Graves Disease II: Pathophysiology

Graves’ disease is an autoimmune disorder characterized by the production of thyroid-stimulating immunoglobulins (TSI) that activate TSH receptors, leading to excessive synthesis and release of thyroid hormones (T3 and T4) and resulting in hyperthyroidism.

Among all causes of hyperthyroidism, Graves’ disease is the most common and can happen at any age, though it is more frequent in women. It produces a hypermetabolic state with features such as weight loss, tachycardia, tremor, and heat intolerance.

Pathophysiology

The disease begins with a loss of immune tolerance. Helper T cells stimulate B cells to produce TSI antibodies, which bind to TSH receptors on thyroid follicular cells. These antibodies mimic TSH and continuously activate the receptor, bypassing normal feedback control and causing excessive production of T3 and T4.

Microscopically, follicular cells become tall columnar, increase in number, and vascularity rises. Follicles appear small and crowded, with scalloped colloid due to rapid hormone utilization. Although elevated T3 and T4 suppress pituitary TSH via negative feedback, antibody-mediated stimulation persists.

Autoimmunity also affects extra-thyroid tissues expressing TSH receptors. In orbital fibroblasts, glycosaminoglycan (GAG) deposition causes edema and exophthalmos. In skin fibroblasts, it leads to pretibial myxedema. Elevated thyroid hormones increase basal metabolic rate, heat production, and sensitivity to catecholamines.

Clinical Manifestations

Patients commonly present with weight loss despite increased appetite, tachycardia, palpitations, fine tremors, heat intolerance, sweating, anxiety, and hyperactivity. Other features include goiter, exophthalmos, pretibial myxedema, muscle weakness, and, in severe cases, arrhythmias or thyroid storm.