Aetiology
Painless thyroiditis is part of the spectrum of autoimmune thyroid disease and considered by many to be a variant presentation of Hashimoto's thyroiditis. This is because individuals with painless thyroiditis may progress to permanent hypothyroidism, which is a characteristic feature of Hashimoto’s thyroiditis.[2][3][4] It is largely accepted that genetic susceptibility plays a role in autoimmune thyroid disease, with multiple studies suggesting a role for the HLA-DR gene locus and genes encoding CD40 and the thyroid-stimulating hormone receptor.[13][14]
Inherited predisposition to autoimmunity combined with environmental or hormonal factors is thought to trigger development of autoimmune thyroiditis.[13][14] These factors may include:[5]
Treatment with immunomodulatory drugs such as interferon alfa, tyrosine kinase inhibitors (e.g., sunitinib), and monoclonal antibodies (e.g., alemtuzumab, ipilimumab, nivolumab)
Note that alemtuzumab-related thyroid dysfunction typically presents 16 to 23 months after the last alemtuzumab treatment for multiple sclerosis, but later cases have been reported[8]
Treatment with lithium (a mood stabiliser used to treat psychiatric conditions such as bipolar disorder and depression)[6]
Treatment with amiodarone (an anti-arrhythmic medicine used to treat heart rhythm disorders such as atrial fibrillation)[15][16]
Radiotherapy
Hormones released during pregnancy
Bacterial and viral infection may also cause thyroiditis; however, these aetiologies typically manifest in a painful form of the disease.[5]
The most common alemtuzumab-related thyroid disorder is Graves' disease (around 60%) followed by hypothyroidism and thyroiditis.[8] Thyroid-stimulating hormone receptor autoantibodies and thyroid peroxidase autoantibodies are the predominant antibodies involved. However, a painless thyroiditis with fluctuating thyroid dysfunction and negative thyroid-stimulating hormone receptor autoantibodies accounts for 5% to 10% of patients with alemtuzumab-related thyroid disease.[8] For more information, see Graves’ disease.
Pathophysiology
The course of painless thyroiditis is generally triphasic. The initial hyperthyroid phase is the result of lymphocytic inflammation of the thyroid gland and subsequent release of preformed thyroid hormone (thyrotoxicosis). The serum concentration of thyrotropin is suppressed, and concentrations of total and free T3 and T4 become raised. A hypothyroid phase then ensues as stores of thyroid hormone become depleted. Thyrotropin concentrations begin to rise as T3 and T4 fall. This is followed by restoration of normal thyroid function, the final phase.[1]
The factors that cause some patients to present with a destructive hyperthyroid phase and others with chronic hypothyroidism are unknown. Histologically, painless thyroiditis is characterised by a lymphocytic infiltrate with disruption of thyroid follicles, extensive fibrosis, and Hurthle cell change. Germinal centres are seen less commonly in painless thyroiditis than in Hashimoto's thyroiditis.[17] Most patients have antithyroid peroxidase antibodies, although these antibodies may be present in low titres.[2][3]
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