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Endocrinology 2 > Adrenal Disorders > Flashcards

Adrenal Disorders Flashcards

1
Q

What 3 stimuli cause aldosterone production?

A

1: Juxtaglomerular cells of kidney secrete renin which cleaves circulating angiotensinogen into angiotensin 1. This travels to the lungs where ACE enzymes cleave angiotensin 1 to angiotensin 2, the active form. Angiotensin 2 binds to a G-stimulatory protein receptor on surface of Zona Glomerulosa activating adenylate cyclase and leading to production of protein kinase A which phosphorylates enzymes in the pathway to make aldosterone.
2: Hyponatremia and Hypokalaemia act as triggers for aldosterone production which increases sodium reabsorption and potassium excretion in distal convoluted tubule.
3: ACTH produced by pituitary also acts on a Gstim protein and activates enzymes needed for aldosterone production.

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2
Q

How is aldosterone synthesis inhibited?

A

Atrial Natriuretic Peptide, released in response to atrial stretch (usually due to high circulating blood volume), binds to a G-inhibitory protein on surface of Zona Glomerulosa. This causes potassium efflux from the cell and subsequent hyperpolarisation, altering enzymatic activity within the cell.

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3
Q

How does aldosterone travel and act?

A

Aldosterone travels in the bloodstream usually bound to transcortin (corticosteroid binding globulin) but can also be bound to albumin. Being a steroid hormone, aldosterone can directly move through lipid bilayer and bind to an intracellular cytosolic receptor which activates a chain of events leading to production of more sodium-potassium transporters. End result is greater sodium reabsoption and potassium excretion.

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4
Q

What is the overall effect of angiotensin 2 on the adrenal cortex?

A 
Activation of:
Side Chain Cleavage
3 Hydroxysteroid dehydrogenase
21 hydroxylase
11 hydroxylase
18 hydroxylase
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5
Q

What is the effect of ACTH on the adrenal gland?

A 
Activation of the following enzymes
Side Chain Cleavage
3 Hydroxysteroid dehydrogenase
21 hydroxylase
11 hydroxylase
17 hydroxylase
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6
Q

What is Addison’s disease?

A

Primary adrenal failure where the immune system decides to destroy the adrenal cortex. Commonest cause worldwide is tuberculosis of the adrenal gland. Pituitary starts secreting lots of ACTH and hence MSH.

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7
Q

What are the skin and GI symptoms of Addison’s?

A

Skin - hyperpigmentation and potential vitiligo
GI - Nausea, diarrhoea, vomiting, constipation, abdominal pain
General - weakness, weight loss, low BP

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8
Q

What are the symptoms of an adrenal crisis?

A

Fever, syncope, convulsions, hypoglycaemia, hyponatremia, severe vomiting and diarrhoea

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9
Q

What are 2 causes of adrenocortical failure?

A
  1. Enzymes in the steroid synthetic pathway not working

2. Adrenal glands are destroyed

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10
Q

What 3 conditions cause adrenocortical failure?

A
  1. Tuberculous Addison’s disease
  2. Common Addison’s disease
  3. Congenital adrenal hyperplasia
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11
Q

What are the 5 main consequences of adrenocortical failure?

A

Fall in blood pressure
Loss of salt in the urine
Increased plasma potassium
Fall in glucose due to glucocorticoid deficiency
High ACTH resulting in increased pigmentation
Eventual death due to severe hypotension

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12
Q

What 2 tests are done to check for Addison’s?

A

9am cortisol tested - cortisol highest at this time due to diurnal rhythm
Short synacthen test - 250 ug synacthen IM given and cortisol response tested. Tests ability of adrenal cortex to produce cortisol in response to ACTH.

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13
Q

What replacement of aldosterone is provided?

A

Fludrocortisone as fluorine does not exist in natural steroids, so its presence slows metabolism substantially. Has a half life 3.5h and effects seen for 18h. Aldosterone cannot be given as it has a very short half life and so not safe for once daily injection. Binds mineralocorticoid receptor and glucocorticoid receptor. 50-100mcg daily.

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14
Q

What is the problem with oral hydrocortisone?

A

Oral hydrocortisone has a short half life: too short for once daily administration and creates harmful late peaks.

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15
Q

What is used instead of oral hydrocortisone?

A

1-2 dehydro-hydrocortisone used instead as it has a longer half life and 2.3x the binding potency of cortisol. It is known as prednisolone. Replacement dose 3-4mg ONCE daily.

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16
Q

What dose of prednisolone is available?

A

1mg, 2.5mg and 5mg. It is not enteric coated which slows absorption. 2-4mg dose required daily as this is equal to 15-25mg of hydrocortisone daily.

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17
Q

What causes congenital adrenal hyperplasia?

A

A deficiency of 21-hydroxylase which can be complete or partial. This interferes with aldosterone and cortisol production.

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18
Q

What are the consequences of a complete 21-hydroxylase absence?

A

Can survive only less than 24 hours without aldosterone and cortisol. Sex steroids and testosterone will be in excess. Presentation usually a neonate with Addisonian crisis as before birth, foetus gets steroids across placenta. Girls may have ambiguous genitalia virilised by adrenal testo.

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19
Q

What are the main problems with a partial 21-hydroxylase deficiency?

A

Girls may present with hirsutism and virilisation in later life and precocious puberty in boys due to adrenal testosterone. May present at any time as long as they survive.

20
Q

What problems are caused by a 11-hydroxylase deficiency?

A

11 deoxycorticosterone behaves like aldosterone so in excess, it can cause hypertension and hypokalaemia. Sex steroids, testosterone and 11-deoxycorticosterone are in excess. Virilisation, hypertension and low K are the main problems.

21
Q

What problems are caused by a 17-hydroxylase deficiency?

A

Cortisol and sex steroids are deficient. 11-deoxycorticosterone and aldosterone (mineralocorticoids) are in excess. Hypertension, low K, sex steroid deficiency and glucocorticoid deficiency (low glucose) are the main problems.

22
Q

List the clinical features of Cushing’s syndrome?

A 
Too much cortisol
Centripetal obesity
Moon face and buffalo hump
Proximal myopathy
Hypertension and hypokalaemia
Red striae, thin skin and bruising
osteoporosis, diabetes
23
Q

What are 4 causes of Cushing’s syndrome?

A

Taking too many steroids
Pituitary dependent Cushing’s disease
Ectopic ACTH from lung cancer
Adrenal adenoma secreting cortisol

24
Q

What are 3 tests conducted to test cause of Cushing’s syndrome?

A
  1. 24 h urine collection for urinary free cortisol
  2. Blood diurnal cortisol levels
  3. Low dose dexamethasone suppression test
25
Q

Why is blood and urinary cortisol tested?

A

Helps to be sure of high cortisol as diurnal rhythm of cortisol as well as conditions like obesity can cause fluctuations in cortisol levels. Should be highest around 9am in the morning.

26
Q

How does low dose dexamethasone suppression test work?

A

Dexamethasone is a cortisol analogue which should suppress ACTH production by the pituitary through negative feedback. Any cause of Cushing’s will fail to suppress while normals will suppress. 0.5 mg 6 hourly for 48 hrs given.

27
Q

What LDDST results constitute a diagnosis of Cushing’s?

A

Basal (9am) cortisol 800 nM

End of LDDST: 680 nM

28
Q

What 2 drugs are used in the treatment of Cushing’s?

A

As Cushing’s is caused by excess cortisol, metyrapone and ketoconazole are used. These are inhibitors of steroid biosynthesis.

29
Q

What 2 drugs are used in the treatment of Conn’s syndrome?

A

As Conn’s syndrome is caused by excess aldosterone, spironolactone and epleronone are used. These are mineralocoticoid receptor antagonists.

30
Q

What are the actions and mechanisms of action of metyrapone?

A

It is a 11beta-hydroxylase inhibitor and so arrests steroid biosynthesis at the 11-deoxycortisol level in Zona Fasciculata. In Zona Glomerulosa, it prevents conversion of 11-deoxycorticosterone into corticosterone but aldosterone can be made because aldosynthase converts it directly into aldosterone. It has no negative feedback effect on the hypothalamus and pituitary gland.

31
Q

What are the uses of metyrapone?

A
  1. Controls Cushing’s symptoms prior to surgery - oral dose adjusted to achieve a serum cortisol of between 150-300nmol/L. Improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc)
  2. Used to control Cushing’s symptoms after radiotherapy, which is usually slow to take effect.
32
Q

What are some unwanted effects of metyrapone?

A

Deoxycorticosterone accumulates in Zona glomerulosa and as it has aldosterone-like (mineralocorticoid) activity, leads to salt retention and hypertension. Increased adrenal androgen production leads to HIRSUTISM in women.

33
Q

What are the actions and mechanisms of actions of Ketoconazole?

A

Its main use is as an antifungal agent but was withdrawn in 2013 due to risk of hepatotoxicity. At higher concentrations it inhibits steroidogenesis. It acts on 17alpha-hydroxylase and so inhibits cortisol production as pregnenolone cannot be converted into 17-hydroxypregnenolone and progesterone cannot be converted into 17-hydroxyprogesterone.

34
Q

What are the uses of ketoconazole?

A

Similar to metyrapone - controls Cushing’s symptoms prior to surgery and is orally active.

35
Q

What is an unwanted action of ketoconazole?

A

Liver damage - possibly fatal - monitor liver function weekly, clinically and biochemically

36
Q

What are treatments of Cushing’s?

A

If secondary, surgical:
Pituitary surgery (transsphenoidal hypophysectomy)
If primary, surgical:
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass
Medical:
Metyrapone, Ketoconazole

37
Q

What is Conn’s syndrome characterised by?

A

Excess aldosterone usually caused by an adrenal mass called benign adrenal cortical tumour in Zona Glomerulosa. Hypertension and hypokalaemia characterise it.

38
Q

What is the action/mechanisms of action of spironolactone?

A

Used in treatment of primary hyperaldosteronism. It is converted to several active metabolites, including canrenone, a competitive antagonist of the mineralocorticoid receptor (MR). It blocks Blocks Na+ resorption and K+ excretion in the kidney tubules (potassium sparing diuretic).

39
Q

Describe pharmacokinetics of spironolactone

A

Is orally active and metabolised in the liver. Highly protein bound.

40
Q

What are unwanted actions of spironolactone?

A

Menstrual irregularities as activates progesterone receptors and Gynaecomastia due to reduced activity of androgen receptors.

41
Q

What are the actions/mechanisms of action of epleronone?

A

Also a mineralocorticoid receptor (MR) antagonist. Similar affinity to the MR compared to spironolactone. Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated.

42
Q

What are phaeochromocytomas?

A

These are tumours of the adrenal MEDULLA which secrete catecholamines: adrenaline and noradrenaline.

43
Q

What are clinical features of phaeochromocytomas?

A
  1. Hypertension in young people
  2. Episodic severe hypertension (after abdominal palpation)
  3. More common in certain inherited conditions
44
Q

What are consequences of phaeochromocytomas?

A

Severe hypertension can cause myocardial infarction or stroke. High adrenaline can cause ventricular fibrillation + death. Thus this is a medical emergency.

45
Q

How is phaeochromocytoma managed?

A

Patient eventually needs surgery but must be careful as anaesthetic can precipitate a hypertensive crisis.

46
Q

What are the therapeutic steps in management of phaeochromocytomas?

A

First step is alpha blockade and IV fluids may be needed at this stage. Beta blockade added to prevent tachycardia.

47
Q

What are key facts about phaeochromocytomas?

A

10 % are extra-adrenal (sympathetic chain)
10 % are malignant
10 % are bilateral
Phaeos are generally extremely rare.

Endocrinology 2 (11 decks)

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