Grave's Disease Notes

HP Axis and Homeostasis

• The hypothalamic-pituitary (HP) axis is a complex system of neuroendocrine pathways and feedback loops that maintain physiological homeostasis.
• Example: Hypothalamic-Pituitary-Thyroid (HPT) Axis
  • Hypothalamus releases Thyrotropin-Releasing Hormone (TRH).
  • TRH stimulates the pituitary gland to release Thyroid-Stimulating Hormone (TSH).
    • Negative feedback from TSH to the hypothalamus.
  • TSH stimulates the thyroid gland to release thyroid hormones (T3 & T4).
    • Negative feedback from T3 & T4 to the hypothalamus and pituitary.

Physiological Effects of Thyroid Hormones

• Metabolic Rate and Heat Production
  • Affects Basal Metabolic Rate (BMR).
  • Induces lipolysis or lipid synthesis based on metabolic status.
  • Increases carbohydrate metabolism.
  • Anabolism of proteins at normal doses, but catabolism at high doses.
• Regulation of Gene Expression
  • Increases or decreases protein synthesis by entering the cell nucleus.
• Enhances Catecholamine Effects
  • Enhances enzymes that synthesize catecholamines in the adrenal medulla.
    • Tyrosine hydroxylase
    • Dopamine beta-hydroxylase
  • Increases expression and activity of adrenergic receptors, increasing tissue responsiveness to catecholamines.
• Neural Development and Maturation of the CNS
  • Critical for proliferation, differentiation, and migration of neural stem cells.
  • Regulates gene expression essential for neural development.
  • Formation of synapses.
• Skeletal Muscle Maturation
  • Increases metabolic rate and protein synthesis, promoting muscle mass and strength.
  • Stimulates expression of genes involved in muscle growth, such as Insulin-like Growth Factor 1 (IGF-1).
• Bone Ossification
  • Increases bone turnover and mineralization.
  • Stimulates proliferation and differentiation of osteoblasts.
  • Increases activity of osteoclasts.
• Reproductive Function
  • Females: Boosts ovarian cycle.
  • Males: Boosts spermatogenesis.

Types of Hyperthyroidism

• Primary Hyperthyroidism
  • Toxic Adenoma
    • Excessive thyroid hormone production due to genetic mutations or unknown causes.
  • Grave's Disease
  • Toxic Multinodular Goiter
    • Multiple nodules in the thyroid gland produce excessive thyroid hormones.
    • Can result from genetic mutations or radiation exposure.
• Secondary Hyperthyroidism
  • Pituitary Adenoma
    • Tumor causes excess TSH production, leading to increased thyroid hormone production.
• Tertiary Hyperthyroidism
  • Hypothalamic dysfunction
    • Damage or dysfunction of the hypothalamus leads to overproduction of TRH.

Pathogenesis of Grave's Disease

• B cells, with the help of T cells (CD4+), mediate autoimmunity.
  • Produce IgG antibodies called Thyroid Receptor Antibodies (TRAB) or Thyroid-Stimulating Immunoglobulins (TSI), which bind and attack the TSH receptor.
    • Type 2 hypersensitivity: non-cytotoxic mechanism + antibody-mediated cellular dysfunction.
    • Tissue-specific.
    • Antibody-mediated.
  • Autoantibodies continuously stimulate thyrotropin receptors.
    • Increases Sodium/Iodide (Na/I) symporter activity, leading to increased iodide uptake.
    • Increased thyroglobulin synthesis.
      • Increased iodination of thyroglobulin.
    • Upregulation of cAMP and PLC pathways, increasing thyroid hormone production.
      • Hyperplasia of the gland.
  • Increased TSH leads to goiter formation.
    • Hoarseness and dysphagia.
    • Thyroid gland bruit.
  • Thyroid hormone acts as a negative feedback on the pituitary gland, decreasing TSH production.

Formation of Goiter

• Grave's Disease
  • TSI stimulates the thyroid gland to enlarge.
    • Follicular cells become hypertrophic and hyperplastic.
    • Lymphocytes and plasma cells infiltrate the gland, forming lymphoid follicles.
    • TSI antibodies target the thyroid receptor on follicular cells.
      • Stimulation leads to overproduction of T3 & T4, causing thyroid enlargement and goiter.
• Hashimoto's Thyroiditis
  • Lymphocytes (T & B cells) react to self-thyroid antigens.
    • Lymphocytes infiltrate the thyroid gland.
      • T cells are activated, causing destruction of the thyroid gland.
        • Inflammation and loss of normal thyroid gland architecture.
          • If the thyroid gland is significantly inflamed and fibrotic, it presents as a goiter (enlarged and lobular).

Physical Examination Findings

• Palms are red and sweaty due to increased blood flow and overactive sweat glands.
• Presence of neck swelling.
  • TSI regulates growth and binds to TSH receptors, resulting in an enlarged gland.
• Protruding, watery, puffy eyes.
  • Antibodies attack the eyes, leading to inflammation.
• Thyroid Function Test (TFT)
  • Autoimmune disease where antibodies bind to the TSH receptor, causing T3 and T4 to rise.
  • Negative feedback loop restricts TSH secretion from the anterior pituitary.

Treatment for Grave's Disease

• Beta-blockers (e.g., Propranolol)
  • Regulate heart rate.
• Radioiodine Therapy
  • Radioactive iodine pills destroy follicular cells and thyroglobulin.
    • Not for pregnant women.
    • May lead to hypothyroidism.
• Surgery
  • Partial thyroid removal may cause hypothyroidism.

Contrast: Hashimoto's Thyroiditis vs. Grave's Disease

• Grave's Disease
  • Autoantibodies: TSI or TSAB production.
  • Thyroid hormone production: TSI stimulates TSH receptors, causing excess T4 and T3 production, resulting in hyperthyroidism.
  • Pathological Causes
    • Increased levels of thyroid hormones leads to systemic effects
      • Increased metabolic rate.
      • Weight loss.
      • Anxiety.
      • Goiter.
• Hashimoto's Thyroiditis
  • Increased TSH and anti-TPO antibodies.
  • Decreased T4.
  • Autoantibodies destroy thyroid cells.
  • Progressive loss of thyroid function.

Risk Factors

• Family heredity
• Smoking
• Gender (women)
• Pregnancy
• Age
• Other autoimmune diseases
• Stress