Adrenal Disorders Flashcards
-> Function of endocrine glands: Summarise the function of the key endocrine glands, including the synthesis, regulation and physiological effects of their hormones. -> Endocrine disorders: Describe the clinical features and treatment options of endocrine disorders. (103 cards)
1
Q
What is the steroid precursor?
A
- Cholesterol
2
Q
Which part of the adrenal cortex secretes aldosterone (mineralocorticoid)?
A
- Zona glomerulosa
3
Q
Which part of the adrenal cortex secretes cortisol (glucocorticoid)?
A
- Zona fasiculata
4
Q
Which part of the adrenal cortex secretes androgens and oestrogens (sex steroids)?
A
- Zona reticularis
5
Q
What are the four main enzymes involved in aldosterone synthesis within the adrenal cortex?
A
- 3-hydroxysteroid dehydrogenase
- 21-hydroxylase
- 11-hydroxylase
- 17-hydroxylase
6
Q
What is the overall effect of aldosterone (3)?
A
- Reduces potassium (Potassium excretion)
- Regulates sodium (sodium reabsorption)
- Maintains blood pressure
7
Q
Which adrenal hormones are predominantly insufficient in Addison’s disease (primary adrenocortical failure) (complete or partial 21 hydroxylase deficiency) (2)?
A
- Aldosterone
- Cortisol
8
Q
What type of rhythm is exhibited by cortisol secretion?
A
- Diurnal rhythm (daily)
9
Q
What are the causes of Addison’s disease (primary adrenocortical failure) (3)?
A
- Tuberculous Addison’s disease (commonest worldwide)
- Autoimmune Addison’s disease (commonest in UK)
- Congenital adrenal hyperplasia
10
Q
What is the main cause of Addison’s disease (primary adrenocortical failure) in the UK?
A
-
Primary adrenocortical failure (destruction of adrenal glands)
- Autoimmune induced destruction of the adrenal cortex
- Atrophy of the adrenal glands
11
Q
What is the main cause of Addison’s disease (primary adrenocortical failure) worldwide?
A
- Tuberculosis of the adrenal gland
12
Q
What are the clinical features of Addison’s disease (primary adrenocortical failure) (8)?
A
- Increase pigmentation & autoimmune vitilgo
- Low blood pressure (syncope)
- Weight loss
- Fatigue
- Hyponatremia
- Hypoglycaemia
- Hyperkalaemia
Eventual death due to severe hypotension
13
Q
Why do patients with Addison’s disease (primary adrenocortical failure) have a good tan (5 steps)?
A
1.Increase in pro-opio-melanocortin (POMC)
2. Increase in ACTH & endorphins
3. Increase in MSH
4. Increase in melanin
5. Increase pigmentation & autoimmune vitilgo
14
Q
What is the large precursor protein of ACTH?
A
- Pro-opio-melanocortin (POMC)
15
Q
What are the peptides that are formed from the cleavage of POMC (4)?
A
- ACTH
- MSH
- Endorphins
- Enkephalins
16
Q
Which peptide is cleaved from POMC subsequently being responsible for hyperpigmentation within patients with Addison’s disease (primary adrenocortical failure)?
A
- alpha-MSH (Melanocortin-stimulating hormone)
17
Q
Where is pro-opio melanocortin synthesised?
A
- Synthesised within the pituitary gland
18
Q
What clinical investigations are conducted for a patient suspected with Addison’s disease (primary adrenocortical failure) (3)?
A
- Low 9am cortisol
- High ACTH
- Short synACTHen test to measure the cortisol response (low response)
Short synACTHen test: Give 250 ug synacthen IM & Measure cortisol response
19
Q
At what time is cortisol level usually elevated?
A
- 9am
20
Q
What is a synACThen test?
A
- ACTH is administered to patients through intramuscular injections (250ug), and the cortisol response is measured
21
Q
What type of injections are administered during an synACTHen test?
A
- Intramuscular injections
22
Q
What are the 3 treatments available for adrenal failure?
A
- Hydrocortisone
- Prednisolone
- Fludrocortisone
23
Q
What is the half-life for oral hydrocortisone?
A
- Short half-life therefore requires more than once daily administration
24
Q
How often per day is oral hydrocortisone administede?
A
- Thrice daily
25
Which drug replacement therapy in Addison's disease closely mimics the circadian rhythm?
* Prednisolone
26
What is the stereochemical difference between prednisolone and cortisol?
* There is an **additional double bond**, subsequently giving a **longer half life and potency** in comparison to cortisol
27
What are the pharmacological advantages of prednisolone to cortisol (3)?
* Longer half life
* More potent that cortisol
* x2.3 binding affinity
28
What 3 doses are available for prednisolone?
* 1mg
* 2.5mg
* 5mg
29
What is the recommended dose for prednisolone replacement therapy?
* 2mg-4mg once daily
30
What is the equivalent dose for an intermediate acting prednisolone?
* 3mg
31
What is the relative glucocoritcoid potency for prednisolone?
* x7
32
What pharmacological treatment is available for primary adrenocortical failure?
* Fludrocortisone 50-100mg daily
33
How long are the effects of fludrocortisone seen for?
* 18 hours
34
Which two receptors are interacted with by fludrocortisone?
* **Mineralocorticoid receptors**
* **Glucocorticoid receptors**
35
Which atom is added to fludrocortisone?
* **Fluorine**
36
What pharmacodynamic effect does fluorine have in fludrocortisone?
* Fluorine does not exist in natural steroids, so its presence **slows metabolism substantially**
* ****Binds to **both mineralocorticoid and glucocorticoid receptors**
* Has a longer half life (3.5h and effects seen for 18h)
37
Which congenital condition is associated with primary adrenocortical failure?
* **Congenital adrenal hyperplasia**
38
Which adrenal hormones are predominantly insufficient in congenital adrenal hyperplasia (complete or partial 21 hydroxylase deficiency)?
* **Aldosterone**
* **Cortisol**
39
Which hormones are increased in congenital adrenal hyperplasia (complete or partial 21 hydroxylase deficiency)?
* Sex steroids (androgen production)
40
What is the most common enzyme deficiency in congenital adrenal hyperplasia?
* 21-hydroxylase deficiency
41
What stage does 21-hydroxylase catalyse in aldosterone synthesis?
* Hydroxylation of progesterone to 11-deoxy corticosterone
42
What stage does 21-hydroxylase catalyse in cortisol synthesis?
* 17-OH progesterone to 11-deoxycortisol
43
How long can a patient survive with diagnosed congenital adrenal hyperplasia (complete 21 hydroxylase deficiency)?
* Less than 24 hours
44
What is the age of presentation of congenital adrenal hyperplasia (complete 21 hydroxylase deficiency)?
* As a **neonate** with a salt losing **Addisonian crisis**
* Before (while in utero) foetus gets steroids across placenta
* Girls will be born with ambiguous genitalia due to excess testosterone production
45
Which hormone is concerned with the salt-washing feature of an Addisonian crisis?
* Aldosterone
46
What is the main difference between a partial 21-hydroxylase deficiency and complete deficiency?
* Aldosterone and cortisol is still produced in smaller quantities (responsive to ACTH)
47
What are the clinical features for females with congenital adrenal hyperplasia (complete or partial 21 hydroxylase deficiency) (7)?
* **Labial fusion**
* **Ambiguous genitalia**
* **Ambiguous in physical characteristics**
* **Weight loss**
* **Vomiting**
* **Hypotension**
* **Hyperpigmentation**
48
What are the main associated symptoms of congenital adrenal hyperplasia (partial 21 hydroxylase deficiency) that present later in life in boys (2)?
* **Precocious puberty** in boys due to adrenal testosterone
* **Hyperplastic muscles**
49
What are the main associated symptoms of congenital adrenal hyperplasia (partial 21 hydroxylase deficiency) that present later in life in girls (5)?
* **Hirsutism & virilisation**
* Male pattern **baldness**
* **Facial hair**
* **Clitomegaly**
* **Hyperplastic muscles**
50
Which 3 hormones are in excess in a congenital adrenal hyperplasia (11 hydroxylase deficiency)?
* Sex steroids
* Testosterone
* 11-deoxycorticosterone
51
What are the problems associated with a congenital adrenal hyperplasia (11 hydroxylase deficiency) (3)?
* **Virilisation**
* **Hypertension**
* **Hypokalaemia** (due to elevations in 11-deoxycorticosterone)
52
What stages of aldosterone synthesis is catalysed by 11-hydroxylase?
* 11-deoxy-corticosterone hydroxylation into corticosterone
53
What stage of cortisol synthesis is catalysed by 11-hydroxylase?
* 11-deoxycortisol hydroxylation into cortisol
54
Which aldosterone precursor behaves analogous to aldosterone?
* 11 deoxycorticosterone
55
In excess, what effects can be caused by 11 deoxycorticosterone (3)?
* Hypertension
* Hypokalaemia
* Virilisation
56
What are the associated problems with a congenital adrenal hyperplasia (17-hydroxylase deficiency) (4)?
* **Hypertension**
* **Hypokalaemia**
* **Sex steroid deficiency**
* Glucocorticoid deficiency (**hypoglycaemia**)
57
What stage is catalysed by 17-hydroxylase?
* Progesterone hydroxylation into 17-OH-progesterone
58
Which hormones are deficient in a congenital adrenal hyperplasia (17-hydroxylase deficiency) (2)?
* Cortisol
* Sex steroids
59
Which hormones are in excess in a congenital adrenal hyperplasia (17-hydroxylase deficiency) (2)?
* Aldosterone
* 11-deoxycorticosterone
60
What are the main causes of Cushing's syndrome (ACTH dependent 2 / ACTH independent 3)?
* ACTH dependent:
* Pituitary dependent **Cushing's disease**
* Ectopic ACTH from **lung cancer**
* ACTH independent:
* Overdose of oral **corticosteroids**
* **Adrenal adenoma** secreting cortisol
* **Adrenal nodular hyperplasia**
61
What are the clinical signs of Cushing's disease (2)?
* **Excess cortisol**
* **Hypokalaemia**
62
How is ACTH affected in ACTH dependent causes of Cushing's disease?
* **Increase in ACTH**
63
How is ACTH affected in ACTH independent causes of Cushing's disease?
* **Decrease in ACTH** (due to negative feedback)
64
What are the symptoms of Cushing's disease (7)?
* Centripetal **obesity**
* **Moon face** and buffalo **hump**
* **Proximal myopathy**
* **Hypertension**
* Red striae, thin skin, and bruising
* **Osteoporosis**
* Diabetes **(T2DM)**
65
What are the investigations that are conducted to determine the cause of Cushing's syndrome (3)?
* **24H urine collection** for urinary free cortisol
* Basal (9am) cortisol 800nm
* **Blood diurnal cortisol levels**
* Cortisol usually highest at 9am and lowest at midnight (if asleep)
* Low dose **dexamethasone suppression test** (680nM) (dexamethasone is an artificial steroid)
* 0.5mg 6 hourly for 48 hours
* Normal will supress Vs Cushing's disease will fail to suppress
66
What are the treatments available for Cushing's disease (5)?
* Surgical:
* Transphenoidal hypoplysectomy
* Bilateral adrenalectomy
* Unilateral adrenalectomy
* Pharmacological:
* Metryapone
* Ketoconazole
67
What pharmacological interventions are implemented for patients with hypersecretion of hormones of the adrenal cortex (i.e. Cushing's Syndrome) (2)?
* Metryapone
* Ketoconazole
| Inhibitors of steroid biosynthesis
68
What is the mechanism of action of metryapone?
* **Inhibition of 11B-Hydroxylase**, this arrests steroid synthesis within the zona fasciculata at the 11-deoxycortisol stage
69
Does 11-deoxycortisol exert negative feedback on the hypothalamus?
* There is **no negative feedback** effect on the hypothalamus and pituitary gland
70
How should cortisol be controlled and regulated in patients taking metryapone?
* **Adjust oral dose according to cortisol level** (aim for mean serum cortisol 150-300nmol/L)
71
What are the advantages of using metryapone preoperatively?
* **Improves patient's symptoms** and **promotes** better **post-operative recovery** (better wound healing, less infection)
72
What are the adverse actions of metryapone (2)?
* **Hypertension** on long-term administration
* **Hirsutism** (increased adrenal androgen production in women)
73
What are the side effects of using metryapone on aldosterone synthesis?
* **Deoxycorticosterone accumulates within the zona glomerulosa,** exhibiting aldosterone-like (mineralocorticoid) activity, leading to **salt retention & hypertension**
74
Where does deoxycorticosterone accumulate in patients taking metryapone?
* Accumulates in the **zona glomerulosa**
75
What type of effects are exerted by deoxycoticosterone?
* Mineralocorticoid activity
76
Which enzyme is inhibited by ketoconazole?
* 17-alpha hydroxylase
77
What toxic risk is associated with ketoconazole?
* **Hepatotoxicity**
* Therefore monitor liver function weekly, clinically and biochemically
78
What follow up investigations should be conducted in patients prescribed with ketoconazole?
* Weekly **liver function tests** due to hepatotoxicity risks (P450 poison)
79
What are the surgical interventions for the treatment of Cushing's?
* Transsphenoidal hypophysectomy
* Bilateral adrenalectomy
* Unilateral adrenalectomy for adrenal mass
80
What is the 1st line of treatment for a patient with an ACTH-secreting pituitary adenoma?
* **Pituitary surgery** (transsphenoidal hypophysectomy)
81
What type of hyperaldosteronism is Conn's syndrome?
* Priamry hyperaldosteronism
82
What is the main cause of Conn's syndrome?
* **Benign adrenal cortical tumour of the zona glomerulosa** resulting in an excess production of aldosterone
83
What impact does Conn's syndrome have on the Renin-angiotensin system?
* **RAAS should be suppressed** (exclude secondary hyperaldosteronism)
84
What are the associated clinical signs of Conn's syndrome (3)?
* Hypertension
* Hypokalaemia
* Hypernatremia
85
What two main drugs are prescribed in patients with Conn's syndrome?
* Spironolactone
* Epleronone
## Footnote
Mineralocorticoid receptor antagonist
86
What is the mechanism of action of spironolactone?
* Converted to several active metabolites, including canrenone, a competitive **antagonist of mineralocorticoid receptors** (MR)
* Blocks sodium reabsorption and potassium excretion in the kidney tubules (potassium sparing diuretic)
* **Antihypertensive**
87
Which metabolite is formed through the conversion of spironolactone?
* Canrenone
88
Which receptors are antagonised by spironolactone metabolites?
* **Mineralocorticoid receptors**
89
Describe the pharmacokinetics of spironolactone?
* **Orally active**
* Highly protein bound and **metabolised in the liver**
90
What are the unwanted actions of spironolactone (2)?
* **Menstrual irregularities** (+progesterone receptor)
* **Gynaecomastia** (inhibits androgen receptors)
91
What type of antagonist is epleronone?
* **Mineralocorticoid receptor antagonist**
92
Which Conn's syndrome drug is better tolerated?
* Epleronone
93
Why is epleronone better tolerated than spironolactone?
* **Less binding to androgen and progesterone receptors** compared to spironolactone
94
What is a phaechromocytoma?
* **Tumours of the adrenal medulla** which secrete catecholamines
95
What are the associated risks with a phaeochromocytoma (4)?
* **Family history** of endocrine disorders
* **MEN**
* **Von-Hippel-Lindau syndrome**
* **Germline mutations** in the succinate dehydrogenase
96
What is the main clinical feature of a phaeochromocytoma?
* Sustained or paroxysmal **hypertension**
* Cases of hypertension may proceed after abdominal pain episodically, in comparison to Conn's syndrome (smooth secretion of aldosterone)
97
What is the classic triad of symptoms for patients with a phaeocromocytoma?
* **Palpitations**
* **Headaches**
* **Diaphoresis** (excessive sweating)
98
What are the potential risks with a phaeochromocytoma?
* Elevations in adrenaline typically manifest as **severe hypertension** causing potential **myocardial infarctions or strokes**, as well as **ventricular fibrillation** within patients becoming a medical emergency
99
Which hormone can be measured in urine and blood as a marker for phaeochromocytoma associated release of adrenaline?
* **Metanephrine** (has a long half life)
100
What is the first line of treatment of a phaeochromocytoma?
* Anti-hypertensive agents
| Alpha-blockade & Beta-blockade
101
Why is an alpha-blockade administered in the management of a phaeochromocytoma?
* Inhibition of alpha-receptors minimises the impact of vasoconstriction induced by noradrenaline/adrenaline, therefore **reducing blood pressure**
* IV fluids to compensate for potential hypotensive crisis
102
Why is a beta-blockade administered in the management of a phaeochromocytoma?
* Administer **atenolol / metoprolol / propanolol** to prevent **tachycardia & arrhythmia**
103
What are the precautions required for patients with a phaeochromocytoma surgical excision?
* Careful preparation as anaesthetic can precipitate a hypertensive crisis
