Hypothyroidism II: Pathophysiology

Hypothyroidism is classified by the level of dysfunction. Primary hypothyroidism results from intrinsic thyroid gland dysfunction causing reduced hormone production. Secondary hypothyroidism arises from inadequate TSH secretion by the pituitary. Tertiary hypothyroidism results from deficient TRH production by the hypothalamus. Secondary and tertiary forms are collectively called central hypothyroidism.

The hypothalamus releases TRH, which stimulates the pituitary to secrete TSH. TSH then signals the thyroid to produce T4 and T3 hormones. These thyroid hormones provide negative feedback, reducing TRH and TSH release when levels are adequate. This feedback loop maintains hormonal balance and regulates metabolism.

In primary hypothyroidism, the thyroid fails to produce adequate T4 and T3, so loss of negative feedback causes TSH and TRH to rise persistently. In secondary hypothyroidism, pituitary dysfunction prevents adequate TSH secretion, resulting in low TSH and low thyroid hormones. The feedback mechanism responds differently depending on where the dysfunction originates.

Primary hypothyroidism causes include Hashimoto thyroiditis, thyroidectomy, radioactive iodine therapy, medications like lithium and amiodarone, and iodine deficiency. It is characterized by high TSH and low T4. Central hypothyroidism results from pituitary or hypothalamic dysfunction, presenting with low TSH and low thyroid hormones, making diagnosis more challenging.

When the pituitary fails to secrete adequate TSH due to tumors, trauma, surgery, radiation, or genetic defects, thyroid stimulation decreases. Without sufficient TSH signaling, the thyroid reduces hormone synthesis, leading to low circulating T4 and T3 levels. TSH may appear normal but is inappropriately low relative to reduced thyroid hormone levels.

Insufficient hypothalamic TRH production reduces pituitary TSH release, which then decreases thyroid hormone synthesis. This tertiary hypothyroidism results from hypothalamic tumors, trauma, infiltrative diseases, or congenital TRH deficiency. TSH may be normal or slightly elevated but biologically inactive, requiring TRH stimulation testing to confirm diagnosis.

Thyroid hormones T4 and T3 regulate metabolism, energy balance, and multiple organ systems throughout the body. When thyroid hormone production is insufficient, metabolic rate decreases and organ system function becomes impaired. This widespread effect explains why hypothyroidism affects energy, temperature regulation, cardiovascular function, and complications of diabetes mellitus may also occur in metabolic disorders.