Definition

• Thyrotoxicosis: a hypermetabolic condition caused by an inappropriately high level of circulating thyroid hormones irrespective of the source.
• Hyperthyroidism: a condition characterized by the overproduction of thyroid hormones by the thyroid gland; can cause thyrotoxicosis
  • Overt hyperthyroidism
    • ↓ Serum TSH levels with ↑ serum free T4 and/or T3 levels
    • Patients typically experience symptoms of thyrotoxicosis.
    • E.g., Graves disease, toxic MNG, and toxic adenoma
  • Subclinical hyperthyroidism
    • ↓ Serum TSH levels with normal serum free T4 and T3 levels
    • Patients are normally asymptomatic or mildly symptomatic.
    • May progress to overt hyperthyroidism
    • If the negative feedback regulation mechanism is intact, increased T3 and T4 lead to TSH suppression, which in turn leads to reduced stimulation of thyroid follicular cells. Thyroid hormone levels may then be normal.

Epidemiology

Etiology

Pathophysiology

Thyroid hormone synthesis

1. Synthesis of thyroglobulin (TG)
2. Uptake of iodide
3. Iodination of thyroglobulin
   • Thyroid peroxidase (TPO)
     1. Oxidation of iodide (I^- → I₂)
     2. Organification of the generated I₂ by covalently linking it with the tyrosine residues present in TG.
        • Generates single (TG + H₂O₂ + I₂ = monoiodotyrosine, MIT) or double-iodinated species of tyrosine (TG-MIT + H₂O₂ + I₂ = diiodotyrosine, DIT)
     3. Coupling reaction: conjugation of iodinated tyrosine residues
        1. Two DIT molecules form tetraiodothyronine: DIT + DIT = T4
        2. One MIT and one DIT form triiodothyronine: MIT + DIT = T3
4. Storage
5. Release
6. Transport
   • Most of the circulating thyroid hormones are inactive and bound to transport proteins. Only a very small fraction (∼ 0.3%) is unbound and biologically active.
   • Transport protein: Thyroxine-binding globulin (TBG)
     • TBG binds most of the serum T3/T4.
     • The bound fraction of T3/T4 is biologically inactive.
     • Hyperestrogenemia (e.g., pregnancy, OCP use) → ↑ TBG synthesis → ↓ free T3/T4 in serum → ↑ thyroid hormone synthesis
     • Hypoproteinemia (e.g., nephrotic syndrome, chronic liver disease) → ↓ TBG synthesis → ↑ free T3/T4 in serum → ↓ thyroid hormone synthesis

Clinical features

• Musculoskeletal
  • Fine tremor of the outstretched fingers
  • Hyperthyroid myopathy: a condition of muscle weakness, pain, and atrophy associated with hyperthyroidism (e.g., from Graves disease, thyroiditis)
    • Predominantly affects individuals > 40 years of age
    • Can develop acutely or several weeks to months after the onset of hyperthyroidism.
    • Typically affects proximal muscles (e.g., hip flexors, quadriceps) more than distal muscles
    • Serum creatine kinase levels are most often normal
• Osteopathy: osteoporosis due to the direct effect of T3 on osteoclastic bone resorption, fractures (in the elderly)
  • In long-standing hyperthyroidism
• Endocrinological
  • Female: oligo/amenorrhoea, anovulatory infertility, dysfunctional uterine bleeding
    • Serum sex hormone-binding globulin (SHBG) levels are high in hyperthyroidism → low serum free (unbound) estradiol concentrations
  • Male: gynecomastia, decreased libido, infertility, erectile dysfunction

Diagnostics

Nuclear medicine thyroid scan and radioactive iodine uptake measurement

• Subacute thyroiditis: The inflammatory disruption of the follicle membranes inhibits the transport of iodine across the thyroid cells.

Treatment

Thionamides

• Examples
  • Methimazole (MMI)
  • Carbimazole
  • Propylthiouracil (PTU)
• Mechanism of action
  • Inhibits thyroid hormone production via inhibition of thyroid peroxidase → blockade of iodide oxidation, organification, coupling
  • Propylthiouracil also lowers peripheral conversion of T4 to T3 by inhibiting 5'-deiodinase.
• Adverse effects
  • Allergy/hypersensitivity
    • The most common side effect is a pruritic rash (particularly with methimazole)
  • Hematologic side effects
    • Agranulocytosis
      • Rare but dangerous (affects ∼ 0.5% of patients; more common in elderly and those taking high doses)
      • Rapidly reversible with discontinuation of treatment
    • Aplastic anemia
  • Hepatotoxicity (seen with propylthiouracil use)
  • Teratogenicity: increased risk of congenital malformations with carbimazole and methimazole (e.g., aplasia cutis)

Potassium iodides

In the event of a nuclear accident, potassium iodide is given prophylactically to protect the thyroid from excessive accumulation of radioactive ¹³¹I.