Hashimoto's Thyroiditis

Hashimoto's thyroiditis (HT) is a chronic autoimmune thyroiditis characterized by positivity for thyroid-specific autoantibodies (TPOAb, TGAb) and lymphocytic infiltration, and is a major cause of hypothyroidism in iodine-sufficient regions. ^[1] Chronic autoimmune thyroiditis is the most common cause of hypothyroidism, although drugs (such as amiodarone, lithium and immune checkpoint inhibitors), radioactive-iodine treatment and thyroid surgery are also frequent causes, and severe iodine deficiency was historically the most common cause. ^[2] In areas with adequate nutritional iodine, Hashimoto thyroiditis is the cause of primary hypothyroidism in up to 85% of patients with hypothyroidism. ^[3] The prevalence of HT has increased significantly, and the disease is about four times more common in adult women than in men. ^[1] Within the spectrum of autoimmune thyroid disease, HT is the hypothyroid phenotype, marked by antibodies against thyroid peroxidase and thyroglobulin, whereas Graves-Basedow disease is the hyperthyroid phenotype, marked by antibodies against the TSH receptor. ^[4] In about 20% of patients, autoimmune thyroid diseases are associated with other organ-specific or systemic autoimmune disorders. ^[5]

HT is thought to result from genetic susceptibility combined with environmental factors and epigenetic influences, causing a loss of immunological tolerance and an autoimmune attack on thyroid tissue. ^{[5] [6]} Cellular and humoral immunity both drive the disease, and histology shows lymphoplasmacytic infiltration, lymphoid follicles with germinal centers, parenchymal atrophy and frequently Askanazy (oxyphilic) cells. ^[6] The chronic inflammatory lymphocytic infiltrate, especially of T cells, causes follicular destruction that leads to gradual atrophy and fibrosis, with chemokines and cytokines playing an important role in the immune pathogenesis. ^[5] Because thyroid cells are progressively destroyed, autoimmune thyroid disease can lead to subclinical or overt hypothyroidism. ^[7] HT often co-occurs with celiac disease and non-celiac wheat sensitivity, which one review attributes to a damaged intestinal barrier and increased intestinal permeability that let antigens activate the immune system or cross-react with extraintestinal tissues. ^[8] Dysbiosis of the gut microbiota

Diagnosis of HT rests on clinical characteristics, serum antibodies against thyroid peroxidase and thyroglobulin, thyroid ultrasound features and, where performed, lymphocytic infiltration on cytological examination. ^{[6] [1]} On thyroid function tests, overt primary hypothyroidism is defined as elevated TSH with free thyroxine below the reference range, and subclinical hypothyroidism as elevated TSH with free thyroxine within the reference range. ^[9] Subclinical hypothyroidism affects up to 10% of the adult population, is most often caused by Hashimoto thyroiditis, and carries a greater risk of progression to overt hypothyroidism in patients with circulating thyroid peroxidase antibodies. ^[10] Serum TSH rises with age in people without thyroid disease and may exceed the traditional upper reference limit of 4 to 5 mU/L in elderly patients, which has likely led to overestimation of subclinical hypothyroidism in persons older than 70 years. ^[10] Symptoms of hypothyroidism are nonspecific, including fatigue (68%-83%), weight gain (24%-59%) and cognitive issues (45%-48%), so the diagnosis is made on biochemical testing.

Levothyroxine monotherapy is the standard treatment for hypothyroidism, being safe and inexpensive and improving symptoms in most patients, yet 10% of patients have persistent symptoms despite biochemically normal thyroid function tests. ^[2] Initial levothyroxine doses should be tailored, with lower starting doses in older patients or those with atrial fibrillation and coronary artery disease, and TSH should be checked 6 to 8 weeks after starting or changing the dose and then annually once at goal to avoid over- or undertreatment. ^[3] Subclinical hypothyroidism may be associated with increased risk of heart failure and coronary heart disease events, but the effect of levothyroxine on cardiovascular endpoints remains uncertain because the largest randomized trial (TRUST) was underpowered for cardiovascular outcomes. ^{[10] [13]} A review summarizes that several endocrine society guidelines recommend treating subclinical hypothyroidism when TSH is higher than 10 mIU/L, with clearer benefit in younger people and continuing controversy over 65 years, while a review focused on older adults suggests considering levothyroxine at 65 years or older only when TSH is persistently 7 mIU/L or higher. ^[14]