ENDORINOLOGY PT2

• Thyroid gland


  • Also known as the butterfly-shaped gland
  • Consists of two lobes located in the lower part of the neck, just below the voice box
  • Lobes connected by a narrow band called the isthmus
• Follicle


  • The fundamental structural unit of the thyroid gland
  • Site of synthesis and storage of thyroid hormones
• Thyroglobulin


  • A glycoprotein with a positive periodic acid schiff staining
  • Acts as a preformed matrix containing tyrosyl groups
  • Stored in the follicular colloid of the thyroid gland
• Types of cells in the thyroid gland

  • Follicular cells – T3 and T4
  • Parafollicular or C cells – Calcitonin
• Biosynthesis of Thyroid Hormones: Triiodothyronine and Tetraiodothyronine


  1. Hypothalamic-pituitary-thyroid axis (HPTA) regulates production and secretion of thyroid hormones

  2. By 11th week of gestation, the gland begins to produce measurable amounts of thyroid hormones

  3. TSH stimulates synthesis of thyroid hormones through the cellular uptake of dietary iodine

  4. Thyroglobulin (Tg) is a glycoprotein secreted by the follicles specifically in the rough endoplasmic reticulum

  5. Iodination of tyrosyl residues in thyroglobulin is catalyzed by the thyroid peroxidase (TPO), which results in formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT)

  6. The coupling of MIT and DIT to form T3 and T4 is also mediated by TPO

  7. T4 is the prehormone of T3, and T3 is produced in the cytoplasm from the removal of one iodine-outer ring of T4

  8. Almost 75% to 80% of T3 is produced from the tissue deionidination of T4

  9. T4 and T3 are released from the prohormone via lysosomal lysis and the process of secretion into the circulation are all mediated by TSH

  10. Both T4 and T3 are released into the blood circulation from the thyroid cells, and they are bound to proteins while the free forms cross the cell membrane

  11. Protein-bound thyroid hormone are the sources for the formation of free thyroid hormones

  12. For the synthesis of reverse T3 (rT3), it is formed from the removal (deiodination) of one iodine-inner ring of T4

  13. rT3 is the biologically inactive (no biological activity) metabolite of T4 and bound to TBG

  14. Type 1 iodothyronine 5'-deiodinase catalyzes the deiodination of T4 producing both the rT3 and T3 while the Type 2 iodothyronine 5'-deiodinase maintains constant levels of T3 in the CNS
• Key points


  • If a mother has normal thyroid function, small amounts of maternal thyroid hormone crossing the placenta protect the fetus during development
  • Thyroid hormone is critical in fetal neurologic development
  • Activity of thyroid hormones depends on the location and number of iodine atoms
  • The free thyroid hormones (FT3 and FT4) are the physiologically active portions of the thyroid hormones
  • Thyroid hormones affect synthesis, degradation, and intermediate metabolism of adipose tissue and circulating lipids
  • The thyroid hormones create a negative feedback on hypothalamus and pituitary gland to maintain a TSH concentration within defined limits
• Iodine


  • The most important element in the biosynthesis of thyroid hormones
  • When iodine sources is diminished, MIT is produced in greater quantities, leading to increased T3 formation and release
  • Iodine intake below 50 ug/day is an indication of the deficiency of hormone secretion
• Thyrocalcitonin


  • A 32-amino acid monomeric peptide
  • Synthesized in the parafollicular cells from the cleavage and post-transitional modification of pre-procalcitonin then procalcitonin
  • It maintains the balance of calcium and phosphorus in plasma
• Procalcitonin (PCT)


  • A protein that responds to systemic inflammatory conditions
  • Marker for bacterial sepsis and part of the panel of tests for COVID-19
  • It is a 116-amino-acid protein; discovered as a prohormone of calcitonin produced by C-cells of the thyroid gland. Intracellularly cleaved by proteolytic enzymes into the active hormone, with circulating levels in healthy subjects below the detection limit
• Functions of Thyroid Hormones (T3 and T4)


  • Tissue growth
  • Mental development
  • Development of the central nervous system
  • Heat production
  • Control of oxygen consumption
  • Influence carbohydrate and protein metabolism
  • Energy conservation
• Triiodothyronine (T3)

  • The metabolically active form of thyroid hormones
  • Its principal application is in diagnosis of T3 thyrotoxicosis
  • It is a better indicator of recovery from hyperthyroidism as well as recognition of recurrence of hyperthyroidism
  • Helpful in confirming the diagnosis of hyperthyroidism especially in patients with no or minimally elevated T4
  • An increase in plasma level of T3 is the first abnormality seen in cases of hyperthyroidism
  • Method: Immunoassay
  • Reference range: 80 – 200 mg/dL (1.23 - 3 nmol/L)
• Tetraiodothyronine (T4)


  • The principal secretory product of the thyroid gland
  • It has the major fraction of organic iodine in the circulation
  • Completely synthesized in the thyroid gland
  • Its plasma concentration is a good indicator of the thyroid secretory rate
  • In the peripheral tissue, T4 is converted to T3
  • Elevated thyroxine causes inhibition of TSH secretion, and vice versa
  • Method: Immunoassay
  • Reference range: Adult: 5.5 – 12.5 ug/dL (71 – 161 nmol/L), Neonate: 11.8 – 22.6 ug/dL (152 – 291 nmol/L)
  • FT4 Reference range: 0.9 – 2.3 ng/dL (12 – 30 pmol/L)
• Thyroxine-Binding Globulin (TBG)


  • Transports majority of T3
  • Transports 70% of total T4
  • It binds rT3
  • The affinity of T3 to TBG is lower compared to T4
  • Reference range: 10 – 26 ug/dL (10 – 26 ug/L)
• Thyroxine-Binding Prealbumin (Transthyretin)


  • Transports 20% of total T4
  • T3 has no affinity for prealbumin
• Albumin


  It transports T3 and 10% of T4
• Free T3 (FT3) and Free T4 (FT4)


  • These are more specific indicators of thyroid function than the measurements of total hormone because the values are not affected by the TBG
  • FT3 and FT4 can cross the cell membrane unlike the protein-bound thyroid hormones
  • Free T3 is responsible for the metabolic activity of thyroid hormones
  • Free T4 and TSH are the best indicators of thyroid status
  • Small percentages of T4 (0.03%) and T3 (0.3%) remain unbound to protein
• Screening of thyroid disorders is recommended when a person reaches 35 years old and every 5 years thereafter
• Hyperthyroidism


  • Refers to an excess of circulating thyroid hormone
  • Signs and symptoms: Tachycardia, tremors, weight loss, heat intolerance, emotional lability, and menstrual changes
  • Primary hyperthyroidism: FT3 and FT4 increased (T3 and T4 are also increased), TSH decreased
  • Secondary hyperthyroidism: FT3, FT4, and TSH increased (due to primary lesion in the pituitary gland)
  • TSH may be normal in secondary hyperthyroidism
  • Thyroid malignancy and anterior pituitary tumors may lead to hyperthyroidism
• Grave's Disease (Diffuse Toxic Goiter)


  • The most common cause of hyperthyroidism
  • An autoimmune disease in which antibodies are produced, activating the TSH receptor – goiter and hyperthyroidism are induced by thyroid-stimulating antibodies that resembles the action of TSH
  • It occurs 6x more commonly in women than in men, and commonly observed in younger age
  • Features: Exophthalmos (bulging eyes) and pritibial myxedema
  • Autoantibody test: (+) TRAb, TPOAb, and TgAb
• Thyrotoxicosis


  • Applied to a group of syndromes caused by high levels of free thyroid hormones in the circulation
  • Plummer disease or toxic multinodular goiter is considered to be the second most common cause of hyperthyroidism and mostly occur in the fifth decade of life in both males and females
  • T3 thyrotoxicosis or Plummer disease: FT3 increased, FT4 normal or low, and TSH low
  • T4 thyrotoxicosis: T3 normal or low, T4 increased, and TSH low
  • Autoantibody test: Negative or low levels
• Subacute Granulomatous Thyroiditis


  • Associated with neck pain, low grade fever, and swings in thyroid function tests
  • Laboratory result: T3 and T4 transient markedly increased then decreased, TSH increased/decreased, increased ESR, decreased RAIU; (+) giant cells microscopically
  • Autoantibody test: (-) TPOAb
• Subclinical Hyperthyroidism


  It shows no clinical symptoms but TSH level is low, and FT3 and FT4 are both normal
• Hypothyroidism


  • Develops whenever insufficient level of thyroid hormone are available to tissues
  • Treated with thyroid hormone replacement therapy (levothyroxine)
  • Signs and symptoms: Bradycardia, weight gain, coarsened skin, cold intolerance, and mental dullness
• Primary Hypothyroidism


  • Due to failure of the gland to secrete adequate thyroid hormones
  • Mostly caused by ablation of the thyroid gland with radioactive iodine or thyroidectomy
  • May also be due to deficiency of elemental iodine
  • Laboratory results: FT3 and FT4 decreased (T3 and T4 are also decreased) and TSH increased
  • Other causes: Radiotherapy of the neck and drugs such as lithium
• Hashimoto's Disease


  • The most common cause of primary hypothyroidism
  • Characterized by thyroid replaced by a nest of lymphoid tissue – sensitized T lymphocytes/autoantibodies bind to cell membrane causing cytolysis and inflammatory reaction
  • Autoimmne destruction of gland by THYROPEROXIDASE
  • Associated with enlargement of the thyroid gland (goiter)
  • It is a type of "painless" thyroiditis
  • Laboratory results: TSH high, ESR normal, and RAIU variable
  • Autoantibody test: (+) TPOAb
• Myxedema


  • Describes the peculiar nonpitting swelling of the skin
  • The skin becomes infiltrated by mucopolysaccharides
  • Myxedema coma is the severe form of primary hypothyroidism, the advanced stage of thyroid hormone deficiency
  • Clinical features: "Puffy" face, weight gain, slow speech, eyebrows thinned, dry and yellow skin, and anemia
• Secondary Hypothyroidism


  • Due to pituitary destruction or the presence of pituitary adenoma
  • Laboratory result: T3 and T4 decreased, TSH normal/decreased
• Tertiary Hypothyroidism


  • Caused by a hypothalamic disease
  • Laboratory result: T3 and T4 decreased, TSH normal/decreased
• Subclinical Hypothyroidism


  • Without typical symptoms of hypothyroidism
  • Laboratory result: T3 and T4 normal, but TSH is slightly increased