THYROIDITIS – A REVIEW

Thyroiditis is a group of inflammatory thyroid disorders. Clinical presentation of different types of thyroiditis is diverse. Management of different thyroiditis depends on clear understanding of natural history of the disease and their presentation. This review will emphasize the clinical presentation along with laboratory investigations of different thyroiditis which ultimately guide their management. Definition and classification of thyroiditis: The term “thyroiditis” encompasses a diverse group of diseases that have inflammation, fibrosis or lymphocytic infiltration as the most prominent feature. Although classified as thyroiditis, each disease varies in etiology and natural history. The most useful classification of thyroiditis is based on the onset of signs and symptoms, duration of inflammation or cellular infiltration and persistence of thyroid pathology.

1. Medicine Specialist, United Hospital.physician Hashimoto in 1912.It is the most common inflammatory condition of the thyroid gland and the most common cause of goiter in the United States. 1,2,3It is an autoimmune condition characterized by high titers of circulating antibodies to thyroid peroxidase and thyroglobulin. 4ronic lymphocytic thyroiditis is the most common cause of hypothyroidism in the United States, and euthyroid persons with Hashimoto's disease develop hypothyroidism at a rate of approximately 5 percent per year. 5Up to 95 percent of cases of chronic lymphocytic thyroiditis occur in women, usually between 30 and 50 years of age. 6Chronic lymphocytic thyroiditis is also the most common cause of sporadic goiter in children. 6,7The incidence of Hashimoto's disease has risen exponentially over the past 50 years, and this increase may be related to an increased iodine content in the North American diet. 7genetic predisposition to thyroid autoimmunity exists; it is inherited as a dominant trait. 8

REVIEW ARTICLES
in patients with chronic lymphocytic thyroiditis.Hashimoto's disease has been linked to other autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, diabetes mellitus and Sjögren's syndrome. 6though Hashimoto's thyroiditis is usually asymptomatic, some patients may complain of a feeling of tightness or fullness in the neck; however, neck pain and tenderness are rare. 7,8At the time of diagnosis, symptoms of hypothyroidism are present in 20 percent of patients. 7Very rarely, patients may present with hyperthyroidism, although this is thought to indicate the coexistence of Graves' disease. 9Physical examination generally reveals a firm, irregular, nontender goiter. 8Regional lymphadenopathy may be present, or the goiter may be large enough to cause dysphagia or recurrent laryngeal nerve dysfunction.The erythrocyte sedimentation rate (ESR) and white blood cell count are normal.The definitive indicator of chronic lymphocytic thyroiditis is the presence of thyroidspecific autoantibodies in the serum.The three main targets for thyroid antibodies are thyroglobulin, thyroid microsomal antigen (also called thyroid peroxidase) and the thyroid-stimulating hormone (TSH) receptor. 8Low levels of circulating antibodies are common in other thyroid diseases, such as multinodular goiter and thyroid malignancy.Antithyroid microsomal antibodies in titers greater than 1:6,400 or antithyroid peroxidase antibodies in excess of 200 IU per mL, however, are strongly suggestive of chronic autoimmune thyroiditis. 8esting of thyroid autoantibodies and measurement of serum thyroglobulin levels will confirm the diagnosis. 8Radioactive iodine uptake (RAIU) is variable and can be depressed, normal or increased, depending on the extent of follicular destruction.Patchy uptake is common, providing little diagnostically useful information. 8Ultrasonography shows an enlarged gland with a diffusely hypoechogenic pattern in most patients.RAIU and thyroid ultrasonography are not necessary parts of the work-up for this disease.A dominant nodule in a patient with Hashimoto's disease should prompt a fine-needle aspiration biopsy to exclude malignancy. 8cause thyroiditis is usually asymptomatic and the goiter is small, many patients do not require treatment. 6When hypothyroidism is present, treatment with thyroxine (T 4 ) is indicated. 8Thyroid hormone replacement therapy is also indicated in patients with a TSH level in the normal range, to reduce goiter size and prevent progression to overt hypothyroidism in high-risk patients. 8Lifetime replacement of levothyroxine is indicated in hypothyroid patients, at a starting dosage of 25 to 50 µg per day, with gradual titration to an average daily dosage of 75 to 150 µg.A lower starting dosage (12.5 to 25 µg per day) and a more gradual titration are recommended in elderly patients and in patients with cardiovascular disease.The dosage may be increased in these patients 25 to 50 µg every four to six weeks until the TSH level is normal. 7,8 patients with an elevated TSH level and a normal thyroxine (T 4 ) level (subclinical hypothyroidism), indications for treatment are less clear.If the TSH level is greater than 20 mU per mL (20 mU per L) with a normal T 4 level, there is a high probability that the patient will develop hypothyroidism.If the TSH level is elevated but is less than 20 mU per mL and the antimicrosomal antibody titer is greater than 1:1,600, hypothyroidism will develop in 80 percent of patients. 6Therefore, it is recommended that treatment be initiated in patients with symptoms of hypothyroidism, in patients with a serum TSH level greater than 10 mU per mL and in patients with a high risk of progression to hypothyroidism (e.g., those with high antibody titers) 9 .Because of the risk of developing hypothyroidism, patients with a history of chronic lymphocytic thyroiditis require annual assessment of thyroid function 9 .

Subacute Lymphocytic Thyroiditis:
Subacute lymphocytic thyroiditis occurs most often in the postpartum period but may also occur sporadically. 8,10Therefore, it is subdivided into two groups, postpartum thyroiditis and sporadic painless thyroiditis.Antimicrosomal antibodies are present in 50 to 80 percent of patients, while antithyroid peroxidase antibodies are present in nearly all patients. 4,7,8A strong association also exists between these types of thyroiditis and the presence of lymphocytic infiltration on thyroid sampling (similar to that found in Hashimoto's disease or chronic lymphocytic thyroiditis) and a high prevalence of HLA-DR3, HLA-DR4 and HLA-DR5 haplotypes.Sub acute lymphocytic thyroiditis starts with an initial hyperthyroid phase, followed by subsequent hypothyroidism and, finally, a return to the euthyroid state.In the postpartum patient, thyrotoxicosis usually develops in the first three months following delivery and lasts for one or two months.Then the patient returns to a euthyroid state or hyperthyroidism ensues for several months. 11atients with an initial episode of postpartum subacute lymphocytic thyroiditis have a notably high risk of recurrence in subsequent pregnancies. 1,7,12erum TSH testing is indicated in symptomatic patients.
There is a regional variation in the prevalence of this painless thyroiditis, with 90 percent of reported cases occurring in the Great Lakes region. 13Outside of the Great Lakes, painless thyroiditis probably accounts for 1 to 5 percent of newly diagnosed cases of thyrotoxicosis.Postpartum thyroiditis may be found in 3.9 to 8.2 percent of patients screened four to 12 weeks after delivery. 14bacute lymphocytic thyroiditis comprises 29 to 50 percent of all cases of thyroiditis 4 and occurs most often in women between 30 and 50 years of age. 7,12here is a higher incidence of antimicrosomal antibodies in the postpartum form (80 percent) of the disease than in the sporadic form (50 percent).A family history of autoimmune thyroid disease is found in 50 percent of patients with the postpartum form of thyroiditis.The severity of the hypothyroid phase correlates directly with the antimicrosomal antibody titer.A titer of 1:1,600 or greater early in pregnancy is associated with a high risk of postpartum hypothyroidism. 15Approximately 6 percent of patients who have the postpartum form develop chronic hypothyroidism. 7,16e clinical presentation of painless thyroiditis is similar to that of subacute granulomatous thyroiditis in that patients are usually between the ages of 30 and 40 years and women are more commonly affected than men (4:1 ratio).Patients usually present with acute symptoms of hyperthyroidism, such as tachycardia, palpitations, heat intolerance, nervousness and weight loss. 7,12Postpartum depression appears to be more common in women with postpartum thyroiditis, although postpartum thyroiditis does not appear to be the cause of most cases of postpartum depression.A small painless goiter is present in 50 percent of patients. 7,12The absence of anterior neck pain and tenderness clinically distinguishes painless thyroiditis from subacute granulomatous (painful) thyroiditis.
Painless thyroiditis is more difficult to distinguish from Graves' disease, but it is imperative for the clinician to distinguish between these two diseases since important therapeutic differences exist.The ESR and white blood cell count are normal.T 4 and triiodothyronine (T 3 ) levels are initially elevated, with a disproportionate increase in T 4 compared with T 3 . 12RAIU is decreased in the hyperthyroid phase of the disease and is almost always less than 3 percent.This situation contrasts markedly with the elevated RAIU found in patients with Graves' disease. 4,6,11,12ute symptoms of hyperthyroidism are managed primarily with beta blockers. 4,7,8,12Antithyroid drugs, which inhibit the production of new T 4 , are not indicated in the management of patients with hyperthyroidism because symptoms are caused by the release of preformed T 3 and T 4 from the damaged gland. 7,12Replacement of thyroid hormone in the hypothyroid phase is indicated if the patient's symptoms are severe or of long duration. 8If the hypothyroid phase lasts longer than six months, permanent hypothyroidism is likely. 17

Subacute Granulomatous Thyroiditis:
Subacute granulomatous thyroiditis, first described by de Quervain in 1904 is the most common cause of a painful thyroid gland. 8It is most likely caused by a viral infection and is generally preceded by an upper respiratory tract infection. 8Numerous etiologic agents have been implicated, including mumps virus, echovirus, coxsackievirus, Epstein-Barr virus, influenza and adenovirus. 4,8The presence of antithyroid antibodies in many patients suggests an autoimmune process during the disease course.Antibodies may be the result of T lymphocytes sensitized against thyroid antigens released during the inflammatory process.Additionally, there may be genetic factors, such as the presence of HLA-Bw35, that render an individual more susceptible to certain viral agents and the subsequent development of subacute granulomatous thyroiditis.
Women are three to five times more likely to be affected than men.The average age of onset is 30 to 50 years. 8The disorder tends to be geographical and seasonal, occurring most often in the summer and fall. 7,8bacute granulomatous thyroiditis presents clinically with acute onset of pain in the thyroid region.The pain may be exacerbated by turning the head or swallowing, and may radiate to the jaw, ear or chest. 4,6,7Symptoms of hypermetabolism may be present, and the ESR usually is markedly elevated. 7,8 normal ESR essentially rules out the diagnosis of subacute granulomatous thyroiditis. 8The thyroid is firm, nodular and exquisitely tender to palpation.The leukocyte count is normal or slightly elevated. 8hyrotoxicosis is present in 50 percent of patients in the acute phase, and the serum T 4 concentration is disproportionately elevated relative to the T 3 level. 8Serum TSH concentrations are low to undetectable. 8Thyroglobulin is elevated.A normal thyroglobulin level essentially rules out the diagnosis of subacute granulomatous thyroiditis. 7The RAIU is notably low, often less than 2 percent at 24 hours. 8ltrasound examination may also be useful in establishing the diagnosis, with multiple hypoechogenic areas present in thyroid parenchyma. 18In summary, the physical examination, an elevated ESR, an elevated thyroglobulin level and a depressed RAIU confirm the diagnosis.
The natural history of subacute granulomatous thyroiditis involves four phases that generally unfold over four to six months.The acute phase of thyroid pain and thyrotoxicosis may last three to six weeks or longer.Transient asymptomatic euthyroidism follows.Hypothyroidism often ensues and may last weeks to months or may be permanent (in up to 5 percent of patients). 6The final phase is a recovery period, during which thyroid function tests normalize.
Therapy with antithyroid drugs is not indicated in patients with subacute granulomatous thyroiditis because this disorder is caused by the release of preformed thyroid hormone rather than synthesis of new T 3 and T 4 . 7,8Therapy with beta blockers may be indicated for the symptomatic treatment of thyrotoxicosis.Because the thyrotoxic state in subacute granulomatous thyroiditis is induced by the release of preformed T 4 and T 3 treatment with propylthiouracil and methimazole (Tapazole), which block synthesis of T 4 and T 3 is ineffective.
Nonsteroidal anti-inflammatory drugs are generally effective in reducing thyroid pain in patients with mild cases.Patients with more severe disease require a tapering dosage of prednisone (20 to 40 mg per day) given over two to four weeks. 4Up to 20 percent of patients experience the recurrence of thyroid pain on discontinuation of prednisone. 8RAIU can assist clinicians in determining patients at high risk for relapse.Low RAIU uptake implies ongoing inflammation, and steroid therapy should be continued. 4If damage to the thyroid is extensive, a hypothyroid phase may occur until disrupted follicular cells fully recover.Hypothyroidism develops in about one-third of patients and persists up to several weeks.Patients with hypothyroid symptoms during this phase may benefit from thyroid hormone replacement therapy.
Overall, phases may continue over four to six months, although all patients may not exhibit all of the phases.Permanent hypothyroidism may develop in up to 5 percent of cases. 19Many of these patients have coexistent autoimmune thyroid disease, such as chronic lymphocytic thyroiditis.Therefore, it is prudent to perform periodic thyroid hormone testing in all patients after recovery.

Microbial Inflammatory Thyroiditis:
Microbial inflammatory thyroiditis, also known as acute suppurative thyroiditis, is a rare subtype most often caused by the presence of Gram-positive bacteria in the thyroid gland.Staphylococcus aureus is the most common infectious agent, 8 but other organisms have also been implicated.Unusual pathogens that may infect the thyroid are Mycobacterium tuberculosis, syphilis, aspergillus, Coccidioides immitis, cytomegalovirus and Pneumocystis carinii. 20,21This disorder is rare because of the inherent resistance of the thyroid gland to infection.Infectious agents reach the thyroid via lymphatic spread from areas of pharyngitis or mastoiditis, from hematogenous seeding from distant sites or from seeding from piriform sinus fistulas.
Microbial inflammatory thyroiditis occurs most often in women 20 to 40 years of age. 6,12Most patients have a preexisting thyroid disorder, usually nodular goiter. 4,6,12Anterior neck pain and tenderness are common.Other clinical features include fever, pharyngitis and dermal erythema. 6,12The pain is typically worse during swallowing and radiates locally. 6,12,22Tachycardia is common, along with leukocytosis and an elevated ESR level. 4,6,12,22TSH, T 4 and T 3 levels are typically normal, while RAIU may be normal or show cold nodules in areas of abscess formation. 6,12,23Computed tomographic (CT) scans may be useful in early diagnosis by evaluating the iodine content of the gland. 24he cause of infection is first determined by culture and sensitivity of samples obtained through fineneedle aspiration.
When the cause of the infection is determined, appropriate parenteral antibiotics should be prescribed. 6,12,22Patients with abscesses require surgical drainage and, possibly, a thyroid lobectomy. 6,12,22Heat, rest and aspirin provide symptomatic relief; steroids may offer additional benefit. 23The disease is usually self-limited, lasting weeks to months. 23vasive Fibrous Thyroiditis: First described by Riedel in 1898, this remains the rarest type of thyroiditis.In addition to the development of dense fibrosis of the thyroid gland itself, extracervical sites of fibrosis frequently occur as inflammatory fibrosclerotic processes, including sclerosing cholangitis, retroperitoneal fibrosis and orbital pseudotumor. 12,25,26Studies suggest that one third of patients with fibrous thyroiditis develop multifocal fibrosclerosis. 25,27The mean age at presentation is 47.8 years, and 83 percent of all cases occur in females. 27A stone-hard or woody mass that extends from the thyroid is common. 12,25,27ymptoms vary according to the structures involved and most commonly result from a thyroid mass that produces dyspnea, dysphagia and, occasionally, stridor. 12,22,25,27The thyroid mass may grow suddenly or slowly, and is usually unilateral. 25IU is decreased in affected areas of the gland. 22,26ost patients remain euthyroid, and the ESR is frequently elevated. 6,12,25,27Thyroid autoantibodies are present in appreciable quantities in 45 percent of patients. 6,12,25,27Because of the similarity between fibrous thyroiditis and thyroid carcinoma, diagnosis must be made using open biopsy. 6,12,22,25he disease is usually self-limited, with surgical wedge resection of the thyroid isthmus being the mainstay of treatment in symptomatic patients. 6,12,22,25

Conclusion
Thyroiditis is a heterogeneous disease with several subtypes.These subtypes mimic other diseases as well as each other.Differentiation of the subtypes of thyroiditis requires an understanding of their unique clinical presentations, radiologic studies, laboratory data and indications for pharmacotherapy.