Common symptoms

• Fast or irregular heartbeat, palpitations
• Feeling hot, sweating, heat intolerance
• Unintentional weight loss despite normal or increased appetite
• Tremor, anxiety, irritability, poor sleep
• Tiredness and proximal muscle weakness
• Frequent bowel movements
• Light or irregular periods
• Enlarged thyroid (goiter)

Usual causes

1. Graves disease: autoimmune stimulation of the thyroid, and the most common cause. It can cause eye symptoms such as bulging eyes, gritty eyes, double vision, or lid retraction.
2. Toxic multinodular goiter or a toxic thyroid nodule.
3. Thyroiditis: inflammation causing temporary release of stored hormone, sometimes after pregnancy.
4. Iodine exposure, some medicines such as amiodarone, or excessive thyroid-hormone intake. The Washington Manual of Medical Therapeutics, p. 919.

Diagnosis

Treatment

• Beta-blocker: reduces tremor, palpitations, and fast heart rate while hormone levels are being controlled.
• Antithyroid medication: usually methimazole; propylthiouracil is used in selected situations, including parts of pregnancy.
• Radioactive iodine: definitive treatment for some people, but not used in pregnancy and may be unsuitable with active thyroid eye disease.
• Thyroidectomy: considered for a large goiter, suspicious nodules, severe eye disease, need for rapid definitive control, or when other treatments are unsuitable.

Seek urgent care now if there is

• Chest pain, shortness of breath, fainting, or a very rapid/irregular heartbeat
• High fever, severe agitation or confusion, vomiting/diarrhea with severe weakness

Normal physiological production of TSH, T3, and T4

Hypothalamus → TRH → Anterior pituitary → TSH → Thyroid gland → T4 + T3
                         ↑                                      ↓
                         └──────── negative feedback ───────────┘

1. TRH production

• The hypothalamus secretes thyrotropin-releasing hormone (TRH) into the hypophyseal portal circulation.
• TRH stimulates thyrotroph cells of the anterior pituitary to synthesize and release TSH.

2. TSH production and action

• TSH means thyroid-stimulating hormone, also called thyrotropin.
• It is a glycoprotein hormone released from the anterior pituitary, commonly in a pulsatile pattern with a nocturnal rise.
• TSH binds the TSH receptor on thyroid follicular cells, mainly activating the cAMP signaling pathway.
• It promotes all major stages of thyroid hormone synthesis and release:
  • iodide uptake
  • iodination and coupling reactions
  • synthesis of thyroglobulin
  • endocytosis of colloid
  • release of T4 and T3
  • growth and vascularity of the thyroid gland

3. T4 and T3 synthesis in the thyroid

1. Iodide trapping: Iodide from blood enters the follicular cell via the sodium-iodide symporter.
2. Transport to colloid: Iodide moves into the follicular lumen.
3. Oxidation and organification: Thyroid peroxidase converts iodide to iodine and attaches it to tyrosine residues in thyroglobulin.
4. Formation of iodotyrosines:
   • One iodine + tyrosine = MIT
   • Two iodines + tyrosine = DIT
5. Coupling:
   • MIT + DIT → T3 (triiodothyronine)
   • DIT + DIT → T4 (thyroxine)
6. Hormones are stored in colloid, then released into blood when stimulated by TSH.

4. Relative production and activation

• The thyroid secretes predominantly T4, roughly 90% of its hormonal output.
• It secretes a smaller amount of T3, about 10%.
• T4 acts largely as a prohormone. In the liver, kidney, muscle, brain, and other tissues, deiodinase enzymes convert T4 to T3.
• T3 is the more biologically active hormone. It enters cells, binds nuclear thyroid-hormone receptors, and changes gene transcription.

5. Negative feedback

• they suppress TSH release from the anterior pituitary
• they suppress TRH release from the hypothalamus

• TRH and TSH rise
• thyroid hormone synthesis and secretion increase

Key point

Comparison of T3 and T4

1. Production

• DIT + DIT → T4
• MIT + DIT → T3

Thyroid gland:  T4  >>>  T3
Peripheral tissues:  T4 --deiodinase--> T3

• Type 1 and type 2 deiodinases convert T4 to active T3.
• Type 3 deiodinase inactivates T4 to reverse T3 and converts T3 to T2.

2. Transport in blood

1. Thyroxine-binding globulin (TBG): highest affinity and major carrier
2. Transthyretin (TTR)
3. Albumin: low affinity but high capacity

• T4 has a larger circulating reservoir
• T4 is cleared slowly and has a long half-life
• T3 is cleared more rapidly and has a shorter half-life

3. Cellular entry and action

1. Enters the nucleus.
2. Binds thyroid hormone receptors, mainly TRα and TRβ.
3. The receptor-hormone complex binds DNA at thyroid-response elements.
4. Gene transcription changes, resulting in altered protein and enzyme synthesis.

4. Physiological actions

High-yield summary

• T4 = produced in larger quantity, strongly protein-bound, long half-life, stable circulating reserve, mainly converted to T3 in tissues.
• T3 = produced in smaller quantity, more potent, shorter half-life, binds nuclear receptors more effectively, produces most biological actions.