Adrenal Disorders Flashcards
What 3 stimuli cause aldosterone production?
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.
How is aldosterone synthesis inhibited?
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.
How does aldosterone travel and act?
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.
What is the overall effect of angiotensin 2 on the adrenal cortex?
Activation of: Side Chain Cleavage 3 Hydroxysteroid dehydrogenase 21 hydroxylase 11 hydroxylase 18 hydroxylase
What is the effect of ACTH on the adrenal gland?
Activation of the following enzymes Side Chain Cleavage 3 Hydroxysteroid dehydrogenase 21 hydroxylase 11 hydroxylase 17 hydroxylase
What is Addison’s disease?
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.
What are the skin and GI symptoms of Addison’s?
Skin - hyperpigmentation and potential vitiligo
GI - Nausea, diarrhoea, vomiting, constipation, abdominal pain
General - weakness, weight loss, low BP
What are the symptoms of an adrenal crisis?
Fever, syncope, convulsions, hypoglycaemia, hyponatremia, severe vomiting and diarrhoea
What are 2 causes of adrenocortical failure?
- Enzymes in the steroid synthetic pathway not working
2. Adrenal glands are destroyed
What 3 conditions cause adrenocortical failure?
- Tuberculous Addison’s disease
- Common Addison’s disease
- Congenital adrenal hyperplasia
What are the 5 main consequences of adrenocortical failure?
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
What 2 tests are done to check for Addison’s?
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.
What replacement of aldosterone is provided?
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.
What is the problem with oral hydrocortisone?
Oral hydrocortisone has a short half life: too short for once daily administration and creates harmful late peaks.
What is used instead of oral hydrocortisone?
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.
What dose of prednisolone is available?
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.
What causes congenital adrenal hyperplasia?
A deficiency of 21-hydroxylase which can be complete or partial. This interferes with aldosterone and cortisol production.
What are the consequences of a complete 21-hydroxylase absence?
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.