Thyroid Flashcards
What do the paraythyroid glands do?
- Sense Ca2+ 2. Secrete PTH
Where do you find C cells?
In between follicles
What would an underactive follicle look like?
- Flattened thyroid epithelial cells - Increased colloid
What would an overactive follicle look like?
- Tall columnar epithelial cells - Reduced colloid
What is a cause of congenital hypothyroidism?
- Failure of the gland to develop due to a PAX8 mutation
What can the thyroid leave behind when it migrates from the back of the pharynx to
- Lingual thyroid (between posterior 1/3 and anterior 2/3 of tongue) 2. Restrosternal thyroid The thyroid starts at the back of the oropharynx and migrates down from there, passing in front of the hyoid bone and then behind it
What would you leave behind when you have failure of thyroglossal duct to atrophy?
Thyroglossal cyst
What is the colloid made of?
Thyroglobulin
What are the normal epithelial cells of the thyroid?
Cuboidal (more sphere like) NB. they have villi and secretory products on their surface 1. They make thyroid hormones
What is calcitonin?
- Peptide hormone 2. Antagonises PTH :. calcium goes down
What does TSH stimulation cause?
- Increased cAMP 2. Increased iodination of thyroglobulin 3. Increased no. of microvilli and length at luminal cell surface so it can process and secrete more thyroglobulin 4. Increase intracellular volume and endocytosis of colloid droplets 5. Increased thyroid hormone release (so more thyroglobulin can re-secreted) 6. Increased iodide influx into the cell - relatively late effect as activation of the iodide pump requires protein synthesis 7. Increased cellular metabolism 8. Increased protein synthesis (inc. thyroglobulin) 9. Increased DNA synthesis (mitosis and cell division are limited in adult thyroid)
How is iodide taken up?
- Taken up from blood by thyroid epithelial cells 2. Via sodium iodide symporter 3. Once inside cell, iodide transported into lumen of follicle via pendrin
What is the role of thyroid peroxidase?
- Found in apical (colloid facing) membrane of thyroid epithelium 2. Causes organification (addition of iodide to tyrosine) through an oxidation reduction –> need hydrogen peroxide which is made separately in the cell by NADH and oxygen 3. Causes coupling to make T3 or T4 from two iodotyrosines NB. Even when coupled the tyrosine is stuck to thyroglobulin in colloid
How do you liberate the T3/4 from the colloid?
- Endocytosis of colloid at apical border 2. Lysosomal degradation to release free hormone (contains proteases in acidic env.) 3. Diffusion of T4/3 into blood 4. Recycling of liberated MIT/DIT (not all is converted into T4/3)
How is T3/4 transported in blood?
- 99.9% bound to 3 different proteins:
- Thyroxine binding protein (binds both T3 and 4) - 75%
- Transthyreitin - 20%
- Albumin -5%
- Only 0.1% is free - biologically active as protein bound cannot enter plasma membrane
What are the physiological actions of T3/4?
- Increase basal metabolism - generates heat to regulate body temperature
- Promote growth and development with GH
- Cardiovascular (ionotropic and chronotropic)
- Regulates alertness and development of fetal brain
- Modulare actions of other hormones:
- Antagonises insulin
- Decreases TRH (this is made in hypothalamus and causes the release of TSH from AP) secretion and release
- Decreases GHRH secretion
- Syngergistic with adrenaline:
- Increases lipolysis
- Increases glycogenolysis
- Increases heart rate
How are T3 and T4 transported across membranes?
Through active transport
How does deiodination of T4 occur?
- Activation:
* Outer ring deiodination by D1/D2 - Inactive reverse T3:
* Inner ring deiodination by D3 - Complete inactivation:
* Both inner and outer ring deiodination by D3 and D1/D2
How does T3 cause transcription?
- T3 binds to nuclear receptor (member of steroid-thyroid hormone receptor and bound to DNA in resting state)
- 3 states:
- Active repression:
* RXR + TR with corepressors on TRE - Active transcription:
* RXR + TR + T3 = recruits coactivators :. histones are acelyated which opens so DNA is ready to be transcribed - Permissive transcription:
- In between state
- Still have co-activator complex around
- Genes are still transcribed at lower level as no ligand bound hormone receptor but not actively repressed
What are the different thyroid hormone receptors?
- Two genes:
- TRalpha
- TRbeta
- Alpha and beta can split into:
- TRalpha1 and 2
- TRbeta1 and 2
- These are tissue specific
NB. Mutated TRbeta genes means there is less negative feedback leading to more hormone in circulation
What intracellular structure does T3 target?
- Mitochondria
- Induces mitochondrial proliferation
- Basal metablism :. increase
What are the effects of thyroid hormones in different parts of the body?
- Control of body temperature
- Leptins stimulates TRH and TSH
- Beta cell maturation in pancreas
- Stimulates muscle regeneration and repair
- Stimulates fatty acid and bile acid synthesis
- Activation of sympathetic nervous system - burns fat in WAT and BAT
What are the general clinical features of thyrotoxicosis?
- Weight loss, normal appetite
- Sweating and heat intolerance
- Agitation
- Tremor
- Fatigue
- Palpitations/tachycardia/atrial fibrillation
- Angina
- Generalised muscle weakness - proximal myopathy
- Diarrhoea
- Oligomenorrhea (irregular periods) and infertility
- Goitre
- Eyelid retraction and lid lag (eye lid pulled back due to sympathetic activity)
What are symptoms which are specific to Grave’s disease?
- Periorbital odeoma (bags around eyes)
- Proptosis (eyes coming out of socket)
- Diplopia
- Corneal ulceration
- Loss of visual acuity
- Pretibial myxoedema - thickening around skin of ankle
- Thyroid acropachy (digital clubbing and swelling of digits )
What are possible causes of hyperthyroidism?
- Grave’s disease
- Multinodular goitre or toxic adenoma
- Thyroiditis: subacute, Hashimoto, De Quervain
- Ectopic TSH: hCG in early pregancy, rTSH
- Drugs: Amiodarone, exogenous iodine (Jod-Basedow), thyroxine
- Ectopic thyroid tissue: metastases from thyroid carcinoma, struma ovarii
- Pituitary disease: TSHoma (pretty rare)
What is Grave’s disease?
- Autoimmune disease
- Autoantibody against TSH receptor
- binds and activates the receptor
- mimics the TSH receptor
What is special about Grave’s disease?
- TSH- R Abs not subject to negative feedback like TSH
- Therefore thyroid stimulation persists
What is special about TSH-R autoantibodies?
Two types produced:
- TSI - Thyroid stimualting Abs
- TBII - TSH-R binding inhibitory immunoglobulins
- Patients can produce both which accounts for when in remission and then relapses again
- TBII causes hypothyrodism
What is the immunology of Grave’s disease?
- Genetic predisposition: HLA DR17, DQ2 (maybe env. trigger)
- T cell infiltration
- B and plasma cells
- Cytokine production
- Anti TSH-Abs produced
What autoimmune associations does Grave’s disease have?
- Polyglandular autoimmune syndrome type 2:
- Type 1 DM
- Addison’s disease
- Pernicious anaemia
- Vitiligo
- Hypoparathyroidism
Can induce it in people by giving them immunostimulatory drugs in order to kill melanomas and lung cancer and this can stimulate thyroid disease
What causes thyroid eye disease?
- TSI binds to orbital muscle Ag
- Inflammatory cell infiltrate, secretion of cytokines
- Fibroblasts secrete Glycosaminoglycans
- Glycosaminoglycans are hydrophilic and absorbs water
- Oedema due to water retention, fibrosis so eyes are pushde forward
What are diagnostic tests for hyperthyroidism?
- Thyroid autoantibodies:
- Anti-thyroid peroxidase (TPO) and anti-thyroglobulin
- non-specific
- insensitive
- Anti TSH-R Abs:
- specific for Grave’s disease
- Thyroid scintigram
- Inject Tc-labelled pertechnate:
- taken up by INS in thyroid
- Scan under gamma camera
What does a toxic nodule uptake scan show?
- Single adenoma in centre overproducing thyroid hormones
What does an uptake scan for thyroiditis look like?
- Poor uptake
- Also seen in iodine overload
- Destroyed by immune system: release of hormone in gland
- Thyroid unable to absorb any tracer because it is being destroyed
What is the treatment for hyperthyroidism?
- Anti-thyroid drugs (PTU, carbimazole)
- Useful for Grave’s disease (50% remit at 18 months)
- Toxic MNG/adenoma will not remit
- Rash/urticaria/arthralgia (up to 10%)
- Agranulocytosis (0.2%)
- Lugol’s iodine
- blocks production of T3/4 by Wolff-Chaikoff effect (it is an overdose of iodine which would turn iodine off)
- Usually use in surgery to take out thyroid
- Effective for 10 days
- Then becomes hyperthyroid (Jod-Basedow effect)
- blocks production of T3/4 by Wolff-Chaikoff effect (it is an overdose of iodine which would turn iodine off)
What do the anti-thyroid drugs do?
- Block thyroid peroxidase
How does radio-iodine work?
- Specifity of iodide uptake by thyroid tissue because of NIS
- High energy beta-particles plus gamma radiation
- Especially effective for toxic MNG/adenoma
- Also used for Grave’s disease
Side effects:
- Hypothyroidsm eventually in 70-80%
- Worsening of thyroid eye disease
Pregnancy:
- Advised not to get pregnant for 6 months after treatment
When would you have complete thyroid removal through surgery?
- Unable to take drugs or very large thyroid pressing on trachea and oesophagus
- Complications:
- Hypothyroidism
- Recurrent laryngeal nerve injury (1%)
- Hypoparathyroidism (often transiet, 2% permanent)
- Heamorrhage
- Infection
What are the signs and symptoms of hypothyroidism?
- Tiredness
- Constipation
- Weight gain
- Intolerant of cold
- Periods heavier
- Slow heart rate
- Slow relaxing reflexes
- Neck swelling - goitre
- Subfertility, menorrhagia
- Undetectable T3/T4
What can cause hypothyroidism?
- Autoimmune hypothyrodism
* More common in women than men - Iatrogenic: surgery, radioactive iodine, anti-thyroid drugs
- Thyroiditis: e.g. Hashimoto’s (first hyper and then hypo)
- Iodine deficiency: mountaineous areas SE Asia, Latin Am, Africa
- Congenital: Thyroid dyshormogenesis or athyreosis
- Secondary hypothyroidism: pituitary disease or surgery (producing less TSH)
What is congenital hypothyroidism?
- 1:4000 live births in an iodine replete region
- Danger of cretinism: severe neurological impairment
Causes:
- Iodine deficiency
- Dyshormogenesis (defect in thyroid synthesis)
- Athyreosis (no thyroid at all e.g. PAX8 defect)
:. Screen all new borns with heel prick test for raised TSH and treat with T4 ASAP
What is the minimum amount of iodine required?
50 micrograms
What can iodine insuffiency cause?
- Endemic goitre
- Profound cretinism
How can the thyroid compensate for iodine?
- Increase iodide uptake
- Increase iodide recycling in thyroid
- MIT preferentially formed over DIT :. T3:T4 ration incr.
- This will maintain euthyroid status for a while
Where do you find iodine suplemments?
- Salt
- Bread
- Iodised oil (depot injections)
- Iodised oil reduces incidence of cretinism/deafmutism
What are the main sources of iodine?
- Drinking water
- Fish
- Seafood
- Milk
- Iodised salt
What is secondary hypothyroidism?
- Pituitary/hypothalamic disease
eg. surgery, head trauma, tumour
TSH is low or low-normal in these cases and can be look “oddly normal” given the low T4, T3
What are the general treatments for hypothyroidism?
- Levothyroxine (T4)
* Half life 1 week - Liothyronine (T3)
* Half life 3-6 hours - Thyroid extract:
- Cow, pigs
- T3>T4, not suitable
- Treat and titrate to normal TSH
