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 abcess has also been reported due to a fourth branchial arch sinus fistula (11). In the immuno-compromised host, fungal infection may occur (12-15). Occasionally, acute bacterial supporative 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. Streptococcus, staphylococcus, pneumococcus, salmonella (17-19), bacteroides, t. pallidum, pasteurella spp (16), multocida (16a) and m. tuberculosis (21-23) have all been described.) The subject has been extensively reviewed (13,24,25). In addition, certain fungi, including coccidioides immitis, aspergillus, actinomycosis (26, 26a, 26b), candida albicans (27), nocardia(28), acinobacter baumanii(29) and cryptococcus (30) have also been associated with thyroiditis. In the latter cases, the hosts have often been immuno-compromised, either due to malignancy or to AIDS (31). Malignancy may also be associated with thyroid abscess due to a fistulous connection (33) and a thyroid abcess due to clostridium septicum is almost always associated with carcinoma of the colon (34). Metastatic breast cancer has been described as presenting clinically with acute thyroiditis (35). 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 (35a) and also being causative in a case of secodary infection with necrosis in a patient with papillary thyroid carcinoma(35b). 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 (4-6,25,36). This tract is thought to represent the course of migration of the ultimo branchial body from the site of its embryonic origin in the fifth pharyngeal pouch (7). Careful histopathological studies of these fistulae have demonstrated that they are lined by squamous columnar or ciliated epithelium and occasionally form branches in the thyroid lobe (4,6). In addition, occasional cells positive for calcitonin have been found in the fistulae and increased numbers of C-cells were noted in the thyroid lobe at the point of termination of the tract. The predominance of acute thyroiditis in the left lobe of the thyroid gland, particularly in infants and children, is explained by the fact that the right ultimo branchial body is often atrophic and does not develop in the human (as well as in other species such as reptiles). The reason for this phenomenon is not known. Acute thyroiditis may involve a normal gland, or arise in a multinodular goiter. At times, no source of infection can be demonstrated. The possibility of a persistent thyroglossal duct should be considered for patients with midline infections (9).

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

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

The dominant clinical symptom is pain in the region of the thyroid gland which may subsequently enlarge and become hot and tender. The patient is unable to extend the neck and often sits with the neck flexed in order to avoid pressure on the thyroid gland. Swallowing is painful. There are usually signs of infection in structures adjacent to the thyroid, local lymphadenopathy as well as temperature elevation and, if bacteremia occurs, chills. Gas formation with suppurative thyroiditis has been noted (32). 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. 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 (30) 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 (16a, 21). The adult thyroid gland contains approximately 600 ug of T4/g (38). Given a typical 15 to 20 g gland, sufficient hormone can be released to cause transient thyrotoxicosis.

Pain in the anterior neck will usually lead to a consideration of the possibility of thyroiditis. Since the major differential diagnosis will lie between acute suppurative thyroiditis and subacute thyroiditis, it is critical to compare the history, physical, and particularly laboratory data in these two conditions (see Table 19-1). In general, the patient with acute thyroiditis appears septic, has greater and more localized pain in the thyroid gland, may have an associated upper respiratory infection, has lymphadenopathy and may be immuno-compromised. Localization of the tenderness to the left lobe should suggest the possibility of an infection as should any erythema or apparent abscess formation. The presence of an elevated white blood count with a shift to the left would argue for infection, however, elevations in sedimentation rate are common in both acute and subacute thyroiditis. As mentioned, patients with bacterial thyroiditis are not hyperthyroid, but exceptions do occur. This is more common, but, by no means universal in patients with subacute thyroiditis.

Depending on the age and clinical circumstances, one may wish to proceed with invasive or non-invasive studies. The most discriminating tests for recognizing a difference between the two conditions are either an iodine uptake or scan showing a very low value in subacute thyroiditis with a normal value found in the patient with localized bacterial thyroiditis (25). 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 (39). Gallium scans are sometimes performed in the course of an evaluation for a fever of unknown origin. Localization of gallium to the thyroid gland is a very useful finding confirming thyroid inflammation as the source of the problem (27). 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 (39a). 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.

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. 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 (40). Trypanosomiasis of the thyroid has also been reported (25).

In some patients with thyroiditis, the destruction may be sufficiently severe that hypothyroidism results. Thus, patients with a particularly diffuse thyroiditis should have follow-up thyroid function studies performed to determine that this has not occurred. Surgical removal of a fistula or branchial pouch sinus (41) is required to prevent recurrence when this is present.

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 (25,42). 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.

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 (43,44).

Although the search for a viral cause has usually been unrewarding, a few cases seem to be due to the virus that causes mumps (42,45). 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 (45a), myocarditis, cat scratch fever, and coxsackie virus (Figure 19-1) (46). Two comprehensive studies (47,48) 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 (49).

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, 23 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 (46). 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 19-1, above) Histo-compatibility studies show that 72% of patients with subacute thyroiditis manifest HLA-Bw35 (50). Familial occurrence of subacute thyroiditis associated with HLA-B35 has been reported (51,52, 52a). 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 (49). A reported association between subacute thyroiditis and acute febrile neutrophilic dermatosis (Sweet's syndrome) (53) 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 a subacute thyroiditis (54). Infusion of interleukin 2 caused hyperthyroxinemia with a low radioiodine uptake in six patients who received this in combination with TNF  or  interferon (55). 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 develped subacute thyroiditis after influenza vacccination (55a) 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 (55). IFN can exacerbate previous thyroid autoimmunity and cause destructive thyroidal changes de novo. Subacute thyroiditis has recently been noted in patients treated with combination therapy of IFN plus ribavirin for this disease (56,57), as well as during treatment of hepatitis B with Interferon (58). The condition has also been reported in association with Takayasu's arteritis suggesting an immune abnormality (59). 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 (60, 60a). Other reports of subacute thyroiditis for example with renal cell carcinoma (61) or after gastric bypass (62) do not contribute to its etiology.

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

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

The macroscopic pathologic picture of subacute thyroiditis frequently bears a striking resemblance to cancer. The lesion is firm to dense in consistency, pale white in color, and has poorly defined margins that encroach irregularly on the adjacent normal thyroid. Microscopically, one sees a mixture of subacute, chronic, and granulomatous inflammatory changes associated with zones of parenchymal destruction and scar tissue. Early infiltration with polymorphonuclear leukocytes is replaced by lymphocytes and macrophages. The normal follicles may be largely replaced by an inflammatory reaction, but a few small follicles containing colloid remain (Fig. 19-2, 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 (63). The most distinctive feature is the granuloma, consisting of giant cells clustered about foci of degenerating thyroid follicles (Fig. 19-2). 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 (64). Data on the mechanism of inflammation and the pathogenesis of subacute thyroiditis at the cellular level are sparse. However a study of apoptosis and expression of Bcl 1-2 family proteins in 11 patients with SAT has suggested that apoptotic mechanisms may be involved in the development of SAT(67). A detailed immunohistochemical study of growth factors in SAT (68) has shown that growth factor rich monocytes/macrophages (containing VEGF, beta FGF, PDGF and TGF beta 1) mediate the granulomatous stage. EGF is important in the regenerative stage as it has mitogenic effects on the thyrocyte. VEGF and betaFGF contribute to the angiogenesis at both these stages of the disease. In a recent analysis of factors influencing the severity of the acute phase response during the course of SAT, it was found that serum interleukin -1 receptor antagonist may have a significant anti-inflammatory role in the condition (69).

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 (70).

Figure 2. Subacute thyroiditis. Note the discrete granulomas, with giant cells, and the diffuse fibrosis (85 X).