Adrenal

Question 1

What are the three zones of the adrenal cortex?

Answer 1

zona glomerulosa
zona fasciculata
zona reticularis

Question 2

What hormones are made by the zona glomerulosa?

Answer 2

salts:

mineralocorticoids
aldosterone

Question 3

What hormones are made by the zona fasciculata?

Answer 3

sugars

glucocorticoids
cortisol

Question 4

What hormones are made by the zona reticularis?

Answer 4

sex steroids
progesteroid
androgens
estrogen precursors

Question 5

What area is in the center of the adrenal gland?

Answer 5

medulla

Question 6

What hormones are made by the medulla?

Answer 6

catecholamines

Question 7

What does ACTH actually stimulate within the adrenal gland?

Answer 7

movement of choletserol into mitochondria where the CYP enzymes are located so it can be turned into hormone

Question 8

What’s the classic triad for pheochromocytoma?

Answer 8

paroxysmal hypertension
headache
generalized sweating

Question 9

What lab tests should be ordered to confirm a diagnosis of pheochromocytoma?

Answer 9

1. 23 hr urine fractionated metanephrines
2. 24 hr urine catecholamines
3. plasma free fractionated metanephrines

(do just urine metanephrines if pre-test probability is low and all three if high)

Question 10

What are metanephrines and why are they elevated in pheos?

Answer 10

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

Question 11

Why is the measurement of urine metanephrines preferred over measurement of plasma or urine catecholamines?

Answer 11

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

Question 12

True or false: metanephrine levels correlate with pheo tumor size.

Answer 12

true!

Question 13

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?

Answer 13

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

Question 14

Why aren’t HVA and VMA used for the diagnosis or monitoring of pheochromocytoma?

Answer 14

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

Question 15

What enzyme deficiency accounts for over 95% of congenital adrenal hyperplasia cases?

Answer 15

21-hydroxylase deficiency

Question 16

Describe what happens to the hormone levels in 21-hydroxylase deficiency?

Answer 16

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

Question 17

What’s the clinical presentation of 21 hydroxylase deficiency?

Answer 17

prenatal masculinization (ambiguous genitalia) in females and postnatal virilization in both sexes

Question 18

What are the clinical and laboratory differences in patients with partial or complete 21-hydroxylase deficiency?

Answer 18

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

Question 19

Very high levels of what precursor are diagnostic for 21 hydroxylase def?

Answer 19

17-hydroxyprogesterone

Question 20

What are the electrolyte abnormalities that can occur in classic congenital adrenal hyperplasia?

Answer 20

hyponatremia
hypochloremia
hyperkalemic acidosis

(due to the aldosterone deficiency - so this only occurs in complete enzyme loss)

Question 21

What’s considered the gold standard for diagnosing congenital adrenal hyperplasia?

Answer 21

ACTH cosyntropin stimulation test

Question 22

What is the second most common cause o congenital adrenal hyperplasia and what lab findings would be expected?

Answer 22

11-beta hydroxylase deficiency

elevated 11-deoxycortisol levels

Question 23

How does 11-beta hydroxylase deficiency differ from 21-beta hydroxylase deficiency clinically?

Answer 23

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

Question 24

What are the common signs and symptoms of hypercortisolism (Cushing’s syndrome)?

Answer 24

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

Question 25

Why do patients with Cushing's syndrome become hypertensive?

Answer 25

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

Question 26

What three tests are recommended options to screen for Cushing's syndrome?

Answer 26

24-hr urinary cortisol late night salivary cortisol overnight low dose dexamethasone suppression test (measure serum cortisol 9 hours later)

Question 27

What is on the differential diagnosis for Cushing's syndrome?

Answer 27

``` 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) ```

Question 28

How is the low-dose dexamethasone test performed and interpreted?

Answer 28

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)

Question 29

What is the high dose dex suppression test and what is it used for clinically?

Answer 29

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)

Question 30

Why is dexamethasone used in the suppression test and not other steroids?

Answer 30

measurement of cortisol is unaffected by dexamethasone, whereas other steroids cross-react with the cortisol assay and would give falsely elevated cortisol results

Question 31

Once Cushing's SYNDROME has been confirmed, how do you establish the cause?

Answer 31

Measure the ACTH on 2 separate days (due to episodic nature of secretion)

Question 32

If ACTH is low, what should be the next step?

Answer 32

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

Question 33

If the ACTH is intermediate, what should the next test be?

Answer 33

a corticotropin releasing hormone stimulation test. Give the CRH and look to see what the ACTH level does.

Question 34

If the ACTH does not respond to the CRH stim test, what do you do?

Answer 34

go back down the low ACTH route and check an adrenal CT/MRI

Question 35

If the ACTH level does go up appropriately in the CRH test, what do you do?

Answer 35

You go down the workup path for an ACTH-dependent Cushing's syndrome workup

Question 36

If you decide the patient has an ACTH-dependent cushing's syndrome, what are your next two diagnostic options?

Answer 36

either the CRH stim and dex supp test OR go straight to pituitary MRI

Question 37

If the pituitary MRI reveals a tumor, what is the next step?

Answer 37

an inferior petrosal sinus sampling for ACTH levels

Question 38

If there is no central step-up of ACTH from the IPPS, what's the diagnosis?

Answer 38

ectopic ACTH secretion from some other cancer

Question 39

What are the common signs and symptoms of chronic adrenal insufficiency (Addison's disease)?

Answer 39

``` weakness/fatigue anorexia GI symptoms salt craving orthostatic hypotension muscle/joint aches weight loss hyperpigmentation vitiligo auricular calcifications ```

Question 40

What lab abnormalities will be seen in addison's disease?

Answer 40

``` hyponatremia hyperkalemia hypercalcemia azotemia anemia eosinophilia (interesting) ```

Question 41

What findings are helpful for distinguishing primary adrenal insufficiency from secondary or tertiary adrenal insufficiency?

Answer 41

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

Question 42

What lab tests are used to establish a diagnosis of adrenal insufficiency?

Answer 42

1. random 8 am serum cortisol and ACTH 2. if abnormal, do an ACTH stim test (measure cortisol at baseline and after IV cosyntropin) 3. if abnormal, eval for the underlying cause

Question 43

How do you go about evaluating for the underlying cause of primary adrenal insufficiency?

Answer 43

1. measure anti-adrenal antibodies 2. If CAH is suspected, measure adrenal androgens 3. Screen for TB, adrenoleukodystrophy, adrenomyeloneuropathy, and adrenal hypoplasia congenita (whatever those are)