Thyroid gland function and pathopysiology

• Thyroid gland


  Small butterfly shaped gland in the front of the neck just below the Adam's apple, weighing approximately 20 g
• Development of thyroid gland

  Developed as soon as the 11th week of gestation under stimulation of maternal TSH
• Thyroid gland


  • Consists of 2 lobes
  • Thousands of circular follicles (made of epithelial cells surrounding a giant vacuole, the colloid) of 200-300 μm diameter, inside a dense capillary network
  • Colloid is mainly made of thyroglobulin, a big glycoprotein which contains iodinated tyrosine groupings on its surface, (in fact T3 and T4)
  • Follicle cells synthesise thyroid hormone
  • Calcitonin cells
  • Capillary (Endothelial cell)
  • Thyroid follicle (stimulated)
  • Colloid (contains thyroglobulin)
• Synthesis of thyroid hormones

  1. Iodination of the tyrosine grouping (TPO complex, present at apical membrane of the follicle cell, facing the colloid in the follicle lumen)

  2. Iodide, taken up by the Na/I symporter, transport stimulated by TSH

  3. Thyroglobulin, dimeric glycoprotein (3,000 aa with 14 tyrosine groups on its surface which can be iodinated), secreted into the lumen by follicle cell

  4. Coupling (TPO complex)

  5. Reuptake into the follicle cells and proteolysis

  6. T3 and T4 leave the cell, reach the capillaries
• Thyroid hormones (T3 and T4)

  Stored in the thyroid as peptide-linked amino acids in thyroglobulin, but are released into the blood stream as free amino acids so secretion must be preceded by proteolysis of the thyroglobulin
• Release of thyroid hormones

  1. Following TSH stimulation, the colloid is retrieved inside the follicular cells and then the thyroglobulin droplets fuse with lysosomes

  2. The proteolytic action of the lysosomes allows the release from the lysosomes of T3 and T4, which leave the cell and reach the capillary plexus to enter the bloodstream
• Regulation of thyroid gland function

  • The most important regulator is the Hypothalamo-pituitary axis with TRH-TSH
  • Iodide itself can also regulate thyroid gland function
  • Sustained TSH stimulation caused the hypertrophy and hyperplasia of the follicular cells, meanwhile the capillaries proliferate
• Transport of thyroid hormones

  • T4 and T3 are carried by plasmatic protein, such as thyroxine-binding globulin (TBG or thyropexin)
  • Only a minute fraction of free hormone is immediately available to tissues (as only 0.03% of T4 and 0.3% of T3 are free)
  • Half-life: 8 days for T4, 1 day for T3. Consequently, T4 is found mainly in circulation, while T3 is found mainly intracellularly
• Action of thyroid hormones on target cells

  • Thyroid hormones are transported into cells by a specific carrier-mediated uptake mechanism, that is energy dependent
  • T4 is usually converted to T3 by de-ionidases, mainly in liver and kidney, but also in muscles and brain
  • T4 may also act as an hormone, but with much lower potency. Consequently T4 can be considered a prohormone (a circulating resevoir of thyroid hormones)
• Thyroid hormone receptors


  • Bind to Thyroid hormone Response Elements (TRE's) in specific target genes
  • After binding to thyroid hormone, the receptor induces changes in gene expression by stimulating or repressing transcription
  • Mainly found in the nucleus and are tightly associated with chromatin
  • Two genes for thyroid hormone receptor α and β subtypes and two isoforms for each subtypes
  • All tissues express the alpha-1, alpha-2 and beta-1 isoforms, but beta-2 is synthesized almost exclusively in hypothalamus, anterior pituitary and developing ear
  • Receptor alpha-1 is the first isoform expressed in the embryo, and there is a profound increase in expression of beta receptors in brain shortly after birth
  • The β1 receptor preferentially activates expression from several genes known to be important in brain development (e.g. myelin basic protein)
• Genes positively regulated by T3

  • Fatty acid synthetase
  • Growth hormone
  • Lysozyme silencer
  • Malic enzyme
  • Moloney leukemia virus enhancer
  • Myelin basic protein
  • Myosin heavy chain α
  • Phosphoenolpyruvate carboxykinase
  • RC3
  • Spot 14 lipogenic enzyme
  • Type I 5'-deiodinase
  • Uncoupling protein
• Genes negatively regulated by T3

  • Epidermal growth factor receptor
  • Myosin heavy chain β
  • Prolactin
  • Thyroid-stimulating hormone α
  • Thyroid-stimulating hormone β
  • Thyrotropin-releasing hormone
  • Type II 5'-deiodinase
• Metabolic effects of thyroid hormones

  • Increase the basal rate of oxygen consumption and heat production
  • Increase energy expenditure and metabolic rates
  • Increases Glucose and fatty acid oxidation
  • Increase cardiac output ensuring sufficient oxygen delivery to the tissues. Heart rate, volume, myocardial contraction are enhanced
  • Increase glucose absorption from the gastrointestinal tract and potentiate the stimulatory effect of epinephrine, NE, cortisol, glucagon on gluconeogenesis, on lipolysis, ketogenesis and proteolysis
  • Increase cholesterol utilisation
• Effects of thyroid hormones on growth and development

  • During development: Stimulates ossification, linear growth of bone and maturation of the epiphyseal bone centres, Accelerates growth in part by facilitating GH effects and also stimulating its production, Crucial during the maturation of the CNS, Enhances the maturation of chondrocytes (cartilage)
  • In adults: Important in the regeneration of skin and hairs, and in ossification, Regulation of reproductive function, Function of skeletal muscles
• During development, Thyroid hormones appear to have their most profound effects on the terminal stages of brain differentiation, including synaptogenesis, growth of dendrites and axons, myelination and neuronal migration
• Toward the end of the first trimester of pregnancy in humans a significant fraction of the thyroid-stimulating activity is from hCG (human chorionic gonadotropin secreted by placenta which has a similar structure)
• Cold exposure


  Increases thyroid hormone secretion, by activating the hypothalamus-pituitary-thyroid axis
• Physical exercise


  Increases production of thyroid hormones, which in turn increases metabolism
• Rich diet


  Increases thyroid hormone production
• Fasting


  Decreases thyroid hormone production
• Sepsis


  Decreases thyroid hormone production
• The thyroid gland helps to produce enough thyroid hormones to meet our needs and helps to maintain a body temperature of around 37°C
• Cold exposure increases thyroid hormone secretion, by activating the hypothalamus-pituitary-thyroid axis
• During physical exercise, the thyroid gland increases production of the thyroid hormones, which in turn increases metabolism
• The thyroid gland helps to dispose of the excess of calories by increasing metabolism
• Regulation of thyroid hormone production

  1. When levels of thyroid hormone decrease, or when demand increases, the hypothalamus detects this and orders the endocrine system to produce more thyroid hormone

  2. The hypothalamus sends an instruction in the form of a hormone called TRH (thyrotropin-releasing hormone) to the pituitary gland which in turn sends a message in the form of TSH (thyroid-stimulating hormone) to the thyroid gland which causes it to secrete more thyroid hormones
• Symptoms of hyperthyroidism


  • Moist, flushed skin
  • Rapid pulse rate and palpitations
  • Increased body temperature
  • Muscle weakness
  • Diarrhoea
  • Irritable and agitated, mood swings
  • Tendency to lose weight regardless of intake
  • Protrusion of the eyes and eye problems
  • Nervousness
  • Insomnia
  • Goitre or swelling of the neck
  • Period problems
  • Heat intolerance
  • Increase sweating
• Symptoms of hypothyroidism


  • Exhaustion
  • Depression
  • Dry coarse skin
  • Weight gain
  • Low basal temperature
  • Cold and/or heat sensitivity
  • Poor memory and brain fog
  • Palpitations but low pulse rate
  • Gynaecological disorders
  • Skin pallor
  • Nervousness
  • Hearing sensitivity
  • Muscle pain and swollen muscles
  • Deepening of the voice as the vocal chords thicken
  • Loss of hair
• Loss of hormone production as part of the aging process
• The body may produce antibodies against its own thyroid gland resulting in its destruction (autoimmune thyroiditis, Hashimoto's disease)
• Possible causes of hypothyroidism

  • Loss of hormone production as part of the aging process
  • The body may produce antibodies against its own thyroid gland resulting in its destruction (autoimmune thyroiditis, Hashimoto's disease)
  • Disturbed utilisation in the tissues (blood transport, conversion of T4 to T3, may be due to selenium deficiency?)
  • An iodine deficiency in the diet (can be very frequent in some countries)
  • Problem with TSH or TRH (the gland resisting the effects of TSH, not enough TSH, not enough TRH, rare)
  • Thyroid hormone resistance
• High TRH and TSH levels (feedback)

  • Overstimulation of the thyroid gland (without production of thyroid hormones)
  • Thyroid gland enlargement
  • Non toxic goitre (not associated with inflammation or cancer)
  • Low thyroid hormone levels
  • Endemic goitre (present continuously in a community, iodine deficiency in the diet)
  • Sporadic goitre
  • Induced by goitrogenic foods or goitrogenic drugs (decrease thyroid hormone production)
• Examples of goitrogenic foods or drugs

  • rutabagas
  • cabbage
  • soybeans
  • peanuts
  • peaches
  • strawberries
  • spinach
  • radishes
  • lithium
  • cobalt
  • iodides (high concentration)
  • phenylbutazone
• Iodine deficiency


  • Requirement: 50 mg/yr (1 mg/wk; 35 μg T3/day)
  • Reach 1.5 billion people at least 110 countries
  • Can cause: cretinism (severe mental and physical stunting, prevalence can reach 10% in some community), endemic goitre, stillbirth, miscarriages, paralysis, hearing & speech problem. Stunted growth, muscular disorders
  • Is the greatest cause of preventable brain damage and mental disability
  • Could be eradicated: Iodising salt supply, iodised oil injection (a single injection corrects severe iodine deficiency for periods of three to five years)
  • The use of iodized salt in alimentation (approx 24 gm/ton is enough to prevent the deficiency (sea salt does not content enough iodine)
• Selenium deficiency


  • In fact there are two types of endemic cretinism, associated with hypothyroidism: neurological cretinism (iodine deficiency) and myxedematous cretinism (selenium deficiency)
  • Selenium critical for: Glutathione Peroxidase (Gpx) that detoxifies H2O2 produced in excess in thyroid cells and in deiodinase that converts in some tissues T4 to T3
• Hashimoto's disease (chronic thyroiditis)


  • -more frequently affects middle-age women, but also children, (incidence 0.1-1%, may be underdiagnosed), but can develop slowly and remains subclinical, may occur transiently during pregnancy, co-occurrence with other autoimmune diseases (diabetes typeI…)
  • -usually antithyroid peroxidase (anti-TPO) antibodies progressively destroyed the functional tissue but the gland can swell (goitre possible), paradoxically it can be transiently associated with hyperthyroidism
  • - when the major part of the gland has been destroyed can lead to the life-threatening myxedema
• Myxedema


  severe hypothyroidism in adults, symptoms include a dry swelling of the skin (cause the facial tissue to swell and look puffy), slowed speech and mental awareness, deepened voice, intolerance to cold, fatigue and weakness, and nonspecific degeneration of the heart
• Symptoms of Myxedema


  • goitre (75%) or atrophic thyroid gland (25%)
  • headache, difficulty to swallow
  • and the classical symptoms of hypothyroidism: weight gain, cold intolerance, dry skin, puffy face, constipation, fatigue, loss of libido
• Treatment of Myxedema


  1. Replacement therapy with thyroid hormones, levothyroxine (T4) or Lyothyronine (T3) in emergency

  2. Regular monitoring by a physician to insure proper hormone levels are maintained
• Grave's disease


  • most common form of hyperthyroidism (incidence .4 % pop. minimum, highest incidence in young and older women, -maybe up to 2% in older women)
  • The immune system produces antibodies against TSH receptors, which they erroneously stimulate
  • Consequences: overproduction of thyroid hormones, which cannot be regulated by the normal negative feed-back
  • Antibodies also attach themselves to tissues at the back of the eye, causing inflammation and oedema of the extra ocular muscles. The resulting protrusion of the eyes and eye lid lag or retraction, is known in medical terms as exophtalmos