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THYROIDITIS

REF:   NEJM Volume 348:2646-2655  June 26, 2003

Types of Thyroiditis (Terminology for Thyroiditis) Hashimoto's thyroiditis (Chronic lymphocytic thyroiditis, Chronic autoimmune thyroiditis, Lymphadenoid goiter) - TPO (Thyroid peroxidase) antibodies:  high titer, persistent; ESR: Normal; RAIU: variable Painless postpartum thyroiditis (Postpartum thyroiditis, Subacute lymphocytic thyroiditis) - TPO antibodies: high titer, persistent; ESR: Normal; RAIU: <5% Painless sporadic thyroiditis (Silent sporadic thyroiditis, Subacute lymphocytic thyroiditis) - TPO antibodies: high titer, persistent; ESR: Normal; RAIU: <5%   Painful subacute thyroiditis (Subacute thyroiditis, de Quervain's thyroiditis, Giant-cell thyroiditis, Subacute granulomatous thyroiditis, Pseudogranulomatous thyroiditis) - TPO antibodies: low titer, or absent, transient; ESR: high; RAIU: <5% Suppurative thyroiditis  -  The disease may prove fatal if diagnosis and treatment are delayed.   (Infectious thyroiditis, Acute suppurative thyroiditis, Pyrogenic thyroiditis, Bacterial thyroiditis) - TPO antibodies: absent; ESR: high; RAIU: Normal Drug-induced thyroiditis (amiodarone, lithium, interferon alfa, interleukin-2) Riedel's thyroiditis (Fibrous thyroiditis) - TPO antibodies: usually present; ESR: Normal; RAIU: low or normal Hashimoto's thyroiditis, painless sporadic thyroiditis, and painless postpartum thyroiditis all have an autoimmune basis.

Hashimoto's Thyroiditis The most common type of thyroiditis The most frequent cause of hypothyroidism and goiter, in an occasional patient, hyperthyroidism alternates with hypothyroidism, most likely owing to the intermittent presence of thyroid-stimulating and thyroid-blocking antibodies. It is characterized by the presence of high serum thyroid antibody concentrations and goiter. EXAM:  A firm, bumpy, symmetric, painless goiter is frequently the initial finding About 10 percent of patients with chronic autoimmune hypothyroidism have atrophic thyroid glands (rather than goiter), which may represent the final stage of thyroid failure in Hashimoto's thyroiditis. TESTS: - High serum thyroid peroxidase antibody concentrations are present in 90% of these patients. - High serum thyroglobulin antibody concentrations are present in 20-50% of these patients. - The thyroid appears hypoechogenic on ultrasound examination.   - The 24-hour radioactive iodine RAIU (iodine-123) uptake is not helpful in establishing the diagnosis. RX:  Once overt hypothyroidism or subclinical hypothyroidism (with high serum thyroid antibody concentrations) is present, levothyroxine sodium is the treatment of choice. The goal of replacement therapy with levothyroxine sodium is normalization of serum thyrotropin values. In patients with Hashimoto's thyroiditis and a large goiter, thyrotropin-suppressing doses of levothyroxine sodium can be given over the short term (i.e., six months) to decrease the size of the goiter. In most patients with Hashimoto's thyroiditis (whether their condition is euthyroid or hypothyroid), goiter size will decrease by 30 percent after six months of therapy with levothyroxine sodium.  Replacement doses should be resumed if the size of the goiter does not decrease.  Because serum thyroid antibody concentrations do not decrease with levothyroxine sodium therapy, except in some patients with hypothyroidism, monitoring of these concentrations is not indicated once the diagnosis of Hashimoto's thyroiditis has been made. Although thyroid lymphoma is very rare, the risk of this disease is increased by a factor of 67 in patients with Hashimoto's thyroiditis. Patients with Hashimoto's thyroiditis and a dominant thyroid nodule should undergo fine-needle aspiration biopsy to rule out lymphoma and thyroid carcinoma. When thyroid carcinoma occurs in patients with this type of thyroiditis or other lymphocytic infiltration, the prognosis appears to be more favorable than when it does not.

Painless Postpartum Thyroiditis It occurs within the first few months after delivery.  It occurs in up to 10 percent of women in the United States. It is most common in women who have - high serum thyroid peroxidase antibody concentrations during the first trimester of pregnancy or immediately after delivery - other autoimmune disorders, such as type 1 diabetes mellitus, or with a family history of autoimmune thyroid disease. CLINICAL COURSE: Thyrotoxicosis typically begins one to six months after delivery and lasts for one to two months. That phase may be followed by a hypothyroid phase starting four to eight months after delivery and lasting four to six months. Clinical course may show thyrotoxicosis during the first three months, followed by hypothyroidism for three months and then by euthyroidism. Eighty percent of women recover normal thyroid function within a year; in one follow-up study, however, permanent hypothyroidism developed within seven years in 50 percent of the women studied. After a first episode of painless postpartum thyroiditis, there is a 70% chance of recurrence with subsequent pregnancies. Chronic hypothyroidism is more likely in multiparous women or in those with a history of spontaneous abortion. EXAM:  In most cases a small, nontender, firm goiter is present. TESTS: - in only 1/3 of patients will the classic triphasic thyroid hormone pattern develop (Figure 2) - High serum concentrations of thyroid peroxidase antibodies, thyroglobulin antibodies, or both, are also present. - The erythrocyte sedimentation rate is normal. - The 24-hour 123I uptake (RAIU) is low (<5%), distinguishing it from postpartum Graves' disease whereas it is elevated. This test should be performed in patients with symptomatic thyrotoxicosis when there are no clear signs of Graves' disease, such as large goiter or ophthalmopathy. Because radioactive iodine is secreted in breast milk and 123I has a half-life of 13 hours, nursing mothers need to pump and discard milk for at least two days after the test. RX:  Mild thyrotoxicosis rarely requires therapy, but when the disease is severe, it is treated with beta-blockers. Antithyroid drug therapy is contraindicated, because there is no excess thyroid hormone production. Treatment of the hypothyroid phase may not be necessary, but if this phase is prolonged or if the patient is symptomatic, levothyroxine sodium should be given, then withdrawn after six to nine months to determine whether thyroid function has normalized.

Painless Sporadic Thyroiditis Painless postpartum thyroiditis and painless sporadic thyroiditis are indistinguishable except by the relation of the former to pregnancy.   It may represent a subacute form of Hashimoto's thyroiditis. It may account for about 1 percent of all cases of thyrotoxicosis. The clinical course is similar to that of painless postpartum thyroiditis. Although abnormalities in thyroid function resolve in most patients, 20 percent of patients will have residual chronic hypothyroidism.  Overall recurrence rates have not been well established. Symptoms are usually mild. EXAM:  A small, nontender, very firm, diffuse goiter is present in 50 percent of these patients. TESTS: - High serum thyroid peroxidase antibody concentrations are present in 50 percent of patients at the time of diagnosis, with lower titers, on average, than in Hashimoto's thyroiditis. - The 24-hour 123I uptake (RAIU) is low (<5%) can be diagnostic, and the test should be performed when the cause of the thyrotoxicosis is unclear, in order to avoid inappropriate treatment with antithyroid drugs. RX:  Therapy is the same as that for painless postpartum thyroiditis.

Painful Subacute Thyroiditis   It is a self-limited inflammatory disorder, is the most common cause of thyroid pain. It occurs in up to 5 percent of patients with clinical thyroid disease.   It frequently follows an upper respiratory tract infection, and its incidence is highest in summer, correlating with the peak incidence of enterovirus. A viral cause of subacute thyroiditis has therefore been proposed, but so far clear evidence for it is lacking. SX:   - Subacute thyroiditis begins with a prodrome of generalized myalgias, pharyngitis, low-grade fever, and fatigue. - Patients then present with fever and severe neck pain, swelling, or both. - Up to 50 percent of patients have symptoms of thyrotoxicosis. CLINICAL COURSE: In most patients, thyroid function will be normal after several weeks of thyrotoxicosis, and hypothyroidism will subsequently develop, lasting four to six months, as in painless sporadic thyroiditis and painless postpartum thyroiditis. Although thyroid function normalizes spontaneously in 95 percent of patients over a period of 6 to 12 months, residual hypothyroidism persists in 5 percent of patients. Painful subacute thyroiditis recurs in only about 2 percent of patients. TESTS: - A markedly elevated erythrocyte sedimentation rate is the hall mark of painful subacute thyroiditis   - The C-reactive protein concentration is similarly elevated.  - The leukocyte count is normal or slightly elevated. - Elevated Free T4 and T3, with ratios of T4 to T3 of greater than 20, reflecting the proportions of stored hormone within the thyroid, and - Serum concentrations of thyrotropin  TSH are low or undetectable. - Serum thyroid peroxidase antibody concentrations are usually normal. - The 24-hour 123I uptake is low (<5%) in the toxic phase of subacute thyroiditis, distinguishing this disease from Graves' disease.   Color-flow Doppler ultrasonography may also help to make this distinction; in patients with Graves' disease the thyroid gland is hypervascular, whereas in patients with painful subacute thyroiditis the gland is hypoechogenic and has low-to-normal vascularity. RX: The treatment for painful subacute thyroiditis is to provide symptomatic relief only. Nonsteroidal medications or salicylates are adequate to control mild thyroid pain. For more severe thyroid pain, high doses of glucocorticoids (e.g., 40 mg of prednisone daily) provide immediate relief; doses should be tapered over a period of four to six weeks. Corticosteroids should be discontinued when the 123I uptake returns to normal. Beta-blockade controls the symptoms of thyrotoxicosis. Therapy with levothyroxine sodium is rarely required, because the hypothyroid phase is generally mild and transient, but it is indicated for symptomatic patients.

Suppurative Thyroiditis It is rare Suppurative thyroiditis is usually caused by bacterial infection, but fungal, mycobacterial, or parasitic infections may also occur as the cause. It is most likely to occur in patients with preexisting thyroid disease (thyroid cancer, Hashimoto's thyroiditis, or multinodular goiter), those with congenital anomalies such as a pyriform sinus fistula (the most common source of infection in children), and those who are immunosuppressed (as HIV, AIDS), elderly, or debilitated.   SX & EXAM:  usually acutely ill with fever, dysphagia, dysphonia, anterior neck pain and erythema, and a tender thyroid mass. Symptoms may be preceded by an acute upper respiratory infection. The presentation of fungal infection, parasitic infection, mycobacterial thyroiditis, and opportunistic thyroid infection in patients with AIDS tends to be chronic and insidious. TESTS: - Thyroid function is generally normal in patients with suppurative thyroiditis, but both thyrotoxicosis and hypothyroidism have been reported. - Leukocyte counts and erythrocyte sedimentation rates are elevated. - Suppurative areas appear "cold" on radioactive-iodine scanning. - Fine-needle aspiration biopsy with Gram's staining and culture is the diagnostic test of choice. RX:  The therapy for suppurative thyroiditis consists of appropriate antibiotics and drainage of any abscess. The disease may prove fatal if diagnosis and treatment are delayed.

Drug-Induced Thyroiditis     Many medications can alter thyroid function or the results of thyroid-function tests. However, only a few are known to provoke autoimmune or destructive inflammatory thyroiditis. Amiodarone   Amiodarone-induced hypothyroidism occurs in up to 20 percent of patients in iodine-sufficient regions.   Patients with preexisting thyroid autoimmunity are at increased risk for the development of hypothyroidism while receiving amiodarone. Amiodarone-induced thyrotoxicosis occurs in up to 23 percent of patients receiving amiodarone and is far more prevalent in iodine-deficient regions. Two Types of Amiodarone-induced Thyrotoxicosis Type I amiodarone-induced thyrotoxicosis is defined as synthesis and release of excessive thyroid hormone; it is iodine-induced, and it is more likely to occur in patients with preexisting subclinical thyroid disorders, especially nodular goiter. RX:  It is best treated with high doses of antithyroid drugs (methimazole/Tapazole or propylthiouracil/PTU), sometimes with the addition of potassium perchlorate to prevent further uptake of iodine by the thyroid. - Lithium has also been suggested as therapy for type I disease. - Iopanoic acid has recently been reported to be effective in patients with type I disease who require thyroidectomy. Type II amiodarone-induced thyrotoxicosis is a destructive thyroiditis that causes the release of preformed thyroid hormone from the damaged thyroid gland. RX:  It responds to high-dose corticosteroids. - Iopanoic acid has recently been reported to be effective in patients with type II amiodarone-induced thyrotoxicosis, although less so than corticosteroids. Distinguishing between the two forms of amiodarone-induced thyrotoxicosis is difficult, especially since some patients have both types. Although the serum interleukin-6 concentration was initially reported to be more elevated in type II amiodarone-induced thyrotoxicosis than in type I, subsequent studies have not replicated this finding. TESTS: In patients in the United States, 123I uptake values are typically low in type I and type II amiodarone-induced thyrotoxicosis. Color-flow Doppler ultrasonography may show hypervascularity in type I disease but reduced blood flow in type II. Careful examination of the thyroid, base-line thyroid-function tests, and measurements of serum concentrations of thyroid peroxidase and thyroglobulin antibodies should be performed before amiodarone therapy is instituted, and thyroid function should be monitored every six months as long as patients are receiving the drug. RX:  Treatment with levothyroxine sodium is indicated in hypothyroid patients, and amiodarone may be continued. The dose of levothyroxine sodium needed to normalize the serum concentration of thyrotropin is often higher than the usual dose, because amiodarone decreases 5'-deiodinase activity in peripheral tissues, thus also decreasing production of T3. Lithium   In patients with preexisting thyroid autoimmunitiy, lithium may increase the serum thyroid antibody concentrations and lead to subclincal or overt hypothyroidism.   Estimates of the prevalence of high serum thyroid antibody concentrations in patients receiving long-term treatment with lithium range from 10-33%. In addition, thyrotoxicosis has been reported after long-term lithium use, possibly caused by lithium's direct toxic effects on thyroid cells or by lithium-induced painless sporadic thyroiditis.   Interferon Alfa and Interleukin-2 Thyroid-function tests and measurements of serum thyroid antibodies should be performed before therapy with interferon alfa or interleukin-2 is initiated and every six months thereafter. In up to 15% of patients during interferon alfa therapy may develop high serum thyroid peroxidase antibody concentrations or thyroid dysfunction Interferon alfa has also been reported to cause destructive inflammatory thyroiditis. High serum thyroid peroxidase antibody concentrations in such patients and in patients receiving interleukin-2 therapy may be associated with overt or subclinical hyperthyroidism (Graves' disease)  or hypothyroidism   The measurement of 123I uptake RAIU helps to distinguish between drug-induced Graves' disease, in which the uptake is elevated, and drug-induced inflammatory thyroiditis, in which the uptake is low, in patients with thyrotoxicosis. RX: When Graves' disease develops in patients receiving interferon alfa therapy, they should be treated with antithyroid drugs. While treatment with interferon alfa or interleukin-2 is continued The thyrotoxic phase of inflammatory thyroiditis can be treated with beta-blockers and, if necessary, with nonsteroidal antiinflammatory drugs or corticosteroids The hypothyroidism can be treated with levothyroxine sodium. Although thyroid function usually normalizes when cytokine therapy is discontinued, affected patients are at increased risk for autoimmune thyroid dysfunction in the future.

Riedel's Thyroiditis (Fibrous thyroiditis) Riedel's thyroiditis, a local manifestation of a systemic fibrotic process, is a progressive fibrosis of the thyroid gland that may extend to surrounding tissues. The prevalence of this disease is only 0.05 percent among patients with thyroid disease requiring surgery, and its cause is unknown. SX:  symptoms due to tracheal or esophageal compression or hypoparathyroidism due to extension of the fibrosis into adjacent parathyroid tissue. Most patients are euthyroid at presentation but become hypothyroid once replacement of normal thyroid tissue is nearly complete. EXAM:  a rock-hard, fixed, painless goiter. TESTS:  High serum thyroid antibody concentrations are present in up to 67 percent of patients, but it is unclear whether the antibodies are a cause or effect of the fibrotic thyroid destruction. DX:  A definitive diagnosis is made by open biopsy. RX:  The treatment is surgical, although therapy with glucocorticoids, methotrexate, and tamoxifen has been reported to be successful in the early stages of the disease.

Thyroid Autoimmunity

Thyroid antibodies:

Genetic Susceptibility

The genetics of autoimmune thyroid disease are complex.¹³ Association of Hashimoto's thyroiditis and painless postpartum thyroiditis with HLA-DR3, HLA-DR4, and HLA-DR5 has been reported in white persons,^14,15,16 but other associations have been observed in other racial and ethnic groups.

Environmental Factors  

Among patients with Hashimoto's thyroiditis, hypothyroidism is more likely to develop in smokers than in nonsmokers.  An increased prevalence of painless postpartum thyroiditis has also been noted among smokers.   In addition, geographic variations in the incidence of Hashimoto's thyroiditis, painless postpartum thyroiditis, and painless sporadic thyroiditis suggest that dietary iodine insufficiency may be protective against autoimmune thyroiditis.

Clinical and Biochemical Changes in Thyroiditis

The various forms of thyroiditis may cause thyrotoxicosis, hypothyroidism, or both .

Clinical Course of Painful Subacute Thyroiditis, Painless Postpartum Thyroiditis, and Painless Sporadic Thyroiditis.
Measurements of serum thyrotropin (TSH) and iodine-123 (¹²³I) uptake show thyrotoxicosis during the first three months, followed by hypothyroidism for three months and then by euthyroidism. T₄ denotes thyroxine.

 
Thyrotoxicosis

In painless sporadic thyroiditis, painless postpartum thyroiditis, and painful subacute thyroiditis, inflammatory destruction of the thyroid may lead to transient thyrotoxicosis as preformed thyroid hormones are released from the damaged gland. As thyroid hormone stores are depleted, there is often a progression through a period of euthyroidism to hypothyroidism. The first biochemical change in inflammatory thyroiditis before the onset of thyrotoxicosis is an increase in the serum concentration of thyroglobulin.  As in other forms of thyrotoxicosis, the serum concentration of thyrotropin is suppressed, and concentrations of total and free triiodothyronine (T₃) and thyroxine (T₄) are elevated. Serum T₄ concentrations are proportionally higher than T₃ concentrations, reflecting the ratio of stored hormone in the thyroid gland (whereas in Graves' disease and in toxic nodular goiter, T₃ is preferentially elevated). The signs and symptoms of thyrotoxicosis due to thyroiditis are usually not severe.

Hypothyroidism

The hypothyroid phase of thyroiditis results from the gradual depletion of stored thyroid hormones. Although chronic hypothyroidism is most closely associated with Hashimoto's thyroiditis, all types of thyroiditis may progress to permanent hypothyroidism. This outcome is more likely in patients with higher serum concentrations of thyroid antibodies or in patients in whom a more severe hypothyroid phase develops. As thyroid function diminishes, serum thyrotropin concentrations rise. The combination of elevated serum thyrotropin concentrations and normal free T4 and T3 concentrations is term "subclinical hypothyroidism," and "mild thyroid failure."   As thyroid failure progresses, serum T₄ concentrations fall, and the combination of elevated thyrotropin concentrations and low T₄ concentrations is termed "overt hypothyroidism." Serum total and free T₃ concentrations may not fall until the disease is far advanced, because increased serum thyrotropin concentrations stimulate the thyroid to release T₃. In most patients, once the serum T₃ concentrations fall below the normal level, the classic symptoms and signs of hypothyroidism appear.

         2006

REF: NEJM Volume 348:2646-2655  June 26, 2003