Week 4 Endocrine Lectures Flashcards
What are steroid hormones derived from?
The enzymatic modification of cholesterol
How is steroidogenesis regulated?
involves control of the enzymes which convert cholesterol into the steroid hormone desired
Where are enzymes which produce steroid hormones found?
mitochondria and smooth ER
What are the properties of steroid hormones?
They are lipid soluble and freely permeable to membranes
How are steroid hormones stored?
They are not stored but synthesized and immediately released
How are steroid hormones transported in the blood?
Since they are not water soluble they must be carried complexed to specific binding globulins
What carries cortisol in the blood?
Corticosteroid binding globulin
Where are the adrenal glands found?
In the abdomen above the kidney
Why are the adrenal glands yellow?
They have high cholesterol
What are the two parts of the adrenal glands?
- Cortex -composed of zones, each of which has characteristic histology and secretes different hormone
- Medulla –embryologically and histologically distinct
What is the blood supply to the adrenal glands?
The superior, middle and inferior suprarenal arteries
What is the venous drainage of the adrenal glands?
The medullary vein which emerges from the hilum of each gland before forming the suprarenal veins which eventually joins the inferior vena cava (RHS) and left renal vein (LHS)
What are the histological layers of the cortex of the adrenal gland?
- zona glomerulosa
- Zona fasciculata
- Zona reticularis
What is the arrangement of the zona glomerulus of the adrenal gland?
Clusters of small cells.
Fewer lipids than other layers
What is the arrangement of the zona fasciculata of the adrenal gland?
Large cells arranged in cords
What is the arrangement of the zona reticularis of the adrenal gland?
Smaller cells in a haphazard arrangement
What is synthesised in the Zona glomerulosa of the adrenal gland?
Mineralocorticoids
What is synthesised in the Zona fasciculata of the adrenal gland?
Glucocorticoids
What is synthesised in the Zona reticularis of the adrenal gland?
adrenal androgens (DHEA and DHEAS)
How is the production of adrenal androgens in the Zona reticularis regulated?
ACTH
What are examples of glucocorticoids?
Cortisol or corticosterone
How is the production of glucocorticoids in the Zona Fasciculata regulated?
ACTH
What are glucocorticoids important for?
Carbohydrate regulation
How is the production of mineralocorticoids in the Zona glomerulosa regulated?
RAS
What are mineralocorticoids important for?
Sodium/BP homeostasis
What is the first enzymatic step of steroid hormone production?
The conversion of cholesterol to pregnenolone
What enzyme catalyses the conversion of cholesterol to pregnenolone?
Cytochrome P450 located in the inner mitochondrial membrane
What is the rate limiting step of the conversion of cholesterol to pregnenolone?
is the transport of free cholesterol from cytoplasm into mitochondria.
What enzyme carries out conversion of cholesterol to pregnenolone?
Steroidogenic Acute Regulatory Protein (StAR)
Where can cholesterol come from?
can be taken up from circulation or synthesised de novo from acetyl CoA or also taken up by the cell in the form of low-density lipoprotein (LDL).
What is the rate-limiting enzyme in cholesterol biosynthesis?
HMG-CoA reductase
What is LDL made up of?
cholesterol, phospholipids, triglycerides, and proteins (proteins and phospholipids make LDL soluble in blood)
How is LDL taken into cells?
via LDL receptors
How is LDL turned into cholesterol to synthesize steroid hormones?
broken down into esterified cholesterol, and then free cholesterol
what are the 6 domains of steroid receptors?
A-F
What do A/B domains on steroid receptors do?
N-terminal domain controls which gene is activated
What does the C domain on steroid receptors do?
DNA binding domain (Highly conserved) contains 2 zinc fingers which bind to specific sequences DNA (HREs)
What does the D domain on steroid receptors do?
Hinge region-controls movement of the receptor to nucleus
What does the E domain on steroid receptors do?
Ligand binding domain-binds steroid (Highly conserved)
What does the F domain on steroid receptors do?
C-terminal Domain
How do steroid hormones get into cells?
Diffuses through the plasma membrane
What is the mechanism of steroid hormones once they get inside the cell?
- Binds to intracellular cytosolic receptor-member of steroid receptor superfamily
- Receptor-hormone complex enters the nucleus and binds to a glucocorticoid response element (DNA Sequence) in 5’ flanking region of target genes
- Binding initiates gene transcription to produce mRNA
- mRNA is translated to protein which mediates the effects-target cell response
Where are mineralocorticoid receptors found?
Distal Nephron, Salivary glands, sweat glands, large intestine, Brain, vascular tissue, heart
What is the effect of cortisol on the liver?
- Stimulates gluconeogenesis in liver. This results in the synthesis of glucose from non-hexose substrates such as amino acids and lipids
- Permissive effect on glucagon (Glucagon causes the liver to convert stored glycogen into glucose)
What is the effect of cortisol on adipose tissue?
Stimulation of lipolysis in adipose tissue: fatty acids released are used for production of energy in tissues like muscle and the released glycerol provides another substrate for gluconeogenesis.
What do glucocorticoids do to insulin release?
They act as an insulin agonist and suppress the release of insulin
What effect does cortisol have on skeletal muscle?
Increased breakdown of skeletal muscle protein
What is the effect of aldosterone on the nephron?
causes Na+ reabsorption (and water which follows sodium) and concomitant K+ and H+ excretion.
Where does aldosterone act on the nephron?
mineralocorticoid receptors (MR) in the principal cells of the distal tubule and the collecting duct of the nephron
What happens when aldosterone binds to MR receptors in the nephron?
- upregulates/ activates basolateral Na/K pumps
- upregulates epithelial sodium channel (ENaC) increasing apical membrane permeability for Na+
- stimulates the secretion of K+ into the lumen
- stimulates secretion of H+ via the H+/ATPase in the intercalated cells of the cortical collecting tubules
What happens when ACTH binds to its receptor? (G-protein receptors)
Conformation changes in receptor stimulate adenyl cyclase, causing an increase in cAMP, activation of PKA and calcium influx
What is the long term effect of ACTH biding to its receptor?
Increased transcription of genes coding for steroidogenic enzymes e.g. 11B-hydroxylase
What is the rapid effect of ACTH binding to its receptor?
Stimulation of cholesterol delivery to the mitochondria
When is RAS activated?
In response to lowered blood pressure and potassium sodium levels
What does the activation of RAS lead to?
production of Angiotensin II
What is the direct effect on BP of angiotensin II?
vasoconstriction
What is the indirect effect on BP of angiotensin II?
aldosterone, thirst
What is the effect of angiotensin II binding to its receptor?
- AngII binds to 7TMD G-protein coupled receptor
- Activates phospholipase C
- Hydrolyses phosphatidylinositol bisphosphate (PIP2) to form 2nd messengers inositol triphosphate (IP3) and diacyl glycerol (DAG).
- IP3 causes stored Ca2+ to be released.
- Rise in intracellular calcium ([Ca2+]i) activates Ca2+-calmodulin dependent protein kinases (CaMKs) which stimulate the transcription of StAR and cholesterol uptake into mitochondria
What happens in primary aldosteronism?
- High levels of Aldosterone
Increased sodium reabsorption, Volume expansion, Hypokalaemia (Potassium excretion), Alkalosis (hydrogen excretion), Low PRA, Hypertension
What are the most common causes of primary aldosteronism?
Aldosterone producing adenoma (unilateral)
Bilateral adrenal hyperplasia
What is Cushing’s syndrome?
High levels of cortisol
What are the signs and symptoms of Cushing’s syndrome?
Moon face, weight gain, High BP, Red face, extra fat around face, stretch marks
What are causes of Cushing’s syndrome?
ACTH producing adenoma (pituitary)
Cortisol producing adenoma (adrenal)
What is Addison’s disease?
Primary adrenal insufficiency or hypoadrenalism
What is the adrenal gland not making in Addison’s disease?
cortisol and aldosterone
What are the signs and symptoms of Addison’s disease?
Fatigue (lack of energy or motivation), Muscle weakness, Low mood, Loss of appetite and weight loss, increased thirst, pigmentation
What happens to aldosterone levels when potassium levels increase?
Increases
What is the osmolality of solution in the body maintained at the expense of?
Volume
How much of body fluid is intracellular?
2/3
What is plasma osmolality?
ratio of plasma solutes (sodium, glucose and urea) and plasma water
What is the most plentiful solute in plasma?
Sodium
How is the serum sodium concentration mainly determined?
By the amount of extracellular water in the body
What are the main mechanisms that regulate the extracellular water of the body?
Thirst and ADH
What is the main role of ADH?
To regulate water status of the body
What is ADH produced in response to?
- Decreased plasma volume (sensed by baroceptors in atria/veins/carotids)
- Increased plasma osmolality (sensed by osmoreceptors in hypothalamus)
What receptor does ADH mainly act on?
AVP2
Where is AVPR2 receptors found?
Basolateral membrane of kidney collecting ducts
What happens when ADH binds to its receptor?
Aquaporin channels are inserted to increase renal water reabsorption
What is the osmolality of solution in the body maintained at the expense of?
Volume
How much of body fluid is intracellular?
2/3
What is plasma osmolality?
ratio of plasma solutes (sodium, glucose and urea) and plasma water
What is the most plentiful solute in plasma?
Sodium
How is the serum sodium concentration mainly determined?
By the amount of extracellular water in the body
What are the main mechanisms that regulate the extracellular water of the body?
Thirst and ADH
What is the main role of ADH?
To regulate water status of the body
What is ADH produced in response to?
- Decreased plasma volume (sensed by baroceptors in atria/veins/carotids)
- Increased plasma osmolality (sensed by osmoreceptors in hypothalamus)
What receptor does ADH mainly act on?
AVP2
Where is AVPR2 receptors found?
Basolateral membrane of kidney collecting ducts
What happens when ADH binds to its receptor?
Aquaporin channels are inserted to increase renal water reabsorption
What effect does aldosterone action have on the kidney?
increases sodium reabsorption and potassium excretion in the distal nephron. This increase in sodium status also increases plasma volume (where sodium goes water follows) and raises blood pressure
When is someone classed as being hyponatraemic?
Serum sodium <135mmol/l
What are the potential causes of SIADH?
- Cancer: lung/lymphoma/ leukaemia
- Chest disease: pneumonia
- CNS disorders: infections, injury
- Drugs: opiates, thiazides, anticonvulsants, proton pump inhibitors, anti-depressants
How is a diagnosis of SIADH reached?
- Hyponatraemia with inappropriate low plasma osmolality
- Urine osmolality> plasma osmolality
- Urine sodium> 30 mmol/l
- Absence of adrenal, thyroid, pituitary or renal insufficiency
- No recent use of diuretic agents
What are the three classifications of causes of hyponatraemia?
Hypovolaemia
Euvolemia
Hypervolemia
What happens in hypovolaemic hyponatraemia?
Decreased total body water
Decreased total body Na+
What happens in euvolemic Hyponatraemia?
Total body water is increased as water is being retained
Na+ is normal
What happens in hypervolemic Hyponatraemia?
Total body water is increased and Na+ is high as well but it is being diluted meaning the concentration is still low
What are the renal causes of hypovolemic hyponatraemia?
- Diuretic excess
- Mineralocorticoid deficiency
- Salt-losing nephritis
- bicarbonaturia
- Renal tubular acidosis
- Ketonuria
- Osmotic diuresis
What are the extrarenal causes of hypovolemic hyponatraemia?
- Vomiting
- Diarrhoea
- Pancreatitis
- Traumatized muscle
What are the causes of euvolemic hyponatraemia?
- Glucocorticoid deficiency
- Hypothyroidism
- Pain
- Psychiatric disorders
- drugs
- Syndrome of inappropriate ADH secretion
What are the causes of hypervolemic hyponatraemia?
- Nephrotic syndrome
- Cardiac failure
- Cirrhosis
- Acute and chronic renal failure
How is hypernatremia managed?
- Treat underlying cause!
- Estimate total body water deficit if possible
• To guide fluid regimen - Avoid overly rapid correction
• Aim for ↓ 10 mmol/l in 24 hours
• Concern is cerebral oedema - Use IV 5% dextrose
How is a diagnosis of SIADH reached?
- Hyponatraemia with inappropriate low plasma osmolality
- Urine osmolality> plasma osmolality
- Urine sodium> 30 mmol/l
- Absence of adrenal, thyroid, pituitary or renal insufficiency
- No recent use of diuretic agents
What happens in the brain when serum [Na] is low?
water moves into cells to increase plasma osmolality causing cell swelling
What is the best way to correct hyponatraemia for the brain?
If corrected slowly then brain osmolality and volume are returned to normal
What happens to the brain if there is a sudden drop in Na?
Cerebral oedema
what happens if there is a sudden increase in Na?
Osmotic demyelination syndrome
What are the clinical features of Hyponatraemia?
Can be asymptomatic but the symptoms worsen as plasma Na falls
- Mild confusion
- Gait instability
- Marked confusion
- Drowsiness
- Seizures
How is severe and acute hyponatraemia managed?
- Unconscious or seizures
- Give infusion of hypertonic (3%) saline – in small volumes (100ml or so)
- Can increase quickly (but not quite back to normal) (5-10mmol/24hr)
What is the effect of PTH on calcium and phosphate metabolism?
The net effect is an increase in plasma Ca concentration with no change or a decrease in plasma Phosphate concentration
What are the main causes of hypernatremia?
- Insensible/ Sweat losses ( severe burns/sepsis)
- GI losses
- Diabetes insipidus
- Osmotic diuresis due to hyperglycaemia
How is hypernatremia managed?
- Treat underlying cause!
- Estimate total body water deficit if possible
• To guide fluid regimen - Avoid overly rapid correction
• Aim for ↓ 10 mmol/l in 24 hours
• Concern is cerebral oedema - Use IV 5% dextrose
How is water deficit calculated?
Water deficit= current TBW x ((serum Na/140 ) -1).
TBW is 50-60% of lean body weight
What are sources of calcium in the body?
- GI tract
- Bones
- Kidney
How is calcium obtained in the GI tract?
Absorbed throughout the small intestine from dietary sources (approx. 10% is absorbed)
This is dependent on vitamin D
How are the bones a source of calcium?
Calcium reservoir
How do the bones regulate plasma Ca?
Via action of osteoblasts and osteoclasts
How much Ca is reabsorbed by the kidney?
97-99% of Ca is reabsorbed in the kidney
What effect does vitamin D have on Ca?
- Increases GI absorption
- Increases bone resorption
Increased renal reabsorption
How is the cause of hypercalcaemia diagnosed?
Measure the PTH
If PTH is decreased then malignancy is likely
If PTH is normal or increased then the most likely cause is primary hyperparathyroidism
What are the classic symptoms of hypercalcaemia?
Moans and bones, stones and groans
What are the renal symptoms of Hypercalcaemia?
- polyuria
- Polydipsia
- Nephrolithiasis
- Nephrocalcinosis
- Distal renal tubular acidosis
- Nephrogenic diabetes insipidus
- Acute and chronic renal insufficiency
What are the GI symptoms of Hypercalcaemia?
- Anorexia
- Nausea and vomiting
- Bowel hypomobility and constipation
- Pancreatitis
- Peptic ulcer disease
What are the MSK symptoms of Hypercalcaemia?
- Muscle weakness
- Bone pain
- Osteopenia/ Osteoporosis
What are the neuro symptoms of Hypercalcaemia?
- Decreased concentration
- Confusion
- Fatigue
- Stupor, coma
What are the ECG changes in hypercalcaemia?
- Shortened QTC interval
- Bradycardia
What can cause hypercalcaemia?
- Primary hyperparathyroidism
- Malignancy
How can primary hyperparathyroidism cause hypercalcaemia?
Increased bone resorption and Increased GI absorption
How is hypocalcaemia treated?
- Intravenous calcium replacement if tetany or cardiac manifestations
- May also need magnesium infusion
- Chronic management:
• Vitamin D (D2 or D3)
• Oral calcium salts - Treat underlying cause
How is the cause of hypercalcaemia diagnosed?
Measure the PTH
If PTH is decreased then malignancy is likely
If PTH is normal or increased then the most likely cause is primary hyperparathyroidism
How is hypercalcaemia managed with rehydration?
- Patients often hypovolaemic
- Hypovolaemia impairs renal clearance of calcium
- Isotonic (0.9%) saline infusion corrects hypovolaemia
• Be careful of fluid overload - Will not normalise calcium unless only mildly elevated
How is hypercalcaemia managed with bisphosphonate therapy?
- Inhibit bone resorption by inhibiting osteoclasts
• Commonly used to treat osteoporosis - Agents of choice for treating hypercalcaemia of malignancy
• Zoledronic acid is most commonly used - Delayed effect, maximal at 2-4 days after treatment
What causes secondary adrenal insufficiency?
- Lack of ACTH stimulation
- -> pituitary/ hypothalamic disorders
- exogenous steroid use
What can happen with tetany in acute hypocalcaemia?
- Increased neuromuscular excitability
- Peri-oral numbness, muscle cramps, tingling of hands/feet
- If severe: carpopedal spasm, laryngospasm, seizures
What are the cardiac complications of acute hypocalcaemia?
Dysrhythmia
Hypotension
What are the potential causes of hypocalcaemia?
- Low PTH
- High PTH
- Dugs
- Hypomagnesaemia
When can low PTH cause hypocalcaemia?
- After parathyroid surgery
- Autoimmune hypoparathyroidism
Why can Hypomagnesaemia cause hypocalcaemia?
Leads to PTH resistance
How is hypocalcaemia treated?
- Intravenous calcium replacement if tetany or cardiac manifestations
- May also need magnesium infusion
- Chronic management:
• Vitamin D (D2 or D3)
• Oral calcium salts - Treat underlying cause
What are examples of primary adrenal insufficiency?
- Addison’s disease
- Adrenal TB/ malignancy
- Congenital adrenal hyperplasia (CAH)
In adrenal insufficiency what are renin/ aldosterone levels expected to be?
Increased renin
Decreased aldosterone
What does Congenital adrenal hyperplasia result in?
Deficiency of cortisol and aldosterone but increased adrenal androgens
What causes secondary adrenal insufficiency?
- Lack of ACTH stimulation
- -> pituitary/ hypothalamic disorders
How much of the adrenal cortex is destroyed before people become symptomatic of Addison’s disease?
> 90%
What other autoimmune diseases are associated with Addison’s disease?
Type 1 DM, Autoimmune thyroid disease, pernicious anaemia
What are the clinical features of Addison’s disease?
- Anorexia, Weight loss
- Fatigue/ Lethargy
- Dizziness and low BP
- Abdo pain, vomiting, diarrhoea
- Skin pigmentation
How is adrenal insufficiency diagnosed?
- ‘suspicious biochemistry’
- Short synACTHen test
- ACTH levels
- Renin/aldosterone levels
- Adrenal autoantibodies
What constitutes ‘suspicious biochemistry’ when trying to diagnose adrenal insufficiency?
Decreased Na
Increased K
Hypoglycaemia
What is the short synACTHen test?
- Measure plasma cortisol before and 30 minutes after iv ACTH injection
- Normal: baseline >250nmol/L, post ACTH >480
In adrenal insufficiency what are ACTH levels expected to be?
Increased a lot (causes skin pigmentation)
In adrenal insufficiency what are renin/ aldosterone levels expected to be?
Increased renin
Decreased aldosterone
How is adrenal insufficiency managed?
Do not delay treatment until the diagnosis is confirmed
- Hydrocortisone is given as a cortisol replacement
- Fludrocortisone is given as an aldosterone replacement
- Educate the patient on steroid treatment
Why must patients on long term steroids have ID?
Steroid treatment cannot be stopped suddenly
How do the clinical features of secondary adrenal insufficiency differ to those of Addison’s?
Skin is pale (no raised ACTH)
- Aldosterone production is intact
How is Secondary adrenal insufficiency treated?
Hydrocortisone replacement
What are the clinical features of cortisol excess?
Easy bruising, facial plethora, Striae, Proximal myopathy
What are the two types of Cushing’s?
ACTH dependent and ACTH independent
What can cause ACTH dependent Cushing’s?
- Pituitary adenoma (68%) Cushing’s Disease
- Ectopic ACTH 12% (carcinoid/ carcinoma)
- Ectopic CRH <1%
What can cause ACTH independent Cushing’s?
- Adrenal adenoma 10%
- Adrenal carcinoma 8%
- Nodular hyperplasia 1%
What are the steps of diagnosing Cushing’s syndrome?
- Establish cortisol excess
2. Establish source of excess
How is cortisol excess determined when diagnosing Cushing’s disease?
- Dexamethasone suppression testing
- 24 hour urinary free cortisol
- Late night salivary cortisol (should be low at bedtime)
What are the surgical options for Cushing’s management?
- transphenoidal pituitary surgery
- Laparoscopic adrenalectomy
- Removal of ACTH source
What are the medical options for Cushing’s management?
- Inhibit cortisol production - Metyrapone/ ketoconazole
What is transphenoidal surgery?
Up through the nose and through the sphenoid sinus to the pituitary
What is iatrogenic Cushing’s syndrome?
The most common cause of cortisol excess - due to prolonged high dose steroid therapy
Why does long term steroid therapy cause iatrogenic Cushing’s syndrome?
Chronic suppression of pituitary ACTH production and adrenal atrophy
What are the implications of adrenal suppression?
- Unable to respond to stress (illness/surgery)
- Need extra doses of steroid when ill/surgical procedure
- Cannot stop treatment suddenly
- Gradual withdrawal of steroid therapy if >4-6 weeks
What is primary aldosteronism?
Autonomous productions of aldosterone independent of its regulators (angiotensin II/ potassium)
What can cause primary aldosteronism?
Wither single adrenal adenoma or bilateral adrenal adenomas
What are the clinical features of primary aldosteronism?
- Significant hypertension
- Hypokalaemia (in up to 50%)
- Alkalosis
How is Primary aldosteronism diagnosed?
- Biochemistry
- suppression testing
- Adrenal CT
What is the biochemistry like in primary aldosteronism?
Increased plasma aldosterone
Decreased plasma renin
How is suppression testing used in the diagnosis of primary aldosteronism?
IV saline loading
What is the surgical management of primary aldosteronism?
- Unilateral laparoscopic adrenalectomy
- Only if adrenal adenoma
- Cure of hypokalaemia
- Cures hypertension in 30-70% cases
What is the medical management of primary aldosteronism?
In bilateral adrenal hyperplasia
- Use MR antagonists (spironolactone (blocks receptor) or eplerenone)
- Or amiloride (blocks Na reabsorption by kidney)
What is a pheochromocytoma?
Catecholamine secreting tumour of the adrenal medulla
What do pheochromocytomas cause episodes of?
headache, palpitations, pallor and sweating
How is a pheochromocytoma diagnosed?
- Measure urinary catecholamines and metabolites
- CT of adrenals
How is a pheochromocytoma treated?
Adrenolectomy
How is aldosterone secretion controlled?
By RAS and plasma K+
