3.2.7 Thyroiditis

Thyroiditis comprises a diverse group of disorders that are among the most common endocrine abnormalities encountered in clinical practice. These disorders range from the extremely common chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) to the extremely rare invasive fibrous thyroiditis (Riedel’s thyroiditis) (Box 3.2.7.1). Clinical presentations are also diverse, ranging from an incidental finding of a goitre to potentially life-threatening illness, from hypothyroidism to thyrotoxicosis. The term ‘thyroiditis’ implies that the disorders described in this section are inflammatory processes involving the thyroid gland. However, some of the lesions are not inflammatory, but are included in the thyroiditis category largely for convenience. A rational approach to such patients, including history, physical examination, laboratory evaluation, radionuclide or ultrasonographic imaging, and fine-needle aspiration biopsy, will allow the appropriate diagnosis to be made in the vast majority of cases.

This chapter will review the following forms of thyroiditis: Hashimoto’s, subacute, infectious, and Riedel’s. Other forms of thyroiditis are discussed within other chapters, as follows: postpartum thyroiditis (Chapter 3.4.6), radiation thyroiditis (Chapter 3.2.5), drug-induced thyroiditis (Chapter 3.1.4), thyroiditis associated with neoplasms (Chapter 3.5.5), and focal thyroiditis associated with nontoxic nodular goitre (Chapter 3.5.1).

Autoimmune thyroiditis, also known as struma lymphomatosa, chronic lymphocytic thyroiditis, and Hashimoto’s thyroiditis, was first described by Hashimoto in 1912 (Table 3.2.7.1). He described four patients with goitres, the thyroid histology of which were all characterized by diffuse lymphocytic infiltration, atrophy of parenchymal cells, fibrosis, and eosinophilic change in some of the parenchymal cells. While this condition is common, there are several variants that differ somewhat from the one initially described by Hashimoto (1). Classically, the disorder occurs as a painless diffuse goitre (goitrous form) in a young or middle-aged woman and often presents as an incidental finding during a routine physical examination. The atrophic form of Hashimoto’s thyroiditis is less common and is usually diagnosed by serology in the hypothyroid patient with a normal-sized or atrophic thyroid. The hallmarks of this disorder are high circulating titres of antibodies to thyroid peroxidase (primarily) and thyroglobulin (less often).

In iodine-sufficient countries, the most common cause of goitre, hypothyroidism, and elevated thyroid antibody levels is Hashimoto’s thyroiditis. The incidence of autoimmune thyroiditis has increased over the past three generations, perhaps due to the increase in iodine intake that has occurred in the Western world (1). Elevated serum thyroid antibody concentrations are found in approximately 10% of the US population and in up to 25% of US women over the age of 60 (1). About 45% of older women will have lymphocytic infiltration within the thyroid gland. Autoimmune thyroiditis has a female predominance with reported female to male ratios ranging between 5:1 and 9:1.

While it is clear that Hashimoto’s thyroiditis is an autoimmune disease, the nature of the autoimmune process is still debated. These disorders tend to aggregate in families, and a genetic link has been suggested. There have been associations between HLA-DR3, HLA-DR4, and HLA-DR5 and Hashimoto’s thyroiditis; however, this was demonstrated only in a cohort of white individuals (1). While HLA genes may be critical to the development of Hashimoto’s thyroiditis, this weak association makes it clear that there are other genes that have not been identified yet and that play a role in this multigenic disease (see Chapter 3.2.1). Smoking has also been identified both as a risk factor for hypothyroidism (2) and to protect against hypothyroidism (3).

The defect in immunoregulation is also still a matter for debate (see Chapter 3.2.6). Human T-lymphotropic virus type 1 (HTLV1) has been found to be associated with autoimmune diseases and carriers of the virus have been shown to have a higher frequency of thyroid antibody positivity as well as a higher incidence of Hashimoto’s thyroiditis compared to controls (4). Other theories hold that thyrocyte expression of class I and class II genes allows the thyrocyte to present antigen, and thus induce autoimmune thyroid disease; however, in contrast, available evidence indicates that thyrocyte expression of these genes promotes anergy, and thus may protect against autoimmune thyroid disease (5). The prime defect probably lies in antigen-presenting genes in professional antigen-presenting cells, e.g. macrophages, such that specific regulatory T lymphocytes, normally necessary for tolerance, are not fully activated (6). This, together with environmental factors that may serve to down-regulate the immune system, might act together to disturb immunoregulation, and allow for the development of autoimmune thyroid disease.

Many antibodies are often present in patients with Hashimoto’s thyroiditis. Antithyroid peroxidase antibodies are complement fixing and are detectable in about 90% of patients with Hashimoto’s thyroiditis. Antithyroglobulin antibody, a noncomplement-fixing antibody, is found in about 20–50% of patients with Hashimoto’s thyroiditis (7). Thyroid-stimulating hormone (TSH) receptor antibodies that block TSH binding but do not stimulate the thyroid cell function may play a role in the clinical presentation of Hashimoto’s thyroiditis, producing or exacerbating hypothyroidism in the absence of significant thyroid gland destruction (8). Such antibodies have been reported to bind to epitopes near the carboxyl end of the TSH-receptor extracellular domain, in contrast to thyroid-stimulating antibodies, which bind to epitopes near the N-terminus (9). The prevalence of TSH-receptor blocking antibodies in adult hypothyroid patients has been reported to be as high as 10% (10) and a decrease in the titre of these antibodies is likely to be responsible for ‘remission’ of hypothyroidism in some patients with Hashimoto’s thyroiditis (11). Antibodies to colloid antigen, other thyroid autoantigens, thyroxine (T₄) and triiodothyronine (T₃), as well as other growth promoting and inhibiting antibodies may also be present.

Pathologically, there is lymphocytic infiltration of equal proportions of T and B cells and the formation of germinal centres (Fig. 3.2.7.1a). The follicular cells undergo metaplasia into larger, eosinophilic cells known as Hürthle or Askanazy cells which are packed with mitochondria. These cells exhibit high metabolic activity but ineffective hormonogenesis. There is progressive fibrosis, which may be extensive. The quantity of parenchymal tissue left in the thyroid is variable, as the pathological involvement ranges from focal regions to an entire lobe to the entire gland.

Hashimoto’s thyroiditis occurs most frequently in middle-aged women but can occur at any age. The usual presentation is as an incidental finding of a goitre during routine physical examination. While usually asymptomatic, some patients may complain of an awareness of fullness in the neck. The usual course is for slow enlargement of the thyroid over years; however, the thyroid occasionally may enlarge rapidly and can produce compressive symptoms of dyspnoea and/or dysphagia. Rarely, Hashimoto’s thyroiditis may be painful (1, 12) and must be distinguished from subacute thyroiditis (see below). Systemic symptoms of hypothyroidism will be present in up to 20% of patients at the time of diagnosis (13), although this incidence is a little higher with the atrophic form of the disorder. Conversely, Hashimoto’s thyroiditis is found to be the aetiology in the vast majority of patients in the USA with hypothyroidism.

Physical examination typically reveals a firm bumpy nontender goitre, which is generally symmetrical and often has a palpable pyramidal lobe. Regional lymph node enlargement may be observed. While nodular thyroid disease can, and frequently does, occur in Hashimoto’s thyroiditis, single nodules and dominant nodules in a multinodular gland should be evaluated with a fine-needle aspiration biopsy to rule out a coexistent malignancy. Ophthalmopathy is present in a small subset of patients with Hashimoto’s thyroiditis (14). Furthermore, there is evidence of chronic autoimmune thyroiditis in many patients with euthyroid Graves’ ophthalmopathy.

The hallmark of Hashimoto’s thyroiditis is elevated thyroid antibody levels. The majority of individuals with elevated thyroid antibody levels are biochemically euthyroid. Up to 10% of postmenopausal women with an elevated thyroid antibody level will have an increased TSH but a minority of these (c.0.5%) will have overt hypothyroidism (1). Women with elevated thyroid antibody levels have been reported to develop overt hypothyroidism at a rate of 2–4% per year (1, 13, 15) (see Chapter 3.1.7). Mild thyrotoxicosis (‘Hashitoxicosis’) has been reported to be the initial manifestation in some patient’s with Hashimoto’s thyroiditis (16). The clinical course in these patients follows a pattern similar to that observed in sporadic silent or postpartum thyroiditis (Chapter 3.4.6), suggesting that differentiation between these disorders may be largely semantic.

The diagnosis of Hashimoto’s thyroiditis is confirmed by the presence of antithyroid antibodies. Serum T₄ and TSH concentrations depend on the level of thyroidal dysfunction that is present and are not specific to hypothyroidism due to Hashimoto’s thyroiditis. Serum T₃ concentrations are often preserved in all but the most severely hypothyroid patient and, thus, are of little clinical value. Similarly, the radioactive iodine uptake is usually not helpful, as it may be elevated, normal, or depressed. Thyroid isotope scanning usually reveals patchy uptake and, in general, provides little useful information unless a dominant thyroid nodule is present. Ultrasound examination of the thyroid frequently reveals marked hypoechogenicity with pseudonodules (17).

When imaged, an enlarged thymus gland is frequently found in Hashimoto’s thyroiditis and may be important in the pathogenesis of the condition. In both affected patients and their relatives, there is an association with other autoimmune diseases including insulin-dependent diabetes mellitus, pernicious anaemia, Addison’s disease, and vitiligo. Thyroid lymphoma is rare; however, the risk is increased in those individuals with Hashimoto’s thyroiditis by a factor of 67 (1, 18). In patients in whom a fine-needle aspiration biopsy is performed, lymphocyte subsets should be determined on the biopsy specimen if the more typical pathological features of Hashimoto’s thyroiditis are not present.

Treatment of Hashimoto’s thyroiditis consists of thyroid hormone replacement if hypothyroidism is present. l-thyroxine is the hormone of choice for thyroid hormone replacement therapy because of its consistent potency and prolonged duration of action. The average daily adult replacement dose of l-thyroxine sodium in a 68-kg person is 112 μg. Institution of therapy in healthy younger individuals can begin at full replacement doses. Because of the prolonged half-life of thyroxine (7 days), new steady-state concentrations of the hormone will not be achieved until 4–6 weeks after a change in dose. Thus, re-evaluation with determination of serum TSH concentration need not be performed at intervals of less than 4–6 weeks. The goal of thyroxine replacement therapy is to achieve a TSH value in the normal range, as over-replacement of thyroxine suppressing TSH values to the subnormal range may induce osteoporosis and cause cardiac dysfunction (19). In noncompliant young patients, the cumulative weekly doses of l-thyroxine may be given as a single weekly dose which is safe, effective, and well tolerated. In individuals over the age of 60, institution of therapy at a lower daily dose of l-thyroxine sodium (25 μg/day) is indicated to avoid exacerbation of underlying and undiagnosed cardiac disease. Daily doses of thyroxine may be interrupted periodically because of intercurrent medical or surgical illnesses that prohibit taking medications by mouth. A lapse of several days of hormone replacement is unlikely to have any significant metabolic consequences. However, if more prolonged interruption in oral therapy is necessary, l-thyroxine may be given intravenously at a dose 25–50% less than the patient’s daily oral requirements. The treatment of euthyroid asymptomatic patients is not so clear-cut, and the recommendations for treatment of increased TSH without a corresponding low T₄ concentration are divided (19, 20).

In addition to replacement therapy, thyroid hormone therapy may be considered in patients with a serum TSH in the normal range in an attempt to decrease the size of a goitre or as a preventative measure to preclude the development of overt hypothyroidism. While goitre suppression with l-thyroxine is frequently not fruitful, in the subset of patients with Hashimoto’s thyroiditis early in the course of the disease and before fibrosis develops such therapy may be useful. However, goitre suppression with l-thyroxine is unlikely to be successful if the initial TSH is less than 1 mU/l. The goal of l-thyroxine suppression therapy is to decrease the serum TSH into the subnormal range. Patients on l-thyroxine suppression therapy should be re-evaluated periodically and the suppressive hormone dose should be reduced or discontinued if significant goitre reduction is not achieved. In the absence of cancer, surgery is indicated for compressive goitres with local obstructive symptoms.

Subacute thyroiditis, like painless sporadic and postpartum thyroiditis, is a spontaneously remitting inflammatory disorder of the thyroid that may last for weeks to months (1, 21) (Table 3.2.7.1). This disorder has a number of eponyms, including De Quervain’s thyroiditis, giant cell thyroiditis, pseudogranulomatous thyroiditis, subacute painful thyroiditis, subacute granulomatous thyroiditis, acute simple thyroiditis, noninfectious thyroiditis, acute diffuse thyroiditis, migratory ‘creeping’ thyroiditis, pseudotuberculous thyroiditis, and viral thyroiditis. The first description of subacute thyroiditis was in 1895 by Mygind, who reported 18 cases of ‘thyroiditis akuta simplex’ (21). However, the pathology of subacute thyroiditis was first described in 1904 by Fritz De Quervain, whose name is associated with the disorder, when he showed giant cells and granulomatous-type changes in the thyroids of affected patients. Subacute thyroiditis is the most common cause of the painful thyroid and may account for up to 5% of clinical thyroid abnormalities (1, 21). As with other thyroid disorders, women are more frequently affected than men, with a peak incidence in the fourth and fifth decades. This disorder is rarely observed in children and older people. While the term ‘subacute thyroiditis’ connotes a temporal quality that could apply to any thyroidal inflammatory process of intermediate duration and severity, it is actually referring specifically to the granulomatous appearance of the thyroid found on pathological examination. This pathological appearance of the thyroid is specific for the disease.

Although there is no clear evidence for a specific aetiology, indirect evidence suggests that subacute thyroiditis may be caused by a viral infection of the thyroid (22, 23). The condition is often preceded by a prodromal phase of myalgias, malaise, low-grade fevers, fatigue, and frequently by an upper respiratory tract infection. It has been reported most frequently in the temperate zone, and only rarely from other parts of the world. It has been found to occur seasonally; the highest incidence is in the summer months (July through September) which coincide with the peak of enterovirus (echovirus, Coxsackie virus A and B) infection (24). The incidence rate has been shown to vary directly with viral epidemics; during certain viral epidemics, specifically mumps, the incidence of subacute thyroiditis has been found to be higher. Interestingly, antibodies to the mumps virus have even been detected in individuals with subacute thyroiditis who do not have clinical evidence of mumps. Subacute thyroiditis has also been associated withmeasles, influenza, the common cold, adenovirus, infectious mononucleosis, Coxsackie virus, myocarditis, cat-scratch fever, St Louis encephalitis, hepatitis A, and the parvovirus B19 infection. Antibodies to Coxsackie virus, adenovirus, influenza, and mumps have been detected in the convalescent phase of this disease (25). Coxsackie virus is most commonly associated with subacute thyroiditis and, in fact, Coxsackie virus antibody titres have been shown to directly follow the course of the thyroid disease (24). Isolation of a cytopathic virus of possible pathogenic significance from the thyroids of 5 of 28 patients with subacute thyroiditis was reported in 1976 (26).

Certain nonviral infections including Q fever and malaria, have been associated with a clinical syndrome similar to subacute thyroiditis. In addition, a case of subacute thyroiditis occurring simultaneously with giant cell arteritis has been reported. Another case of subacute thyroiditis developed during α-interferon treatment for hepatitis C.

Unlike painless or postpartum thyroiditis, there is no clear association between subacute thyroiditis and autoimmune thyroid disease. Serum thyroid peroxidase and thyroglobulin antibody levels are usually normal. When described, the levels of thyroid peroxidase and thyroglobulin antibodies correlated with the phase of transient hypothyroidism. Antibodies to an unpurified thyroid preparation can be detected for up to 4 years after a bout of subacute thyroiditis.

Antibodies to the thyrotropin (TSH) receptor have been detected only in some patients during the course of subacute thyroiditis (27). In most studies, there was no correlation between the presence of thyrotropin-receptor-binding inhibitory immunoglobulin or of thyrotropin-receptor stimulating immunoglobulin and the thyrotoxic phase of the thyroiditis. On the other hand, there has been some correlation between thyroid-blocking antibodies and the development of hypothyroidism. It is thought that the appearance of the TSH-receptor antibodies results from an immune response that occurs after there is damage to the thyrocytes, specifically membrane desquamation (22, 23). Following recovery from the inflammatory process of subacute thyroiditis, all immunological phenomena disappear (27). The transitory immunological markers that are observed during the course of subacute thyroiditis appear to occur in response to the release of antigenic material from the thyroid, and thus the inflammatory destruction of the gland appears to be a normal physiological response.

There is an apparent genetic predisposition for subacute thyroiditis, with HLA-Bw35 reported in all ethnic groups (21). The relative risk of HLA-Bw35 in subacute thyroiditis is high, ranging from 8.0 to 56 (21). Additional evidence for genetic susceptibility is the simultaneous development of subacute thyroiditis in identical twins heterozygous for the HLA-Bw35 haplotype (28). However, an epidemic of ‘atypical’ subacute thyroiditis was described in a town in the Netherlands where HLA-B15/62 was found in five of 11 patients tested while only one patient tested positive for HLA-Bw35 (29). Finally, a weak association of subacute thyroiditis with HLA-DRw8 has been reported in Japanese patients (30).

The primary events in the pathology of subacute thyroiditis are destruction of the follicular epithelium and loss of follicular integrity; however, the histopathological changes are distinct from those found with Hashimoto’s thyroiditis (Fig. 3.2.7.1b). The lesions are patchy in distribution and are of varying stages of development, with infiltration of mononuclear cells in affected regions and partial or complete loss of colloid and fragmentation and duplication of the basement membrane. Histiocytes congregate around masses of colloid, both within the follicles and in the interstitial tissues, producing ‘giant cells’; often these giant cells consist of masses of colloid surrounded by large numbers of individual histiocytes, and so they more accurately should be termed ‘pseudogiant cells’. The term ‘granulomatous’ thyroiditis, a synonym for subacute thyroiditis, should likewise be changed to ‘pseudogranulomatous’ thyroiditis. However, true giant cells and granulomas do appear in this disease as well.

During recovery, the inflammation recedes and there is a variable amount of fibrosis and fibrotic band formation. In addition, follicular regeneration occurs without caseation, haemorrhage, or calcification. Recovery is generally complete. Only in rare instances is there complete destruction of the thyroid parenchyma that leads to permanent hypothyroidism. In the few electron microscope studies reported, viral inclusion bodies have not been demonstrated. Fine-needle aspiration biopsies often show large numbers of histiocytes, epithelioid granulomas, multinucleated giant cells, and follicular cells with intravacuolar granules (31).

The manifestations may be preceded by an upper respiratory tract infection, or a prodromal phase of malaise, generalized myalgias, pharyngitis, and low-grade fevers. Pain or swelling in the thyroid region develops later accompanied by higher fevers; up to 50% of patients have symptoms of thyrotoxicosis (1). Pain may be moderate or severe but in a few cases symptoms are entirely lacking. Similarly, tenderness may be moderate or severe (or even exquisite), or, conversely, may also be lacking. One of the lobes may be involved initially, and later spread to the opposite lobe (creeping thyroiditis) or it may involve both lobes from the outset. The systemic reaction may be minimal or severe, and fevers may reach 40 °C. Rarely, subacute thyroiditis may present as a nontender solitary nodule. In these cases, the diagnosis has been made after fine-needle aspiration biopsy. Atypical presentations are often misdiagnosed as papillary cancer.

Patients can generally localize the pain to the thyroid region over one or both lobes. They may refer to their symptoms as a ‘sore throat’, but upon specific questioning, it becomes apparent that pain is in the neck, not within the pharynx. Typically, pain radiates from the thyroid region up to the angle of the jaw or to the ear on the affected side(s). The pain may also radiate to the anterior chest or may be centred over the thyroid only. Moving the head, swallowing, or coughing may aggravate the pain. Although some patients have no systemic symptoms, most complain of myalgias, fatigue, and fevers. Malaise can be extreme and can be associated with arthralgias.

On physical examination, most patients appear uncomfortable and flushed on inspection, with variable elevations in temperature. Palpation usually reveals an exquisitely tender hard ill-defined nodular thyroid. The tender region may encompass an entire lobe and mild tenderness may be present in the contralateral lobe. The overlying skin is occasionally warm and erythematous. Cervical lymphadenopathy is rarely present. While the vast majority of patients are only mildly to moderately ill, subacute thyroiditis may have a dramatic presentation, with marked fever, severe thyrotoxicosis, and obstructive symptoms due to pronounced thyroid inflammation and oedema.

During the active/painful phase of subacute thyroiditis, the ESR is usually markedly elevated. In fact, a normal ESR essentially rules out subacute thyroiditis as a tenable diagnosis. The white blood cell count is normal to mildly increased and there is often a normochromic normocytic anaemia. There are also increases in serum ferritin, soluble intercellular adhesion molecule-1, selectin, interleukin-6 levels, and C-reactive protein during the inflammatory phase (4, 22). Alkaline phosphatase and other hepatic enzymes may be elevated in the early phase. It has been suggested that subacute thyroiditis may actually represent a multisystem disease also affecting the thyroid.

In the thyrotoxic phase, the serum T₄ concentration is disproportionately elevated relative to the serum T₃ concentration, reflecting the intrathyroidal T₄:T₃ ratio. In addition, the acute illness decreases the peripheral deiodination of T₄ to T₃, resulting in lower serum T₃ concentrations than expected. Serum TSH concentrations are low to undetectable. Antibodies directed against thyroglobulin and thyroid peroxidase are either absent or present in low titre; these develop several weeks after disease onset and tend to disappear thereafter.

The radioactive iodine uptake during the thyrotoxic phase is low, most often below 2% at 24 h. As with the ESR discussed above, a normal radioactive iodine uptake essentially rules out subacute thyroiditis as a tenable diagnosis. Ultrasound examination may show generalized, multiple, or single regions of hypoechogenicity (32).

Subacute thyroiditis must be differentiated from the other causes of anterior neck pain. The diagnosis should present no difficulties in patients with typical manifestations. However, because ‘sore throat’ is a frequent complaint, many patients are initially misdiagnosed with pharyngitis. Acute haemorrhage into a nodule or cyst and nonthyroidal aetiologies can be differentiated with radio-iodine scanning, as there will be normal function in the nonaffected areas of the gland. Painful Hashimoto’s thyroiditis usually involves the entire gland and antibodies directed against thyroglobulin and thyroid peroxidase are usually present in high titre. Acute suppurative thyroiditis is distinguished by a much greater leucocytosis and febrile response, a greater inflammatory reaction in surrounding tissues, and often a septic focus is evident elsewhere, such as in the urinary or respiratory tracts. The radioactive iodine uptake is usually normal in acute suppurative thyroiditis and the scan will reveal decreased uptake in the region of suppuration.

Rarely, infiltrating cancer of the thyroid can present with a clinical and laboratory picture indistinguishable from subacute thyroiditis, requiring fine-needle aspiration biopsy for the diagnosis. Amiodarone, an iodine-rich antiarrhythmic drug, may cause iodine-induced thyrotoxicosis (Jod-Basedow disease) and, less commonly, thyroiditis, which may occasionally be painful. Both sporadic silent and postpartum thyroiditis follow a similar clinical course as subacute thyroiditis but lack the clinical feature of a painful goitre. In addition, patients with painless or postpartum thyroiditis often exhibit high titres of antithyroglobulin and antithyroid peroxidase antibodies and the ESR is normal to only slightly elevated. Fine-needle aspiration biopsies may be useful, but may show large numbers of histiocytes and thus may be misleading.

Despite the differing aetiologies, the clinical course of subacute thyroiditis is similar to that of painless and postpartum thyroiditis (see Chapter 3.4.6). The initial phase is characterized by pain and thyrotoxicosis in most patients and may last up to 3–4 months. The thyrotoxicosis may not be clinically apparent in some instances, and it is usually mild when it is clinically evident. As noted above, the thyrotoxicosis is due to a disruptive process within the thyroid causing leakage of colloid material into the interstices, where it liberates thyroid hormones, thyroglobulin, and other iodoamino acids into the circulation. If present, β-adrenergic blocking drugs such as propranolol are useful. Antithyroid drugs have no role in the management of subacute thyroiditis as the gland is not hyperfunctioning.

Salicylates and nonsteroidal anti-inflammatory drugs are often adequate to decrease thyroidal pain in mild to moderate cases. In more severe cases, oral glucocorticoids (prednisone up to 40 mg/day) may provide dramatic relief of pain and swelling, often within a few hours of administration and in most cases within 24–48 h. In fact, if thyroidal/neck pain fails to begin to improve after 24 h of corticosteroid therapy, the diagnosis of subacute thyroiditis should be questioned. Despite the clinical response to corticosteroids, the underlying inflammatory process may persist, and symptoms may recur if the dose is tapered too rapidly. Up to one-third of patients will have a recurrence of thyroidal pain upon discontinuation of prednisone, which responds to restarting the corticosteroid. In general, full-dose corticosteroids are given for a week, followed by tapering of the dose over at least 2–4 weeks.

Determination of the radioactive iodine uptake before discontinuing prednisone may be helpful in identifying those patients at high risk for relapse. If the radioactive iodine uptake is still low, the inflammatory process is ongoing and corticosteroids should not be discontinued. If the radioactive iodine uptake has returned to normal, then the corticosteroid can be safely withdrawn. Patients with recurrent exacerbations of symptoms after withdrawal of corticosteroids usually respond to reinstitution or continuation of the corticosteroids for an additional month. While subacute thyroiditis is a self-limited disease and the vast majority of patients respond to the measures discussed above, there are occasional patients who have repeated exacerbations of pain and inflammation. In these patients, therapy with l-thyroxine or l-triiodothyronine has been helpful in preventing exacerbations, suggesting that endogenous TSH may contribute to their occurrence. Rarely, thyroidectomy or thyroid ablation with radioactive iodine may be necessary for management of patients with protracted courses of severe neck pain and malaise.

After the acute phase, a period of transient (1–2 months) asymptomatic euthyroidism follows. Hypothyroidism may occur after several more weeks and may last for 6–9 months. The final recovery phase follows, when all aspects of thyroid function return to normal, including morphology. Hypothyroidism may be permanent in up to 5% of patients and relapse of subacute thyroiditis is rare, occurring in less than 2% of patients (33). However, some patients with a history of subacute thyroiditis were found to be particularly sensitive to the inhibitory effects of exogenously administered iodides, suggesting a persistent thyroid abnormality. Thus, long-term follow-up of patients after an episode of subacute thyroiditis is recommended.

Infectious thyroiditis is also known as acute thyroiditis, suppurative thyroiditis, bacterial thyroiditis, and pyogenic thyroiditis (Table 3.2.7.1). Bacterial infections of the thyroid are rare, with only 224 cases having been reported in the literature from 1900 to 1980 (34) and only 60 cases reported in the paediatric literature (35). Bacterial infections are the aetiology of most cases of infectious thyroiditis and the infections are generally suppurative and acute. Infectious thyroiditis caused by fungal and parasitic infections are more fre quently chronic and indolent. In this section, emphasis will be placed on bacterial infections. The reader is referred to other reviews for further information on the less frequent causes of infectious thyroiditis (21).

The thyroid gland’s high iodine content, significant vascularity, lymphatic drainage, as well as its protective capsule provide the thyroid gland with notable resistance to infection (21). The most common predisposing factor to infections of the thyroid appears to be pre-existing thyroid disease. Simple goitre, nodular goitre, Hashimoto’s thyroiditis, or thyroid carcinoma has been observed in up to two-thirds of women and one-half of men with infectious thyroiditis (34). Patients with AIDS are a population particularly at risk for bacterial thyroiditis. As with other opportunistic infections in AIDS patients, infections of the thyroid gland are often chronic and insidious in onset.

In the adult, Staphylococcus aureus and Streptococcus pyogenes are the offending pathogens in more than 80% of patients and are the sole pathogen in over 70% of cases (21) (Table 3.2.7.2). In children, α- and β-haemolytic streptococcus and a variety of anaerobes account for about 70% of cases, while mixed pathogens are identified in over 50% of cases (35). Other thyroidal bacterial pathogens that have been shown to cause infectious thyroiditis include Salmonella brandenburg, Salmonella enteritidis, Actinomyces naeslundii, Actinobacillus actinomycetemcomitans, Brucella melitensis, Clostridium septicum, Eikenella corrodens, Enterobacter, Escherichia coli, Haemophilus influenzae, Klebsiella sp., Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter baumannii, and Staphylococcus non-aureus (21).

Infection and suppuration may result from direct spread from a nearby infection, or via the bloodstream or lymphatics. The seminal observation regarding the pathogenesis of bacterial thyroiditis was made in 1979 when Takai et al. reported seven cases of infectious thyroiditis due to a fistula originating from the left pyriform sinus (36). Subsequently, studies involving over 100 patients with infectious thyroiditis have identified pyriform sinus fistulae, primarily left-sided, in up to 90% of these patients, especially in those with recurrent episodes (21). Additional reports identified infected embryonic cysts from the third and fourth brachial pouches and thyroglossal duct cysts as routes of thyroidal infection. On pathological examination, the characteristic changes of acute bacterial inflammation, including necrosis and abscess formation, are commonly found.

Bacterial thyroiditis is often preceded by an upper respiratory tract infection, which may induce inflammation of the fistula and promote the transmission of pathogens to the thyroid. Consistent with these observations, bacterial thyroiditis is more common in the late autumn and late spring. Over 90% of patients will present with thyroidal pain, tenderness, fever, and local compression resulting in dysphagia and dysphonia; the pain is often referred diffusely to adjacent structures. Systemic symptoms such as fever, chills, tachycardia, and malaise are seen frequently.

Thyroid function tests are usually normal; however, cases of hypothyroidism and thyrotoxicosis have been reported (21). A nuclear medicine thyroid scan may show the suppurative region as a ‘cold’ area, whereas an ultrasound examination may reveal a cystic or ‘complex’ nodule. The polymorphonuclear leucocyte count and the sedimentation rate are usually elevated. The organism frequently can be identified by Gram’s stain and culture, although sterile cultures are seen in approximately 8% of cases (21).

The diagnosis is made with a fine-needle aspiration, Gram’s stain, and culture. Symptomatically, infective thyroiditis may be difficult to differentiate from subacute thyroiditis in the early phases, although the characteristic thyroid function changes in the latter disease should be helpful in discriminating the two (23). Leucocytosis and an elevated ESR are not discriminatory tests as they are commonly observed in both subacute thyroiditis and infectious thyroiditis. In general, patients with bacterial thyroiditis have a greater febrile response than those with subacute thyroiditis. Once abscess formation has occurred, the local redness, lymphadenopathy, hyperpyrexia, and leucocytosis should lead to the correct diagnosis. Malignant neoplasms and haemorrhages into cysts may sometimes present with manifestations that mimic this disorder.

The prognosis of bacterial thyroiditis is often dependent on the prompt recognition and treatment of this disorder, as mortality may approach 100% if the diagnosis is delayed and appropriate antimicrobial therapy is not instituted. Much depends upon the identification of the microorganism either from needle aspirate, incision, and drainage, or occasionally from blood culture. If no organisms are seen on the Gram’s stain, nafcillin and gentamicin or a third-generation cephalosporin is appropriate initial therapy in adults while a second-generation cephalosporin or clindamycin is reasonable in children. If an abscess develops and prompt response to antibiotics does not occur, incision and drainage is necessary. Sometimes partial lobectomy must be performed, especially if the disease is recurrent. Usually the lesions heal with reasonable speed after initiation of the correct antimicrobial agent, and recurrences are uncommon. Mortality from acute bacterial thyroiditis has markedly improved from the 20–25% reported in the early 1900s, with the extensive review by Berger estimating an overall mortality of 8.6% (34). Recent reviews involving over 100 patients failed to list mortality as a complication of acute bacterial thyroiditis (37).

Sclerosing thyroiditis, also known as invasive fibrous thyroiditis, Riedel’s struma, Riedel’s thyroiditis, struma fibrosa, ligneous (Eisenharte) struma, chronic fibrous thyroiditis, and chronic productive thyroiditis, is a rare disorder of unknown cause, characterized pathologically by dense fibrous tissue which replaces the normal thyroid parenchyma and extends into adjacent tissues, such as muscles, parathyroid glands, blood vessels, and nerves (22) (Table 3.2.7.1). The first report by Riedel in 1896 described cases of chronic sclerosing thyroiditis, primarily affecting women, which frequently caused pressure symptoms in the neck and tended to progress ultimately to complete destruction of the thyroid gland. Riedel’s interesting description was that of a ‘specific inflammation of mysterious nature producing an iron-hard tumefaction of the thyroid’.

This condition is quite rare (1, 22, 38). In thyroidectomies performed for all disorders, an incidence between 0.03 and 0.98% has been reported. At the Mayo Clinic, the operative incidence over 64 years was 0.06%, and the incidence in outpatients was 1.06/100 000. Because the manifestations are likely to lead to surgery, the incidence of invasive fibrous thyroiditis among patients undergoing thyroidectomy is much greater than the incidence in patients with goitres in general.

The cause of this disorder remains unknown. Thyroid antibodies have been reported in up to 67% of patients (39). This observation, in addition to the presence of both B and T cells in the inflammatory infiltrate, suggests a possible autoimmune mechanism, although no direct relationship has been shown. It is not uncommon for those with invasive fibrous thyroiditis to have other autoimmune diseases, such as insulin-dependent diabetes mellitus and Addison’s disease (40–42). One patient was reported to have both invasive fibrous thyroiditis and pernicious anaemia, which is another autoimmune disease. The expression of HLA-DR, heat-shock protein (HSP72), and soluble intercell adhesion molecule-1 (ICAM-1) receptor in invasive fibrous thyroiditis tissue suggests a role for an active cell-mediated immune response early in the evolution of this condition (40–43).

Marked tissue eosinophilia and eosinophil degranulation have been observed in Riedel’s struma (44). These findings may suggest that the release of eosinophil-derived products may play a role in the fibrogenic stimulus. The nature of these products is not yet known.

Whatever the ultimate aetiology is, it will have to account for the extrathyroidal fibrosclerosis as well. This was first noted as early as 1885 and was described as a common accompaniment of invasive fibrous thyroiditis (22). These areas of extrathyroidal fibrosclerosis include salivary gland fibrosis, sclerosing cholangitis, pseudotumours of the orbits, fibrous mediastinitis, retroperitoneal fibrosis, and lachrymal gland fibrosis. Long-term follow-up of patients with invasive fibrous thyroiditis (follow-up time 10 years) has shown that one-third develop fibrosing disorders of the retroperitoneal space (often with ureteral obstruction), chest, or orbit, almost always with a single extracervical site involved. Conversely, less than 1% of patients with retroperitoneal fibrosis have invasive fibrous thyroiditis. The association of certain drugs with retroperitoneal fibrosis has not been observed with invasive fibrous thyroiditis. There does not seem to be a genetic predisposition for this condition.

The age of onset varies between 23 and 78 years, although most cases are diagnosed in the fourth to sixth decades. The female to male ratio varies between 2:1 and 4:1.

The clinical presentation is of a painless goitre that is gradually or rapidly enlarging; constitutional symptoms of inflammation are rare. The extensive fibrosis is progressive and may eventually cause compression of adjacent structures, particularly the trachea and oesophagus. Local compressive symptoms include a marked sense of pressure or severe dyspnoea, with symptoms out of proportion to the size of the goitre. In some patients, the fibrotic process affects the entire gland causing hypothyroidism; the prevalence of hypothyroidism in this population is between 25 and 40%. Hypoparathyroidism can develop when parathyroid gland infiltration occurs and tetany associated with this process has been described.

On examination, the thyroid gland is stony hard, often described as ‘woody’ in texture, densely adherent to adjacent cervical structures (such as muscles, blood vessels, and nerves), and may move poorly on swallowing. The lesion may be limited to one lobe. It has a harder consistency than a carcinoma and is usually nontender. Although adjacent lymph nodes are only occasionally enlarged, when they are present a diagnosis of carcinoma is often suspected.

At presentation, most patients with Riedel’s thyroiditis are euthyroid; however, as mentioned earlier, some patients do develop hypothyroidism. Thyroid antibodies may be detected in the majority of these patients. Calcium and phosphorus levels should be evaluated at presentation to identify those patients who also have concurrent hypoparathyroidism. Thyroid radionuclide imaging can show either a heterogeneous pattern or low isotope uptake; the ‘cold’ areas reflect the fibrosis. The extent of the fibrosis can best be determined on either CT or MRI; the affected regions appear homogeneous and hypointense on T₁- and T₂-weighted MRI images. Ultrasound examinations can be helpful as the areas affected appear hypoechoic; on colour flow Doppler, the fibrotic areas are avascular. The white blood cell count and sedimentation rate are usually normal, but can be elevated.

Pathology consists of an exuberant fibrosis involving part of or the entire thyroid. Fibrotic extension beyond the capsule of the thyroid into adjacent structures such as nerves, blood vessels, muscles, parathyroid glands, trachea, and oesophagus is characteristic. Pathological diagnostic criteria for this condition includes complete destruction of involved thyroid tissue with absence of normal lobulation, lack of a granulomatous reaction, and extension of the fibrosis beyond the thyroid into adjacent muscle, nerves, blood vessels, and adipose. Histological examination reveals almost no thyroid follicles and few plasma cells, eosinophils, and Hürthle cells. Lymphocytes are also sparse, in contrast to the findings in Hashimoto’s thyroiditis, although occasionally a few foci of lymphocytes may be observed. An associated arteritis and phlebitis with intimal proliferation, medial destruction, adventitial inflammation, and thrombosis may also occur. Similar features are observed in the extracervical fibrosclerotic lesions, retroperitoneal and mediastinal regions, orbit, and lachrymal glands, and in sclerosing cholangitis.

The diagnosis is made by biopsy of the goitre in order to differentiate this disorder from carcinoma. However, a fine-needle aspiration biopsy is usually inadequate due to the extreme hardness of the gland and, thus, an open biopsy is often required.

Treatment of Riedel’s thyroiditis is surgical to relieve compressive symptoms. Extensive resection is often impossible due to fibrosis of surrounding structures, but wedge resection, especially over the isthmus to relieve tracheal compression, is often extremely effective. Despite its invasive nature, recurrences of obstruction after resection are rare. Thyroid hormone therapy is indicated only if hypothyroidism is present, as suppression therapy is ineffective. Calcium and vitamin D therapy is indicated in those patients with associated hypoparathyroidism. There have been several reports of disease improvement with glucocorticoid therapy, and relapses have reversed with the reinstitution of steroids; however, it has not been helpful in all instances. Tamoxifen has been reported to cause disease regression in a few case reports. Its mechanism of action is unclear; however, it may play a role in fibroblastic proliferation inhibition (45).

Riedel’s thyroiditis is usually progressive; however, it may stabilize or remit spontaneously. Following surgery, the disease can remit or be self-limiting. Repeat surgery is only rarely required. Mortality rates range from 6 to 10%, with deaths usually attributed to asphyxia secondary to tracheal compression or laryngospasm. However, these mortality rates are derived from older literature, and may not reflect (the presumably lower) current rates. In many instances, the condition is self-limiting, and improvement often persists after isthmic wedge resection.