Endocrinology Mechanisms of Hypothyroidism

Mechanism of Action of Thyroid Hormones

• T4 and T3 dissociate from thyroglobulin proteins and enter cells by diffusion or active transport.
• T4 binds to specific T3 receptor proteins in the nucleus, with alpha and beta forms present.
• Major sites of T3 receptors include the liver, kidney, heart, lungs, skeletal muscles, pituitary, and intestines, with lesser amounts in the brain, spleen, and testes.
• Binding activates receptors, increasing RNA formation and protein synthesis, leading to physiological responses.
• T4 has about 10 times lower affinity for T3 receptors compared to T3.

Chemistry of Thyroid Hormones

• T4 (Thyroxine) is converted to T3 (Triiodothyronine) through deiodination for activation.
• Reverse T3, an inactive form, is also produced.
• All forms of thyroid hormones are levo-isomers.

Pharmacological Effects of Thyroid Hormones

• Thyrotoxicosis:

  • Warm, moist skin; heat intolerance; excessive sweating; thin hair; periorbital dermopathy.
  • Increased basal metabolic rate; hyperglycemia; elevated triglycerides and cholesterol; weight loss.
  • Menstrual irregularities and increased gonad steroid metabolism.
  • Increased erythropoiesis and possible anemia.
  • Mild polyuria; increased renal blood flow; increased GFR.
  • Nervousness; hyperkinesia; emotional liability; insomnia.
  • Increased appetite; frequent bowel movements.

• Hypothyroidism:

  • Pale, cool, puffy skin; dry, brittle hair; brittle nails.
  • Decreased basal metabolic rate; delayed insulin degradation; reduced triglycerides and cholesterol.
  • Infertility, decreased libido, and menstrual irregularities.
  • Decreased erythropoiesis; possible anemia.
  • Decreased renal blood flow; reduced GFR; impaired water excretion.
  • Stiffness, muscle fatigue; decreased deep tendon reflexes.
  • Lethargy; general slowing of mental processes.
  • Decreased appetite; less frequent bowel movements.

Hypothyroidism Overview

• Syndrome resulting from a deficiency of thyroid hormones, reversible but leads to slowing of body functions.
• In infants, can cause growth and developmental retardation, possibly resulting in dwarfism and irreversible mental retardation.
• Diagnosis involves low free T4 and elevated serum TSH levels.

Causes of Hypothyroidism

• Drug-Induced: Medications like lithium, fluoride, thioamide blockers, etc., lead to mild to moderate hypothyroidism.
• Dyshormogenesis: Impaired synthesis of T4 due to enzyme deficiencies; may present with goiter.
• Destruction/Removal: Radiation, thyroidectomy leads to severe hypothyroidism without goiter.
• Congenital: Cretinism due to iodine deficiency; severe hypothyroidism results.
• TSH Absence: Pituitary/hypothalamic disorders lead to mild hypothyroidism.
• Hashimoto's Thyroiditis: Autoimmune destruction of the thyroid; progression from goiter to mild/moderate hypothyroidism is common.

Management of Hypothyroidism

• Withdrawal of drugs causing hypothyroidism, with short-term levothyroxine replacement therapy.
• Levothyroxine dosage for infants is typically 10-15 µg/kg/day, while adults require about 1.7 µg/kg/day.
• Other management techniques involve modifications of tissue response to hormones and surgical interventions.

Thioamides

• Include Methimazole, Carbamizole, and Propylthiouracil; Carbamizole is ten times more effective than Propylthiouracil.
• Mechanism: They prevent hormone synthesis by inhibiting thyroid peroxidase and block iodine organification.
• Side effects may include radiation-induced genetic damage; caution is advised for patients over 40.

Beta Blockers

• Useful for symptom control in thyrotoxicosis as they counteract sympathetic stimulation.
• Propranolol is the most commonly used beta blocker for managing symptoms.

Thyroid Storm

• Acute exacerbation of thyrotoxicosis symptoms; life-threatening condition.
• Treatment includes Propranolol, Diltiazem, potassium iodide, iodinated contrast agents, and corticosteroids.

Thyrotoxicosis in Pregnancy

• Recommended treatment includes subtotal thyroidectomy and Iodine I^131.
• Propylthiouracil is used during pregnancy, and thyroid supplements may be necessary post-surgery.