Chapter 39: Thyroid and Anti-Thyroid Drugs

INTRODUCTION

Thyroid hormone is essential for normal development, especially of the central nervous system (CNS). In the adult, thyroid hormone maintains metabolic homeostasis and influences the function of virtually all organ systems. Thyroid hormone contains iodine that must be supplied by nutritional intake. The thyroid gland contains large stores of thyroid hormone in the form of thyroglobulin. These stores maintain systemic concentrations of thyroid hormone despite variations in iodine availability and nutritional intake. The thyroidal secretion is predominantly the prohormone thyroxine, which is converted in the liver and other tissues to the active form, triiodothyronine. Local activation of thyroxine also occurs in target tissues (e.g., brain and pituitary) and is increasingly recognized as an important regulatory step in thyroid hormone action. Serum concentrations of thyroid hormones are precisely regulated by the pituitary hormone, thyrotropin (TSH), in a negative-feedback system. The predominant actions of thyroid hormone are mediated via nuclear thyroid hormone receptors (TRs) and modulating transcription of specific genes.

Overt hyperthyroidism and hypothyroidism, thyroid hormone excess or deficiency, are usually associated with dramatic clinical manifestations. Milder disease often has a more subtle clinical presentation and is identified based on abnormal biochemical tests of thyroid function. Maternal and neonatal hypothyroidism, due to iodine deficiency, remains the major preventable cause of mental retardation worldwide. Treatment of the hypothyroid patient consists of thyroid hormone replacement. Treatments for hyperthyroidism include anti-thyroid drugs to decrease hormone synthesis and secretion, destruction of the gland by the administration of radioactive iodine, or surgical removal. In most patients, disorders of thyroid function can be either cured or have their diseases controlled. Likewise, thyroid malignancies are most often localized and resectable. Metastatic disease often responds to radioiodide treatment but may become highly aggressive and unresponsive to conventional treatment.

THYROID

The thyroid gland produces 2 fundamentally different types of hormones. The thyroid follicle produces the iodothyronine hormones thyroxine (T₄) and 3,5,3′-triiodothyronine (T₃). The thyroid's parafollicular cells (C cells) produce calcitonin (see Chapter 44).

BIOSYNTHESIS OF THYROID HORMONES. The thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin, a complex glycoprotein made up of 2 apparently identical subunits (330 kDa each) and constituting the vast majority of the thyroid follicular colloid. The thyroid gland is unique in storing great quantities of potential hormone in this way, and extracellular thyroglobulin can represent a large portion of the thyroid mass. The major steps in the synthesis, storage, release, and interconversion of thyroid hormones are summarized in Figure 39–1 and described as follows: