Thyroid Physiology and Thyroid Function tests

Thyroid Anatomy

• Two lobes in the anterior neck on either side of the trachea inferior to the thyroid cartilage. About 25-30g.  About 5cm long
  • Joint by the isthmus and may have an additional ‘pyramidal lobe’ (remnant of the hypoglossal tract)
• Lies deep to the sternothyroid and sternohyoid muscles; parathyroid glands usually lie between the posterior border of the thyroid glands and its sheath; internal jugular vein and common carotids lie postero-laterally; the recurrent laryngeal nerve lies between the trachea and the thyroid
• Highly vascular- supplied by the
  • superior thyroid artery
    • first branch of ECA
  • inferior thyroid arterie
    • branch of the thyrocervical trunk of the subclavian
• Venous drainage from the superior, middle (both into the internal jugular) and inferior (drains into the brachio-cephalic veins) thyroid veins

Histology

• Thyroid tissue is subdivided by capsular septa into lobules containing follicles
  • spherical structures filled with colloid of mostly iodinated thyroglobulin
  • surrounded by follicular cells (produce hormone and Tg), between which are parafollicular cells (including C cells- produce calcitonin)
  • Follicles are the functional unit of the thyroid.  Production of thyroglobulin and thyroid hormone occurs.
    • Involves active transportation of iodine into the cells (stimulated by TSH), oxidation of iodine to I- (by thyroid peroxidase), iodination of tyrosine residues on Tg molecule

Thyroid Physiology

• The thyroid produces and secretes 2 metabolic hormones
  • Thyroxin (T4) and triiodothyronine (T3)
    • Act on many different cellular processes- main effect is an increase in metabolism
      • Effects can be split into two groups
        • Those that take minutes to hours after receptor binding (i.e. do not require protein synthesis)
          • e.g. activation of the membrane bound Na/K/ATPase and mitochondrial oxygen consumption
        • Those that take hours and require new protein synthesis.
          • e.g. effects on growth, proliferation, maturation etc
      • In general, in normal, low concentrations, the effect is anabolic i.e. stimulates growth.  In abnormally high concentrations, the effect is catabolic i.e. increased energy expenditure and protein breakdown.
• Under homeostatic control via a negative feedback loop involving the hypothalamic-pituitary-thyroid axis:
  • Thyroid releasing hormone is produced by the hypothalamus
    • Release is pulsatile and circadian
      • Downregulated by free T3 levels
    • Stimulates TSH formation and release
  • Thyroid stimulating hormone is produced by the anterior pituitary by thyrothroph cells
    • Release is
      • upregulated by TRH
      • downregulated by T4 and T3
    • Stimulates thyroid hormone production and release (possibly indirectly via stimulation of iodine uptake, colloid pino/endocytosis and growth of the thyroid gland)
• A note about thyroid hormone in the plasma and action
  • More than 99% of T3 and T4 is bound to plasma carrier proteins (they are both highly water soluble and would otherwise be delivered straight into the tissues)
    • Majority bound to thyroxine binding globulin (TBG) (~75%)
      • Others include thyroxine binding pre-albumin and albumin, as well as HDLs
  • Only unbound (free) hormone has metabolic activity and physiological effects
    • ~0.03% of T4 and 0.3% of T3
    • NB T3 is 3-7 times more potent than T4
  • T4 is the primary secretory product of the thyroid gland (~70-90μg/day).
  • T3 is derived from 2 sources
    • About 20% directly secreted from the thyroid
    • About 80% (of 15-30μg total) is produced via deiodination of T4 in the periphery (mainly liver)
      • NB In the liver, about 40% is converted to T3, another 40% to reverse T3 (metabolically inactive) and 20% is excreted via bile
  • It is important to measure TBG, total bound thyroxine and free thyroxine in order to judge abnormalities of thyroid function (as TBG can be affected by a number of things e.g. drugs (OCP, clofibrate, heroin/methodone, tamoxifen etc) and conditions e.g. liver disease

Thyroid Function tests

• Remember to always base test requests/interpretation of results on the clinical history and examination
• Hyperthyroidism
  • Low TSH and High T3/T4
    • Common causes
      • Primary hyperthyroidism e.g. Graves’; multinodular goitre; toxic nodule
    • Other common causes with low-radio-iodine uptake
      • transient thyroiditis (post-partum, post-viral, DeQuervain’s)
    • Rare
      • Over medication with thyroxine
      • Iodine induced
      • Amiodarone tx
      • Ectopic thyroid tissue
• ‘Normal’ (Investigation for other symptom e.g. AF) or hypothyroidism
  • Low TSH and normal T3/T4
    • Subclinical hyperthyroidism or medication (thyroxine) for hyperthyroidism
    • Rarer causes include steroids, dopamine/dobutamine infusions
    • Acute illness can also cause this picture
  • Low TSH and low T3/T4
    • Treatment for hyperthyroidism or acute illness are most common causes
    • Rarely, pituitary disease or congenital TSH/TRH deficiencies
• Hypothyroidism
  • Raised TSH, Low T3/T4
    • Common
      • Chronic autoimmun thyroiditis
      • Post radio-iodine/thyroidectomy
      • Transient thyroiditis (hypothyroid phase)
    • Other
      • Post radiotherapy
      • Drugs e.g. amiodarone, lithium
      • Iodine deficiency
      • Congenital causes
  • Raised TSH, normal T3/4
    • Subclinical autoimmune hypothyroidism
    • Drugs e.g. amiodarone, sertraline
    • Recovery post acute-illness
  • Raised TSH, raised T3/4
    • Unusual- causes include amiodarone, TSH-secreting tumours (pituitary), interfering antibodies (test picks up mimics of TSH/T3/T4)