Jane - thyroid Flashcards
Describe how thyroid hormone acts at its receptor to achieve its hormonal response
Upon entry into the cell, most of T4 is converted to T3 by deiodinase.
T3 then binds to its thyroid hormone receptor which is bound by a retinoid X receptor, located near or at the promotor region of thyroid hormone response elements on the DNA
Without T3, the TR-RXR complex typically represses gene transcription by recruiting co-repressors, however upon binding of T3, there is a conformational change in the thyroid hormone receptor causing release of co-repressors and recruitment of co-activators which then activate gene transcription allowing for protein synthesis.
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 iodide trapping by increasing the activity and transcription of NIS carrier protein
(2) Increases proteolysis of stored thyroglobulin, releasing more T3 and T4 into blood
(3) Increases iodination of tyrosine to form more thyroid hormones by increasing activity and transcription of thryoid peroxidase
(4) Increase size, number and secretory activity of thyroid cells.
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, contained within pinocytic vesicles
*These vesicles then fuse with cellular lysosomes and proteases digest the thyroglobulin to release thyroid hormone.
*thyroid hormone then diffuses into the bloodstream and become bound by its transporters.
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
Describe the pathogenesis of hashimoto’s thyroiditis
*The breakdown of self-tolerance results in an immune-mediated destruction of thyroid cells through various mechanisms:
o CD8+ cytotoxic T cells are activated against thyroid antigens and respond by inducing thyrocyte apoptosis through perforin/granzyme release and initiation of the FAS-FAS-L pathway..
o Autoreactive CD4+ Th1 cells produce cytokines, particularly INF-y which attract other immune cells to the thyroid, particularly macrophages, which release further inflammatory cyotkines e.g. TNF-a which amplifies thyroid inflammation causing thyrocyte injury and death.
o B cell activation and subsequent plasma cell formation results in the production of autoantibodies against thyroid peroxidase and thyroglobulin, opsonizing these autoantigens for antibody-dependent-cell mediated cytotoxicity.
*This results in loss of functional thyroid cells, fibrosis, goitre 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.
list 4 indications for thyroidectomy
*Malignant thyroid tumors (e.g., papillary, follicular, medullary, anaplastic cancers).
*Large, symptomatic, or compressive benign thyroid nodules or goiter.
*Hyperthyroidism unresponsive to medical treatment
*Familial conditions (e.g., familial medullary thyroid carcinoma, MEN 2) requiring prophylactic surgery.
Name the 5 histological types of thyroid cancer and their cell of origin
- Papillary –> follicular cell (most common)
- Follicular –> follicular cell
- Medullary –> Parafollicular C-cells
- Anaplastic –> undifferentiated thyroid cells
- Poor differentiated –> Follicular cells with features that show loss of differentiation, often considered a transition from differentiated to anaplastic cancer.
Name 3 physiological effects of thyroid hormone on lipid metabolism
- Increases lipolysis and mobilization of fats from stores by increasing activity of hormone sensitive lipase.
- Increases intracellular fatty acid oxidation for energy derivation.
- Decreases plasma LDL levels by increasing LDL uptake by the liver.
Describe the pathogenesis of hyperthyroidism and goitre formation in grave’s disease
Autoantibodies (TSH receptor antibodies, TRAbs) are produced against the TSH receptor on thyrocytes.
Binding of these antibodies to TSH receptors leads to constitutive receptor activation, stimulating excess thyroid hormone production and causing thyrocyte hyperplasia.
This results in hyperthyroidism and a diffuse, sometimes tender goiter.
Histologically, features include follicular cell hyperplasia, increased vascularity, scalloped colloid and lymphocytic infiltrates.
