PBL 6 - Thyroid Disorders and Grave's disease

• What is the process of sythesising T3 and T4?

  - iodide is taken into the cell through increased activity of TSH, expressing more Na/iodine cotransporter- iodide then leaves the cell into the colloid lumen by pendrin- thyroperoxidase then converts iodide into iodine- follicular cell secretes thryroglobulin- iodination occurs of thyroglobulin - iodine binds to form monoiodothyrine and diiodothyrine- TSH stimulates conjugation of the thyroglobilin to form T4 or T3- endocytosis occurs back into the cell and then proteolysis occurs which forms T4 and T3- secretion via MCT8 then occurs and hyperplasia occurs due to TSH- binds to albumin or TBG in blood
• What is the mechanism of action of the thyroid hormones?

  - T3 and T4 arrive from from the blood into the cytosol through MCT8- monoiodases remove iodine to convert T4 to T3 - binds to thyroid receptor on DNA to transcribe- Na-K pump, gluconeogenic enzymes- respiratory enzymes- myosin heavy chains- UCP1 for brown adipose tissue breakdown
• Where is the thyroid located?

  it wraps around the cricoid cartilage and the second & third rings of the trachea --> just below the thyroid cartilage and laryngeal prominence
• What vertebral levels does the thyroid span?

  C5-T1
• What does the thyroid gland produce?follicular and parafollicular cells

  f : thyroxine (T4) and triiodothyronine (T3)pf: calcitonin - opposes action of PTH
• How is the thyroid gland arranged?

  It has a fibrous capsule which forms lobules which contain follicles (type of arrangement of endocrine gland which secretes hormones into lumen) lined by thyrocytes

  
• What do thyrocytes continuously produce and how are these things stored?

  These thyrocytes continuously produce thyroglobulin (precursor of T3 and T4) which is stored as colloid in the lumen of each follicle

  
• What does thryoglobulin become?

  T3 and T4 hormones following the process caused by TSH activating TPO and membrane transporters
• What is required for the production of T3 and T4?

  iodine from oxidised iodide
• How does iodine reach the colloid?

  TSH increases the activity of the sodium-iodide symporter, which pumps two sodium ions into the cell down their electrochemical gradient, in order to bring one iodide ion into the cell from blood into the thyrocyteThis transporter is found on the basolateral surface of the thryocyteThe iodide is then moved into the colloid by the pendrin transporter which exchanges iodide for chloride where it is converted into iodine by thyroid peroxidase (TPO).

  
• How does iodine and thyroglobulin become T3 and T4?

  Iodine binds to tyrosine molecules within the thyroglobulin (which has many!)One or two molecules of iodine can bind to each, either forming MIT or DIT - again by TPOThese molecules become coupled to form T3 and T4 - again by TPODIT + MIT = T3DIT + DIT = T4 (more common)These are still bound to thryoglobulin and stored in the colloid until TSH causes their endocytosis

  
• What occurs to thyroglobulin with bound T3 and T4 once it is endocytosed?

  Once endocytosed, it fuses with a lysosome containing a proteaseThis protease cleaves T3 and T4 from the thyroglobulin moleculeThis causes the T3 and T4 to become free.They exit the thyrocyte via facilitated diffusion and travel through the blood bound to thyroxine-binding protein

  
• What are the actions of TPO?

  1. oxidises iodide to iodine2. allows the addition of iodine to the tyrosine molecules of thyroglobulin which forms DIT and MIT (tyrosine and iodine forms DIT or MIT which is attached to thyroglobulin)3. couples DIT and MIT to form T3 and T4

  
• What is the active thyroid hormone?

  T3T4 can be converted into T3 within the peripheral tissue via 5'-deiodinase which removes an iodine molecule
• Why is T4 the main thyroid hormone produced?

  Much more stable than T3 Acts as a potential pool
• What happens to excess T4?

  Converted to inactive rT3 which is then metabolised by peripheral tissues This is to prevent high levels of T4
• What controls the production of T3 and T4?

  Hypothalamus-pituitary-thyroid axis
• Explain the HPT axis

  TRH is released from the paraventricular nuclei in the hypothalamusThis acts on the TRH receptors found on the thyrotrophs in the anterior pituitary gland --> stimulates the synthesis and release of TSH into the bloodThe TSH reaches the thyroid gland and binds to TSH receptors on the thyrocyte cells.....causing the production of T3 and T4

  
• How does TRH reach the pituitary gland?

  via the hypophyseal portal system

  
• How does the HPT axis regulate thyroid hormone synthesis?

  circulating T3 and T4 inhibit 2 things via negative feedback:- synthesis of TRH by the hypothalamic nuclei- release of TSH by the thyrotrophs in the anterior pituitary
• Is TSH a peptide hormone?

  YES!!so is TRH
• How do thyroid hormones enter their target cells and how is this possible?

  freely move into cells as they are lipid-soluble
• What are the actions of thyroid hormones?

  Mainly done by T3 (T4 can be converted to T3 in target tissues):1. controls basal metabolic rate2. thermogenesis3. upregulates B-ARs4. Works synergistically with growth hormone to promote long-bone production5. aids normal brain dev.
• How do thyroid hormones exert these effects?

  T3 binds to thyroid hormone receptor in nucleus to form complexNormally, the thyroid hormone receptor, along with a corepressor molecule, is bound to DNA regions called thyroid hormone response elements, and that blocks gene transcription.When T3 binds to its receptor, the corepressor molecule gets displaced, and a coactivator molecule attaches instead - allowing gene transcription to proceed.This inc the transcription of specific genes involved in digestion, metabolic reactions, heartrate etc e.g. gluconeogenic and lipolytic enzymes, Na+K+ pumps, beta adrenergic receptors etc

  
• How can thyroid hormones exert different effects in different tissues?

  Different cells in your body have different kinds of T3-nuclear receptors and in different concentrations. As such, the effect of T3 on a cell is quite variable from tissue to tissue and under various circumstances.
• What is basal metabolic rate?

  the rate at which the body uses energy while at rest to keep vital functions going, such as breathing and keeping warm.AKA making and breaking things down (anabolism and catabolism) to maintain homeostasis to allow normal functioning of the body
• How do thyroid hormones control basal metabolic rate?

  T3 causes the inc. transcription of enzymes involved in metabolic pathways This increases basal metabolic rate by stimulating futile cycles of catabolism and anabolism of proteins and lipids which can be used for gluconeogenesis and B-oxidation, producing ATPTherefore the more T3 you produce, the more attaches to your nuclear thyroid receptors and there is a subsequent inc in the transcription of the stimulated genes...leading to inc futile cycles.A byproduct of these reactions is the release of energy which is dissipated in the form of heat energy... --> this is how thyroid hormones aid thermogenesis along with other mechanisms

  
• What is a futile cycle?

  It occurs when two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat.
• How is normal basal metabolic rate controlled?

  varying levels of T3 and T4 are produced which will affect the metabolic pathways that they are involved in which changes the levels of futile cycles occurring and allows metabolic rate to be kept stable or adjusted when needed
• What can cause an increase in production of T3 and T4 and what effect does this have?

  Certain things such as cold weather can cause an inc production of TSH which in turn inc production and secretion of T3 and T4, inc metabolic rate
• How do thyroid hormone aids thermogenesis?

  upregulate NST in BAT and stimulate futile cycles (result in inc metabolic reactions w/o producing any net product —> heat production)
• How does NST in BAT cause thermogenesis?

  BAT cells have many B3 adrenoreceptors - NA released by inc activity of the SNS due to the cold binds - Gs linked so inc in PKA.PKA activates hormone-sensitive lipase (usually activated in fasting state in WAT by reduced inhibition by insulin)Lipase converts triglycerides into fatty acidsFatty acids used in the Krebs cycle which produces ATP via oxidative phosphorylation (NADH and FADH are oxidised and H+ is split into e- and H+ - energy loss down the chain is used to actively transport H+ ions out-move back across via ATP synthase channels where ATP is produced by the conversion of ADP and phosphates through a process called chemiosmosis)UCP1 channels act as a "H+ leak" - allows some of the H+ ions back inEnergy which would of been used to produce ATP is converted to heat!

  
• How do thyroid hormones cause an increase in NST in BAT?

  T3/4 stimulates the transcription and translation of UCP1 (found on the inner membrane of BAT mitochondria)
• How do thyroid hormones increase sympathetic activity?

  by up-regulating the number of B-ARs on the surface of the heart, skin and skeletal muscle cells
• What is hyperthyroidism?What are the 2 types?

  Syndrome resulting from excess of free T4 and/or free T32 types:Primary - caused by problems in thyroid itselfSecondary - caused by a pituitary or hypothalamic disorder.
• How is hyperthyroidism different to thyrotoxicosis?

  Thyrotoxicosis refers to the clinical syndrome of excess circulating thyroid hormones, irrespective of the source
• What are the common causes of primary hyperthyroidism?

  - Graves - this is the most common (70-80%)- toxic multinodular goitre- toxic adenoma- hCG mediated gestational hyperthyroidism
• What are some causes of thyrotoxicosis without hyperthyroidism?

  Excessive T4 administrationPost-partum ThyroiditisIn postpartum thyroiditis, the immune system attacks the thyroid within around 6 months of giving birth. This causes a temporary rise in thyroid hormone levels (thyrotoxicosis) as they spill out and symptoms of an overactive thyroid gland. Then, after a few weeks, the gland becomes depleted of thyroid hormone. This can then reach normal levels again after a few weeks.

  
• What is the pathophysiology of Grave's?

  It is an autoimmune disorder that causes hyperthyroidism (too high production of thyroid hormones) due to the production of autoantibodies against the thyroid stimulating hormone receptor (imitates TSH) due to problems in central tolerance of B cells (causing them to be self-reactive)—> inc activation and disruption of negative feedbackActivation of SR B cells explained by image - need SR B cells, SR Th cells and inflammation (perfect storm)

  
• What are the risk factors for Grave's?

  - Female sex - more antibodies due to inc activity of B cells due to oestrogen which is higher in females- Family history - genetic link to all autoimmune conditions due to inherited polymorphisms - here its the inheritance of the HLA allele DR3. - Smoking Other autoimmune conditions - often polymorphisms predisposing you to a single autoimmune condition can lead to the acquisition of another autoimmune disorder (again you need the perfect storm of events) specifically rheumatoid arthritis and type 1 diabetes...