Lecture 21 Flashcards
Where is the location of the thyroid gland?
Below the thyroid cartilage (Adam’s apple)
Lies against and in front larynx and trachea, anterior to cricoid cartilage
What are the 2 lobes (left and right) of the thyroid gland joined by?
Isthmus
What is the clinical relevance of the notch between the thyroid and cricoid cartilage?
Site for emergency cricothyrotomy
-introduces an airway (last resort)
Are the thyroid and parathyroid gland the same gland?
No, they are 2 distinct glands.
Parathyroid (4) being involved in calcium homeostasis
Which is the first endocrine gland to develop and how does it develop?
Thyroid gland at 3-4 weeks of gestation
- epithelial proliferation at the base of the tongue which takes several weeks to migrate to final position
- descends through thyroglossal duct passing in front of hyoid bone
- during migration this remains connected to tongue by thyroglossal duct which now degenerates
- detached thyroid continues to its final position
What happens if embryological migration of thyroid cells goes wrong?
Thyroid cells don’t complete the journey, so you get thyroid tissue at back of tongue and larynx
What does a H+E stain of thyroid tissue look like?
Follicular cells arranged in spheres called thyroid follicles
Follicles filled with colloid
COLLOID: protein, extracellular (even though contained within follicular cells), a deposit of thyroglobulin
Where is the thyroid hormone made?
Thyroid follicular cells secrete thyroglobulin which synthesises thyroid hormone
What are thyroid parafollicular cells?
Larger cells around the follicles, producing calcitonin
What produces parathyroid hormone?
Chief cells (parathyroid principle cells)
How are thyroid hormones synthesised?
2 tyrosine residues linked together with iodine at 3/4 positions on the aromatic ring (so you can have 1 or 2 iodines per tyrosine)
Monoiodotyrosine= 1 iodine attached to tyrosine ring
Diiodotyrosine= 2 iodines attached to tyrosine ring
Any combination of these can join together to form:
-triiodothyronine (T3)
-tetraiodothyronine (T4)
Where are the tyrosine residues on which iodisation occurs, found?
Thyroglobulin (acts as a scaffold on which thyroid hormones are formed)
- iodination occurs, tyrosine residues get iodinated
- coupling reactions occur, linking two tyrosine together, forming a thyroid hormone (T3/4)
- subsequent degredation of the protein releases the thyroid hormone
What is the function of thyroid peroxidase?
Membrane bound enzymes which regulates:
- oxidation of iodide to iodine (requires presence of hydrogen peroxide), absorb as iodine, then reduced to iodide in cells and this needs to be oxidised to iodine for coupling reaction to occur
- addition of iodine to tyrosine acceptor residues on thyroglobulin
- facilitates coupling of MIT/DIT to generate thyroid hormones
How do we obtain dietary iodine?
Iodine reduced to iodide before absorption
- dairy (cow milk)
- iodised salt
- grains
- meat
- veg
- eggs
Where is the majority of iodine in the body?
Thyroid hormones and precursors are the only molecules in the body that contain iodine
- thyroid gland contains 90-95% of iodine in the body
- iodide is taken up from blood by thyroid epithelial cells (follicular cells) which have a sodium-iodide symporter (iodine trap)
As well as iodide, what else is transported into the follicular cells?
Amino acids are required for thyroglobulin synthesis in the follicular cells
How is thyroid hormone released once synthesised?
Follicular cells pinch off parts of the colloid via pinocytosis taking colloid inside the cell in a vesicle
- vesicle fuses with a lysosome
- degredative enzymes degrade thyroglobulin protein releasing the thyroid hormone
- deiodinase enzymes recycle any unused iodine
What is the major type of the thyroid hormone secreted?
T4 (90% released)- has a longer half life
However this has less biological activity, the T3 form is much more biologically active
-most of the T4 is converted to T3 by the liver and kidneys
How are T3/4 transported in the blood?
Bound to protein thyroxine-binding globulin- not active when bound
(You can find T3/4 free in the blood, not all is bound)
How is the production of thyroid hormone regulated?
Negative feedback via hypothalamic-pituitary axis
-TRH (thyrotropin releasing hormone) released from hypothalamus
-stimulates anterior pituitary to release TSH
-TSH stimulate thyroid gland to produce TH
Negative feedback
-TH feeds back to anterior pituitary and hypothalamus (to suppress TRH and TSH)
-TSH feeds back to hypothalamus to suppress TRH
What does thyroid hormone affect?
Metabolism
Growth + Development
What is thyroid stimulating hormone?
Glycoprotein hormone
-composed of 2 non-covalently bound subunits (alpha and beta)
(Alpha subunit is same a that found in FSH and LH)
(Beta subunit provides unique biological activity)
What is the action of TSH?
Stimulates the release of TH by activating the TSH receptor on follicular cells (G protein Gs/Gq): cascade of signalling processes which stimulate:
- iodide uptake
- iodide oxidation
- thyroglobulin synthesis/iodination
- colloid pinocytosis
- proteolysis of thyroglobulin
- cell metabolism and growth
How does the G protein TSH receptor work?
Gs: adenylyl cyclase > cAMP > PKA: stimulation of TH synthesis and release
Gq: phosphlipase C > DAG + IP3 > calcium release via IP3 receptor and PCK activation: stimulation of TH synthesis and release
What are the general actions of TH?
- increase in basal metabolic rate and heat production (by increasing number/size of mitochondria, stimulating the synthesis of enzymes in respiratory chain)
- stimulation of metabolic pathways (catabolic more than anabolic)
- sympathomimetic effects (mimics the effects of adrenaline: increases target cell response to catecholamines by increasing receptor number on target cells: cells become more sensitive to NA/A)
Which cells don’t respond to TH to increase basal metabolic rate?
Brain
Spleen
Testis
What metabolic pathways are stimulated by TH?
Lipid metabolism: stimulates lipolysis and B oxidation of fatty acids
Carbohydrate metabolism: stimulates insulin-dependent entry of glucose , increases Gluconeogenesis and glycogenolysis
What are some tissue specific effects of TH?
Cardio: increases hearts response to catecholamines
-increased CO (increased HR and contraction force)
-increased peripheral vasodilation to get extra heat to surface)
Nervous system:
-increased myelination of nerves (TH deficiency in childhood: cretinism)
What are thyroid hormone receptors like?
Nuclear receptors: on DNA
-TH passes through TH transporter
-TH then passes through nuclear pores
(hormone activated transcription factors, acting by modulating gene expression)
-dimer formed of TH receptors and REX receptor, sits on promoter region of genes (hormone response elements) repressing the expression of that gene
-binding of TH to this relieves repression allowing gene to be expressed
-new protein synthesised
-facilitates response
What are some examples of TH activated genes?
- PEPCK (in gluconeogenesis)
- Ca2+ ATPase
- Na/K+ ATPase
- cytochrome oxidase (oxidative phosphorylation- ETC)
What are the normal plasma levels of TH and TSH?
Free T4: 10-25 pM (picomolar rather than millimolar)
Free T3: 3-8 pM
TSH: 1-15 pM
What is goitre?
Enlargement of the thyroid gland
- may accompany hypo/hyperthyroidism
- develops when thyroid gland is overstimulated
What causes goitre?
Lack of dietary iodine
What are the causes of hypothyroidism?
- failure of thyroid gland
- TSH/TRH deficiency
- inadequate supply of iodine
- radioactive iodine
- autoimmunity
- post surgery
- congenital
- anti-thyroid drugs
What are the symptoms of hypothyroidism?
- obesity
- lethargy
- alopecia
- bradycardia
- dry skin
- constipation
- slow reflexes
What levels of TSH and T3/4 would you see in someone with hypothyroidism?
Low T3 and T4
Elevated TSH
What is hypothyroidism known as in infants/adults?
Infants: cretinism
- dwarfed structure
- mental deficiency
- poor bone development
- slow pulse
- muscle weakness
- GI disturbances
Adults: Myxedema
- thick puffy skin
- muscle weakness
- slow speech
- mental deterioration
- intolerance to cold
What is Hashimoto’s disease?
Hypothyroidism
- autoimmune: immune destruction of thyroid follicles
- more common in women
- goitre may/may not be present
How do you treat Hashimoto’s disease?
- ora thyroid hormones
- T4 used due to longer half life
What are some causes of hyperthyroidism?
- autoimmune Grave’s disease
- toxic multinodular goitre
- solitary toxic adenoma
- excessive T3/4 therapy
- ectopic thyroid tissue
What are some general symptoms of hyperthyroidism?
- weight loss
- irritability
- heat intolerance/sweating/warm hands
- tachycardia
- fatigue
- increased bowel movements/appetite
- tremor
- hyper-reflexive
- breathlessness
- loss of libido
- bulging eyes
What is Grave’s disease?
Autoimmune
Thyroid stimulating immunoglobulin (TSI produced)
-continually stimulates TH secretion outside normal negative feedback control
Very low TSH with high T3/4
How can you visualise the thyroid gland?
Thyroid Scintigraphy
-Technetium 99 radioactive isotope used (short half life)
-with gamma camera to see where isotope has been concentrated
(Good for looking at thyroid tissue where it shouldn’t be)
What are anti-thyroid drugs?
Used to treat hyperthyroidism
-blocks formation of TH
E.g. Carbimazole > metabolised to methimazole in the body
-prevents/inhibits thyroid peroxidase from coupling and iodinating tyrosines on thyroglobulin
(Takes 2-3 months to see effect of drug as we have a large store of TH)
What is another name T4?
Thyroxine
