Endo 6: Hyperadrenal disorders

Question 1

What is cushings

Answer 1

hyperadrenal- too much cortisol

Question 2

Clinical features of cushings

Answer 2

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

Question 3

Causes of cushings

Answer 3

Steroids e.g. for inflammatory conditions (exogenous)
Pituitary dependent cushings DISEASE
Ectopic ATCH Lung cancer
Adrenal adenoma secreting cortisol

Question 4

Investigations to determine cause of cushings

Answer 4

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

Question 5

Outline Low dose dexamethasone suppression test

Answer 5

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

Question 6

Treatment for Cushing’s

Answer 6

Inhibitors of steroid biosynthesis : metryapone and ketoconazole

Question 7

How does metyrapone work

including effect on aldosterone production

Answer 7

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

Question 8

Indications for metyrapone

Answer 8

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)

Question 9

Problem with metyrapone

Answer 9

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

Question 10

How does ketoconazole work

Answer 10

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

Question 11

Use of ketoconazole

Answer 11

Same as metyrapone (treatment and symptom control before surgery) orally active

Question 12

Problem with ketoconazole

Answer 12

Liver damage possibly fatal so you need to measure liver function weekly biochemically and clinically

Question 13

Treatment of cushings

Answer 13

Depends on cause:
Pituitary surgery (transsphenoidal hypophysectomy)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass

Question 14

What is Conn’s syndrome

Answer 14

zona glomerulosa benign adrenal cortical tumour - aldoesterone in excess

Question 15

Sign of conn’s syndrome

Answer 15

Hypertension and hypokalaemia

Question 16

How can you check for conn’s

Answer 16

Renin angiotensin system should be surpressed

Question 17

Drug for conn’s

Answer 17

MR antagonist e.g. spironolactone and epleronone

Question 18

Mechanism of spironolctone

Answer 18

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

Question 19

Unwatned action of spironolactone

Answer 19

Menstrual irregularities (+progesterone receptor)
Gynaecomastia (antagonist of the androgen receptor so blocks androgen in men leading to breast tissue formation)

Question 20

Mechanism of eplelerone

Answer 20

Also MR antagonist, similar affinity to spironolactone, less binding to androgen and progesterone receptors compared to spir. so better tolerated (more selective for MR)

Question 21

Clinical features of phaeochromocytoma

Answer 21

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

Question 22

Management of phaeo

Answer 22

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

Question 23

Key facts for phae

Answer 23

10% outside adrenal (sympathetic chain)
10% bilateral
10% malignant
Very rare

Question 24

Differentiate primary and secondary hyperaldosteronism

Answer 24

Primary- conn’s (adenoma)

Secondary- reduced RBF e.g. due to renal artery stenosis/heart failure activating RAAS

Question 25

What is phaechromocytoma

Answer 25

Tumour of adrenal medulla which secrete catecholamines