ENDOCRINOLOGY - ADRENAL Flashcards
What is congenital adrenal hyperplasia?
A group of autosomal recessive metabolic disorders characterised by defects in certain genes which results in a partial or total lack of an enzyme involved in steroids genesis within the adrenal cortex which leads to large adrenal glands. (Low cortisol -> pituitary releases more ACTH -> continuous stimulation of adrenal gland -> adrenal gland hyperplasia)
Whats the most common enzyme deficiency in congenital adrenal hyperplasia?
21 hydroxylase deficiency
Whats the function of 21 hydroxylase?
Catalyses the conversion of progesterone to deoxycorticosterone in the mineralocorticoid synthesis pathway
And conversion of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway
Outline the pathology of 21 hydroxylase deficinecy?
It causes a cortisol and aldosterone deficiency
17 hydroxyprogesterone and 17 hydroxypregnenolone fail to be used in the cortisol pathways, they get shunted in the zona reticularis and will increase the androgen pathway
What symptoms does 21 hydprxylase deficiency cause?
masculization of females, early onset of puberty
vomiting, dehydration and hypotension
hypoglycaemia
Why does 21 hydrxylase deficiency cause masculization of females or early onset puberty?
The andorgen pathway is hyperstimulated
Why does 21 hydrxylase deficiency cause vomiting, dehydration and hypotension ?
Reduced mineralocorticoid pathway = low aldosterone = salt is not retained but instead enters urine = salt wasting
Why does 21 hydrxylase deficiency cause hypoglycaemia?
Reduced cortisol synthesis as glucocorticoid pathway cannot happen
Depleted cortisol increases insulin sensitivity
Other than 21 hydroxylase, what other enzyme deficiencies can cause congenital adrenal hyperplasia?
11 beta hydroxylase
17 alpha hydroxylase
Whats the function of 11 beta hydroxylase?
Converts deoxycorticosterone to corticosterone in the mineralocorticoid pathway
Converts 11 deoxycortisol to cortisol
Outline the pathology of 11 beta hydroxylase deficiency?
Mineralocorticoid and glucocorticoid pathways can’t happen = low aldosterone and low cortisol
17 hydroxypregnenolone and 17 hydroxyprogesterone are used in the androgen pathway instead
Different from 21 hydroxylase deficiency as there is a deoxycorticosterone excess (acts like a weak mineralocorticoid)
How does 11 beta hydroxylase deficiency present?
masculization of females, early onset of puberty
Hypertension
Hypoglycaemia
Why does 11 beta hydroxylase deficiency cause hypertension?
As there’s a build up of deoxycorticosterone which acts as a weak mineralocorticoid = retains salt and fluids
Whats the function of 17 alpha hydroxylase?
Converts pregnenolone and progesterone to 17 hydroxypregnenolone and 17 hydroxyprogesterone respectively
Whats the pathology of 17 alpha hydroxylase deficiency?
Low levels of 17 hydroxypregnenolone and 17 hydroxyprogesterone prevents androgen and glucocorticoid pathways happening = low cortisol and low dihydrotestosterone
This pregnenolone and progesterone are used for the mineralocorticoid pathway which causes raised corticosterone and 11-deoxycorticosterone
(Aldosterone levels may vary depending on RAAS)
How does 17-alpha hydroxylasew deficiency present?
Hypertension
ambiguous genitalia and undescended testes in males. In females it can cause a lack of secondary sex characteristics
Hypoglycaemia
How is congenital adrenal hyperplasia treated?
Exogenous glucocorticoids (hydrocortisone), mineralocorticoids (fludrocortisone), sex steroid replacement, antihypertensives
Atypical genitalia correction therapy
How can virilization in Congenital adrenal hyperplasia-affected girls be prevented?
Prenatal treatment with dexamethasone
Where is aldosterone produced? Whats its function?
Zona glomerulosa
Increase sodium, decrease potassium , increase blood volume
What stimulates aldosterone release?
Angiotensin 2
Outline aldosterone moa?
it stimulates Na+/K+ pumps on principal cells to drive K+ into cells and Na+ out of cells and into the blood
Aldosterone also stimulates the proton ATPase pumps in alpha intercalated pumps which causes more H+ to be excreted into the urine and HCO3- into the extracellular space = increasing pH
What are primary causes of hyperaldosteronism?
Idiopathic adrenal hyperplasia
Conn syndrome - adrenal adenoma
Familial hyperaldosteronism
What is conn syndrome?
Primary hyperaldosteronism
What are secondary causes of hyperaldosteronism?
excessive activation of the renin-angiotensin-aldosterone system (RAAS). This activation can be due to a renin-producing tumor, renal artery stenosis, or edematous disorders like left ventricular heart failure, pregnancy, cor pulmonale, or cirrhosis with ascites.
What electrolyte changes does hyperaldosteronism cause?
Hypokalaemia, hypernatraemia
Metabolic alkalosis
What symptoms does hyperaldosteronism cause?
Headaches flushing - from hypertension
Constipation, weakness, heart rhythm changes - hyperkalaemia symptoms
How do we diagnose hyperaldosteronism?
plasma aldosterone/renin ratio
Primary will show high aldosterone and low renin due to neg feedback
Secondary will show high renin and high aldosterone
high-resolution CT abdomen and adrenal vein sampling is used to differentiate between unilateral and bilateral sources of aldosterone excess
if the CT is normal adrenal venous sampling (AVS) can be used to distinguish between unilateral adenoma and bilateral hyperplasia
How is hyperaldosteronism treated?
If adrenal adenoma -> surgery
If B/L adrenocorticala hyperplasia ->Aldosterone antagonist e.g. spironolactone
Whats the difference between adrenal adenoma and adrenal carcinoma?
Adenomas are benign
Carcinomas are malignant
What is Cushing syndrome?
A disorder where excess cortisol is in the blood - caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids
This has neg feedback so less CRH and ACTH produced which means zona fasciculata gets less stimulation to make cortisol - adrenal glands shrink
What is Cushing disease”
When a pituitary adenoma making excess ACTH
What are the functions of cortisol??
Increase gluconeogenesis, proteolysis and lipolysis in times of stress
Increases sensitivity of peripheral blood vessels to catecholamines
Dampens inflammatory and immune responses by decreasing the production and release of prostaglandins and interleukins and inhibiting T lymphocytes
Influence on mood and memory?
What are the effects of the high cortisol in Cushing syndrome?
Severe muscle, bone and skin breakdown. High blood glucose so high insulin. High insulin activates lipoprotein lipase in adipocyte which causes accumulation of more fat cells. This leads to central obesity
Individual is more susceptible to infections as immune system is dampened
High cortisol amplifies the effects of catecholamines on blood vessels. It also can bind to mineralocorticoid receptors and trigger their effect = both increase bp
Impairs normal brain function
Inhibits GnRH which interferes with normal ovarian and testicular function
What are the causes of Cushing syndrome?
Long term steroid use
Excess production of glucocorticoids e.g. Pituitary adenoma, ectopic production, adrenal adenoma, adrenal carcinoma
Whats the most common cause of ectopic production of ACTH?
Small cell lung cancer
What causes of Cushing syndrome are ACTH dependant? Why?
Cushing disease and ectopic sources of ACTH
Both produce ACTH = stimulates more cortisol production
(Therapeutic corticosteroid use and adrenal tumours are ACTH independent as they don’t rely on ACTH stimulation to produce cortisol)
What are the main symptoms of Cushing syndrome?
Weight gain - full moon face. Buffalo hump, central obesity
Fatigue
Depression
Skin changes e.g. striae and ulcers
Muscle wasting
Thin arms and legs
Easy bruising
Diabetes
Gonadal dysfunction/irregular menses
Osteoporiss
Psychological problems
How do we diagnose Cushing syndrome?
8 mg overnight dexamethasone suppression test is first line
24-hour urinary free cortisol
late-night salivary cortisol
9am and midnight Plasma ACTH levels for localisation
MRI of pituitary, CT of adrenals or site of suspected ectopic site
What are the 2 types of dexamethasone suppression test?
Low dose - helps in the initial diagnosis of Cushing syndrome, as a screening or a confirmatory test
High dose - helps determine the cause
Why is dexamethasone the steroid of choice for evaluating the HPA axis?
Dexamethasone is a potent synthetic corticosteroid with high affinity for the glucocorticoid receptors and long duration of action. It possesses minimal mineralocorticoid activity and unlike other glucocorticoids, it does not interfere with cortisol measurement in the plasma, urine or saliva.
How do you carry out the dexamethasone suppression test?
Give dexamethasone at 10pm at night
Measure cortisol and ACTH at 9am the next morning
What is the low dose dexamethasone suppression test?
Using 1mg dexamethasone
This determines whether the pt has Cushing syndrome
Normally dexamethasone would suppress CRH release and ACTH release = reduction in cortisol
In Cushing syndrome you have high cortisol to begin with so the dexamethasone isnt enough to cause any suppression - body is used to higher levels of glucocorticoids
What is the high dose dexamethasone suppression test?
Using 8mg dexamethasone
This determines the cause of Cushing syndrome
In Cushing disease, this large dose of dexamethasone can suppress the anterior pituitary = reduced cortisol
In adrenal tumours producing cortisol, this dexamethasone will block CRH and CTH but has no effect on adrenal gland = cortisol will remain high and ACTH is low
In ectopic production of ACTH, dexamethasone has no effect on this area = cortisol remains high and ACTH is high
