Hashimoto’s thyroiditis: pathophysiology and therapy

Hashimoto’s thyroiditis (HT) is the leading cause of hypothyroidism in iodine-sufficient regions, and it is the most frequent autoimmune thyroid diseases (AITD), comprising also Graves’ disease. HT is associated with thyroid autoantibodies, such as thyroid peroxidase (AbTPO) and thyroglobulin (AbTg) antibodies, that are serological markers of the disease. The pathogenesis of HT is complex and multifactorial, arising from a delicate interplay between genetic susceptibility and environmental triggers. Genome-wide association studies have identified key susceptibility loci, including immune-modulating genes such as HLA-DR, CTLA4, and PTPN22, alongside thyroid-specific genes like those encoding thyroglobulin and the TSH-receptor. Environmental factors—including iodine intake, selenium deficiency, viral infections, and psychological stress—act as risk factors in genetically predisposed individuals, initiating an aberrant immune response. HT is characterized by Th1 cell-mediated cytotoxicity with chronic lymphocytic infiltration leading to the destruction of thyrocytes, resulting in fibrosis and glandular atrophy. In HT, current management focuses on achieving biochemical euthyroidism through hormone replacement. Patients with HT and hypothyroidism are treated with substitutive levothyroxine (L-T4; 1.5-1.6 μg/kg/day) therapy. However some patients experience different conditions of L-T4 malabsorption or drug interference and need higher dosage of L-T4 to obtain a biochemical euthyroidism. In the above reported patients recently new L-T4 formulations such as the liquid one, or the soft gel capsule have been developed to overcome the L-T4 malabsorption. However, as our understanding of the thyroid-immune axis deepens, research is shifting toward personalized immunotherapies for HT, aimed at the resolution of disease manifestations, restoring immune tolerance. Currently, established clinical modalities coexist with preclinical experimental approaches (including animal models, cytokine-targeted strategies, and nanoparticle-based therapies), but no immunotherapy is established as a disease-modifying treatment for HT in routine clinical practice.