Adrenal Flashcards
What are the three zones of the adrenal cortex?
zona glomerulosa
zona fasciculata
zona reticularis
What hormones are made by the zona glomerulosa?
salts:
mineralocorticoids
aldosterone
What hormones are made by the zona fasciculata?
sugars
glucocorticoids
cortisol
What hormones are made by the zona reticularis?
sex steroids
progesteroid
androgens
estrogen precursors
What area is in the center of the adrenal gland?
medulla
What hormones are made by the medulla?
catecholamines
What does ACTH actually stimulate within the adrenal gland?
movement of choletserol into mitochondria where the CYP enzymes are located so it can be turned into hormone
What’s the classic triad for pheochromocytoma?
paroxysmal hypertension
headache
generalized sweating
What lab tests should be ordered to confirm a diagnosis of pheochromocytoma?
- 23 hr urine fractionated metanephrines
- 24 hr urine catecholamines
- plasma free fractionated metanephrines
(do just urine metanephrines if pre-test probability is low and all three if high)
What are metanephrines and why are they elevated in pheos?
Pheos are catecholamine-secreting tumors that arise from the adrenal medulla.
NE and Epi are metabolized to normetanephrine and metanephrine intratumorally and will then spill into the plasma and are excreted in excess into the urine
Why is the measurement of urine metanephrines preferred over measurement of plasma or urine catecholamines?
Intratumoral metabolism of the catecholamines occurs continuously and independently of catecholamine release, so the levels of metanephrines in the urine will be consistently elevated
catecholamine levels, on the other hand, will vary significantly as release varies; increasing significantly during paroxysms and then returning to normal in between
True or false: metanephrine levels correlate with pheo tumor size.
true!
Why are urine homovanillic acid (HVA) and vanillylmandelic acid (VMA) measured for the diagnosis of neuroblastoma and not metanephrines, since it is also a catecholamine-secreting tumor?
Neuroblastomas originate from sympathetic ganglion cells have contain MAO, but not COMT. This means they produce norepinephrine and dopamine, but no epinephrine
intratumoral inactivation of the NE and dopamine leads to HVA and VMA, not the metanephrines
Why aren’t HVA and VMA used for the diagnosis or monitoring of pheochromocytoma?
Dopamine-producing pheos are super rare, so HVA isn’t elevated
Pheos have MAO, but much much more COMT, so the VMA level is negligible compared to the VMA from metabolism of sympathetic nerve NE
What enzyme deficiency accounts for over 95% of congenital adrenal hyperplasia cases?
21-hydroxylase deficiency
Describe what happens to the hormone levels in 21-hydroxylase deficiency?
There is decreased to no cortisol production, so you get excessive ACTH
this then stimulates the adrenal cortex, but the precursors are shunted to the androgen biosynthetic pathway leading to the accumulation of progesterone and 17-hydroxyprogesterone
What’s the clinical presentation of 21 hydroxylase deficiency?
prenatal masculinization (ambiguous genitalia) in females and postnatal virilization in both sexes
What are the clinical and laboratory differences in patients with partial or complete 21-hydroxylase deficiency?
Mild form/partial: the increase in ACTH is able to keep cortisol at normal levels and the 17-OHP in excess causes only a mild salt-wasting with up-regulation of aldosterone in response
the Severe form/complete: low/no aldosterone or cortisol with dehydration due to salt wasting
Very high levels of what precursor are diagnostic for 21 hydroxylase def?
17-hydroxyprogesterone
What are the electrolyte abnormalities that can occur in classic congenital adrenal hyperplasia?
hyponatremia
hypochloremia
hyperkalemic acidosis
(due to the aldosterone deficiency - so this only occurs in complete enzyme loss)
What’s considered the gold standard for diagnosing congenital adrenal hyperplasia?
ACTH cosyntropin stimulation test
What is the second most common cause o congenital adrenal hyperplasia and what lab findings would be expected?
11-beta hydroxylase deficiency
elevated 11-deoxycortisol levels
How does 11-beta hydroxylase deficiency differ from 21-beta hydroxylase deficiency clinically?
they both have ambiguous genitalia in females due to androgen excess, but 11-b hydroxylase deficiency also causes hypertension due to 11-deosycortisone’s action as a mineralocorticoid
you also get low renin which may result in HYPOkalemia instead of hyperkalemia
What are the common signs and symptoms of hypercortisolism (Cushing’s syndrome)?
truncal obesity facial plethora glucose intolerance weakness HTN psych changes easy brusing hirsutism oligo or amenorrhea impotence acne/oily skin abdominal striae ankle edema polydipsia/polyuria hyperpigmentation headache
Why do patients with Cushing’s syndrome become hypertensive?
cortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor, but 11 beta hydroxysteroid dehydrgenase type 2 usually inactivates cortisol to prevent its action at the MR
however, with cortisol excess, this enzyme is overwhelmed, so you get activation of the MR with Na retention and HTN
What three tests are recommended options to screen for Cushing’s syndrome?
24-hr urinary cortisol
late night salivary cortisol
overnight low dose dexamethasone suppression test (measure serum cortisol 9 hours later)
What is on the differential diagnosis for Cushing’s syndrome?
Cushing's disease (pituitary adenoma) ectopic ACTH syndrome Ectopic CRH syndrome Adrenal adenoma adrenal carcinoma micronodular hyperplasia macronodular hyperplasia psueo-cushing's syndrome (major depressive disorder or alocoholism)
How is the low-dose dexamethasone test performed and interpreted?
Dex inhibits ACTH production
Low dose (1 mg) is an overnight screening
patients with cushing’s syndrome will generally not suppress cortisol (however, some cases of cushing’s do suppress, so another test must be used to confirm diagnosis)
What is the high dose dex suppression test and what is it used for clinically?
8 mg
used to differentiate Cushing’s disease from Cushing’s syndrome
ACTH secretion in CUshing’s disease is only relatively resistant to dex suppression, so in a pituitary adenoma, it will NOT suppress at low dose, but WILL suppress at high dose
(non-pituitary cancer doesn’t give a shit and will never suppress)
Why is dexamethasone used in the suppression test and not other steroids?
measurement of cortisol is unaffected by dexamethasone, whereas other steroids cross-react with the cortisol assay and would give falsely elevated cortisol results
Once Cushing’s SYNDROME has been confirmed, how do you establish the cause?
Measure the ACTH on 2 separate days (due to episodic nature of secretion)
If ACTH is low, what should be the next step?
If ACTH is low, that means, it’s ACTH-independent Cushing’s syndrome and can’t be pituitary or ACTH-like
next step will be to check an Adrenal CT or mRI to look for an adrenal tumor secreting cortisol
If the ACTH is intermediate, what should the next test be?
a corticotropin releasing hormone stimulation test.
Give the CRH and look to see what the ACTH level does.
If the ACTH does not respond to the CRH stim test, what do you do?
go back down the low ACTH route and check an adrenal CT/MRI
If the ACTH level does go up appropriately in the CRH test, what do you do?
You go down the workup path for an ACTH-dependent Cushing’s syndrome workup
If you decide the patient has an ACTH-dependent cushing’s syndrome, what are your next two diagnostic options?
either the CRH stim and dex supp test
OR go straight to pituitary MRI
If the pituitary MRI reveals a tumor, what is the next step?
an inferior petrosal sinus sampling for ACTH levels
If there is no central step-up of ACTH from the IPPS, what’s the diagnosis?
ectopic ACTH secretion from some other cancer
What are the common signs and symptoms of chronic adrenal insufficiency (Addison’s disease)?
weakness/fatigue anorexia GI symptoms salt craving orthostatic hypotension muscle/joint aches weight loss hyperpigmentation vitiligo auricular calcifications
What lab abnormalities will be seen in addison’s disease?
hyponatremia hyperkalemia hypercalcemia azotemia anemia eosinophilia (interesting)
What findings are helpful for distinguishing primary adrenal insufficiency from secondary or tertiary adrenal insufficiency?
Hyperpigmentation! It’s secondary to the elevated ACTH (increased MSH as a cleavage byproduct - increased melanin synthesis) - will ONLY be seen in primary adrenal insufficiency
mineralocorticoid deficiency only present in primary because aldosterone will be preserved in secondary and tertiary and can be stimulated by the RAS - means you won’t see the hyponatremic hyperkalemic hypotension
What lab tests are used to establish a diagnosis of adrenal insufficiency?
- random 8 am serum cortisol and ACTH
- if abnormal, do an ACTH stim test (measure cortisol at baseline and after IV cosyntropin)
- if abnormal, eval for the underlying cause
How do you go about evaluating for the underlying cause of primary adrenal insufficiency?
- measure anti-adrenal antibodies
- If CAH is suspected, measure adrenal androgens
- Screen for TB, adrenoleukodystrophy, adrenomyeloneuropathy, and adrenal hypoplasia congenita (whatever those are)
