Adrenals Flashcards
what foetal tissue does the adrenals come from
mesoderm
describe how the adrenals develop
SF1 expression is crucial in adrenal gland development.
Cells secreting high SF1 levels from the adrenal primordium.
Migrating neural crest cells enter the AP, forming the adrenal medulla.
Surrounding mesenchymal cells form a capsule.
what also develops at the urogenital ridge
the kidney
what are the two parts of the adrenal gland
cortex
medulla
what are the three layers of the adrenal cortex
zona glomerulusa
zona fasciularis
zona reticularis
describe the adrenal blood supply
- The blood flow in the adrenal gland starts on the outside and delivers blood to the plexus of blood vessels just under the capsule
- The blood flow goes through the adrenal cortex in to the medulla
Give an example of how the cortex and medulla are linked
- hormones in the cortex such as cortisol can have an effect on the adrenal medulla hormones
- for example cortisol produced in the cortex goes via the blood to the adrenal medulla
- this is where it upregualtes an enzyme that allows the adrenal medulla to produce adrenaline this helps the body to deal with stress
what is the medulla composed of
- groups and columns of chromaffin cells
- smaller islands of these are scattered through the cortex
what does a chromaffin cell look like
The cells are large, with large nuclei, and contain fine cytoplasmic granules which stain brown with chromium salts (and are therefore named phaeochromocytes).
what cells secrete what in the medulla
.- 80% of the medulla cells secrete adrenaline
- 20% noradrenaline,
- a few dopaminergic cells
what causes the adrenal cortex to grow
ACTH
Name some types of stress
- Starvation
- Infection
- Severe volume loss
why do the areas of the cortex look different
- they look different as they contain different amounts of fat
name some function of the adrenal cortex and medulla
- have mechanism to put the blood pressure up if they do it too much you get hypertension
- Response to infection leads to hypoerpfustion and hypotension – steroids dampen down response to inflammation
- Adrenal gland avoids starving to death – helps you breakdown fat, bone and protein in order to provide substrate for gluconeogenssi
what happens if you have too much cortisol versos what happens if you have too little cortisol
Too much cortisol
- immunosuppressed, hypertension, diabetes, breakdown muscle,
hypertrophy
Too little cortisol
– hypotensive, hypoglycaemia and wont respond to stresses
How do you provide multiple different hormones from the same organ
- uses cholesterol and depending on what cell type it allows cholesterol to cause factors that allow you to turn it into different hormones
describe the cortex layers and what allows them to produce what they produce
In the zona glomerulus – characterised by CYP11B2 means you can produced aldosterone
In the zona fasciculus characterised by CYP11B1 allows you to produce cortisol
In the zona reticularus you produce CYP17A1 to produce testosterone
Why are mineralocorticoids called mineralocorticoids
- named because on the effect that they have on minerals
What is an example of mineralocorticoids
aldosterone
Where are mineralocorticoids produced
- zona glomuerlusa
what stimulates release of aldosterone
- rise in potassium
- low blood pressure - therefore an increase in angiotensin II from RAAS and ACTH
What does aldosterone do
- increases sodium reabsorption
- therefore causes then increase in the reabsorption of water
- therefore increases the overall circulating volume
- causes potassium excretion
can lead to a metabolic alkalosis
How does aldosterone do what it does
- aldosterone binds to the mineralocorticoid receptor
- this increases sodium reabsorption - this happens as the mineralocorticoid inserts more sodium ENac channels in the collecting duct for absorption
- intercalated cells upregualte the sodium potassium ATPase
How does the renal system acts on aldosterone
- via the principal cell
- via the intercalated cell
what can aldosterone lead to
- metabolic alkalosis
What is the condition called for primary hyperaldosteronism
Conns syndrome
how much does primary hyperaldosteronisim cause hypertension
- Conn’s syndrome – 29% cause of hypertension
how is conns syndrome caused
- develop hypertension
- this is because there is suppressed plasma renin activity and increased aldosterone secretion
what is conns syndrome caused by
- Aldosterone producing adenoma
- Bilateral adrenal hyperplasia
How do you diagnose conns syndrome
Aldosterone:Renin Ratio
- measure the aldostoenre and renin ratio, if renin levels are 0 and aldosterone is high then conns syndrome
Saline suppression test
- the low fluid volume increases aldosterone production therefore if you give them a bag of saline which raises the fluid level and there aldosterone levels are still high then this is pathological
CT Adrenal
Adrenal venous sampling
- this is when you insert a catheter into the groin and measure the aldosterone level form each adrenal gland
Metomidate PET
How do you treat Conns syndrome
Spironolactone = Mineralocorticoid receptor antagonist.
Describe how you can get an mineralocorticoid excess
- lycosrol has an active ingredient which inhibits 11BetaHSD2
- this increases the level of cortisol that comes into contact with the mineralocorticoid
- this causes more mineralcoritcoids to develop
-excess mineralocorticoid excess can also be genetic
What does 11betaHSD2 usually do
- ## it usually binds to the kidney and inactivates cortisol prevention mineral corticoid receptor binding
How do you diagnose a mineralcorticoid excess
- Diagnosis is made on the basis of elevated urinary cortisol to cortisone ratio on a 24 hr urine collection.
What is a syndrome in which there is low to normal aldosterone release
Liddles syndrome
What causes low aldosterone release in Liddles syndrome
Low plasma renin activity, reduced aldosterone output therefore.
What does Liddles syndrome lead to
- Hypertension
- Hypokalemia
- Metabolic alkalosis
What is liddles syndrome
Liddle syndrome is a rare hereditary disorder involving increased activity of the epithelial sodium channel (ENaC), which causes the kidneys to excrete potassium but retain too much sodium and water, leading to hypertension
- even though there is low renin and low aldosterone , sodium channels are spontaneously placed on the collecting duct
describe the HPA axis for cortisol secretion
- CRH stimulates ACTH which stimulates cortisol then there is a negative feedback in which cortisol inhibits CRH and ACTH
what does CRH stand for
corticotropin releasing hormone
what is ACTH also know as
- ACTH is also called corticotropin
describe how POMC is produced in the anterior pituitary and how this leads to ACTH being produced
- Produces POMC this is cleaved by the same enzymes that cleave insulin and PTH
- Cleavage of POMC produces ACTH
what receptors does ACTH bind to
- ACTH this binds to the melanocortin-2 receptor (MC2R)
- this is in the Zona fasciularus and causes the cells to produce cortisol
Too little ACTH and hereofre cortisol can cause
Addisons disease
How can ACTH cause aldosterone production
- CYP11B2 AND CYP11B1 – similar structurally and genetically as they are on the same gene
- When ACTH binds to the ZF it up-regulates CYP11B2, if you have a mistake being made in division of these cells you can end up where the promoter region for 11b-hydroxylase is attached to the coding region of aldosterone synthase therefore ACTH leads to increase aldosterone secretion instead of cortisol
when ACTH causes aldosterone production how do you treat it
- Can treat this condition by lowering the levels of ACTH –
- Quickest way to do that is steroids
- This is glucocorticoid remediable aldosteronism
describe the circadian rhythm in regards to cortisol
Cortisol follows a circadian rhythm, increasing around 3 am and peaking at 7 am; it
decreases after this.
what can inhibit the production of cortisol
- opiates
- oxytoxcin
- ANP
what also inhibits ACTH
- CRIF
what can increase ACTH
- Angiotensin II, IL1, IL6, IL2, LIF increases ACTH
if you suspect Addisons when do you measure cortisol
- need to measure it in the morning to see if it is lower than normal
if you suspect bushings when do you measure cortisol
- need to measure it at bed time to see if it is higher than normal
what are the symptoms of Cushing syndrome
- Skinny arms and legs as they are breaking down fat and subcutaneous fat and muscles
- Weight gain - increase in the amount of visceral fat
- Dermatological changes.
- Muscle weakness.
- Hypertension.
- Loss of libido.
- Depression.
- Kidney stones.
- breakdown of bones - osteoporosis
how does Cushing syndrome act on the visceral fat versus the subcutaneous fat
Cushings increases the amount of visceral fat and lowers the amount of subcutaneous fat
What are the causes of Cushings syndrome
- Iatrogenic
- Corticotroph adenoma of the pituitary- most common cause
- Ectopic ACTH secreting neuroendocrine tumour
- Cortisol secreting adrenal adenoma
- Bilateral adrenal hyperplasia
How do you diagnose Cushing syndrome
Overnight dexamethasone suppression test
– give tablet of dexamethasone at bedtime and measure the next morning they should be 0 or less than 20 nano meteres, if there not then there is a cortisol problem
24 hour urine free cortisol
LDDST: 0.5mg dexamethasone every 6 hours for 48 hours
Cortisol day curve plus midnight sleeping cortisol – measures cortisol throughout the day, if you have cushings disease the levels of cortisol will stay up all long
Blood test – midnight should be low
How do you manage cushings treatment
treat the underline cause
what imaging do you use for Cushings disease
- MRI Pituitary
- CT Adrenals
- Inferior petrosal sinus sampling
- NM: Octreotide uptake scan
What is the treatment of Cushings disease
Pituitary
- Transsphenoidal surgery
- External beam radiotherapy
- Stereotactic radiosurgery (gamma knife)
Adrenal
- Adrenalectomy
- Metyrapone/Ketoconazole/Etomidate
What can differitate between a pituitary adenoma and a ectopic ACTH secreting tumour as the cause of Cushings syndrome
- Inferior petrosal sinus sampling distinguishes between a pituitary adenoma and an ectopic ACTH secreting tumour as the cause of Cushing’s syndrome
- Blood is drawn directly from the venous sinuses around the pituitary.
High ACTH in the petrosal veins in a patient with confirmed Cushing’s compared to the periphery =
Pituitary Source of ACTH
ACTH in the petrosal veins equal to the periphery with confirmed Cushing’s = Peripheral source of ACTH
what can be used to locate the ectopic neuroendocrine tumour
- octreotide scan
what is Addisons disease due to
• Primary adrenal failure
– Autoimmune
– Tuberculosis
what are the symptoms of Addisons disease
• Vague symptoms initially
– Fatigue, weakness, myalgia
– Anorexia, weight loss
– Hyperpigmentation
describe Addison crisis symptoms
- Failure to response to stress Low Blood pressure Low glucose Low sodium High potassium
How do you diagnose Addison disease
Low 9am cortisol
High ACTH
Short Synacthen Test – synthetic ACTH – if adrenal glands are working expect to increase the amount of cortisol that is being produced
what is congenital adrenal hyperplasia
- 2 1 -hydroxylase – if this doesn’t work
- Cortisol falls
- ACTH rises
- And if you have high levels of ACTH
- It stimulates cholesterol process and they end up producing more androgens
- This is called Congenital Adrenal Hyperplasia
What is an congenital adrenal hyperplasia due to
- due to 21-hydroxylase deficiency
What are the symptoms of a congenital adrenal hyperplasia
Salt-losing
Adrenal Insufficiency
Virilisation
Adrenal hyperplasia
what does the adrenal medulla do
catecholamine biosynthesis
Where are chomaffin cells
Adrenal medulla Para-aortic sympathetic chain Organ of Zuckerkandl Wall of urinary bladder Neck and mediastinal sympathetic chain
what are the two types of tumours from chromaffin cells
phaeochromocytoma
paraganglioma
- These together are called PPGL
where do the two types of tumours from chromaffin cells originate from
• Phaeochromocytoma
– Arising from within the adrenal medulla
• Paraganglioma
– Extra-adrenal tumours
name the adrenoreceptors and what they do
- alpha 1
- alpha 2
- b1
- b2
- b3
- d1
- d2
- α1 vascular and smooth muscle contraction
- α2 presynaptic, inhibitory to noradrenaline release - suppresses BP
- β1 positive inotropic and chronotropic in the heart; increased renin; lipolysis
- β2 bronchial, vascular, uterine smooth muscle relaxation; glycogenolysis
- β3 Lipolysis, energy expenditure, eg at brown fat tissue
- D1 cerebral, renal, mesenteric, coronary vasculature dilatation
- D2 presynaptic inhibition of noradrenaline and prolactin release
what are the symptoms of catecholamine excess
- Impending doom
- Diaphoresis
- Dyspnea
- Headache
- Hypertension
- Palpitation
- Tremor
- Nausea and vomiting
- Fatigue
- Orthostatic hypotension
- Hyperglycemia
- Weight loss
- Epigastric and chest pain
- Congestive heart failure
What are the main producers of catecholamine
chromaffin cells
How do you detect PPGL
- Hyperadrenergic spells
- Resistant hypertension and desceibed panic attacks should be thinking about PPGL
- Familial syndrome
- Incidentally discovered adrenal mass
- Pressor response during general anaesthesia
- Early onset hypertension
- Dilated cardiomyopathy
how do you make a diagnosis of PPGL
• 24 hour urine metanephrines • Plasma metanephrines • CT/MRI adrenals and abdomen • 123I-MIBG scintigraphy - MIBG – tracer taken up ny neuroendocrine cells and localise din the granules where they caetcholamines are made
What is the treatments of PPGL
• Surgical resection
• Pre-operative alpha and beta-blockade – because the symptoms of these tumours are due to too much alpha and beta cell stimulus, can lead to anaesthetic bad reaction without these
– Phenoxybenzamine 10mg bd and titrate
– Propranolol 10mg qds and titrate
• Acute crisis: IV phentolamine or nicardipine
• Avoid opiates – adrenal cells have opiate receptors on them
• 131I-MIBG therapy for malignant disease
What would happen if you treatment a patient with a phaemochromocytoma with beta blockers alone
- the tumour balances the catecholamine with stimulus of A1 and b2 adrenoreceptor
- A1 causes vasoconstriction and b2 causes vasodilation
- if you were to use a beta blocker you would block B2 and therefore block vasodilation
- therefore vasoconstriction would happen and this would cause the blood pressure to increase
