Hashimoto's thyroiditis

Thyroiditis is the thyroid disorder most commonly encountered by the clinician. 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.

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Acute Thyroiditis

Acute thyroiditis, also referred to as suppurative, bacterial or pyogenic thyroiditis, is a rare infectious disorder caused by bacteria, fungi, mycobacteria or parasites.[1] 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.

Bacteria that most commonly cause acute thyroiditis are upper respiratory pathogens such as Staphylococcus aureus or other staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae or other streptococci and, less commonly, Enterobacteriaceae, Haemophilus influenzae and anaerobic organisms. Unusual pathogens that may infect the thyroid are Mycobacterium tuberculosis, syphilis, aspergillus, Coccidioides immitis, cytomegalovirus and Pneumocystis carinii.[1,2]

Acute thyroiditis occurs more often in women than in men.[1] Most cases occur in persons between the ages of 20 and 40 years, although infants and elderly individuals may also be affected.[1] The majority of patients (61 percent) have a preexisting thyroid disorder.

Individuals with acute thyroiditis typically present with anterior neck pain and swelling, fever, dysphagia and dysphonia. Physical examination typically reveals a warm, erythematous, tender thyroid. Pharyngitis or pharyngeal pain is often present as well.

Laboratory findings include leukocytosis with a shift to the left. Thyroid hormone levels are usually normal, unless the inflammation is so extensive that disruption and release of follicular stores of thyroxine ([T.sub.4]) and triiodothyronine ([T.sub.3]) occur.

On thyroid scan, the radioactive iodine uptake (RAIU) is variable, but the scan typically shows a "cold" area corresponding to the infected tissue. Computed tomographic (CT) scans may be useful in early diagnosis by evaluating the iodine content of the gland.[3]

Treatment includes fluid support, appropriate antimicrobial therapy, and surgical incision and drainage of any fluctuant lesions or abscesses. Permanent damage to the thyroid is uncommon unless extensive destruction of tissue has occurred, in which case hypothyroidism may eventually ensue. Recurrent infections are unlikely; a recurrent infection suggests the presence of an anatomic conduit for infection, such as a thyroglossal duct or internal fistula.

Subacute Thyroiditis

Subacute thyroiditis is divided into two distinct diseases, subacute granulomatous thyroiditis (also known as de Quervain's thyroiditis or painful thyroiditis) and painless thyroiditis (also known as silent thyroiditis or subacute lymphocytic thyroiditis).

SUBACUTE GRANULOMATOUS THYROIDITIS

Subacute granulomatous thyroiditis, first described by de Quervain in 1904, is the most common cause of anterior neck pain in the region of the thyroid gland. Symptoms frequently develop after a respiratory infection or viral prodrome. Most cases occur in the summer and fall months. Viruses are believed to be the cause of subacute granulomatous thyroiditis, with adenovirus, coxsackievirus, influenza, infectious mononucleosis, mumps, echovirus and enteroviruses most commonly implicated.

The 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.

Affected individuals are usually aged 40 to 50 years, and women are affected more often than men, by a ratio of 4:1. Patients often report a viral prodrome with myalgias, low-grade fever, lassitude, sore throat and dysphagia. The anterior neck pain is characteristically abrupt in onset, unilateral or bilateral, and can radiate to the ear or the mandible. Patients may also present with symptoms of diaphoresis, tachycardia, palpitations or weight loss consistent with thyrotoxicosis. Physical examination often reveals a low-grade fever and the classic findings of a firm to hard, tender thyroid gland with occasional overlying erythema. Although uncommon, pronounced thyroidal swelling may produce obstructive symptoms of the airway or esophagus.

Laboratory findings include mild anemia and a normal to slightly elevated white blood cell count. An elevated erythrocyte sedimentation rate, usually greater than 50 mm per hour, is so common that the presence of a normal sedimentation rate should make the clinician consider an alternative diagnosis. Abnormally high thyroid hormone levels are present in 50 percent of cases and are caused by the release of follicular stores of [T.sub.4] and [T.sub.3] into the circulation. The release is usually abrupt, and patients can often identify exactly when their hypermetabolic symptoms began.

The abrupt onset of symptoms and presence of thyroid pain help distinguish patients with subacute granulomatous thyroiditis from patients with Graves' disease. Thyroid hormone levels are usually mild to moderately increased, with [T.sub.4] levels disproportionately higher than [T.sub.3] levels (reflecting the higher intrathyroidal concentrations of [T.sub.4] compared with [T.sub.3]). Thyroglobulin is also released during the inflammatory process, and serum levels are invariably elevated. The inflammation and destruction of thyroid follicular cells result in an inability of the thyroid to trap iodine; therefore, the RAIU is suppressed to less than 5 percent and often to less than 3 percent.

The diagnosis of subacute granulomatous thyroiditis is usually confirmed by physical examination and the presence of an elevated erythrocyte sedimentation rate, elevated serum thyroglobulin level and suppressed RAIU. Ultrasound examination may also be useful in establishing the diagnosis, with multiple hypoechogenic areas present in thyroid parenchyma.[4]

Treatment is supportive. Nonsteroidal anti-inflammatory agents are used to relieve neck pain. Occasionally, oral prednisone, 20 to 40 mg per day in divided doses, may be required to relieve pain and reduce swelling.[5] The course of prednisone is usually tapered for two to four weeks. Rebound swelling and pain occur in approximately 20 percent of patients when the prednisone is discontinued.

Symptoms of thyrotoxicosis are best treated with beta-adrenergic blocking drugs such as propranolol (Inderal). Because the thyrotoxic state in subacute granulomatous thyroiditis is induced by the release of preformed [T.sub.4] and [T.sub.3], treatment with propylthiouracil and methimazole (Tapazole), which block synthesis of [T.sub.4] and [T.sub.3], is ineffective.

The initial phase of inflammation, pain and thyrotoxicosis usually lasts from three to six weeks. As thyroid hormone stores are depleted, [T.sub.4] and [T.sub.3] levels fall to normal and a euthyroid phase ensues.

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If 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.

After a period of hypothyroidism, the majority of patients will enter the recovery phase and return to a euthyroid state. The clinician must remember to stop the patient's thyroid replacement therapy and reevaluate thyroid status.

Overall, the three 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.[6] Many 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.

PAINLESS THYROIDITIS

Painless thyroiditis can present sporadically or postpartum.[7] The sporadic form of painless thyroiditis accounts for 5 to 33 percent of patients with thyrotoxicosis. There is a regional variation in the prevalence of painless thyroiditis, with 90 percent of reported cases occurring in the Great Lakes region.[8] Outside 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.[9]

Both painless thyroiditis and postpartum thyroiditis are believed to have an autoimmune etiology. Available evidence shows a high association with the presence of antithyroid antibodies, with antibody testing positive in 50 percent of patients with painless thyroiditis and 80 percent of those with postpartum thyroiditis. A 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.

The 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 typically report an abrupt onset of thyrotoxic symptoms, but unlike patients with subacute granulomatous thyroiditis, they do not have anterior neck pain.

While patients with painless thyroiditis most often present with symptoms of thyrotoxicosis, they may have symptoms of hypothyroidism later in the course of the disease. Women with postpartum thyroiditis may present either with thyrotoxicosis, generally six weeks to three months after delivery, or with symptoms of hypothyroidism, typically three to six months after delivery. Postpartum 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.

Physical examination reveals a small, slightly firm, nontender goiter in 50 percent of patients. The 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.

Patients with Graves' disease typically have insidious onset of thyrotoxic symptoms, in contrast to the often abrupt onset of symptoms in patients with painless thyroiditis. Infiltrative ophthalmopathy is exclusive to Graves' disease and is not seen in patients with painless thyroiditis. In the absence of Graves' ophthalmopathy, the RAIU is the most reliable way to distinguish Graves' disease from painless thyroiditis. In painless thyroiditis and postpartum thyroiditis, follicular cells are diffusely inflamed and damaged, causing the RAIU to be decreased to less than 3 percent. This is in contrast to the markedly increased RAIU found in Graves' disease.

In painless thyroiditis or postpartum thyroiditis, other laboratory tests are non-specific and include a normal white blood cell count and erythrocyte sedimentation rate, although thyroglobulin levels are usually elevated.

The clinical course of painless thyroiditis is similar to that of subacute granulomatous thyroiditis and consists of roughly three phases: an initial thyrotoxic phase, a hypothyroid phase and a recovery phase. Again, patients may not exhibit all of these phases, and while most patients typically present in the thyrotoxic phase, they may also present in the hypothyroid phase.

As in subacute thyroiditis, antithyroid drugs (propylthiouracil or methimazole) are not effective in the treatment of painless thyroiditis, and beta blockers are the most useful in controlling hypermetabolic symptoms. Glucocorticoids may shorten the duration of the thyrotoxicosis, but they do not change the overall prognosis and are generally not indicated. Patients who exhibit symptoms during the hypothyroid phase may benefit from short-term levothyroxine replacement therapy. The physician must remember to reevaluate the patient's continued need for levothyroxine therapy.

Although total recovery is the rule for patients with painless thyroiditis, up to 50 percent may have persistent goiter or antithyroid antibodies, or both. Long-term studies show that as many as 6 percent of patients will have permanent hypothyroidism.[10] Yearly monitoring of thyroid hormone status is warranted, since permanent hypothyroidism has developed years after an attack of painless thyroiditis.

Chronic Lymphocytic Thyroiditis

Chronic lymphocytic thyroiditis, or Hashimoto's thyroiditis, was first described by the Japanese physician Hashimoto in 1912. It is the most common cause of non-iatrogenic hypothyroidism and has been found in up to 2 percent of women at autopsy.[11] Markedly elevated antithyroid antibodies, typically found in chronic lymphocytic thyroiditis, are not exclusive to this disease and may be present in 7 to 10 percent of unselected populations.

Chronic lymphocytic thyroiditis is an autoimmune disorder that is typically associated with the presence of antibodies to thyroglobulin (antithyroglobulin) and the microsomal fraction of the thyroid cell (antimicrosomal). Antibodies to colloid antigens, [T.sub.4], [T.sub.3] and the thyrotropin (TSH) receptor have also been reported. HLA-B8 and HLA-DR5 haplotypes are most commonly found in patients with chronic lymphocytic thyroiditis. Coexisting autoimmune disorders, including Graves' disease, primary adrenal insufficiency, diabetes mellitus, autoimmune oophoritis, systemic lupus erythematosus, rheumatoid arthritis and pernicious anemia may be present in the proband or family members.

Up to 95 percent of patients with chronic lymphocytic thyroiditis are women, usually between the ages of 30 and 50 years, although the disease may occur in any age group. Patients are most often asymptomatic and have a small- to medium-sized goiter as an incidental finding. About 20 percent of patients present with hypothyroid symptoms. Very rarely, patients may present with hyperthyroidism, although this is thought to indicate the coexistence of Graves' disease.[12] Physical examination may reveal findings of hypothyroidism, but typically only reveals a diffuse, mild to modest enlargement of the thyroid, which is firm with a lobulated or bosselated surface. Regional lymphadenopathy may be present, or the goiter may be large enough to cause dysphagia or recurrent laryngeal nerve dysfunction.

Antithyroid antibodies (antimicrosomal or antithyroglobulin) are present in 90 percent of patients. Titers of these antibodies, especially antimicrosomal antibodies, are often quite high. The presence of hypothyroidism is documented by decreased [T.sub.4] and elevated TSH levels.

A thyroid RAIU and scan are not indicated in most patients. However, if performed, the RAIU measurement is variable and the scan typically reveals a diffuse, patchy uptake pattern. The only indication for measurement of the RAIU or a thyroid scan is diagnosis of a coexisting subacute granulomatous or painless thyroiditis or palpation of a discrete solitary nodule. For most patients, the presence of a firm, bosselated goiter and positive tests for antithyroid antibodies are sufficient indications for the diagnosis of chronic lymphocytic thyroiditis. The ability of the thyroid to maintain adequate hormone production is easily documented with [T.sub.4] and TSH measurements.

If hypothyroidism is found, thyroid hormone replacement therapy with levothyroxine is indicated for life. The average replacement dosage of levothyroxine is 75 to 150 [mu]g per day, or 1.5 to 1.7 [mu]g per kg per day.[13] Lower doses are often required in elderly individuals. Therapy is usually initiated with 25 to 50 [mu]g of levothyroxine per day, and the daily dosage is increased by 25 to 50 [mu]g every four to six weeks until the TSH level is normal. Elderly individuals or individuals with cardiovascular disease require a lower initial dosage and cautious increments in the regimen.

Treatment is more difficult in patients who have an elevated TSH level but normal [T.sub.4] level (a condition often termed pre-clinical or subclinical hypothyroidism). Physiologically, the thyroid is able to maintain normal [T.sub.4] levels at the expense of an increased stimulatory signal from the pituitary gland (elevated TSH). Guidelines for thyroid replacement include the presence of a moderate to large goiter or a significantly elevated TSH level.

If the patient has a significantly large goiter, thyroid hormone therapy may be used to prevent further growth. If the TSH level is greater than 20 [mu]U per mL (20 mU per L), the chances are high that the patient will eventually become overtly hypothyroid.[14] If the TSH level is above the normal range but is less than 20 [mu]U per mL (20 mU per L), and the antimicrosomal antibody titer is greater than 1:1600, 80 percent of patients will eventually develop hypothyroidism.[14,15] Although these results[14] were originally reported in elderly patients, it is reasonable to cautiously apply similar criteria to younger individuals. Patients with chronic lymphocytic thyroiditis who do not receive levothyroxine therapy are at risk for the development of hypothyroidism and require periodic monitoring of thyroid hormone status.

Riedel's Thyroiditis

Riedel's thyroiditis (also known as Riedel's struma, invasive fibrous thyroiditis or chronic sclerosing thyroiditis) is a rare disorder occurring mainly in middle-aged or elderly female patients. The underlying process is a diffuse (70 percent) or partial (30 percent) sclerosing fibrosis that eventually turns the thyroid into a woody or stony-hard mass that is often fixed to surrounding structures. As the disease progresses, the trachea, esophagus or recurrent laryngeal nerve may be obstructed or compressed.

Laboratory evaluation may reveal a mildly elevated white blood cell count and erythrocyte sedimentation rate. Thyroid hormone testing is normal until extensive destruction of the gland has occurred, at which time hypothyroidism develops. Testing for antimicrosomal antibodies is positive in 40 to 50 percent of patients. The diagnosis is difficult with fine-needle aspiration, and usually an open surgical biopsy is required. Once pressure symptoms develop, surgical treatment is the only useful therapeutic approach.

REFERENCES

[1.] Berger SA, Zonszein J, Villamena P, Mittman N. Infectious diseases of the thyroid gland. Rev Infect Dis 1983;5:108-122. [2.] Gallant JE, Enriquez RE, Cohen KL, Hammers LW. Pneumocystis carinii thyroiditis. Am J Med 1988; 84:303-6. [3.] Bernard PJ, Som PM, Urken ML, Lawson W, Biller HF. The CT findings of acute thyroiditis and acute suppurative thyroiditis. Otolaryngol Head Neck Surg 1988;99:489-93. [4.] Birchall IW, Chow CC, Metreweli C. Ultrasound appearances of de Quervain's thyroiditis. Clin Radiol 1990;41:57-9. [5.] Autoimmune thyroid diseases - Graves' and Hashimoto's. Ann Intern Med 1978;88:379-91. [6.] Tikkanen MJ, Lamberg BA. Hypothyroidism following subacute thyroiditis. Acta Endocrinol 1982; 101:348-53. [7.] Sakiyama R. Silent thyroiditis. J Fam Pract 1986;23: 367-9. [8.] Vitug AC, Goldman JM. Silent (painless) thyroiditis. Evidence of a geographic variation in frequency. Arch Intern Med 1985;145:473-5. [9.] Roti E, Emerson CH. Clinical review 29: postpartum thyroiditis. J Clin Endocrinol Metab 1992;74:3-5. [10.] Hamburger JI, Meier DA. Are silent thyroiditis and postpartum silent thyroiditis forms of chronic thyroiditis or different (new) forms of viral thyroiditis? In: Hamburger JI, Miller JM, eds. Controversies in clinical thyroidology. New York: Springer-Verlag, 1981:21-67. [11.] Masi AT. Hashimoto's disease. An epidemiological study based on a community-wide hospital survey. J Chron Dis 1965;18:33-57. [12.] Tamai H, Nakagawa T, Ohsako N, et al. Changes in thyroid functions in patients with euthyroid Graves' disease. J Clin Endocrinol Metab 1980;50: 108-12. [13.] Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine. Ann Intern Med 1990;113:450-4. [14.] Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly. Microsomal antibodies as discriminant for therapy. JAMA 1987;258:209-13. [15.] Tunbridge WM, Brewis M, French JM, et al. Natural history of autoimmune thyroiditis. Br Med J [Clin Res] 1981;282:258-62.

ROLAND SAKIYAMA, M.D. is associate clinical professor in the division of family medicine at the UCLA School of Medicine, Los Angeles. He is associate residency director and director of the UCLA family medicine inpatient service. He is a graduate of the UCLA School of Medicine, where he received training in endocrinology and internal medicine before joining the faculty.

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