Endocrine - Thyroid, parathyroid and adrenal Flashcards
What are the proportions of T3 and T4 secreted by the thyroid gland
T3 - 10%
T4 - 90%
Compare the half lives of T3 and T4
T3 - 24 hours
T4 - 7 days
Compare the protein binding of T3 and T4 in blood. What is the purpose of this protein binding
T3 - Albumin (99.7% bound)
T4 - thyroglobulin
Provide a large reservoir of thyroid hormone which delays onset of symptoms of hypothyroidism
How much T4 is converted to T3 and what is the rest of T4 converted into
50% T4 converted to T3
50% T4 converted to rT3 (reverse T3) –> inactive hormone
How does tri-iodothyronine (T3) exerts its effect
Diffuses across cell membranes to reach the cell nucleus where it regulates gene transcription
Which tissues are not affected by triiodothyronine
Thyroid
spleen
What are the effects on metabolism of hypo and hyperthyroidism
Hyperthyroidism
- -> Increased BMR
- -> Increased Lipolysis
- -> increased gluconeogenesis
- -> increased avaiability of ffas and glucose
Opposite in hypothyroidism
How does T3 affect growth
Hypothyroidism in childhood causes growth retardation
It stimulates neuronal myelination and nerve axon growth (CNS)
How does hyperthyroidism affect the respiratory system
Increased O2 consumption and CO2 production –> increased Ve
How does hyperthyroidism affect the CVS
Increased T3 –> increased number of B-adrenergic receptors in the heart –> increased HR and contractility and therefor CO
How does hypo and hyperthyroidism influence the CNS
Hypothyroidism –> depressed mood and psychosis
Hyperthyroidism –>Anxiety
How does hyperthyroidism affect the muscles
T3 induces protein catabolism of proximal muscles leading proximal myopathy
Describe the microanatomy of the thyroud
Multiple follicles interspersed with parafollicular C cells and endothelial cells.
A follicle contains follicular cells arranged in a sphere surrounding a core of thyroglobulin or ‘colloid’
Draw a diagram and describe the mechanism of thyroid hormone synthesis
Page 393 Chambers
How is Iodide transported from the capillary into the follicular lumen
I- is transported via the Na+/I- cotransporter into the follicular cell after which it diffuses into the follicular lumen
What happens to Iodide once it is in the follicular lumen
TSH stimulates thyroid peroxidase using H2O2 to oxidise it into more reactive Iodine (I2).
What happens to I2 (Iodine) in the follicular lumen>
I2 bings to tyrosine residues on the thyroglobulin molecule forming mono-iodotyrosine MIT (One iodine binds) and Di-iodotyrosine DIT (Two iodines bind)
How are T3 and T4 formed and released into circulation
Oxidative coupling promoted by TSH in the follicular lumen creates T3 (MIT + DIT) and T4 (DIT + DIT) which are endocytosed linked to throglobulin by follicular cells (TSH). The T3 and T4 are then removed from thyroglobulin and released into circulation.
How long can the thyroid glands store of T3 and T4 meet the bodies requirements
1 - 3 months
Descirbe the hypothalmo-pituitary-thyroid axis
TRH –> + TSH –> (T4) + T3 –> - TRH –> - TSH
Only unbound T3 can inhibit hypothalamus
What is the most common cause of hypothyroidism. Describe the pathophysiology
Hashimotos thyroidisits –> autoimmune attache of thyroid peroxidase (I- –> I2) or thyroglobulin –> Reduced T3 and T4 secretion –> increased TRH and TSH
What is the most common cause of hyperthyroidism. Describe the pathophysiology
Graves disease: autoimmune antibodies that bind to and active the TSH (or thyrotropin) receptor on the thyroid leading to autonomous production of T3 and T4 –> decreased TRH and hence TSH
Describe and classify the clinical effects of Grave’s disease
EFFECTS DUE TO HYPERTHYROIDISM Symptoms - palpitations - heat intolerance - weight loss - fine tremor - diarrhoea - Excessive sweating
Signs
- Tachycardia
- Atrial Fibrillation
- Lit lag
- Goitre
EFFECTS DUE TO AUTOANTIBODIES
- Exophthmalmos
- Proptosis
- Conjunctivitis
Describe the three treatment options in hyperthyroidism
- Treat hyperadrenergism (beta blockade)
- Atenalol 25 - 50 mg daily up to 200 mg daily to get HR < 90 if BP allows - Thionamides (inhibit thyroid peroxidase and conversion Iodide to Iodine) –> prevent T3/T4 synthesis: both oxidation of I- and oxidative coupling (thyroid peroxidase)
- Methimazole
- Propylthiouracil
- Carbimazole - Radioiondine
- -> I- is concentrated by the thyroid gland
- -> likewise 131 I is concentrated (radioactive)
- -> Beta - radiation emtted causes damage and necrosis of thyroid tissue - Surgery
- -> total thyroidectomy
What is the mechanism of action of thionamides
Methimazole
Propylthiouracil
Carbimazole
MOA:
- Inhibit thyroid peroxidase
- -> Inhibit conversion of iodide to iodine (I2) –> No MIT/DIt formation
- -> reduced oxidative coupling of MIT and DIT –> reduced T3/T4 synthesis
Propylthiouracil only:
2. Inhibit peripheral conversion of T4 to T3
NB these drugs:
- Do not inactivate T3 and T4 stores in the peripheral blood and thyroid
- Do not interfere with replacement (exogenous) thyroid hormones
Do the thionamides inactivate peripheral and thyroid stores of T4 and T3
No
Do the thionamides interfere with replacement (exogenous) thyroid hormones
No
What are the risks associated with total thyroidectomy
Recurrent laryngeal nerve palsy
Parathyroid gland damage
Postoperative hematoma –> airway obstruction
How is orbitopathy of Graves disease treated
- Corticosteroids
2. Surgical debulking
Why should a CT scan be ordered prior to thyroid surgery
To identify compression of surrounding structures
- Trachea - stridor
- SVC obstruction - Syncope
- Sympathetic chain (Horner’s - Ptosis/Miosis/Anhidrosis
- Recurrent laryngeal nerve (Hoarse voice)
What are the options for airway management in a severely compressed trachea
- Gas induction
- Awake flexible scope endotracheal intubation
- Tracheostomy under local anaesthesia
If recurrent laryngeal nerve monitoring is used –> what are the implications and why is this done
To determine bilateral RLN injury and requirement of tracheostomy prior to extibation. Its on some specialized ETT tubes the electrodes of which is carefully placed between the cords during endotracheal intubation
Muscle Relaxants can’t be used. So Reminfentanyl infusion is commonly used
List the postoperative complications of Thyroid surgery
- Haemorrhage –> rapid airway obstruction (remove clips compress and back to theatre)
- Recurrent Laryngeal nerve palsy (if bilateral –> complete vocal cord paralysis –> tracheostomy)
- Severe hypocalcaemia –> damaged parathyroid glands –> severe hypocalcaemia may cause laryngospasm.
- Tracheomalacia
- -> Flaccid tracheal cartilage which collapses on inspiration especially in patients with long standing goitres. (Deflate ETT cuff prior to extubation to check for air leak.
Explain the mechanism for Trousseau’s and Chvostek’s sign
Hypocalcaemia
Calcium is integral to the normal function of the cell membrane Na+ channels. Hypocalcaemia BRINGS THE THRESHOLD POTENTIAL NEARE TO RMP resulting in more likely spontaneous depolarization of neurons –> tetany and paraesthesias.
List the physiological functions of calcium
- Structure - bones
- Haemostasis (Essential cofactor)
- RMP (Threshold)
- Neurotransmitter release (exocytosis)
- Excitation-contraction coupling (actin-myosin)
- Cell signalling (2nd messenger)
Describe the distribution (%) of calcium in the body
Bone –> 99%
Teeth and soft tissue –> 1%
ECF –> 0.1 % ( 1/3 of this in the plasma)
What percentage of plasma calcium is free in the active ionized form
45% (1.1 - 1.4 mmol/L)
total plasma calcium range: 2.2 - 2.6 mmol/L
How is ionized calcium affected by changes in albumin
Its unchanged
What is the formula for corrected calcium
Corrected Ca = Measure Ca + 0.02(40 - serum ALB)
Ca (mmol/L)
ALB (g/L)
Each 1 g/L decrease in serum ALB leads to a decrease in plasma Ca by 0.02 mmol/L
Logically, how can plasma Calcium levels be altered
- Increased/Decrease GIT absorption
- Increase/Decrease Renal excretion
- Movement of Ca between body compartments
Name the hormones involved in Calcium homeostasis
- Parathyroid hormone –> increase Ca
- Vitamin D –> increase Ca
- Calcitonin –> Decrease Ca
Where are the parathyroid glands located
There are four of them located on the posterior surface of the thyroid gland
What stimulates the secretion of PTH from the parathyroid glands?
Fall in plasma Calcium concentration
Describe the action of parathyroid hormone
- GIT (indirect effect)
- upregulates renal enzyme 1 alpha-hydroxylase –> increased activatoin of Vitamin D –> increased GIT absorption of Ca and PO4 - Kidneys
- Increase Ca absorption
- Decrease PO4 absorption - Bone
- Stimulate osteoclasts to resorb bone –> released stored Ca
Describe the synthesis of vitamin D. What is the rate limiting step and what controls this rate limiting step?
Vitamin D is a steroid hormone
SKIN
7- dehydrocholesterol –> UV light –> cholecalciferol
DIET
Absorption of cholecalciferol (Vitamin D3)
LIVER
Cholecalciferol –> 25 hydroxylase –> Calcidiol (25 hydroxycholecalciferol)
KIDNEY
Calcidiol –> 1 alpha hydroxylase –> Calcitriol (1,25 hydroxycholecalciferol) This is the biologically active form of Vitamin D.
The rate limiting step is the action of 1 alpha hydroxylase (kidney). PTH controls the activity of 1 alpha hydroxylase and therefore PTH controls the plasma concentration of active vitamin D
Describe the actions of 1,25 hydroxycholecalciferol = Calcitriol = Active vitamin D
- GIT
- Increased absorption of Ca and PO4 - Kidney
- Increased absorption of Ca and PO4
Describe the secretion of calcitonin
Secreted by the parafollicular C cells of the thyroid gland. Secreted when total plasma calcium is above 2.4 mmol/L
Describe calcitonin’s role in Calcium homeostasis
Minor role.
Only secreted when Total Plasma Calcium > 2.4 mmol/L.
DECREASES plasma calcium by
- GIT
- decreases absorption of Ca and PO4 - Kidneys
- decrease reabsorption of Ca and PO4
- decreases activity 1 - alpha - hydroxylase (decrease active Vit D) - Bone
- decrease osteoclast activity –> decreased bone resoprtion
What unexpected effect does PTH have with regards to phosphate homeostasis and explain the effect of this on plasma calcium concentration.
Unlike, 1,25 hydroxycholicalciferol (active vit D), PTH causes reduced PO4 reabsorption in the proximal convoluted tubule in the kidney.
Reduced plasma phosphate –> reduced formation with calcium with insoluble salts –> increased free ionized calcium.
What hormones apart from PTH, Vit D and calcitonin have an impact on calcium homeostasis
Gonadal steroids –> increase bone density
Corticosteroids –> decrease bone density
GH –> increase bone density
and hence all affect calcium homeostasis
Summarise the endocrine response to hypocalcaemia
Low calcium sensed by parathyroid glands. PTH release. PTH –> increased GIT absorption Calcium and increased renal reabsorption calcium. PTH also increase the rate of activation of Vitamin D. Vitamin D also has the same effect as PTH on Ca absorption in the kidneys and GIT. PTH leads to bone resorption and Vit D leads to bone calcification so the effect on bone is negligible.
Summarise the endocrine response to hypercalcaemia
High calcium sensed by PTH glands. Reduced PTH reduced Ca absorption kidneys and GIT. Reduced rate of activation vitamin D. Reduced Ca absorption kidneys and GIT.
Also calcitonin is released from parafollicular C cells
Overall effect is reduced Vit D absorption GIT, reabsorption kidney.
Where does 25 hydroxylation of vitamin D occur
The liver
Where does 1 alpha hydroxylation of Vitamin D occur
The kidneys
Explain the mechanism of renal osteodystrophy and how is it treated
CKD –> reduced 1 alpha hydroxylation of Vitamin D –> Reduced activated Vitamin D and hypocalcaemia results. PTH secretion increases which results in extensive demineralization of bone as Calcium is redistributed to the ECF.
Rx: Supplemental activated vit D = Calcitriol (1,25 hydroxycholecalciferol)
Explain the mechanism of bone disease in cirrhosis (chronic liver disease)
More complex than in CKD
- Alcoholism is associated with dietary Ca deficiency
- Haemochromatosis is complicated by gonadal failure –> osteoporosis
- Severe liver dysfunction –> impaired 25 hydroxylation of vit d therefore –> deficient active vit D
What vertebral level are the adrenals
T12
Describe the anatomy of the adrenals
ADRENAL CORTEX (mnemonic is GFR) Zona glomerulosa (mineralocorticoid) Zona fasciculata (glucocorticoid) Zona reticularis (androgens)
ADRENAL MEDULLA
Modified sympathetic ganglion innervated by T5-T9 pre-ganglionic sympathetic neurons.
–> SNS + –> chromaffin cells release granules containing
1. Adrenalin (80%)
2. Noradrenalin (20%)
What is the name of the cells in the adrenal medulla that release adrenalin
chromaffin cells
What are the names of the weak andorgens secreted by the Zone Reticularis of the adrenal cortex and what is the fate of these hormones
Androstenedione
dehydroepiandrosterone
Converted to testosterone by peripheral tissues
What % of mineralocorticoid activity is contributed by aldosterone. What contributes the remainder
Aldosterone 95%
Cortisol 5%
What are the four triggers for aldosterone secretion
- Angiotensin II (RAAS)
- Hyperkalaemia –> directly triggers renal cortex to release aldosterone
- Acidaemia –> directly triggers renal cortex to release aldosterone
- ACTH (main role is for the release of cortisol)
Summarise the functions of cortisol
METABOLIC
- -> increase plasma [glucose]
1. Gluconeogenesis stimulated
2. Amino acids mobilized from skeletal muscle
3. Accelerated lipolysis –> glycerol used in gluconeo
4. Reduced peripheral glucose utilization
CARDIOVASCULAR
- Increased vasculature sensitivity catecholamines
- Increased plasma volume (mineralocorticoid)
What additional effects does cortisol have in chronic excess (e.g. Cushings)
- Osteoporosis
- Anti-inflammatory and immunosuppressive
- CNS –> euphoria, psychosis and memory loss
- Peptic ulceration
Summarise the regulation of cortisol release
Diurnal pattern of CRH release by hypothalamus or increased release during times of physiological stress.
Hypothalamus –> CRH –> Anterior Pituitary –> ACTH –> Zona fasciculata (adrenal cortex) –> cortisol
Cortisol 90% bound by cortisol binding protein and albumin
Cortisol 10% unbound –> biologically active –> unbound cortisol inhibits hypothalamus from secreting CRH.
What is the final step in the biosynthesis of cortisol and how does etomidate affect this
Final step: hydroxylation of 11-deoxycortiisol by the enzyme 11 - beta - hydroxylase.
This enzyme is reversibly inhibited by etomidate.
Describe the structure of catecholamines
BENZENE RING with 2 OH- groups
AMINE side chain
What are catecholamines derived from. What are the two possible sources for this molecule
Tyrosine
Sources
- diet
- hydroxylation of phenylalanine in the liver
Where are catecholamines synthesized
In chromaffin cells in the adrenal medulla
What is the rate limiting step of catecholamine synthesis
Conversion of tyrosine to L-DOPA
Draw a diagram which describes synthesis and metabolism of catecholamines
See page 399 Chambers
Why can’t adrenalin be synthesized at sympathetic nerve terminals
PNMT (Phenylethanolamine N-methyl Transferase) which converts adrenalin to Noradrenalin is only present in the Adrenal Medulla
Is catecholamine controlled by a negative feedback loop?
How is secretion controlled>
No.
Stimuli (Exercise/trauma/pain/hypovolaemia/hypothermia/anxiety)
–> Hypothalamus increase SNS output –>AP’s in pre-ganglionic SNS nerves that terminate on chromaffin cells in the adrenal medulla. Acetylcholine is released at the terminal synapse.
–> Ach –> activates nicotinic receptors on chromaffin cell membrane –> increased membrane Na and K permeability –> net depolarization –> open voltage gated Ca channels –> influx Ca leads to exocytosis of the catecholamine containing granules –> exoctyosis of granules
What are the physiological effects of adrenalin
METABOLIC
- Adrenalin stimulates glycogenolysis
- Adrenalin also increase release of ffa’s and aa’s from adipose tissue
HEART
- B1 receptors: inotropy and chronotropy
VASCULATURE
- a1 vasoconstriction (peripheral tissues)
- B2 vasodilation (skeletal muscle)
LUNGS
- B2 bronchodilatation
What are the physiological effects of noradrenalin
METABOLIC
- promotes gluconeogenesis
- promotes lipolysis
VASCULATURE
- alpha 1 vasoconstriction with reflex bradycardia
CNS
- normal functioning
What are the half lives of adrenalin and noradrenalin
both: 2 minutes
How are adrenalin and noradrenalin metabolized
Both: sequentially metabolized by COMT and MAO
Catechol-O-methyltransferase = COMT
Monoamine Oxidase = MAO
Metanephrine and normetanephrine are intermediates of metabolism
Vanillylmandelic acid (VMA) is produced
How is phaeochromocytoma often diagnosed with regard to catecholamine metabolism
Urinary metanephrine/ Vanillylmandelic acid levels
