Adrenal Disorders Flashcards
1
Q
What does the adrenal cortex produce?
A
Corticosteroids
- mineralocorticoids (aldosterone)
- glucocorticoids (cortisol)
- sex steroids (androgens and oestrogens)
2
Q
What is the precursor for corticosteroids?
A
Cholesterol
3
Q
What is the effects of angiotensin II on the adrenal glands?
A
Activation of a series of hydroxylase enzymes to make aldosterone
4
Q
How does angiotensin II activate enzymes?
A
By side chain cleavage
5
Q
What is the action of aldosterone?
A
Controls blood pressure, sodium and lowers potassium
6
Q
What is the effect of ACTH on the adrenal glands?
A
Activates a series of hydroxylase enzymes to make cortisol
7
Q
What does 17 hydroxylase catalyse?
A
the conversion of progesterone to 17-OH progesterone
8
Q
What does 21 hydroxylase catalyse?
A
conversion of progesterone to 11-deoxycorticosterone
9
Q
What does 11 hydroxylase catalyse?
A
- 11-deoxycorticosterone to corticosterone or cortisol
10
Q
What does 18 hydroxylase catalyse?
A
the conversion of corticosterone to aldosterone
11
Q
What rhythm does cortisol have?
A
Diurnal (peaks at 8:30)
12
Q
What is Addison’s disease?
A
- Primary adrenal failure
- Autoimmune disease where the immune system destroys the adrenal cortex
- most commonly tuberculosis of the adrenal glands worldwide
13
Q
What is the result of Addison’s disease
A
The pituitary gland secretes a lot of ACTH and therefore MSH
14
Q
What are the symptoms of Addison’s Disease?
A
- Hyperpigmentation
- Autoimmune vitiligo
- low blood pressure (no cortisol or aldosterone)
- weakness
- weightloss
- GI effects (diarrhea, nausea, vomiting, constipation, pain)
15
Q
What are the general causes of adrenocortical failure?
A
- adrenal glands are destroyed (by tuberculosis, autoimmune or congenital adrenal hyperplasia)
- enzymes in the steroid synthetic pathway not working
16
Q
What are the consequences of adrenocortical failure?
A
Increase: - ACTH - pigmentation - plasma K+ Decrease: - blood pressure (can cause death) - plasma Na+ - glucose (due to glucocorticoid deficiency)
17
Q
Why does high ACTH levels cause increased pigmentation?
A
- POMC (pro-propio-melanocortin) is a large precursor protein which is cleaved to form ACTH, MSH and endorphins
- increased ACTH = increased POMC = increased MSH
18
Q
Where is Pro-propio melanocortin synthesised?
A
In the pituitary
19
Q
How do you test for Addison’s disease?
A
- 9 am cortisol (low)
- ACTH (high)
- short synACTH test
- give 250ug synACTHen (IM) and measure cortisol response
20
Q
What results would you expect when doing a short synACTH test in someone with Addison’s disease?
A
No cortisol response
21
Q
Why isn’t aldosterone administered in HRT during adrenal failure?
A
The half-life of aldosterone is too short for safe 1 x daily administration so you replace cortisol instead
22
Q
What is the risk of replacement prednisolone?
A
- excess steroid exposure
- sub-clinical Cushing’s syndrome
23
Q
What is the general treatment given for adrenal failure?
A
- Hydrocortisone 3 x daily (10+5+2.5)
OR - Prednisolone 3mg 1 x daily
- Fludrocortisone 50-100mcg 1 x daily
24
Q
What is the most common cause of congenital adrenal hyperplasia?
A
21-hydroxylase deficiency
25
What hormones will be absent in COMPLETE 21-hydroxylase deficiency?
- aldosterone
- cortisol
26
How long can you survive with COMPLETE 21-hydroxylase deficiency with no treatment?
<24 hours
27
What hormones will be in excess with COMPLETE 21-hydroxylase deficiency?
- Sex steroids
- testosterone
28
At what age does COMPLETE 21-hydroxylase deficiency present?
- neonate in a salt losing crisis
- Pre-birth (in utero), foetus gets steroids from across the plasma
- Sex steroid + T excess may cause ambiguous genitalia in females (virilisation)
29
What hormones are deficient in PARTIAL 21-hydroxylase deficiency?
- cortisol
- aldosterone
30
Which hormones are in excess in PARTIAL 21-hydroxylase deficiency?
- sex steroids
- testosterone
31
At what age does PARTIAL 21-hydroxylase deficiency present?
- any age as survival is likely, still have some aldosterone and cortisol
32
What is the main problem associated with PARTIAL 21-hydroxylase deficiency?
```
In later life:
- hirsutism in girls
- virilisation in girls
- precocious puberty in boys
due to the adrenal testosterone
```
33
What does 11-deoxycorticosterone behave like?
Aldosterone
34
What can excess 11-deoxycorticosterone cause?
- hypertension
- hypokalaemia
35
What hormones are deficient in 11-hydroxylase deficiency?
- cortisol
- aldosterone
36
Which hormones are in excess in 11-hydroxylase deficiency?
- sex steroids
- testosterone
- 11-deoxycorticosterone
37
What problems are associated with 11-hydroxylase deficiency?
- virilisation
- hypertension
- low potassium
38
What hormones are deficient in 17-hydroxylase deficiency?
- cortisol
- sex steroids
39
What hormones are in excess in 17-hydroxylase deficiency?
- 11-deoxycorticosterone
- aldosterone
(mineralcorticoids)
40
What problems are associated with 17-hydroxylase deficiency?
- hypertension
- low potassium
- sex steroid deficiency
- glucocorticoid deficiency (low glucose)
41
What are the clinical features of Cushing's disease?
- excess cortisol
- centripetal obesity
- moon face
- buffalo hump
- proximal myopathy
- hypertension
- hypokalaemia
- red striae, thin skin and bruising
- osteoporosis
- diabetes
42
What are the causes of Cushing's syndrome?
- excess steroid exposure
- pituitary dependent Cushing's disease
- Ectopic ACTH (from lung cancer)
- Adrenal adenoma secreting cortisol
43
What are the investigations used to confirm Cushing's disease?
- 24hour urine collection (for urinary free cortisol)
- blood diurnal cortisol levels
(cortisol highest at 9am, lowest at midnight)
- low dose dexamethasone suppression test
44
What is involved in a low dose dexamethasone suppression test?
- 0.5mg every 6 hours for 48 hours
(dexamethasone=artificial steroid)
- normal will suppress cortisol to 0
- ANY cause of Cushing's will fail to suppress
45
What values would confirm a diagnosis of Cushing's disease?
- basal (9am) cortisol, 800nM
- end of low dose dexamethasone test, 680nM
46
What drugs are involved in the manipulation of steroids?
- Enzyme inhibitors
- Receptor blocking drugs
47
Which drugs are inhibitors of steroid biosynthesis?
- metyrapone
- ketoconazole
- osilidrostat
48
What is the action of metyrapone?
- The inhibition of 11beta-hydroxylase
- steroid synthesis (in zona fasiculata) is arrested at the 11-deoxycortisol stage
- 11-deoxycortisol has NO negative feedback effects on the hypothalamus and the pituitary gland
49
What are the main 2 uses of Metyrapone?
- control of Cushing's syndrome prior to surgery
- Control of Cushing's symptoms after radiotherapy (slow to take effect)
50
How can metyrapone be used to control Cushing's syndrome prior to surgery?
- adjust oral dose according to cortisol, aim: serum cortisol = 150-300nmol/l
- improves patients symptoms and promotes better post-op recovery
51
What are the unwanted side effects of metyrapone?
- hypertension with long term use
- hirsutism
52
How does metyrapone cause hypertension in the long term?
the excess 11-deoxycorticosterone accumulates in the zona glomerulosa, has aldosterone-like activity causing salt retention and therefore, hypertension.
53
How does metyrapone cause hirsutism in women?
Increased adrenal androgen production
54
What is the actions of ketoconazole?
- main use: antifungal (withdrawn due to hepatotoxicity risk)
- at higher concentrations, inhibits steroidogenesis (use in Cushing's is off label)
55
What is the mechanism of action of ketoconazole?
Blocks 17alpha-hydroxylase, inhibiting cortisol production
56
What is ketoconazole used for?
treatment and control of Cushing's symptoms prior to surgery
| orally active
57
What is the unwanted actions of ketaconazole?
```
Liver damage (possibly fatal)
- monitor liver function weekly (clinically and biochemically)
```
58
What are possible treatments of Cushing's disease?
```
Depends on the cause
Surgical:
- pituitary surgery (transsphenoidal hypophysectomy)
- bilateral adrenalectomy
- unilateral adrenalectomy (for adrenal mass)
Medication:
- metyrapone
- ketoconazole
```
59
What are the characteristics of Conn's syndrome?
- benign adrenal cortical tumour (zona glomerulosa)
- aldosterone in excess
- hypertension (increases renal sodium reabsoption)
- hypokalaemia (increases renal potassium excretion)
60
What are the key aspects of Conn's syndrome required for diagnosis?
- primary hyperaldosteronism
- renin-angiotensin system is suppressed (excludes secondary hyperaldosteronism)
61
What type of drugs are involved in treating Conn's disease?
Mineralcorticoid Receptor antagonists:
- spironolactone
- elperonone
62
What is the mechanism of action of spironolactone?
- Competitive antagonist of the mineralocorticoid receptor (MR)
- Blocks sodium resorption and potassium excretion in the kidney tubules
(potassium sparing diuretic)
63
What are the unwanted actions of spironolactone?
- menstrual irregularities (+progesterone receptor)
- gynaecomastia (-androgen receptor)
64
What is the difference between spironolactone and epleronone?
Also an MR antagonist but Epleronone binds less to andorgen and progesterone receptors, adn therefore is better tolerated.
65
What are Phaeochromocytomas?
tumours of the adrenal medulla which secretes catecholamines
(adrenaline or nor-adrenaline)
66
What are the clinical features of a Phaeochromocytoma?
- hypertension (young people)
- episodic severe hypertension post abdominal palpation
- more common in certain inherited conditions.
- severe hypertension > myocardial infarction or stroke
- high adrenaline > ventricular fibrillation and death (medical emergency)
67
What is the management of a Phaeochromocytoma?
- First step: alpha blockade (prevents vasoconstriction)
- may need to be accompanied by IV fluids
- addition of beta blockade to prevent tachycardia
- Need surgery eventually BUT careful prep as anaesthetic can cause a hypertensive crisis
68
How is Conn's definitively diagnosed?
The presence of excess aldosterone with suppressed renin
69
What does 11-hydroxylase deficicency cause?
accumulation of 11-deoxycorticosterone
70
What is the action of 11B-hydroxysteroid dehydrogenase (11BHSD)?
- converts cortisol into inactive cortisone
- prevents excess cortisol from binding to aldosterone receptors (MR)
71
What is the mechanism of osilidrostat?
Similar to ketoconazole and blocks several enzymes in the steroid synthetic pathway, mainly 11 and 17 hydroxylase
