Jessica R. Smith, Ari J. Wassner
Thyroiditis refers to any disorder that causes inflammation of the thyroid gland. Thyroiditis can be acute or chronic and can be categorized by etiology, pathology, and/or clinical features. Painful thyroiditis is typically due to infection or trauma, whereas painless thyroiditis is often autoimmune-mediated or due to drug exposure.
Depending on the etiology and phase of illness, patients with thyroiditis may be euthyroid, hypothyroid, or thyrotoxic. The classic pattern of thyroid function changes in transient forms of thyroiditis (such as subacute thyroiditis and painless thyroiditis) is thyrotoxicosis, followed by hypothyroidism and then restoration of euthyroidism. The thyrotoxicosis (elevated thyroid hormone levels) caused by thyroiditis is not due to increased thyroid hormone synthesis (in contrast to Graves disease) but rather to leakage of preformed thyroid hormone into the circulation from the damaged gland, which can last up to 60 days. In some cases, hypothyroidism can persist after transient thyroiditis.
Treatment for patients with thyroiditis is typically aimed at alleviating the pain and addressing the symptoms of the thyrotoxicosis such as tachycardia, palpations, and tremors. Non-steroidal anti-inflammatory drugs (NSAIDs) are usually effective in alleviating thyroid tenderness. If pain is severe, a short course of steroids (prednisone) can be considered. Given that the thyrotoxicosis is due to release of preformed thyroid hormone, antithyroid drugs are usually not effective. Rather, treatment with β-blockers (atenolol or propranolol) to help control the cardiovascular symptoms is useful. Thyroid function tests should be monitored every 6-8 wk, and if hypothyroidism is prolonged or overtly symptomatic, then replacement with thyroid hormone can be considered.
Acute infectious (suppurative) thyroiditis is uncommon in children. It is typically preceded by a respiratory infection or pharyngitis, and the left lobe is more often affected. The infection may be caused by gram positive or gram negative organisms, and abscess formation can occur. The most common organism is α-hemolytic streptococci and Staphylococcus aureus followed by gram negative organisms and anaerobic bacteria. Other pathogens including mycobacteria, fungi, and pneumocystis cause more indolent infection and occur mostly in immunocompromised patients. Recurrent episodes or detection of mixed bacterial flora suggests that the infection arises from a piriform sinus fistula or, less commonly, from a thyroglossal duct remnant. Acute infectious thyroiditis is characterized by sudden onset of neck pain, tenderness of the gland, swelling, erythema, dysphagia, and decreased range of motion of the neck. Fever, chills, sore throat, and leukocytosis are commonly present. Thyroid function is usually normal, but thyrotoxicosis can occur due to leakage of preformed thyroid hormone. Thyroid ultrasound can visualize an abscess if present, and fine needle aspiration can help to identify the responsible microorganisms. When abscesses form, incision and drainage and administration of parenteral antibiotics are indicated. After the infection subsides, a CT scan with contrast is indicated to search for a fistulous tract, and if one is found, surgical removal is typically required.
Subacute thyroiditis (de Quervain disease, subacute granulomatous thyroiditis) is thought to have a viral or post-viral etiology and is usually transient. It typically presents with low-grade fever, minimal thyroid tenderness, and laboratory evidence of thyrotoxicosis (suppressed TSH and elevated T4 and T3 ) caused by leakage of preformed thyroid hormone from the inflamed gland into the circulation. Mild symptoms of thyrotoxicosis may be present, but radioiodine uptake is depressed in the thyrotoxic phase. The erythrocyte sedimentation rate (ESR) is increased. The course is variable but usually characterized by four phases: thyrotoxic, euthyroid, hypothyroid, and remission to euthyroidism usually occurring in several months. There is a strong association with HLA-B35.
Radiation thyroiditis can occur in children who are treated with radioiodine for Graves disease. Thyroid pain and tenderness can develop 2-5 days later due to radiation-induced destruction of the thyroid follicular cells and subsequent release of preformed thyroid hormone. The neck pain is responsive to antiinflammatory therapies.
Palpation- or trauma-induced thyroiditis can be a result of direct trauma to the thyroid gland, typically from surgery, accidental trauma, biopsy, or rarely vigorous palpation of the thyroid gland.
Chronic lymphocytic thyroiditis is the most common cause of thyroid disease in children and adolescents and accounts for many of the formerly designated adolescent or simple goiters. It is also the most common cause of acquired hypothyroidism, with or without goiter. One to 2% of school-age children and 6–8% of adolescents have positive antithyroid antibodies as evidence of autoimmune thyroid disease.
This typical organ-specific autoimmune disease results from inheritance of susceptible genes involved in immunoregulation and from environmental triggers, both as yet poorly characterized. Early in the disease, there may be thyroid hyperplasia only. This is followed by infiltration of lymphocytes and plasma cells between the follicles and subsequent follicular atrophy. Lymphoid follicle formation with germinal centers is almost always present, and the degree of atrophy and fibrosis of the follicles varies. Certain human leukocyte antigen (HLA) haplotypes (HLA-DR4, HLA-DR5) are associated with an increased risk of goiter and thyroiditis, and others (HLA-DR3) are associated with the atrophic variant of thyroiditis.
A variety of different autoantibodies to thyroid antigens are also present. Thyroperoxidase antibodies (TPO-Abs) or thyroglobulin antibodies (Tg-Abs) are demonstrable in the sera of 95% of children with chronic lymphocytic thyroiditis and in many patients with Graves disease. TPO-Abs are involved in activation of the complement cascade and in antibody-dependent, cell-mediated cytotoxicity. Tg-Abs do not appear to play a role in the autoimmune destruction of the gland. Thyrotropin receptor-blocking antibodies (TRBAb) may cause thyroid atrophy and have been demonstrated in 18% of patients with severe hypothyroidism (TSH > 20 mU/L) caused by autoimmune thyroiditis. Antibodies to pendrin, an apical membrane protein on thyroid follicular cells, have been demonstrated in 80% of children with autoimmune thyroiditis. Antibodies also have been found against the sodium–iodide symporter (NIS), but their pathogenic role is unclear.
The disorder is 4-6 times more common in females than in males. It can occur during the first 3 yr of life but becomes more common after 6 yr of age and reaches its peak incidence during adolescence. The most common clinical manifestations are goiter and growth deceleration. The goiter can appear insidiously and may be variable in size. In most patients, the thyroid is diffusely enlarged, firm, and nontender. In approximately 30% of patients, the gland is asymmetric. Most affected children are clinically euthyroid and asymptomatic. Some children have clinical signs and symptoms of hypothyroidism, but others who appear clinically euthyroid have laboratory evidence of overt hypothyroidism. Some children have manifestations suggestive of thyrotoxicosis, such as tremulousness, irritability, increased sweating, and hyperactivity, and laboratory evaluation may show that they are in the Hashitoxic phase of disease, characterized by thyrotoxicosis due to autoimmune thyroid destruction. Ophthalmopathy can occur in autoimmune thyroiditis even in the absence of Graves disease.
The clinical course is variable. The goiter might spontaneously regress, or it might persist unchanged for years while the patient remains euthyroid. Most children who are euthyroid at presentation remain euthyroid, although a percentage of patients acquire hypothyroidism gradually within months or years. In children who initially have subclinical hypothyroidism (elevated serum TSH, normal free thyroxine [T4 ]), approximately 35% revert to euthyroidism, 50% continue to have subclinical hypothyroidism, and approximately 15% develop overt hypothyroidism (elevated serum TSH, subnormal free T4 ) over 5 years.
Familial clusters of chronic lymphocytic thyroiditis are common, and the incidence in siblings or parents of affected children may be as high as 25%. TPO-Abs and Tg-Abs in these families appear to be inherited in an autosomal dominant fashion, with reduced penetrance in males. The concurrence within families of patients with chronic lymphocytic thyroiditis, hypothyroidism, and Graves disease provides evidence for a basic relationship among these three conditions.
The disorder is associated with many other autoimmune disorders. Autoimmune thyroiditis occurs in 10% of patients with type 1 autoimmune polyglandular syndrome (APS-1), characterized by autoimmune polyendocrinopathy, candidiasis, and ectodermal dysplasia (APECED) . Patients with APS-1 have at least 2 of the triad of hypoparathyroidism, Addison disease, and mucocutaneous candidiasis. This rare autosomal recessive disorder occurs in childhood and is caused by mutations in the autoimmune regulator (AIRE) gene (see Chapter 586 ).
Autoimmune thyroid disease occurs in 70% of patients with type 2 autoimmune polyglandular syndrome (APS-2) . APS-2 consists of the association of autoimmune thyroiditis with Addison disease (Schmidt syndrome), type 1 diabetes mellitus (Carpenter syndrome), or other autoimmune conditions including pernicious anemia, vitiligo, and alopecia. TPO-Abs are found in approximately 20% of Caucasian and 4% of African American children with type 1 diabetes mellitus. APS-2 typically occurs in later childhood or early adulthood. Its cause is unknown but may be related to predisposing genetic factors that are shared among these autoimmune conditions (see Chapter 586 ). Autoimmune thyroiditis has also been described in children with immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome , which includes early-onset diabetes and colitis (see Chapter 586 ).
Chronic lymphocytic thyroiditis occurs frequently in patients with celiac disease and those with certain chromosomal disorders, particularly Turner syndrome (8–30%) and Down syndrome (7–10%). Males with Klinefelter syndrome also appear to be at risk for autoimmune thyroid disease.
Table 582.1 compares the characteristics of chronic lymphocytic thyroiditis to other thyroiditis syndromes.
Table 582.1
Characteristics of Thyroiditis Syndromes
| CHARACTERISTIC | CHRONIC LYMPHOCYTIC THYROIDITIS | PAINLESS THYROIDITIS | SUBACUTE THYROIDITIS | ACUTE INFECTIOUS THYROIDITIS | FIBROUS THYROIDITIS |
|---|---|---|---|---|---|
| Sex ratio (F:M) | 4-6 : 1 | 2 : 1 | 5 : 1 | 1 : 1 | 3-4 : 1 |
| Cause | Autoimmune | Autoimmune | Unknown (probably viral) | Infectious (bacterial) | Unknown |
| Pathologic findings | Lymphocytic infiltration, germinal centers, fibrosis | Lymphocytic infiltration | Giant cells, granulomas | Abscess formation | Dense fibrosis |
| Thyroid function | Usually euthyroidism; some hypothyroidism | Hyperthyroidism, hypothyroidism, or both | Hyperthyroidism, hypothyroidism, or both | Usually euthyroidism | Usually euthyroidism |
| TPO antibodies | High titer, persistent | High titer, persistent | Low titer, or absent, or transient | Absent | Usually present |
| ESR | Normal | Normal | High | High | Normal |
| 24 hr 123 I uptake | Variable | <5% | <5% | Normal | Low or normal |
ESR , erythrocyte sedimentation rate; 123 I, iodine 123; TPO , thyroid peroxidase.
Data from Farwell AP, Braverman LE: Inflammatory thyroid disorders. Otolaryngol Clin North Am 4:541–556, 1996.
Thyroid function tests are often normal, although the level of TSH may be slightly or even moderately elevated in some patients with a normal free T4 level, a pattern termed subclinical hypothyroidism. The fact that children with chronic lymphocytic thyroiditis often have goiters despite having normal TSH levels indicates that the goiter is caused primarily by the lymphocytic infiltration of the gland. Young children with chronic lymphocytic thyroiditis have serum TPO-Abs, but Tg-Abs are positive in <50%. TPO-Abs and Tg-Abs are found equally in adolescents with chronic lymphocytic thyroiditis. When both tests are used, approximately 95% of patients with thyroid autoimmunity are detected. Levels in children and adolescents are lower than those in adults with chronic lymphocytic thyroiditis, and repeated measurements are indicated in questionable instances because titers might increase later in the course of the disease. In adolescent females with overt hypothyroidism, measurement of TSH receptor antibodies may identify patients at future risk of having babies with transient congenital hypothyroidism.
Thyroid scintigraphy and ultrasonography usually are not needed. If they are done, thyroid scintigraphy reveals irregular, patchy, and overall decreased radioisotope uptake. Thyroid ultrasonography shows heterogeneous echogenicity along with an increased number of benign-appearing hyperplastic lymph nodes in the neck. The definitive diagnosis can be established by biopsy of the thyroid, which is rarely clinically indicated.
If there is evidence of overt hypothyroidism (elevated TSH with low free T4 ), treatment with levothyroxine is indicated at doses specific for size and age. The goiter usually shows some decrease in size but can persist for years. In a euthyroid patient, treatment with suppressive doses of levothyroxine is unlikely to lead to a significant decrease in size of the goiter. Antibody levels fluctuate in both treated and untreated patients and persist for years. Because the disease is self-limited in some instances, the need for continued therapy may be reevaluated periodically, particularly after growth and pubertal development are complete. Untreated patients should also be checked periodically. There is some controversy about the management of patients with subclinical hypothyroidism. This condition has not been demonstrated to have clinically significant adverse effects, but studies are small and of limited quality. Therefore many clinicians prefer to treat such children until growth and puberty are complete, and then reevaluate their thyroid function.
Painless thyroiditis (silent thyroiditis) is characterized primarily by transient thyrotoxicosis, followed sometimes by hypothyroidism, and then recovery. It accounts for 1 to 5% of cases of thyrotoxicosis. It can also occur in the postpartum period as well as in response to certain types of drugs (see below).
Drug-induced thyroiditis can be due to specific drugs including lithium, amiodarone, interferon-α, interleukin-2, and tyrosine kinase inhibitors. Patients taking lithium are susceptible to both lithium-induced hypothyroidism and painless thyroiditis. Amiodarone is an antiarrhythmic containing a high concentration of iodine, and it can cause two types of thyrotoxicosis. Type 1 is true hyperthyroidism (overproduction of thyroid hormone) and is typically seen in patients with underlying thyroid autoimmunity. Type 2 is a destructive thyroiditis and causes excessive release of preformed thyroid hormone.
Fibrous thyroiditis (invasive or Riedel thyroiditis) is very rare in children and is characterized by extensive fibrosis and macrophage and eosinophil infiltration of the thyroid gland. The thyroid becomes enlarged, hard, and affixed to surrounding structures. Typically, thyroid function tests are normal, and fine needle aspiration may reveal mononuclear cells and fibrous tissue. However, a biopsy is typically required to confirm the diagnosis. Glucocorticoids may alleviate symptoms.