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© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59

Thyroiditis
NK Agrawal*

T

Introduction

hyroiditis is defined as inflammation of the thyroid. The clinical picture varies from hyper to hypothyroidism during the natural course of the disease (Table 1).

Etiology
The etiological factors are divided depending on the acute, subacute or chronic disease caused.1 Acute thyroiditis Usually bacterial, acute thyroiditis can also be fungal, mycobacterial or parasitic (Fig. 1). Mostly, there is preexisting thyroid disease (carcinoma, Hashimoto’s thyroiditis, or multinodular goiter), congenital anomalies (e.g. pyriform sinus fistula in children) or patients are immunocompromised (elderly or debilitated). Patients are acutely ill, have fever, dysphagia, anterior neck pain, erythema and a tender thyroid mass with abscess. Presentations of fungal infection, parasitic infection and opportunistic thyroid infection in patient with AIDS usually tend to be chronic and insidious. The leukocyte count and ESR are raised; however, thyroid function is usually normal. The radioiodine scanning shows “cold” suppurative area. Fine needle aspiration biopsy (FNAb) with staining (gram, AFB or fungal stain) and culture is diagnostic. Most patients with a first episode and all patients with recurrent episodes should undergo a CT or MRI of the neck to look for a communicating fistula. Pyriform fossa must be surgically excised.2 Appropriate antibiotic therapy should be initiated and drainage of abscess should be considered. Subacute thyroiditis Painful subacute thyroiditis, 5% of clinical thyroid disease, often follows a viral upper respiratory illness (mumps, coxsackie, influenza and adenovirus).2 It is the commonest cause of thyroid pain. Fever, dysphagia, malaise, fatigue, anxiety, sweats may occur. Thyroid is exquisitely tender, hard, mild to moderately enlarged and often nodular. The pain in neck or thyroid is constant or dull, often aggravated by neck movements or Table 1 : Etiological classification
Acute Infective: Bacterial : staphylococcus, streptococcus and enterobacter Fungal: aspergillus, candida , histoplasma, pneumocystis Radiation thyroiditis (131I therapy) Drug: Amiodarone induced thyroiditis Subacute Infective: Viral (or granulomatous) thyroiditis Mycobacterial infection Silent Thyroiditis (including postpartum thyroiditis) Chronic Autoimmune: focal thyroiditis, Hashimoto’s thyroiditis, atrophic thyroiditis Reidel’s thyroiditis Infective: Parasitic : Echinococcosis, cysticercosis Traumatic : after palpation
* Associate Professor and Head Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005. INDIA

swallowing, and may radiate to the jaw, ear or occiput. Initial thyrotoxicosis (lasting 3-6 weeks) is followed by transient hypothyroid phase (4-6 months). In active phase, the ESR is often more than 100 mm/hr associated with elevated C-reactive protein (CRP), increased thyroglobulin (Tg) level and low radioactive iodine uptake (RAIU). The serum T3:T4 (ng/dl: µg/ dl) ratio is less than 20. High thyroglobulin level differentiates it from exogenous thyroxine ingestion. Thyroid autoantibodies are negative or low in titre; Doppler study reveals hypoechogenic glands with low to normal vascularity. In contrast, the gland is hypervascular in Graves’ disease. Subacute thyroiditis is usually self-limiting; euthyroidism is achieved in 95% patients over 6-12 months with rare relapse rate (up to 4%). Nonsteroidal anti-inflammatory drugs suffice for mild to moderate pain. In severe cases, oral prednisolone up to 40 mg/ day decreases pain and swelling often within a few hours.2 The diagnosis of subacute thyroiditis be reconsidered if pain does not improve after 72 hours. b blockers such as propranolol are useful for sympathetic effects of thyrotoxicosis. If hypothyroid phase is prolonged, levothyroxine (50-100µg daily; low dose to allow TSH mediated recovery) may be initiated. Thyroid tuberculosis is rare; a tubercular abscess, usually subacute, can mimic acute thyroiditis. FNAb and history of tuberculosis can be diagnostic. Treatment with antitubercular drugs results in complete recovery.3 Autoimmune thyroid disorder (AITD) AITD is the most common organ specific autoimmune disorder comprising of Graves’ disease, Hashimoto’s thyroiditis (goitrous), atrophic thyroiditis, postpartum thyroiditis, silent thyroiditis and thyroid associated ophthalmopathy.3 These may occur sequentially and sometimes synchronously, in the same patient. These disorders share antibodies against thyroglobulin (Tg Ab), thyroid peroxidase (TPO Ab) and TSH receptor (TSH-R Ab) besides some minor antigen such as Na-I transporter.4 Middle age women and men are commonly affected. About 2-4% of women and up to 1% of men are affected worldwide. It is more common with advancing age; more than 10% of population of age above 75 years is affected.5 Clinical features, autoantibody status, ultrasonographic features and FNAb findings are very useful in diagnosis of AITD.

Fig. 1 : Acute suppurative thyroiditis

symmetrically enlarged thyroid gland. 3). AITD is a component of some rare monogenic syndromes.12 Atrophic thyroiditis present with features of hypothyroidism without significant thyroid enlargement. Thyroid antibodies have been found in nearly half of the relatives of AITD patients against only 8-27% in general population. higher prevalence of AITD has been found in patients and their relatives. in association with anti-thyroid antibodies and a high normal or elevated TSH level is virtually diagnostic of Hashimoto’s thyroiditis. removal of causative agent (such as iodine) or recovery from destructive thyroiditis.11 The most common presentation in Graves’ disease is diffusely enlarged firm goitre with hyperthyroidism and thyroid associated ophthalmopathy (Fig.8 Environmental factors Environmental factors either trigger or enhance development of thyroid autoimmunity. Epstein Barr virus. Stress disorders are shown to be associated with Graves’ disease probably by altering neuroendocrine interaction with immune system. The risk of AITD in female sibling and children of patient with Graves’ disease is 5-8% against the background frequency of 0. Thyroid ultrasonography could be useful for diagnosis of autoimmune thyroiditis especially in . It is 80 times more common in patients with Hashimoto’s thyroiditis than in general population. AITD is more common in women. 2). Thyroid lymphoma is a very rare but serious complication of chronic autoimmune thyroiditis. with additional environmental and hormonal factor that trigger or contribute to the development of disease. CTLA-4 gene is a major candidate gene for common autoimmune disorders like Graves’ disease. 3 : Graves’ disease Predisposition Each patient has a background inherited predisposition to autoimmunity. is its key negative regulator. Autoimmune hypothyroidism affects patient with type 1 polyendocrinopathy. 59 47 Fig. interferon-α and amiodarone exacerbate AITD. The lymphomas are usually of non-Hodgkin’s B–cell type and tend to occur in older women. HLA-A10. Proptosis and other eye manifestations of thyroid disease can occur in these patients.© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. AITD continue to occur after the menopause and it is seen in many women so perhaps it is the X chromosome that is responsible element in female susceptibility. ‘polyendocrinopathy’ and enteropathy [IPEX]. Hashimoto’s thyroiditis. Drugs like lithium. Hashimoto’s thyroiditis presents with small to large firm and painless goiter (Fig. Graves’ disease is associated with thyrotoxicosis and diffuse goitre. Patients slowly develop progressive hypothyroidism. Female sex steroid may be responsible for this difference.6%. 2 : Hashimoto’s thyroiditis Fig. Hashimoto’s thyroiditis is associated with other autoimmune diseases including pernicious anemia.7 Cytotoxic T lymphocyte antigen-4 (CTLA-4). hypothyroidism without goitre could be due to atrophic thyroiditis. 4 : Heterogenous echotexture in thyroiditis in smokers. yersinia and recently. Fig.5 In other autoimmune disorders. Type-1 diabetes and Hashimoto’s thyroiditis. but are usually less severe than in Graves’ disease.13 Diagnosis of autoimmune thyroid disorders A firm. The predisposition to Graves’ disease is genetic in 79% case while only 21% cases are due to non genetic (environmental and hormonal) factors. High dietary iodine intake enhances thyroglobulin immune reactivity. Different alleles of MHC class I molecule are shown to be associated with Graves’ disease in different ethnic group e. postpartum thyroiditis in the initial phase can present with thyrotoxicosis and goiter. immune dysregulation. organisms like rubella. Hypothyroid patient may recover after the loss of TSH-receptor blocking antibody. but a smaller number with moderate or even severe hypothyroidism eventually become euthyroid. sporadic thyroiditis. 6. retrovirus have been implicated.10 Graves’ ophthalmopathy is common Clinical Features of Autoimmune Thyroid Disorders The clinical features depend upon type and stages of the disease. It is also associated with a central nervous system disorder called Hashimoto’s encephalopathy which is associated with anti-thyroid antibodies and respond to glucocorticoids. Genetic factors The concordance rate in monozygotic twins is 35-55% as compared to less than 5% in dizygotic twins. an immunomodulatory molecule expressed on the surface of activated T cell.g.9 Pathogenic role of infective agents in initiating AITD is unclear. Thyrotoxicosis could be initial presentation in few cases. Women have two X chromosomes therefore would receive twice the gene dose. B8 and DQw2 is seen in India.

colloid is scanty in amount. Estimation of thyroid autoantibodies and TSH. Methimazole and propylthiouracil) are initial treatment of choice in Graves’ disease. breast-feeding should be stopped for 3 days. Initial cases may show focal lesions accidentally biopsied with the help of ultrasonography. In thyrotoxic phase. A characteristic feature is the well developed follicular lesion that consists of a central core of colloid surrounded by the multinucleated giant cells that arise from the fusion of macrophages. Nearly 80% of the women completely recover with normal thyroid function with very high chance of recurrence (70%) in subsequent pregnancies.15 In Hashimoto’s thyroiditis. with 3 fold increase risk of PPT in women with type 1 diabetes. Lymphoid germinal centers are absent with few. which is defined as the presence of fetal cells in maternal tissues during and after pregnancy. 4. however. Thyroid enlargement with diffuse hypoechogenecity favour autoimmune thyroid disease. plasma cell and macrophages. During breast-feeding. Color flow Doppler (CFD) is helpful for semiquantitative measurement of blood flow to thyroid gland. 5 : Thyroiditis with micronodules Fig. plasma cells with normalization of histological changes once disease subsides. Propranolol and other long acting b-blocker are useful in controlling of adrenergic symptoms. Fibrosis is present in more long standing disease. interruption of breast-feeding for only 24 hours is required. and are thrown in to papillary folds that extend into the lumina of the follicles. T3:T4 are useful in diagnosis of AITD. 6). Carbimazole is started at a dose of 30-45 mg / day and propylthiouracil is started at the dose of 200-400 mg/day. some follicular cells are atrophic or damaged and many are hyperplastic or metaplastic. These remaining thyroid follicular cells may be large and show oxyphilic changes in the cytoplasm.4 In Graves’ disease thyrotropin levels are suppressed. Intrathyroidal fetal immune cells may be activated because of postpartum loss of placental immune suppression. the so-called oxyphilic cell / Hurthle cells/ Askanazy cells. 59 Fig. DR-5 and thyroid autoantibodies have shown association with PPT. There is transient thyrotoxicosis (1-2 months) followed by transient hypothyroidism (2-9 months). disrupted follicles with micro abscesses form as some follicles are filled with polymorphonuclear leukocytes. maintenance therapy continued for a period of 12 to 24 months. the administration of Iodine131 is contraindicated. So both follicular cells and colloid are destroyed focally. It may also occur after loss of pregnancy at 5–20 wk gestation. Radioactive iodine uptake study helps differentiating Graves’ disease and thyroiditis associated transient hyperthyroidism. A potential immunomodulatory factor for PPT is fetal microchimerism. Thyrotoxic phase may be treated with β-blocker while it is pragmatic to treat all postpartum hypothyroid women for 1 year then to stop thyroxin for reevaluating thyroid function. Vascularity is increased and there is a varying heterogeneous infiltration by lymphocytes and plasma cells and may form infrequent germinal centers (Fig. HLA-DR3. . Painless postpartum thyroiditis (PPT) Postpartum thyroiditis is destructive thyroiditis during the first 12 month postpartum. 6 : Increased vascularity children where biopsy and antibodies are not feasible in each case. DR-4. Fine needle aspiration biopsy (FNAb) is very much useful in diagnosis of AITD. By using technetium (99 mTc) pertechnetate. Routine measurement of TSHR antibodies titres are not performed for diagnosis of Graves’ disease. In Graves’ disease there is hypertrophy and hyperplasia of thyroid follicles. In Hashimoto’s thyroiditis there is raised TSH level and raised antiTPO antibodies. Suppurative thyroiditis is characterized by abscess formation while Riedel’s thyroiditis characterized by dense fibrosis. Sporadic thyroiditis and postpartum thyroiditis fall into the spectrum of autoimmune thyroid disease with less remarkable lymphocytic infiltration. Germinal centre with giant cell is also seen. When I123 is used. Other treatment options for Graves’ disease include radioiodine therapy and surgery. Antithyroid drugs (Carbimazole. Ophthalmopathy and TSH receptor antibody (TSHR-Ab) are absent unless there is coexisting Graves’ disease. microscopic findings are characterized by extensive infiltrate with lymphocytes. ESR is normal with low radioactive iodine uptake (RAIU). Regardless of chosen antithyroid drugs. Half of the women developed permanent hypothyroidism in next 7 year underscoring the need of long term follow-up. Others features include obliteration of thyroid follicles by widespread apoptosis.14 Children may initially have normal ultrasonography but characteristic changes can appear after several months (Figs. 5). It occurs in 5-9% of unselected postpartum women. Classic triphasic thyroid hormone pattern is seen in only one third of patient. Doppler finding in Graves’ disease is characterized by distinct CFD pattern with marked increased in signals with patchy distribution. In subacute thyroiditis. high titres of TPO or Tg antibodies or both are seen.48 © SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. Treatment Hashimoto’s thyroiditis with hypothyroidism is best treated with L-thyroxine replacement. If thyrotoxicosis presents at about 14 weeks postpartum.15 Both cellular and humoral immune reactions are involved. if any. the cells are tall columnar.

Drug should be discontinued. Autoimmune thyroiditis can be seen in children and adults. although there is no immediate benefit as it has prolonged half-life and storage.19 Baseline assessment by TSH and TPO-Ab measurements and follow-up assessments every 6 months by TSH should be done. Tg-Ab measurements should be performed before therapy.20 Conclusion • Thyroiditis is inflammation of the gland. The two forms of AIT are difficult to distinguish from each other. The pathogenesis is either augmentation of pre-existing autoimmunity or by direct action of lithium on hormone secretion. Corticosteroids are generally contraindicated in hepatitis C patients. Frequently. Severe hypothyroidism is unusual but does occur as does the loss of parathyroid function. • • • . recurrent laryngeal nerve). with the addition of potassium perchlorate (500mg BD for 2-6 weeks) to prevent further uptake of iodine. Genetic factors and hepatitis C virus infection itself also play an important role. There is fibrosis of thyroid and adjacent structures. Amiodarone may compete with T3 for binding to the thyroid hormone receptor and also inhibits deiodinases.17 Lithium may cause hyperthyroidism due to thyroiditis (silent. the drug resembles T4 and contains 37% of iodine by weight. and increased thyroid hormone clearance. TPO-Ab. if possible. The thyroid toxicity includes hypothyroidism and sunitinib-induced thyroiditis. colourflow doppler ultrasound may reveal hypervascularity in type I disease while in type II disease. However.© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. IFNα can induce or aggravate autoimmunity. GD is less common. a destructive thyroiditis (transient thyrotoxicosis followed by reversible hypothyroidism). Hashimoto’s thyroiditis (HT) is commonest and patients have pre-existing TPO antibodies. and Sunitinib. Hashimoto’s thyroiditis (HT) or thyroid autoantibodies production without clinical disease (TAb’s)] or non-autoimmune [destructive thyroiditis or non-autoimmune hypothyroidism]. Symptoms are due to compression of adjacent structures (trachea.16 Drug induced thyroiditis The drugs known to provoke autoimmune or destructive inflammatory thyroiditis are lithium. Type I AIT is best treated with high doses of antithyroid drugs (methimazole or propylthiouracil). If the TSH level is normal and TAb’s negative. increased MIBI retention occurs due to increased uptake of 99mTc-sestaMIBI scan in epithelial cells with high numbers of mitochondria. There is stony hard usually asymmetrical goitre without involvement of regional lymph nodes. but TAb’s are positive. About 23% of patients receiving amiodarone can develop amiodaroneinduced-thyrotoxicosis (AIT). TSH. sometimes granulomatous) or rarely Graves’ disease indicating lithium induced direct damage to thyroid cells. Subacute thyroiditis has high ESR and is self limiting mostly requiring NSAIDS.It can be differentiated from GD based on negative TSHR-Ab and low thyroid RAIU. TSH levels should be monitored every three months until completion of IFNα course. Graves’ disease after IFNα therapy is treated with radioiodine thyroid ablation with and/or surgery. interferon. The acute thyroiditis mostly affects immunocompromised. Possible pathophysiologic mechanisms are impaired thyroid hormone synthesis. and sometimes steroids. esophagus. Interferon induced thyroiditis [IIT] may be autoimmune [Graves’ disease (GD). and children with pyriform sinus fistula. Upto 50% of IIT cases usually manifests as self-limited destructive thyroiditis .18 Amiodarone Structurally. thyroid surgery is appropriate. AIT is more prevalent in males and in regions with iodine-deficiency. leading to goiter and hypothyroidism. The etiology could be immune or directs thyroid toxic effects of IFNα. amiodarone. Interferon Alfa Interferon induced thyroiditis (IIT) is a common complication of interferon a (IFNa) therapy of chronic hepatitis C with up to 10% of patients developing clinical thyroiditis and up to 30% developing subclinical autoimmune thyroiditis. and may be associated with fibrosis in retroperitoneal area or elsewhere. in hyperfunctioning thyroid tissue. Lithium has also been suggested as therapy for type I disease. acute due to bacteriae. TSH. emerging as novel cancer therapies in renal cell carcinoma and gastrointestinal stromal tumours. Type II AIT is a destructive thyroiditis with release of preformed thyroid hormone. Hypothyroidism develops twice as frequently as would be expected among a mixed-age population. Radioactive iodine 131I therapy is also feasible now by increasing the 24-h RAIU with the use of recombinant TSH. Circulating thyroid autoantibodies are less common and RAIU may be normal or low. Thyrotoxic phase of inflammatory thyroiditis can be treated with b-blockers. Reidel’s thyroiditis It is a rare chronic sclerosing thyroiditis. interleukin-2. Antithyroid drugs can worsen the thyroid dysfunction. It also provides a huge amount (37%) of iodide. FT4 and TPO antibodies are measured before therapy and annually while on treatment or more frequently in thyroid antibody positive older women. subacute due to viral infections while chronic predominantly due to autoimmune disease. reduced blood flow might be apparent. If amiodarone therapy is necessary. The treatment aims at relief of compressive symptoms surgically. the hypothyroidism is transient and resolves spontaneously upon completion of IFNα therapy. Sunitinib It is a protein tyrosine kinase inhibitor. 59 49 Sporadic / silent thyroiditis Painless PPT and sporadic thyroiditis are indistinguishable except by the relation of the former to pregnancy. Levothyroxine is supplemented and monitored with TSH level as T4 level is often increased due to deiodinase inhibition. Non-autoimmune IIT can also manifest by hypothyroidism without TAb’s. Hypothyroidism can be treated with levothyroxine. measure TSH levels every two months since clinical thyroid disease is much more likely to develop. Type I AIT is iodine-induced and more likely to occur in preexisting nodular goiter. Use of tamoxifen has been successful in some patients. typically occuring in middle aged women. fungi or paasites. Type II amiodarone-induced thyrotoxicosis responds to high-dose corticosteroids (prednisolone 20-40 mg/day). Amiodarone-induced hypothyroidism [AIH] occurs in up to 20 percent of patients preferentially in iodine-sufficient regions between 6 and 18 months of amiodarone treatment and in females with TPO-Ab.19 AIT onset is often sudden with suppressed TSH which returns to normal in half of the cases. If TSH levels are normal. Lithium The common clinical side effects of the drug are goiter (upto 40%) and hypothyroidism (upto 20%). Also.

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