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					   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, [62] 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


         [105] 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



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