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Thyroiditis
NK Agrawal*

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, Hashimotos 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, Hashimotos thyroiditis, atrophic thyroiditis Reidels 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: g/ 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. blockers such as propranolol are useful for sympathetic effects of thyrotoxicosis. If hypothyroid phase is prolonged, levothyroxine (50-100g 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, Hashimotos 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

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Fig. 2 : Hashimotos thyroiditis

Fig. 4 : Heterogenous echotexture in thyroiditis

in smokers. Drugs like lithium, interferon-a and amiodarone exacerbate AITD. AITD is more common in women. Female sex steroid may be responsible for this difference. 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. Women have two X chromosomes therefore would receive twice the gene dose.
Fig. 3 : Graves disease

Predisposition
Each patient has a background inherited predisposition to autoimmunity, with additional environmental and hormonal factor that trigger or contribute to the development of disease. Genetic factors The concordance rate in monozygotic twins is 35-55% as compared to less than 5% in dizygotic twins. The predisposition to Graves disease is genetic in 79% case while only 21% cases are due to non genetic (environmental and hormonal) factors. Thyroid antibodies have been found in nearly half of the relatives of AITD patients against only 8-27% in general population. The risk of AITD in female sibling and children of patient with Graves disease is 5-8% against the background frequency of 0.6%.5 In other autoimmune disorders, higher prevalence of AITD has been found in patients and their relatives. AITD is a component of some rare monogenic syndromes. Autoimmune hypothyroidism affects patient with type 1 polyendocrinopathy; immune dysregulation, polyendocrinopathy and enteropathy [IPEX]. Different alleles of MHC class I molecule are shown to be associated with Graves disease in different ethnic group e.g. HLA-A10, B8 and DQw2 is seen in India. 6,7 Cytotoxic T lymphocyte antigen-4 (CTLA-4), an immunomodulatory molecule expressed on the surface of activated T cell, is its key negative regulator. CTLA-4 gene is a major candidate gene for common autoimmune disorders like Graves disease, Type-1 diabetes and Hashimotos thyroiditis.8 Environmental factors Environmental factors either trigger or enhance development of thyroid autoimmunity. High dietary iodine intake enhances thyroglobulin immune reactivity.9 Pathogenic role of infective agents in initiating AITD is unclear; organisms like rubella, Epstein Barr virus, yersinia and recently, retrovirus have been implicated. Stress disorders are shown to be associated with Graves disease probably by altering neuroendocrine interaction with immune system.10 Graves ophthalmopathy is common

Clinical Features of Autoimmune Thyroid Disorders

The clinical features depend upon type and stages of the disease. Hashimotos thyroiditis presents with small to large firm and painless goiter (Fig. 2). Patients slowly develop progressive hypothyroidism, but a smaller number with moderate or even severe hypothyroidism eventually become euthyroid. Hypothyroid patient may recover after the loss of TSH-receptor blocking antibody, removal of causative agent (such as iodine) or recovery from destructive thyroiditis. Thyrotoxicosis could be initial presentation in few cases. Proptosis and other eye manifestations of thyroid disease can occur in these patients, but are usually less severe than in Graves disease. Hashimotos thyroiditis is associated with other autoimmune diseases including pernicious anemia. It is also associated with a central nervous system disorder called Hashimotos encephalopathy which is associated with anti-thyroid antibodies and respond to glucocorticoids.11 The most common presentation in Graves disease is diffusely enlarged firm goitre with hyperthyroidism and thyroid associated ophthalmopathy (Fig. 3).12 Atrophic thyroiditis present with features of hypothyroidism without significant thyroid enlargement. Thyroid lymphoma is a very rare but serious complication of chronic autoimmune thyroiditis. It is 80 times more common in patients with Hashimotos thyroiditis than in general population. The lymphomas are usually of non-Hodgkins Bcell type and tend to occur in older women.13 Diagnosis of autoimmune thyroid disorders A firm, symmetrically enlarged thyroid gland, in association with anti-thyroid antibodies and a high normal or elevated TSH level is virtually diagnostic of Hashimotos thyroiditis; hypothyroidism without goitre could be due to atrophic thyroiditis. Graves disease is associated with thyrotoxicosis and diffuse goitre. Hashimotos thyroiditis, sporadic thyroiditis, postpartum thyroiditis in the initial phase can present with thyrotoxicosis and goiter. Thyroid ultrasonography could be useful for diagnosis of autoimmune thyroiditis especially in

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Fig. 5 : Thyroiditis with micronodules

Fig. 6 : Increased vascularity

children where biopsy and antibodies are not feasible in each case.14 Children may initially have normal ultrasonography but characteristic changes can appear after several months (Figs. 4, 5). Thyroid enlargement with diffuse hypoechogenecity favour autoimmune thyroid disease. Color flow Doppler (CFD) is helpful for semiquantitative measurement of blood flow to thyroid gland. Doppler finding in Graves disease is characterized by distinct CFD pattern with marked increased in signals with patchy distribution. Estimation of thyroid autoantibodies and TSH, T3:T4 are useful in diagnosis of AITD. In Hashimotos thyroiditis there is raised TSH level and raised antiTPO antibodies.4 In Graves disease thyrotropin levels are suppressed. routine measurement of TSHr antibodies titres are not performed for diagnosis of Graves disease. radioactive iodine uptake study helps differentiating Graves disease and thyroiditis associated transient hyperthyroidism. Fine needle aspiration biopsy (FNAb) is very much useful in diagnosis of AITD.15 In Hashimotos thyroiditis, microscopic findings are characterized by extensive infiltrate with lymphocytes, plasma cell and macrophages. Initial cases may show focal lesions accidentally biopsied with the help of ultrasonography. Germinal centre with giant cell is also seen. Others features include obliteration of thyroid follicles by widespread apoptosis, 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, the so-called oxyphilic cell / Hurthle cells/ Askanazy cells. Fibrosis is present in more long standing disease. In Graves disease there is hypertrophy and hyperplasia of thyroid follicles, colloid is scanty in amount, the cells are tall columnar, and are thrown in to papillary folds that extend into the lumina of the follicles. Vascularity is increased and there is a varying heterogeneous infiltration by lymphocytes and plasma cells and may form infrequent germinal centers (Fig. 6). In subacute thyroiditis, disrupted follicles with micro abscesses form as some follicles are filled with polymorphonuclear leukocytes. So both follicular cells and colloid are destroyed focally. 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. Lymphoid germinal centers are absent with few, if any, plasma cells with normalization of histological changes once disease subsides. Sporadic thyroiditis and postpartum thyroiditis fall into the spectrum of autoimmune thyroid disease with less remarkable lymphocytic infiltration. Suppurative thyroiditis is

characterized by abscess formation while riedels thyroiditis characterized by dense fibrosis.

Treatment
Hashimotos thyroiditis with hypothyroidism is best treated with L-thyroxine replacement. Antithyroid drugs (Carbimazole, Methimazole and propylthiouracil) are initial treatment of choice in Graves disease. Carbimazole is started at a dose of 30-45 mg / day and propylthiouracil is started at the dose of 200-400 mg/day. Propranolol and other long acting -blocker are useful in controlling of adrenergic symptoms. regardless of chosen antithyroid drugs, maintenance therapy continued for a period of 12 to 24 months. Other treatment options for Graves disease include radioiodine therapy and surgery. Painless postpartum thyroiditis (PPT) Postpartum thyroiditis is destructive thyroiditis during the first 12 month postpartum. It occurs in 5-9% of unselected postpartum women, with 3 fold increase risk of PPT in women with type 1 diabetes. It may also occur after loss of pregnancy at 520 wk gestation.15 Both cellular and humoral immune reactions are involved; HLA-Dr3, Dr-4, Dr-5 and thyroid autoantibodies have shown association with PPT. A potential immunomodulatory factor for PPT is fetal microchimerism, which is defined as the presence of fetal cells in maternal tissues during and after pregnancy. Intrathyroidal fetal immune cells may be activated because of postpartum loss of placental immune suppression. There is transient thyrotoxicosis (1-2 months) followed by transient hypothyroidism (2-9 months). If thyrotoxicosis presents at about 14 weeks postpartum, high titres of TPO or Tg antibodies or both are seen. Classic triphasic thyroid hormone pattern is seen in only one third of patient. Nearly 80% of the women completely recover with normal thyroid function with very high chance of recurrence (70%) in subsequent pregnancies. Half of the women developed permanent hypothyroidism in next 7 year underscoring the need of long term follow-up. In thyrotoxic phase, ESr is normal with low radioactive iodine uptake (rAIU). During breast-feeding, however, the administration of Iodine131 is contraindicated. When I123 is used, breast-feeding should be stopped for 3 days. By using technetium (99 mTc) pertechnetate, interruption of breast-feeding for only 24 hours is required. Ophthalmopathy and TSH receptor antibody (TSHr-Ab) are absent unless there is coexisting Graves disease. Thyrotoxic phase may be treated with -blocker while it is pragmatic to treat all postpartum hypothyroid women for 1 year then to stop thyroxin for reevaluating thyroid function.

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Sporadic / silent thyroiditis Painless PPT and sporadic thyroiditis are indistinguishable except by the relation of the former to pregnancy. Reidels thyroiditis It is a rare chronic sclerosing thyroiditis, typically occuring in middle aged women. There is fibrosis of thyroid and adjacent structures, and may be associated with fibrosis in retroperitoneal area or elsewhere. Symptoms are due to compression of adjacent structures (trachea, esophagus, recurrent laryngeal nerve). There is stony hard usually asymmetrical goitre without involvement of regional lymph nodes. Severe hypothyroidism is unusual but does occur as does the loss of parathyroid function. Circulating thyroid autoantibodies are less common and rAIU may be normal or low. The treatment aims at relief of compressive symptoms surgically. Use of tamoxifen has been successful in some patients.16 Drug induced thyroiditis The drugs known to provoke autoimmune or destructive inflammatory thyroiditis are lithium, amiodarone, interferon, interleukin-2, and Sunitinib. Lithium The common clinical side effects of the drug are goiter (upto 40%) and hypothyroidism (upto 20%). The pathogenesis is either augmentation of pre-existing autoimmunity or by direct action of lithium on hormone secretion, leading to goiter and hypothyroidism. Hypothyroidism develops twice as frequently as would be expected among a mixed-age population. TSH, FT4 and TPO antibodies are measured before therapy and annually while on treatment or more frequently in thyroid antibody positive older women.17 Lithium may cause hyperthyroidism due to thyroiditis (silent, sometimes granulomatous) or rarely Graves disease indicating lithium induced direct damage to thyroid cells. 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. Interferon induced thyroiditis [IIT] may be autoimmune [Graves disease (GD), Hashimotos thyroiditis (HT) or thyroid autoantibodies production without clinical disease (TAbs)] or non-autoimmune [destructive thyroiditis or non-autoimmune hypothyroidism]. Hashimotos thyroiditis (HT) is commonest and patients have pre-existing TPO antibodies. GD is less common; IFNa can induce or aggravate autoimmunity. Upto 50% of IIT cases usually manifests as self-limited destructive thyroiditis .It can be differentiated from GD based on negative TSHr-Ab and low thyroid rAIU. Non-autoimmune IIT can also manifest by hypothyroidism without TAbs. Frequently, the hypothyroidism is transient and resolves spontaneously upon completion of IFNa therapy. The etiology could be immune or directs thyroid toxic effects of IFNa. Genetic factors and hepatitis C virus infection itself also play an important role. Thyrotoxic phase of inflammatory thyroiditis can be treated with -blockers. Corticosteroids are generally contraindicated in hepatitis C patients. Graves disease after IFNa therapy is treated with radioiodine thyroid ablation with and/or surgery. Antithyroid drugs can worsen the thyroid dysfunction. Hypothyroidism can be treated with levothyroxine. TSH, TPO-Ab, Tg-Ab measurements should be

performed before therapy. If the TSH level is normal and TAbs negative, TSH levels should be monitored every three months until completion of IFNa course. If TSH levels are normal, but TAbs are positive, measure TSH levels every two months since clinical thyroid disease is much more likely to develop.18 Amiodarone Structurally, the drug resembles T4 and contains 37% of iodine by weight. Amiodarone may compete with T3 for binding to the thyroid hormone receptor and also inhibits deiodinases. It also provides a huge amount (37%) of iodide. About 23% of patients receiving amiodarone can develop amiodaroneinduced-thyrotoxicosis (AIT). AIT is more prevalent in males and in regions with iodine-deficiency.19 AIT onset is often sudden with suppressed TSH which returns to normal in half of the cases. Type I AIT is iodine-induced and more likely to occur in preexisting nodular goiter. Type II AIT is a destructive thyroiditis with release of preformed thyroid hormone. The two forms of AIT are difficult to distinguish from each other. However, colourflow doppler ultrasound may reveal hypervascularity in type I disease while in type II disease, reduced blood flow might be apparent. Also, in hyperfunctioning thyroid tissue, increased MIBI retention occurs due to increased uptake of 99mTc-sestaMIBI scan in epithelial cells with high numbers of mitochondria. Drug should be discontinued, if possible, although there is no immediate benefit as it has prolonged half-life and storage. Type I AIT is best treated with high doses of antithyroid drugs (methimazole or propylthiouracil), with the addition of potassium perchlorate (500mg BD for 2-6 weeks) to prevent further uptake of iodine. Lithium has also been suggested as therapy for type I disease. Type II amiodarone-induced thyrotoxicosis responds to high-dose corticosteroids (prednisolone 20-40 mg/day). If amiodarone therapy is necessary, thyroid surgery is appropriate. radioactive iodine 131I therapy is also feasible now by increasing the 24-h rAIU with the use of recombinant TSH.19 Baseline assessment by TSH and TPO-Ab measurements and follow-up assessments every 6 months by TSH should be done. 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. Levothyroxine is supplemented and monitored with TSH level as T4 level is often increased due to deiodinase inhibition. Sunitinib It is a protein tyrosine kinase inhibitor, emerging as novel cancer therapies in renal cell carcinoma and gastrointestinal stromal tumours. The thyroid toxicity includes hypothyroidism and sunitinib-induced thyroiditis. Possible pathophysiologic mechanisms are impaired thyroid hormone synthesis, a destructive thyroiditis (transient thyrotoxicosis followed by reversible hypothyroidism), and increased thyroid hormone clearance.20

Conclusion
Thyroiditis is inflammation of the gland; acute due to bacteriae, fungi or paasites, subacute due to viral infections while chronic predominantly due to autoimmune disease. The acute thyroiditis mostly affects immunocompromised, and children with pyriform sinus fistula. Subacute thyroiditis has high ESR and is self limiting mostly requiring NSAIDS, and sometimes steroids. Autoimmune thyroiditis can be seen in children and adults.

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Ultrasonography, detection of autoantibodies helps in diagnosis. Hypothyroid patients are replaced with thyroxine titrated to TSH level (~1U/ml).

8.

Oaks MK, Hallett KM. Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J Immunol. 2000;164:5015-8. Papanastasiou L, Vatalas IA, Koutras DA et al. Thyroid autoimmunity in current iodine environment. Thyroid 2007;17:72939. Manto Santos A, Nobre EL, Costa JG, et al. relationship between the number and impact of stressful life events and onset of Graves disease and toxic multinodular goiter .Clinic Endocrinol 2001;55:15-9. Chong J y, rowland LP, Utiger rD. Hashimoto encephalopathy syndrome or myth ? Arch Neurol 2003;60:164-71. Brent GA. Graves disease. N Engl J Med 2008;358:2954-605. Aozasa K, Inoue A, Tajima K et al. Malignant lymphoma of the thyroid gland: analysis of 79 patients with emphasis on histologic prognostic factors .Cancer 1986;58:100-4. Sostre S, reyes MM. Sonographic diagnosis and grading of Hashimotos thyroiditis. J Endocrinol Invest 1991;14:115-21. Weetman AP. Chronic autoimmune thyroiditis. In: Braverman LE, Utiger rD (Eds). Werner and Ingbars The Thyroid (9th edition) Lippincott Williams and Wilkins Hagerstown, MD 2005;536-47. Jung yJ, Schaub Cr, rhodes r et al. A case of reidels thyroiditis treated with Tamoxifen: another successful outcome. Endo Pract 2004;10:483-6. Kirov G, Tredget J, John r, et al. A cross-sectional and a prospective study of thyroid disorders in lithium-treated patients. J Affect Disord. 2005;87:313-7. Tomer y, Menconi F. Interferon induced thyroiditis. Best Pract Res Clin Endocrinol Metab 2009;23:70312. Eskes SA, Wiersinga WM. Amiodarone and thyroid. Best Pract Res Clin Endocrinol Metab. 2009;23:73551. Vetter ML, Kaul S, Iqbal N. Tyrosine kinase inhibitors and the thyroid as both an unintended and an intended target. Endocr Pract. 2008;14:618-24.

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Acknowledgement
These USG photographs are courtesy Prof. rC Shukla, Dr. Sriram S Patwari and Dr. Manali Gupta, Department of radiodiagnosis and Imaging, Institute of Medical Sciences, Banaras Hindu University, Varanasi.

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11. 12. 13.

References
1. Jameson JL, Weetman AP. Disorders of thyroid gland. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J. (Eds). Harrisons Principles of Internal Medicine (17th edition), McGraw Hill Companies, Incorporated New york. 2008;2224-2247. Brent GA, Davies TF, Larsen Pr. Hypothyroidism and thyroditis. In : Kronenberg HM, Melmed S, Polonsky KS, Larsen Pr (Eds). Williams Textbook of Endocrinology (11th edition) Saunders Elsevier Philadelphia PA. 2008;377-409. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-55. Weetman AP. Chronic autoimmune thyroiditis. In: Braverman LE, Utiger rD (Eds). Werner and Ingbars The Thyroid (9th edition) Lippincott fet Williams and Wilkins Hagerstown, MD 2005;702-13. McGrogan A, Seaman HE, Wright JW et al. The incidence of autoimmune thyroid disease: a systematic review of the literature. Clin Endocrinol (Oxf). 2008;69:687-96. Brix TH, Kyvik KO, Christensen K et al. Evidence for a major role of heredity in Graves disease: a population based study of two Danish cohorts. J Clin Endocrinol Metab. 2001;86:930-4. Tandon N, Zhang L, Weetamn AP. HLA association with Hashishmotos thyroiditis. Clin Endocrinol (Oxf). 199;34:383-6.

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