Endo 6: Hyperadrenal disorders Flashcards
What is cushings
hyperadrenal- too much cortisol
Clinical features of cushings
High cortisol Hypertension and hypokalaemia Bruising (can't make protein) Striae Proximal myopathy (shuts down protein metabolism, converts it increases fat) Moon face and buffalo hump Thin skin
Causes of cushings
Steroids e.g. for inflammatory conditions (exogenous)
Pituitary dependent cushings DISEASE
Ectopic ATCH Lung cancer
Adrenal adenoma secreting cortisol
Investigations to determine cause of cushings
24hr urine collection for urinary free cortisol
Blood diurnal cortisol (high in the morning, low at night –>high at 9am low at mignight normally, but always high in Cushing’s)
Low dose dexamethasone suppression test
Outline Low dose dexamethasone suppression test
You give dexamethasone which is a v potent form of cortisol, normally somebody would suppress their cortisol production in response to this BUT ALL forms of cushings will fail to suppress cortisol levels.
The way you determine difference is ACTH. If it’s an adrenal problem, ACTH will be really low with dexamethasone, if it’s a pituitary dependent cushing’s disease, ACTH will remain high as the pituitary adenoma continues to pump out ACTH.
0.5mg 6 hourly or 48hrs
Normal will suppress cortisol to zero but cushings will only slight suppress e.g. 800nM (9am) to 680nM after the LDDST
Treatment for Cushing’s
Inhibitors of steroid biosynthesis : metryapone and ketoconazole
How does metyrapone work
including effect on aldosterone production
Inhibiting 11beta hydroxylase blocker, blocking cortisol synthesis, increasing acth and plasma deoxycortisol increased.
Steroid synthesis in zona fasciculata (for cortisol) is stopped at the 11 de-oxycortisol stage…
aldosterone production affected to lesser extent, because instead of 11b hydroxylase converting 11 deoxycortixosterone to corticosterone (which would then usually be conerted to aldosterone), there is direct conversion of 11 deoxycorticosterone to aldosterone by aldosterone synthase… however, 11 deoxycorticosterone still backs up and this still acts a bit like an MR so increases salt and water retention
Indications for metyrapone
Before surgery as cushing’s patients are not good surgical candidates (better wound healing and also less infection if you reduce cortisol)
Control of cushings after radiotherapy (which is usually slow to work)
You adjust the oral dose according to cortisol (aim for 150-300nmol/L)
Problem with metyrapone
Deoxycortisterone builds up in the z. glomerulus; it has a aldosterone like activity leading to salt retention and hypertension- not good because cushings patients already predisposed to hypertension
Precurosrs funnel into sex steroid synthesis- increase in ADRENAL androgen production- hirsutism and acne
How does ketoconazole work
Blocks production of glucocorticoids and mineralocorticoids and sex steroid synthesis (was originally used as antifungal –> blocks cytochrome p450scc so no cholesterol –> pregnenolone step)
P450 scc is found in the inner mitochondrial matrix of cells at the site of steroid hormone synthesis
Use of ketoconazole
Same as metyrapone (treatment and symptom control before surgery) orally active
Problem with ketoconazole
Liver damage possibly fatal so you need to measure liver function weekly biochemically and clinically
Treatment of cushings
Depends on cause:
Pituitary surgery (transsphenoidal hypophysectomy)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass
What is Conn’s syndrome
zona glomerulosa benign adrenal cortical tumour - aldoesterone in excess
Sign of conn’s syndrome
Hypertension and hypokalaemia
How can you check for conn’s
Renin angiotensin system should be surpressed
Drug for conn’s
MR antagonist e.g. spironolactone and epleronone
Mechanism of spironolctone
It is like a prodrug really, converted into metabolites such as canrenone, a competitive agonist of the mineralocorticoid receptor. This blocks Na+ reabsorption and K+ excretion. So the drug is not reducing the level of aldosterone, it’s reducing its effect at the DCT. POTASSIUM SPARING DIURETIC
Unwatned action of spironolactone
Menstrual irregularities (+progesterone receptor) Gynaecomastia (antagonist of the androgen receptor so blocks androgen in men leading to breast tissue formation)
Mechanism of eplelerone
Also MR antagonist, similar affinity to spironolactone, less binding to androgen and progesterone receptors compared to spir. so better tolerated (more selective for MR)
Clinical features of phaeochromocytoma
Comes and goes:
HTN in young people
Episodic severe HTN (after abdominal palpation)
More common in certain inherited conditions
HTN can cause MI or stroke
High adrenaline can cause ventricular fibrillation and death
Management of phaeo
Eventually surgery, but careful prep needed because anaesthetic can precipitate hypertensive crisis
Alpha blockade
Intravenous fluid as alpha blockade commences
Beta blockade to prevent tachycardia
Key facts for phae
10% outside adrenal (sympathetic chain)
10% bilateral
10% malignant
Very rare
Differentiate primary and secondary hyperaldosteronism
Primary- conn’s (adenoma)
Secondary- reduced RBF e.g. due to renal artery stenosis/heart failure activating RAAS
What is phaechromocytoma
Tumour of adrenal medulla which secrete catecholamines
