Thyroid function and dysfunction

• Thyrotropin releasing hormone secreted from the paraventricular nucleus of the hypothalamus. TRH travels via portal system to stimulate the anterior pituitary gland to produce TSH.
• Thyroid stimulating hormone promotes synthesis and release of thyroid hormones (T3 and T4) from the thyroid gland.
• Triiodothyronine (T3) and free thyroxine (T4) suppress release of TRH and TSH via negative feedback loop.
• • thyroid cells arranged in follicles
  • iodide and sodium ions transported into follicular cells from bloodstream via sodium-iodide symporter
  • iodide ions move into colloid via Pendrin cotransporters
  • thyroid peroxidase oxidises two I- ions to form I2 iodine molecule
• • thyroglobulin acts as synthesis and storage vehicle for T3/T4 in follicles
  • thyroglobulin's tyrosine residues iodinated by thyroid peroxidase
  • iodinated thyroglobulin undergoes endocytosis/pinocytosis to reenter follicular cells
  • iodinated tyrosine residues cleaved, releasing T3/T4
  • T3/T4 leave follicular cells and enter bloodstream via monocarboxylate transporters
• T3 contains 3 iodide ions

  T3 is 3-4 times as potent as T4
• T4 contains 4 iodide ions

  14x as much T4 is produced compared to T3

  T4 converted to T3 in target cells by deiodinases
• Both T3 and T4 are transported bound to proteins such as thyroxine binding globulin, albumin and transthyretin, rendering them inactive. Only free hormones are able to act on target tissues
• • thyroid receptors are found within the nucleus of cells
  • they are abundant in the brain, liver, kidney, muscle and fat
• Thyroid hormones act to increase

  • basal metabolic rate
  • cardiac muscle activity
  • sympathetic nervous system activity (increases sensitivity to catecholamines)
  • metabolism: anabolic effects at low serum levels and catabolic effects at higher levels
  • growth: increases release and effect of growth hormone and IGF-1
• Negative feedback loop

  • excess thyroid hormone will inhibit TRH and TSH production
  • insufficient thyroid hormone will increase/promote release of TRH and TSH
• Hyperthyroidism

  • excess thyroid hormones (T3 and T4) will inhibit TRH and TSH production.
  • low TSH
  • high free T4
• Hypothyroidism

  • insufficient thyroid hormone will increase/promote release of TRH and TSH
  • High TSH
  • Low free T4
• Where is TSH released from?

  Anterior pituitary gland
• TRH stimulates what gland?

  anterior pituitary gland
• TPO (thyroid peroxidase) oxidises two I- ions to I2 iodine molecules
• Iodinated thyroglobulin undergoes endocytosis to be transported back into follicular cells
• Which thyroid hormone is produced more?

  Thyroxine
• What would you expect to happen to other thyroid function tests, in the presence of excess thyroid hormones?

  Low TSH
• What would you expect to happen to other thyroid function tests in the presence of insufficient thyroid hormones?

  High TSH
• Primary Hypothyroidism (damage/disease to thyroid gland)

  • primary hypo
  • increased TSH
  • decreased T4
  • subclinical hypo
  • increased TSH
  • variable T4
• Secondary Hypothyroidism (damage/disease to pituitary gland)

  • decreased/normal TSH
  • decreased T4
• Tertiary hypothyroidism (disease/damage to the hypothalamus or hypophyseal portal system)

  • decreased TRH
  • decreased TSH
  • decreased T4
• TPO antibodies

  • help differentiate an autoimmune cause of hypothyroidism
  • elevated in >90% of patients with autoimmune hypothyroidism
  • can also be positive in autoimmune hyperthyroidism
• Differentials for hypothyroidism

  • autoimmune (hashimoto's) hypothyroitis
  • positive TPO antibodies
  • iodine deficiency
  • postpartum thyroiditis
  • amiodarone induced
  • congenital hypothyroidism
• Hypothyroidism symptoms

  • tiredness, lethargy
  • weight gain
  • cold intolerance
  • menstrual irregularities (oligomenorrhoea, amenorrhoea, menorrhagia)
  • reduced libido
  • neck lump/goitre
• hypothyroidism - clinical signs

  • hair loss (outer third of eyebrows)
  • dry skin
  • goitre
  • bradycardia
  • myxoedema
  • delayed relaxation phase of deep tendon reflexes
• myxoedema - deposition of mucopolysaccharides in the skin leading to swelling
• Associated with autoimmune hypothyroidism

  • other autoimmune conditions (coeliac disease, type 1 diabetes mellitus, pernicious anemia)
  • genetic conditions (turner's and down's syndrome)
• Hypothyroidism management

  • replacement of thyroxine - levothyroxine (synthetic T4)
  • titrate dose according to TSH level - monitor 3 monthly until stable
  • cautions
  • >65 years old with cardiovascular risk
  • pregnancy
  • subclinical hypothyroidism - monitor
• Primary hyperthyroidism (overactive thyroid gland)

  • decreased TSH
  • increased T4
  • Anti-TSHR-Ab-IgG antibodies to TSH receptor (>90% in graves disease)
• secondary hyperthyroidism (rare-excess TSH production)

  • increased TSH
  • increased T4
• Thyrotoxicosis without overactive thyroid gland

  • thyroiditis (excess hormone released)
  • struma ovarii (ectopic thyroid tissue secreting excess)
  • excess levothyroxine ingestion
• TSH receptor antibodies (TRAb) mimic TSH in stimulating thyroid production

  • high levels in 95% of patients with Graves disease (autoimmune hyperthyroidism)
  • high levels of anti-TPO in 70%
• Primary hyperthyroidism differentials

  • autoimmune hyperthyroidism/graves disease (IgG antibodies to TSH receptor)
  • toxic multinodular goitre
  • solitary toxic adenoma
  • amiodarone-induced
  • follicular thyroid cancer
  • beta-hCG related (mimics effect on TSH)
• Thyrotoxicosis without overactive thyroid gland

  • DeQuervain's Thyroiditis (excess hormone released)
  • Struma ovarii (ectopic thyroid tissue secreting excess)
  • excess levothyroxine ingestion
• Hyperthyroidism symptoms

  • neck lump
  • palpitations
  • heat intolerance
  • weight loss
  • diarrhoea
  • amenorrhoea
  • reduced libido
  • gynaecomastia
  • fatigue
  • change in mood
• Clinical signs hyperthyroidism

  • goitre
  • sinus tachycardia/arrhythmias
  • hair loss
  • palmar erythema
  • tremor
• graves clinical signs

  • ophthalmology
  • pretibial myxoedema
  • acropachy
  • thyroid bruit
• Associated conditions with Graves disease

  • other autoimmune conditions
  • type 1 diabetes mellitus
  • coeliac disease
  • rheumatoid arthritis
  • vitiligo
  • pernicious anemia
  • addisons disease