clinical aspects of the adrenal gland Flashcards
what are the different zones of the cortex of the suprarenal gland?
zona glomerulosa, zona fasciculata, zona reticularis
describe zona glomerulosa
- makes mineralocorticoids eg. aldosterone
- outer most layer — under capsule
- nests of cells
describe zone fasciculata
- makes glucocorticoids eg. cortisol
- middle layer
- columns of cells
describe zona reticualris
- bottom layer
- makes sex-steroid precursors
- net-like cells
what is used to form all of the adrenal cortex hormones?
cholesterol
the early action of what enzyme in the zona glomerulosa steers away from sex steroid precursors to aldosterone or cortisol?
HSD3B2 enzyme (3B-hydroxysteroid dehydrogenase)
what enzyme does the zona fasciculata contain for the production of cortisol?
CYP11B2 enzyme (11B-hydroxylase)
what enzyme does the zona reticularis contain for the production of sex steroid precursors such as androstenedione?
CYP17A1
what does the hypothalamus release in the HPA axis and what does it work on?
releases corticotropin-releasing hormone (CRH) — acts on corticosteroids in the anterior pituitary gland
what does the anterior pituitary release in the HPA axis? what does it act on?
ACTH = adrenocorticotropic hormone — acts on adrenal cortex to stimulate cortisol production
what breaks down cortisol in the peripheral tissues? what is it broken down into?
broken down by HSD11B2 to cortisone
what converts cortisone to cortisol in peripheral tissues?
HSD11B1
what is Conn syndrome?
overproduction of mineralocorticoids from zona glomerulosa
what is Cushing syndrome?
overproduction of glucocorticoids in zona fasciculata
what can cause excess sexy steroid precursors (+/- cortisol)?
tumour in zona reticularis
describe primary underproduction in the adrenal cortex
- the entire cortex is affected — all zones destroyed
- Addison disease (autoimmunity), TB/HIV
describe secondary underproduction in the adrenal cortex
hypopituitarism, loss of ACTH (ie. aldosterone secretion preserved)
what is congenital adrenal hyperplasia most commonly due to?
mutation in enzyme 21-hydroxylase —> decreased cortisol production
what is cushing syndrome?
excessive, inappropriate endogenous cortisol secretion characterised clinically and biochemically by:
- features of glucocorticoid excess
- loss of circadian rhythm to cortisol secretion
- disruption of -ve feedback loop
what are signs and symptoms of Cushing syndrome?
how does cortisol increase blood glucose levels? other effects?
- promotes gluconeogenesis
- raises hepatic glucose output
- inhibits glucose uptake by muscle and fat
other effects:
- lipolysis from adipose tissue
- protein catabolism to release amino acids
wha is acanthosis nigricans?
- part of insulin resistance
- cortisol increases blood sugar and insulin resistance
- skin condition that causes dark discolouration in body folds and creases
- typically affects armpits, groin and neck
- main way to diagnose glucocorticoid excess?
identify loss of circadian rhythm
- can’t just measure random cortisol
- measure bedtime/midnight serum or salivary cortisol levels
- diagnosing glucocorticoid excess: measure 24 hour urinary free ______
cortisol
what can you do to aid diagnosis of glucocorticoid excess if overactivity is suspected?
try to suppress it: low dose dexamethasone (a corticosteroid) suppression test
- measure cortisol after low dose of dexamethasone
- 1mg overnight or 0.5 mg QID for 8 doses
- following 9am cortisol should be suppressed (by -ve feedback) — less than 50nmol/L
- if not suppressed — glucocorticoid excess
what needs to be excluded as part of the diagnosis of glucocorticoid excess?
exclude pseudo-cushing syndrome
- clinical features of Cushing syndrome, which disappears when the underlying cause is resolved
- common causes alcohol, depression
cushing syndrome vs cushing disease
Cushing syndrome encompasses all causes of glucocorticoid excess, whereas Cushing disease is reserved only for pituitary-dependent Cushing syndrome
cushing disease - occurs when cushing syndrome is caused by an ACTH-producing pituitary tumour
ectopic ACTH production causing cushing syndrome most often occurs in what?
tissue other than the pituitary gland secretes ACTH
—> small cell lung cancer
after low dose dexamethasone suppression test to diagnose cushing syndrome, what is then checked?
need to determine the exact cause of endogenous cortisol production — check ACTH
low vs high ACTH levels
low ACTH — seen in adrenal adenoma and carcinomas due to negative feedback
high ACTH — seen in Cushing disease and ectopic ACTH production
if high ACTH levels are identified, what is te next step?
perform a high-dose dexamethasone suppression test
- unlike pituitary adenomas, ectopic ACTH production typically doesn’t dampen even with high disease, so blood cortisol remains high
what causes 68% of cushing syndrome?
a corticotroph tumour — cushing disease — increased ACTH levels
what causes 15% of cushing syndrome?
ectopic ACTH-secreting tumour eg. SCC of lungs
what causes 17% of cushing syndrome?
adrenocortical tumour
what test is used to diagnose Cushing SYNDROME?
low-dose dexamethasone suppression test
what test localises cushing syndrome (but is not used as much these days)?
high-dose dexamethasone suppression test
high dose dexamethasone suppression test results:
> 50% suppression of following 9am cortisol
<50% suppression of following 9am cortisol
more than 50% suppression = corticotroph tumour
less than 50% suppression = ectopic ACTH
describe inferior petrosal sinus sampling
Inferior petrosal sinus sampling (IPSS) is an invasive procedure in which adrenocorticotropic hormone (ACTH) levels are sampled from the veins that drain the pituitary gland; these levels are then compared with the ACTH levels in the peripheral blood
eg. higher ACTH levels in left inferior petrosal sinus — indicates adenoma on LHS
cortisol levels fall with high dose dexamethasone for _______ disease
pituitary-dependent
what is used more these days instead of high dose dexamethasone suppression test?
inferior petrosal sinus sampling
what is the life expectancy for Cushing syndrome left untreated?
<5 years (due to metabolic disturbances)
what is 1st line treatment for Cushing disease?
trans-sphenoidal hypophysectomy +/- radiotherapy
- 20-50% may not be permanently cured
- may require bilateral adrenalectomy
what is used in the run up to surgery to treat cushing disease or if not fit for surgery?
medical treatment — block production of cortisol (metyrapone…… ketoconazole, mitotane)
treatment of ectopic ACTH
usually palliative (lung cancer itself is terminal), surgery, DXT/chemotherapy
how are adrenal tumours treated?
adrenalectomy
what can excess cortisol from an adrenocortical carcinoma also cause?
increased sex precursors:
more testosterone —> females: voice change. clitoromegaly, PCOS-like symptoms
more oestradiol —> men: gynaecomastia
what are primary causes of hypoadrenalism?
in the developed world, the most common cause is autoimmunity
- tuberculosis, AIDS
- ADDISON DISEASE/AUTOIMMUNE (T1DM, thyroid disease, pernicious anaemia, vitiligo)
- metastatic tumour
- lymphoma
- intra-adrenal haemorrhage or infarction
- bilateral adrenalectomy
describe secondary hypoadrenalism
- comes from pituitary insufficiency
- normal aldosterone levels but deficient in cortisol as don’t have any ACTH coming from pituitary gland
vs primary = lack of cortisol AND aldosterone
clinical features of hypoadrenalism
why are patients with hypoadrenalism very commonly hyperkalaemic?
due to the effect of aldosterone on K+ levels
glycemic levels in hypoadrenalsim?
LOW because cortisol tends to raise blood sugar
why can pigmentation be seen in hypoadrenalism?
lack of cortisol —> increased ACTH due to loss of -ve feedback —> increaed ACTH precursor = proopiomelanocortin (POMNC) — also gives rise to melanocyte stimulating hormone —> PIGMENTATION
how is hypoadrenalism diagnosed?
- if under-activity, try to stimulate it
- short synacthen test — give ACTH iv/im and measure cortisol 30 mins later. if less than 400 nmol/L, it is inadequate
how is hypoadrenalism treated?
treat with hydrocortisone lifelong (cortisol)
- 10 mg on waking, 5mg mid-afternoon — attempt to restore circadian rhythms
- double in significant illness such as flu — otherwise would lead to an adrenocortical crisis due to a lack of cortisol
- steroid alert bracelet/steroids card
- may need mineralocorticoid replacement — fludrocortisone (aldosterone in synthetic form) to sustain BP/K+ levels
when would mineralocorticoid replacement not be needed in hypoadrenalism treatment?
if it is secondary (ie. pituitary gland is the problem)
what is the definition of endocrine hypertension?
hypertension caused by demonstratable hormone excess, which is cured upon normalising circulating levels (or action) of the hormone
what is a classical presentation of Conn syndrome?
very high BP and hypokalaemic
patients with endocrine hypertension tend to be younger, therefore what causes of non-endocrine hypertension in younger patients should be remembered?
- renal artery stenosis
- coarction of the aorta
what hormones are involved in regulating BP, and all in excess can elevate it?
- angiotensin II
- aldosterone
- cortisol
- adrenaline and noradrenaline
- calcium/PTH
- growth hormone
what is the body’s main mineralocorticoid?
aldosterone
what does aldosterone do?
- promotes Na+ resorption from the urine and K+ excretion — resorts Na+ and therefore water, K+ excreted in exchange
- it increases BP
what is aldosterone biosynthesis regulated primarily by?
- renin-angiotensin system (forming a -ve feedback loop)
- serum K+ concentration
what zone secretes mineralocorticoids?
zona glomerulosa
how does a decreased ECF volume result in aldosterone release and therefore increase ECF volume?
low BP and filtration in kidney activates juxtaglomerular cells —> renin released whcih cnverst angiotensinogen to angiotensin I —> ACE converts angiotensin I to II —> angiotensin II acts on the adrenal cortex to stimulate aldosterone release
aldosterone increases Na and water resorption, therefore increasing ECF volume and hence BP
what is responsible for Na resorption in the DCT?
Na/K ATPase —therefore K+ is excreted here
what else acts on the adrenal cortex ?
K+ and adenocorticotrophin
hypokalaemia vs hyperkalaemia effects on aldosterone
hypokalaemia —> more aldosterone
hyperkalaemia —> less aldosterone
what is spironolactone?
a potassium sparing diuretic like eplerenone that competitively inhibits mineralocorticoid receptors in the distal convoluted tubule to promote sodium and water excretion and potassium retention
people with Addison’s disease have a ___ BP and appear ___
- low
- dehydrated
addison’s disease = autoimmune, causes hypoadrenalsim
conn vs cushing syndrome
conn = mineralocorticoid excess (glomerulosa)
cushing = glucocorticoid excess (fasciculata)
summarise conn syndrome
primary hyperaldosteronism
- causes hypertension
- peak incidence 30-50 years of age
- female: male = 2:1
- symptoms few — high index of suspicion
- hypokalaemia, weakness, lethargy
- headaches dye to hypertension
what are some causes of hypokalaemia?
(apart from hyperadrenalism - conn syndrome - aldosterone excess)
- vomiting (metabolic alkalosis)
- diarrhoea or other fluid loss from the lower bowel (eg. ileostomy, villous adenoma of the rectum)
- insulin therapy
- diuretic use
- rare causes include renal tubular acidosis and Bartter syndrome
what is Bartter syndrome?
Bartter syndrome is a renal tubular salt-wasting disorder in which the kidneys cannot reabsorb sodium and chloride in the thick ascending limb of the loop of Henle. This leads to increased distal delivery of salt and excessive salt and water loss from the body
young person with severe hypertension, high Na+, low K+:
what are you thinking? treatment?
inappropriate aldosterone secretion
- ensure adequate salt intake, replace K+ into normal range
- stop other anti-hypertensives (esp diuretics and beta blockers)
aldosterone acts on the mineralocorticoid receptor in the what?
DCT
what will also bind to the mineralocorticoid receptor and circulates in much higher concentrations?
cortisol
what is the classical triad of symptoms in paheochromocytoma?
hypertension, throbbing bilateral headaches, palpitations
describe phaeochromocytoma
Pheochromocytoma is a type of neuroendocrine tumor that grows from cells called chromaffin cells. These cells produce hormones needed for the body and are found in the adrenal glands. The adrenal glands are small organs located in the upper region of the abdomen on top of the kidneys. About 80-85% of pheochromocytomas grow in the inner layer of the adrenal gland, called the adrenal medulla. About 15-20% of pheochromocytomas grow outside of this area and are called extra-adrenal pheochromocytomas or paragangliomas.
Most pheochromocytomas are benign, which means they are not cancer and do not spread to other parts of the body. Only about 10% of pheochromocytomas spread to other parts of the body.
what are different endocrine neoplasia syndromes?
- paraganglioma/phaechromocytoma syndromes (due to mutations in genes, eg. in su insane dehydrogenase complex)
- MEN2 (type a: thyroid medullary carcinoma, phaeochromocytoma) (type B: as above plus mucosal neuromas)
- Von Hippel Lindau syndrome
- neurofibromatosis
