatworms. The disorder is rare. 2. DeQuervain's thyroiditis, commonly known as subacute thyroiditis but also termed subacute nonsuppurative thyroiditis, granulomatous, pseudotuberculous, pseudo-giant cell or giant cell thyroiditis, migratory or creeping thyroiditis, and struma granulomatosa. This condition, most likely of viral origin, lasts for a week to a few months, with a tendency to recur. The eponym was selected because of its uncertain cause. 3. Autoimmune thyroiditis, commonly referred to as chronic, Hashimoto's, or lymphocytic thyroiditis and also known as lymphadenoid goiter and struma lymphomatosa. This indolent disease usually persists for years and in the Western world is the principal cause of non-iatrogenic primary hypothyroidism. Nonspecific focal thyroiditis, characterised by local lymphoid cell infiltration without parenchymal changes, may be a variant of the autoimmune disease. The condition is covered in detail in Chapter 8. Another form of thyroiditis, also believed to be of autoimmune cause, has recently been described. It has been variably referred to as painless, silent, occult, subacute, subacute nonsuppurative, and atypical (silent) subacute thyroiditis, as well as hyperthyroiditis, transient thyrotoxicosis with low thyroidal RAIU and lymphocytic thyroiditis with spontaneously resolving hyperthyroidism. There is no agreement on an inclusive name. The features of this disease entity overlap deQuervain's thyroiditis and Hashimoto's thyroiditis. The clinical course, with the exception of a very high erythrocyte sedimentation rate and pain in the thyroid are indistinguishable from deQuervain's thyroiditis. Yet, histologically, the condition cannot be differentiated from a milder form of Hashimoto's disease. This condition often occurs in the postpartum period and is also termed postpartum thyroiditis. All forms of autoimmune thyroiditis are considered in Chapter 8. 4. Riedel's thyroiditis, another disorder of unknown etiology. Synonyms include Riedel's struma, ligneous thyroiditis and invasive fibrous or chronic sclerosing thyroiditis. This condition is characterised by overgrowth of connective tissue which often extends into neighboring structures. 5. Miscellaneous varieties of thyroid inflammation or infiltration including local manifestations of a generalized disease processes. Among these are sarcoid and amyloid involvement of the thyroid. Radiation and direct trauma to the thyroid gland may also cause thyroiditis. Infectious Thyroiditis The thyroid gland is remarkably resistant to infection. This has been attributed to its high vascularity, the presence of large amounts of iodine in the tissue, the fact that hydrogen peroxide is generated within the gland as a requirement for the synthesis of thyroid hormone and its normal encapsulated position away from external structures. However, in certain situations, particularly in children (1,2-4), a persistent fistula from the pyriform sinus may make the left lobe of the thyroid particularly susceptible to abscess formation (4-10). Recurrent left-sided thyroid abscess has also been reported due to a fourth branchial arch sinus fistula (11). In a review of 526 cases of congenital fourth branchial arch anomalies (11a) it was noted that they presented with acute suppurative thyroiditis in 45% of cases. Acute thyroiditis from a periapical abscess of an inferior molar has been reported (11b). In the immuno-compromised host, fungal infection may occur (12-15). Occasionally, acute bacterial suppurative thyroiditis occurs in children receiving cancer chemotherapy (16). Rarely, infection will occur in a cystic or degenerated nodule. As will be discussed, the principal differential diagnosis is generally between acute, meaning infectious, and subacute, meaning post- viral (non-infectious) inflammation of the gland. Etiology Virtually any bacterium can infect the thyroid (Table 1). Streptococcus, staphylococcus, pneumococcus, salmonella, klebsiella (17-19,19a,b), 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, blastomycosis (28 30,30a), candida albicans, nocardia (31), actinobacter baumanii (32) cryptococcus (33) and pneumocystis (33a) 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,arise in a multinodular goiter (44a) or even Hashimoto’s thyroiditis . 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). Acute thyroiditis has arisen as the intial presentation of juvenile systemic lupus erythematosus (45a) and has also occurred due to septic emboli derived from infective endocarditis (45b). Pathology 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 (5). Clinical Manifestations Although acute thyroiditis is quite rare (about 2 patients per year in a large tertiary care hospital), cases of suppurative thyroiditis are increasing due to the higher incidence of immunocompromised patients. It may be somewhat more common in the pediatric age group, although it is still quite unusual. 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 chest producing 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. Diagnosis 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 Table3). 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. Table 1 Microbiology of Acute Suppurative Thyroiditis Aerobic Staphlococcus aureus Streptococcus pyogenes Streptococcus epidermidis Streptococcus pneumoniae Anaerobic Gram negative bacilli Peptostreptococcus spp. Rare Bacterial Klebsiella spp. Haemophilus influenzae Streptococcus viridans Salmonella spp. Enterobacteriaceae Treponema pallidum Echinococcus spp Mycobacterium tuberculosis Atypical mycobacteria Fungal Aspergillus spp Blastomycosis Candida spp. Coccidioides immitis Pneumocystis jiroveci Parasitic Trypanosoma Depending on the age and clinical circumstances, one may wish to proceed withinvasive 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.A ‘light guided procedure’ to visualize the tract may also help (49a). 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). Treatment 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. The proper treatment of an acute thyroiditis in children generally requires the surgical removal of the fistula (4-6). Combining this with partial thyroidectomy may further decrease the recurrence rate (11a). This almost always leads to a permanent cure of the condition. Prognosis In some patients with thyroiditis, the destruction may be sufficiently severe that hypothyroidism results (44a). 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. Subacute Thyroiditis Subacute thyroiditis, sometimes referred to as granulomatous or De Quervain's thyroiditis, is a spontaneously remitting inflammatory condition of the thyroid gland that may last for weeks to several months (27, 52, 53). It has a tendency to recur. The gland is typically involved as a whole, and thyroidal RAIU is much depressed. Transient hyperthyroxinemia, elevation of the serum Tg concentration and the erythrocyte sedimentation rate and sometimes the WBC during the early acute phase are characteristic if not pathognomic. Etiology 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) and cytomegalo virus has now been reported in an infant(61a). Figure 1. Viral antibody titers in subacute thyroiditis. The graph shows serial viral antibody titers in 32 patients who had 4-fold changes in the dilution of these antibodies. Only the single viral antibody showing the greatest change in dilution during the period of observation is depicted for each patient. The antibody titers are characteristically high at the onset of the illness and gradually diminish. (From Volpe et al,  with permission.) 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).As stated in a recent review (62a) it seems that the thyroid could respond with thyroiditis after invasion by a variety of different viruses but no single agent is likely to be causative. 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 (6467). 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 alsobeen 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. Pathology 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, expression of Bcl 1-2 family proteins in 11 patients with SAT suggests that apoptotic mechanisms may be involved in the development of SAT (83). Growth factor rich monocytes/macrophages (containing VEGF, beta FGF, PDGF and TGF beta 1) are involved in the granulomatous stage (84). 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. Factors influencing the severity of the acute phase response during the course of SAT include serum interleukin -1 receptor antagonist which may have a significant anti-inflammatory role (85; also, a decrease in TNF alpha results in earlier resolution of experimentally induced granulomatous thyroiditis (86). The role of TNF- related apoptosis-inducing ligand (TRAIL) in promoting resolution of this condition is also being investigated (86a). 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). Figure 2. Subacute thyroiditis. Note the discrete granulomas, with giant cells, and the diffuse fibrosis (85 X). Incidence 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). Clinical Manifestations 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). Some clinical and laboratory features recorded in 2 recent series of SAT are shown in Table 2 (101a,101b). Liver function test abnormalities are found in half the patients and return to normal in a few months (101c). TABLE 2. CLINICAL FEATURES OF SUBACUTE THYROIDITIS Feature Japan Israel Number 852 56 Females(%) 87 70 Season summer-autumn no effect Recurrence 1.60% 9.00% -- Temp >380 28.00% -- Thyrotox symptoms 60.00% -- Hypothyroid phase 55.00% -- Labs-peak levels 1 week -- ATA 25.00% US: Bilat hypoechogenicity 50.00% 70.00% -- Nodules 70.00% -- 77 Disease duration (days) ATA: Antithyroid antibodies. US: Thyroid ultrasound. --: no data Data derived from refs 101a&b. Diagnosis Table 3 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 may obscure the coexistence of papillary carcinoma in cases presenting with ultrasonographically diffuse hypoechoic areas (116a). 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 centers. 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). Table 3. Features Useful in Differentiating Acute Suppurative Thyroiditis and Subacute Thyroiditis Characteristic Acute Subacute Thyroiditis Thyroiditis History Preceding upper respiratory 88% 17% infection Fever 100% 54% Characteristic Acute Subacute Thyroiditis Thyroiditis Symptoms of thyrotoxicosis Uncommon 47% Sore throat 90% 36% Physical Painful thyroid swelling 100% 77% Examinati on of the thyroid Left side affected 85% not specific Migrating thyroid Possible 27% tenderness Erythema of overlying skin 83% not usually Laboratory Elevated white blood cell 57% 25-50% count Elevated erythrocyte 100% 85% sedimentation rate (>30mm/hr) Abnormal thyroid hormone 5-10% 60% levels(elevated or depressed) Alkaline phosphatase, Rare common transaminases increased Characteristic Acute Subacute Thyroiditis Thyroiditis Needle Purulent, bacteria or fungi ~100% 0 Aspiration present Lymphocytes, macrophages, 0 ~100% some polys, giant cells 123I uptake low Uncommon ~100% Radiologic Abnormal thyroid scan 92% — al Thyroid scan or ultrasound 75% — helpful in diagnosis Gallium scan positive ~100% ~100% Barium swallow showing Common 0 fistula CT scan useful Rarely not indicated Clinical Clinical response to Transient 100% Course glucocorticoid treatment Incision and drainage 85% No required Recurrence following 16% No operative drainage Characteristic Acute Subacute Thyroiditis Thyroiditis Pyriform sinus fistula 96% No discovered Modified from Szabo and Allen (27), see also Shabb & Solti (118) Subacute Thyroiditis 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 125 I and Am scans obtained 241 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 mg/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. Figure 3. Serial 125 I scintiscans and 241 Am fluorescent scans in a patient during the course of subacute thyroiditis. The first two fluorescent scans, done at a high sensitivity setting without background subtraction, have much neck "background" but demonstrate virtually no I in the thyroid. (From Rapoport et al, 127  with permission.) 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). Figure 4. Thyroid function in a patient during the course of deQuervain's (subacute) thyroiditis. During the thyrotoxic phase (days 10 to 20), the serum TG concentration was greatly elevated, the FTI was high, and TSH was suppressed; the erythrocyte sedimentation rate was 86 mm/hr, and the thyroidal RAIU was 2 percent. The TG level and FTI declined in parallel. During the phase of hypothyroidism (days 30 to 63), when the FTI was below normal, a modest transient increase in the serum TG level occurred in parallel with the increase in serum TSH. All parameters of thyroid function were normal by day 150, 5 months after the onset of symptoms. Differential Diagnosis 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 rarely 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). The hypoechoic area can reflect the degree of inflammation and thyroid hormone levels(117a). However, a fine needle aspiration is required for a definitive differentation between these two processes (119). Therapy 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, may 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. Because of the possibility of associated papillary cancer further cytological examination should be performed in patients presenting with a persistent hypoechoic area larger than 1 cm by ultrasonography (116a). Prognosis 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. In a retrospective study of 252 patients with SAT permanent hypothyroidism occurred in 5.9% and all these had bilateral hypoechogeneic areas on thyroid ultrasound at initial presentation suggesting that this may be a useful prognostic marker for the development of thyroid dysfunction after SAT (124a). 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). RIEDEL'S THYROIDITIS In 1896 Riedel described a chronic sclerosing thyroiditis, occurring especially in women, that tends to progress inexorably to complete destruction of the thyroid gland and frequently causes pressure symptoms in the neck (127-129). It is exceedingly rare. In the Mayo Clinic series (100) it occurred approximately one-fiftieth as frequently as Hashimoto's thyroiditis. It is more frequent in women (F:M 3.1:1) and is found most often in the 30- to 60 year age group. The thyroid gland is normal in size or enlarged, usually symmetrically involved, and extremely hard. Occasionally involvement may be unilateral. Diagnostic confusion with sarcoma of the thyroid region has been reported (131) and it may occur in a multinodular goiter mimicking thyroid cancer (132). Although the etiology is unknown the disease may develop in the course of subacute thyroiditis (133) and a case of concurrent Riedel’s, Hashimoto’s and acute thyroiditis has been reported (133a). On pathologic examination the gland is replaced by dense fibrosis in which are scattered solitary follicular cells and occasional acini with small amounts of colloid. The fibrosis binds the thyroid firmly to the trachea and the strap muscles, from which it can be separated only with the greatest difficulty (ligneous thyroiditis) (134). The fibrosis may compress the trachea or esophagus. The disease may remain stable over many years, or it may progress slowly and produce hypothyroidism. Dyspnea, dysphagia, hoarseness, and aphonia are caused by the local pressure, and if there is enough pressure on both recurrent laryngeal nerves, there may be stridor. Sometimes the disease is asymptomatic and discovered only incidentally. The pathologic process may advance to complete replacement of the gland, and then symptoms and signs of hypothyroidism appear. Involvement of the parathyroid glands by the fibrotic process may result in hypoparathyroidism (135-139). Rarely, Riedel's thyroiditis may be associated with similar fibrosclerotic processes in other areas, including the lacrimal glands, orbits (140), parotid glands, mediastinum, lung, myocardium, retroperitoneal tissues, and bile ducts in varying combinations in the syndrome of multifocal fibrosclerositis (141, 142,142a). Fluorine-18 fluorodeoxyglucose [FDG] positron emission tomographic images have shown metabolic activity in an abdominal mass and increased glucose metabolism in the thyroid, probably resulting from active inflammation involving lymphocytes, plasma cells and fibroblast proliferation (143). FDG metabolic activity can also be used to assess a patient's response to therapy (144). This mixture of inflammatory cell infiltrate and fibrosis can also be visualised using dynamic magnetic resonance imaging with gadpentate dimeglumine (145) and appropriate T1- and T2- weighted images (146). Subcutaneous fibrosclerosis has also been noted but it is very rare (147). The occurrence of cerebral sinus thrombosis suggests that Riedel's thyroiditis may cause venous stasis, vascular damage, and possibly hypercoaguability (148). The results of laboratory tests of thyroid function are usually normal, but about one-third are hypothyroid. The erythrocyte sedimentation rate is not elevated, as in subacute thyroiditis, and there is no leukocytosis. Antithyroid antibodies are present in 67% of reported cases (129) and a mixed population of B- and T-cells is present in the thyroid, suggesting an autoimmune etiology or association. The B cell proliferation has been shown to be polyclonal (149). The occurrence of marked tissue eosinophilia and the extracellular deposition of eosinophil granule major basic protein suggests a role for eosinophils and their products in the development of fibrosis in Riedel's thyroiditis (150). Fibrosis may also be related to the action of TGF beta 1, as seen in murine thyroiditis (151). The manifestations of Riedel’s thyroiditis can be confusing as exemplified by a patient who, over 18 months after biopsy proven Riedel’s thyroiditis, developed hyperthyroidism, spontaneous primary hypoparathyroidism, acute compressive neck symptoms requiring emergency isthmusectomy, vocal cord paralysis, syncopal-like episodes, and Horner’s syndrome due to compression of the right carotid sheath. This patient is under therapy with glucocorticoids and tamoxifen (138). Management of Riedel's Thyroiditis 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). There are no data on effective therapy with other immunosuppressive agents. 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. RARE INFLAMMATORY OR INFILTRATIVE DISEASES In addition to the varieties of thyroiditis already mentioned, which are diseases specifically of the thyroid gland, generalized or systemic diseases may also involve the thyroid gland (26). The lesions of sarcoid may appear in the thyroid gland of patients with systemic sarcoidosis, and huge deposits of amyloid occasionally causes goiter in amyloidosis. Amyloid goiter with transthyretin activity has been reported (164a). Amyloid goiter may be readily diagnosed by fine needle aspiration biopsy (165). Painless thyroiditis has been noted in a woman with rheumatoid arthritis and secondary amyloidosis infiltrating the thyroid gland (166). Radiotherapy for tonsillar carcinoma has been reported to result in thyroiditis (167) and radiation during 131 I therapy produces thyroiditis, which is occasionally symptomatic. This situation is discussed in Chapters 11 and 18. Irradiation to the thyroid during therapy for breast cancer or lymphoma can also induce hypothyroidism. Therapy should be directed toward the primary disease rather than the thyroid, but administration of thyroid hormone may be necessary if destruction of thyroid tissue is sufficient to produce hypothyroidism. Finally, surgery to the neck has been reported to cause thyroiditis but this is rare (168, 169). SUMMARY The thyroid, like any other structure, may be the seat of an acute or chronic suppurative or nonsuppurative inflammation. Various systemic infiltrative disorders may leave their mark on the thyroid gland as well as elsewhere. Infectious thyroiditis is a rare condition, usually the result of bacterial invasion of the gland. Its signs are the classic ones of inflammation: heat, pain, redness, and swelling, and special ones conditioned by local relationships, such as dysphagia and a desire to keep the head flexed on the chest in order to relax the paratracheal muscles. The treatment is that for any febrile disease, including specific antibiotic drugs if the invading organism has been identified and its sensitivity to the drug established. Otherwise, a broad- spectrum antibiotic may be used. Surgical drainage may be necessary and a search for a pyriform sinus fistula should be made, particularly in children with thyroiditis involving the left lobe. Subacute (granulomatous) thyroiditis is a more common and protracted disease that usually involves the thyroid symmetrically. The gland is swollen and tender, and the systemic reaction may be severe, with fever and an elevated erythrocyte sedimentation rate. During the acute phase of the disorder, tests of thyroid function disclose a diminished thyroidal RAIU and increased serum concentrations of T4, T3, and Tg. The cause of this disease has been established in only a few instances in which a viral infection has been the initiating factor. There may be repeated recurrences of diminishing severity. Usually, but not always, the function of the thyroid is normal after the disease has subsided. Subacute thyroiditis may be treated with rest, non-steroidal anti-inflammatory drugs or aspirin, and thyroid hormone. If the disease is severe and protracted, it is usually necessary to resort to administration of glucocorticoids, but recurrence may follow their withdrawal. Riedel's thyroiditis is a chronic sclerosing replacement of the gland that is exceedingly rare. The process involves the immediately adjacent structures, making any surgical attack very difficult. The cause is unknown, and no treatment is available beyond resecting the isthmus of the thyroid gland to relieve the symptoms of tracheal or esophageal compression. Sarcoid may involve the thyroid, and amyloid may be deposited in the gland in quantities sufficient to cause goiter. In all of these diseases it may be necessary to give the patient levothyroxine replacement therapy if the function of the gland has been impaired. Notes 1. http://www.thyroidmanager.org/Chapter19/19- text.htm#Infectious_Thyroiditis_ 2. http://www.thyroidmanager.org/Chapter19/ch_19__subacute.htm 3. http://www.thyroidmanager.org/Chapter8/8-frame.htm 4. http://www.thyroidmanager.org/Chapter8/8-frame.htm 5. http://www.thyroidmanager.org/Chapter19/ch_19__riedels.htm References 1. Chi H, Lee YJ, Chiu NC, Huang RY, Huang CY, Lee KS, Shih SL, Shih BF. 2002 Acute suppurative thyroiditis in children. 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