Thyroiditis

Pathogenesis

A genetic predisposition for HT is evident in about 75% of cases. Certain HLA class II antigens (such as ARG74 in DR3) carry an increased risk for the development of several autoimmune disorders that include HT, with cytotoxic T-lymphocytes antigen-4 (CTLA-4) also playing a role. A growing number of environmental factors have been implicated in the etiology of HT as well. Interestingly, iodine supplementation programs in areas of iodine deficiency have been associated with rising rates of HT and associated hypothyroidism. The element selenium (Se ⁺⁺ ) is an integral component of the selenoprotein deiodinase enzymes. Deiodinases are present in the thyroid as well as various peripheral tissues regulating deiodination of thyroxine (T4) and triiodothyronine (T3). Reduced serum Se ⁺⁺ levels have been noted with cases of HT. Although some reports indicate benefits of selenium replacement therapy to reduce the occurrence of HT and the development of hypothyroidism, this has not yet been fully proven. However, it should be noted that at the time of this writing, a clinical trial is underway assessing if the combination of selenium and levothyroxine (LT4) therapy improves quality of life and/or reduces levels of immune activity markers in patients with autoimmune driven thyroiditis. Remarkably, tobacco and moderate alcohol use, which have other negative effects, appear to be associated with a reduced risk of autoimmune related hypothyroidism. Although the development of some autoimmune conditions has been reportedly related to previous infectious exposures, no such association has been noted with HT. Although radiation exposure potentially increases the risk of developing thyroid malignancy, it remains to be proven if this predisposes to the development of thyroid autoimmunity. Other studies have reported a connection between vitamin D deficiency and increased risk of autoimmunity as well as vitamin D supplementation reducing TPOAb titers in patients with HT on LT4 replacement therapy. In other autoimmune conditions such as Graves’ disease, stress has been identified as a potential promoting factor, albeit available data has not proven any effect on TPOAb production or development of hypothyroidism. Endogenous factors contributing to the risk for HT include female sex (7:1 female:male ratio), sex hormones such as estrogen, postpartum thyroiditis (PPT), pregnancy, and the presence of fetal microchimerism. Patients with Down’s and Turner’s syndromes also display an increased propensity toward development of autoimmune hypothyroidism.

Clinical Manifestations

Patients with HT may present in a euthyroid state with normal thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels, subclinical hypothyroidism with mild TSH elevations (5 to 10 uIU/mL), and a paucity of symptoms or more significant hypothyroidism with TSH > 10 uIU/mL. Although a goiter may be noted during a physical examination, thyroid morphology associated with HT varies widely and ranges from atrophic, barely palpable glands to slightly enlarged glands to very large goiters. The gland texture may be smooth as in “simple” goiters or contain numerous nodules as seen with multinodular goiters. Although the euthyroid state may persist for many years, about 4% to 5% of initially euthyroid patients with HT will develop hypothyroidism each year. The rate of progression is somewhat dependent on the intensity of the inflammatory reaction and the concomitant rate of induced thyroid follicle destruction. HT is usually not associated with any neck discomfort, but there are instances where individuals will present with anterior neck pain or tenderness, so HT should be considered in the differential diagnosis of patients with neck discomfort. Episodes of more acute thyroiditis with the development of transient thyrotoxicosis have been reported and been referred to as Hashitoxicosis .

Changes from HT noted by thyroid ultrasound, such as heterogeneous parenchyma, may become evident before the ability to measure thyroid antibody titers in the patient’s serum. Although thyroid nodules certainly can be present in the context of HT, focal inflammatory changes due to HT may give the false impression of thyroid nodules. The term pseudonodule refers to instances where there is the appearance of a thyroid nodule in at least one ultrasound view, but it cannot be reproduced on the additional complementary views. Such lesions may not be evident upon future imaging at a later point in time. Therefore in patients with HT, the possibility of a pseudonodule should be considered before proceeding with FNA sampling.

Thyroid enlargement associated with HT may regress with LT4 therapy, particularly if TSH elevation is present at the time of diagnosis. However, some goiters associated with HT will persist or even grow whether or not LT4 suppression is used. If such patients exhibit progressive goiter growth or develop compressive type symptoms, thyroidectomy may need to be considered. If the goiter is large and especially if tracheal deviation or substernal extension is present, then preoperative imaging with computed tomography (CT) of the neck is warranted to better define the anatomy and help plan the surgical approach. Histopathology is typically notable for prominent lymphocytic infiltration, foci of lymphoid germinal centers, and follicle destruction. Controversy exists if HT patients have an increased risk for thyroid cancer and, if so, whether or not HT is associated with a more aggressive disease pattern.

Management

Euthyroid patients with positive thyroid antibody titers can typically be monitored without the institution of thyroid hormone replacement therapy. However, there are some data that pregnant patients with positive thyroid antibody titers may have improved pregnancy outcomes and reduced complications with the institution of LT4 replacement therapy. In non-pregnant patients with hypothyroidism, there are standard recommendations for treatment and monitoring. This usually consist of LT4 therapy and TSH and FT4 monitoring every 6 weeks with adjustments in LT4 dosing until the TSH is within the goal range (typically 1 to 3 uIU/mL) although a higher target range is considered acceptable in the elderly.

Pathogenesis

Many potential causes have been implicated in the pathogenesis of SAT. Predisposing genetic susceptibility loci, autoimmunity, and viral etiologies may interact to ultimately cause this condition. An increased risk of SAT has been noted for specific human leukocyte antigen (HLA) haplotypes (e.g., HLA-Bw35, HLA-B15/62, HLA-DRw8), though the relative risks attributable to these are not well defined. The occurrence of SAT is not clearly associated with thyroid autoimmunity. Thyroid autoantibodies such as TPOAb or TgAb may be identified during recovery from SAT, but these are most typically not elevated. In contrast, TSH receptor antibodies (TRAb) have been detected in patients with SAT. Decreasing titers or complete resolution of TRAb have been noted during follow-up. Whether or not this can be considered pathophysiologically relevant or predictive of risk or natural history is unknown, but generation of TRAb by the immune system in the setting of SAT may be a response to the release of thyroid antigens after initial thyrocyte damage.

In contrast to the limited association with genetic and autoimmune factors, there is more evidence linking the pathogenesis of SAT to a direct or indirect sequelae of a viral infection. Observational evidence in support of this includes a peak incidence in the earth’s temperate zones and during summer months when certain viral infections are at their peak. The condition appears to coincide with prodromal symptoms such as malaise, myalgia, and/or low-grade fever suggestive of a viral etiology and has been associated with numerous viral agents. SAT has also been associated with other noninfectious etiologies.

Clinical Manifestations

The development of neck pain in the region of the thyroid raises the possibility of SAT. Neck pain is typically moderate to severe and may diffusely involve the entire thyroid or follow a more gradual and progressive course in which the condition initially occurs in one lobe of the thyroid and later manifests in the other. Pain may be localized to the thyroid or radiate superiorly to the ear, either unilaterally or bilaterally. A preceding history of viral prodrome (e.g., low-grade fever, malaise, myalgias, upper respiratory track symptoms) may or may not be present. Along with this presentation, many patients will present with classical symptoms of thyrotoxicosis, such as heat intolerance, tremors, palpitations, weight loss, hyperdefication, anxiety, insomnia, or dyspnea. Proptosis or other signs of ophthalmopathy, thyroid bruit, or pretibial myxedema, which are features specific to Graves’ disease, are absent. The presence of higher fever is a notable feature of SAT, potentially reaching 40° C (104° F). Rarely is thyroid pain the only finding present. Pain and thyrotoxicosis are self-resolving over a typical period of 4 to 6 weeks. These and other features help distinguish it from other forms of thyroiditis (see Table 4.1 ). The recovery after the thyrotoxic phase of SAT typically involves biochemical hypothyroidism, though patients may remain asymptomatic. A minority of patients will acquire permanent hypothyroidism after SAT.

On physical examination, patients may manifest nonspecific signs of thyrotoxicosis. Careful examination of the thyroid is often more revealing of the underlying diagnosis. Palpation of the thyroid is often described as “exquisitely” tender, may provoke the patient to withdraw when severe, and may be associated with referred pain to the ear. Again, tenderness may be diffuse or localized. A hard, focal accumulation of inflammation in SAT may be mistaken for a solitary thyroid nodule, raising concern for possible thyroid malignancy. In contrast to invasive thyroid cancer, suspicious cervical lymphadenopathy is not present in SAT. In such cases, ultrasonographic assessment should be performed to show findings more consistent with SAT ( Figure 4.2 ).

There are no laboratory results that are specific for SAT, though some may be helpful in equivocal cases in which the diagnosis is uncertain. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are markedly elevated. Conversely, active SAT should be considered very unlikely in the setting of a normal ESR or CRP result. Other inflammatory markers such as total white blood cell count and ferritin are frequently elevated. Assessment of thyroid hormone status should be performed to evaluate the presence and degree of thyrotoxicosis during the active phase of the condition. TSH is suppressed to low levels but may still be detectable early in the course. Determination of total T4 and T3 concentration facilitates calculation of the total T3/T4 ratio. Because T3 production is increased under TSH receptor stimulation, T3 levels are expected to be higher in states of endogenous hyperfunction such as Graves’ disease, whereas thyroid hormone release found in destruction-mediated thyroiditis is expected to have relatively lower T3. A total T3/T4 ratio < 20 suggests thyroiditis though the precise accuracy of this cut-off is uncertain. Similar assessment of the free T3/T4 ratio has been reported but requires further study.

Imaging modalities may also be informative in the assessment of SAT but are not always necessary when the diagnosis is clinically apparent. Ultrasonographic assessment may reveal characteristic diffuse enlargement and hypoechogenicity or may demonstrate an asymmetric or focal pattern (see Figure 4.2 ). Radioactive iodine uptake using ¹²³ I distinguishes thyroiditis from hyperfunctioning states by demonstrating very low iodine uptake during the thyrotoxic phase, which are typically < 2% to 5% and often undetectable. The absence of uptake using technetium 99m also suggests thyroiditis and may be obtained more rapidly and in patients with recent iodine exposure. Careful attention should be paid to the timing of assessment because uptake can be elevated when obtained during the recovery phase of SAT when TSH may be elevated.