Jane - thyroid Flashcards
Describe how thyroid hormone acts at its receptor to achieve its hormonal response
*Thyroid hormone enters the target cell via a carrier mediated, ATP dependent process.
*Most of T4 is converted to T3 which is more active form of the hormone This occurs mostly in liver and kidneys via deiodinase enzyme.
*Thyroid hormone binds to its nuclear receptor, TR, causing a conformational change allowing it to function as a transcription factor.
*TR forms a heterodimer with retinoid X receptor, forming a complex.
*Complex binds to thyroid response elements on the promotor region of target genes, allowing for modulation of gene expression.
*Co-activators and co-repressors of gene expression are recruited to either enhance or suppress transcription.
*This either increases or decreases mRNA production thereby affected the production of proteins that mediate the physiological effects of thyroid hormones.
Describe the process of iodide trapping
*Sodium-iodide-symporter carriers iodide across the basolateral side of the follicular cell using sodium gradient created by Na/K ATPase.
*Thyroid peroxidase carries out an oxidation reaction converting iodide to iodine.
*Iodine can be transported into the colloid by pendrin protein, across the apical side of the cell.
*Iodine binds to tyrosine residues of thyroglobulin in the colloid forming mono-iodotyrosine (MIT) and Di-iodotyrosine (DIT).
*MIT and DIT undergo coupling reactions catalyzed by Thyroid peroxidase:
o MIT + DIT –>
Triiodothyronine (T3)
oDIT + DIT –> Thyroxine (T4)
*These can be stored in the colloid until needed
Outline how thyroid hormone is transported in blood
- Thyroxine binding globulin (80%)
- Albumin (10%)
- Transthyretrin (10%)
- Free (<1%)
Outline 5 effects of TSH on the thyroid
(1) Increases rate of iodide trapping by increasing the activity of NIS
(2) Increases proteolysis of stored thyroglobulin, releasing more T3 and T4 into blood
(3) Increases iodination of tyrosine to form more thyroid hormones
(4) Increase size, number and secretory activity of thyroid hormones.
Describe the action of TSH at the TSH receptor to cause thyroid hormone secretion
*TRH is released from hypothalamic nerve endings at the median eminence, passing into the hypophyseal portal system to reach the anterior pituitary.
*It binds to its receptors in thyrotropes, activating the inositol triphosphate system, increasing phospholipase C and diacylglycerol to cause TSH secretion.
*TSH travels in the blood stream and binds to the TSH receptor of thyroid cells. This is a GPCR.
*This binding activates adenylyl cyclase, which increases cAMP production and protein kinase A production, causing downstream phosphorylation.
*This causes release of stored thyroid hormone which occurs via pinocytosis of colloid vesicles into the follicular cells before T3 and T4 are released from thyroglobulin and diffuse into the blood stream
Name 4 causes of hypothyroidism
Primary
- Hashimoto’s thyroiditis
- Iodine deficiency
- De Quervains thyroiditis
- Post partum thyroiditis
Secondary
- Sheehans syndrome
- Surgery to pituitary
- Head trauma damaging pituitary
- Radiotherapy to head
What lab results define primary and secondary hypothyroidism
Primary
Elevated TSH, Low T3/T4
Secondary
Low TSH, low T3/T4
What enzyme is responsible for the peripheral conversion of synthethic T4 (levothyroxine) to T3?
De-iodinase (type 1)
Name 4 causes of hyperthyroidism
Primary
o Graves (diffuse hyperplasia of thyroid)
o Solitary toxic thyroid nodule
o Toxic multinodular goitre
o Hyper functional thyroid adenoma
Secondary
Pituitary adenoma
Name 4 clinical features of graves disease
(1) Exophthalmos (protrusion of eyes)
(2) Pre-tibial myxedema
(3) Upper eye lid retraction
(4) Diffuse tender goitre
(5) Weak eye movement
(6) Audible thyroid bruit
(7) Signs of hyperthyroidism
(8) Conjunctivial hemorrhage
Name 3 autoantibodies associated with Graves disease
*TSH-receptor immunoglobulin -> an IgG antibody that binds to the TSH receptor and stimulates it -> thyroid hormone release
*Thyroid growth-stimulating immunoglobulins -> bind TSH and stimulate proliferation of thyroid follicular epithelium.
*TSH-binding inhibitor immunoglobulin -> Antagonise the TSH receptor and prevent TSH from binding -> explains why some people with graves can have a hypothyroidism.
Describe the pathogenesis of exophthalamos
*increased volume of connective tissue and extra-ocular muscles in retro-orbital space cause bulging of eyes due to:
*T cell infiltration into retro-orbital space.
*Oedema and swelling of extra-ocular muscles.
*Accumulations of hyaluronic acid and chondroitin sulfate
*Increased number of adipocyte
Describe the pathogenesis of hashimotos thyroiditis
*Autoimmune destruction of the thyroid gland following failure of self-tolerance.
*CD8+ cytotoxic T cell infiltration into the thyroid gland target thyroid autoantigens resulting in direct cytotoxicity causing thyrocyte apoptosis.
*Th1 CD4+ T cells produce inflammatory cytokines, particularly INF-y which recruit and activate macrophages causing follicle destruction.
*Autoreactive antibodies produced by plasma cells target thyroid peroxidase and thyroglobulin and cause antibody-dependant cell-mediated cytotoxicity, particularly by natural killer cells.
*The result is chronic inflammation, goitre, fibrosis and hypothyroidism.
how does Carbimazole / Propylthiouracil work to treat hyperthyroidism
*Carbimazole is metabolized to its active form, methimazole, after absorption.
*Methimazole inhibits thyroid peroxidase (TPO), preventing the iodination of tyrosine residues on thyroglobulin and the coupling of iodotyrosines (MIT and DIT) to form thyroid hormones (T3 and T4).
*Carbimazole does not affect circulating hormones or those in storage in the thyroid; it only prevents new hormone synthesis, so its affects are gradual
How does radio-iodine treat hyperthyroidism
*Single dose of radioactive iodine (Iodine 131) is drank.
*The thyroid gland takes this up, and the emitted radiation (beta particles) destroys a proportion of the thyroid cells.
*The reduction in the number of cells results in a decrease in thyroid hormone production.
