Adrenocortical Disorders (Rahhal)

Question 1

most cases of endogenous cushing’s syndrome (70%) are caused by a tumor where?

Answer 1

in the pituitary gland, making too much ACTH leading to overproduction of cortisol *15% of the time the tumor is in the adrenal gland and 10% of the time it is ectopic

Question 2

if a patient has high cortisol but low ACTH, where is the tumor?

Answer 2

adrenal gland; it is making cortisol independently of signals from the pituitary

Question 3

What are the 3 screening tests commonly done for Cushing’s syndrome?

Answer 3

1. Urinary free cortisol (UFC) - measure 24 hour excretion
2. Late night salivary cortisol - this is when cortisol should normally be lowest, measured in saliva
3. low dose dexamethosone suppression test (DST) - tests the endogenous cortisol response to steroids - if endogenous cortisol production is not lowered after administration of DST, it means the feedback mechanism isn’t working, ie, an autonomous process like Cushing’s is happening

Question 4

The second step in diagnosing Cushing’s, following a cortisol screening test, is to find out if the ACTH is high or low. What does low ACTH mean?

Answer 4

Low ACTH means that there is a problem with the adrenal gland making too much cortisol

*High ACTH means the problem is at the level of the pituitary gland, telling the adrenal gland to make more cortisol (could also be an ectopic tumor secreting ACTH)

Question 5

How do you determine if ACTH-dependent Cushing’s is pituitary or ectopic?

Answer 5

Give the patient a very high dose of DST (8 mg) - the tumor should be partially responsive at this dose. If the serum cortisol decreases by at least 50%, it is pituitary Cushing’s. If it does not, it is ectopic, because ectopic tumors do not have receptors for cortisol the way that normal ACTH-producing cells of the pituitary do.

Question 6

If surgery is not an option because the patient is too old or too sick, or the cancer is terminal and surgery will not resolve it, what pharmacologic therapy is used for tumors of the pituitary or adrenal gland?

Answer 6

a cortisol receptor blocker (mifepristone) or enzyme inhibitors to block cortical synthesis (metyrapone or ketaconazole)

Question 7

A 41 year old lady presents to your office with 50 pound weight gain in 1 year, new onset diabetes and hypertension. Her blood pressure is 191/98 and she has a BMI of 53.44. You note the presence of hirsutism on the face, thinning of scalp hair, supraclavicular fullness and some posterior dorsal fat deposition. There is acanthosis nigricans and skin tags on the neck (signs of insulin resistance), and her abdomen is obese with violaceous striations.

What screening test would you order?

A. Midnight salivary cortisol

B. 8 mg dexamethasone suppression test

C. Pituitary MRI

D. Abdominal CT

Answer 7

A

Question 8

(Cont…) A 41 year old lady presents to your office with 50 pound weight gain in 1 year, new onset diabetes and hypertension. Her blood pressure is 191/98 and she has a BMI of 53.44. You note the presence of hirsutism on the face, thinning of scalp hair, supraclavicular fullness and some posterior dorsal fat deposition. There is acanthosis nigricans and skin tags on the neck (signs of insulin resistance), and her abdomen is obese with violaceous striations.

Labs reveal the following:

• Midnight salivary cortisol: 0.25 mcg/dl (ref 0.05-0.17)
• 1 mg DST: am serum cortisol 12.6 (ref < 1.8)
• UFC: 143 mcg/24 hours (ref 3.5-45)

What test is next?

A. Pituitary MRI

B. Adrenal CT

C. 8 mg DST

D. ACTH

Answer 8

D. Lab values confirm Cushing’s (too much cortisol) now the next step is to determine whether it is ACTH-dependent or independent. If the ACTH is low, we know the tumor is in the adrenal gland. If it is high, we have to keep looking elsewhere.

Question 9

• (Cont…) A 41 year old lady presents to your office with 50 pound weight gain in 1 year, new onset diabetes and hypertension. Her blood pressure is 191/98 and she has a BMI of 53.44. You note the presence of hirsutism on the face, thinning of scalp hair, supraclavicular fullness and some posterior dorsal fat deposition. There is acanthosis nigricans and skin tags on the neck (signs of insulin resistance), and her abdomen is obese with violaceous striations.*
• Labs reveal the following:*

Midnight salivary cortisol: 0.25 mcg/dl (ref 0.05-0.17)
1 mg DST: am serum cortisol 12.6 (ref < 1.8)
UFC: 143 mcg/24 hours (ref 3.5-45)

ACTH 70 (ref 6-58), elevated, indicating pituitary or ectopic tumor. What test is next?

A. Pituitary MRI

B. Lung CT

C. 8 mg dexamethasone suppression test

D. A and C

Answer 9

C. If this high dose treatment is able to at least partially suppress cortisol production, we know it’s a pituitary adenoma. If not, we know the production of ACTH is happening ectopically where there are no cortisol receptors.

Question 10

the most common cause of hyperaldosteronism is _______

Answer 10

bilateral adrenal hyperplasia (65% of cases); next most common cause is an aldosterone-producing adenoma (30% of cases)

Question 11

if a patient’s hyperaldosteronism is the result of a unilateral disease, the management is surgical - if it is the result of bilateral disease, the management should include what medications?

Answer 11

spironolactone: competes with aldosterone for receptor (MR antagonist)
eplerenone: another aldosterone receptor blocker that is more specific (ie, does not also block ER/PR)
amiloride: indirect MR antagonist that blocks ENaC

Question 12

what is the most common presentation of hyperaldosteronism?

Answer 12

high aldosterone and low renin

Question 13

in the zona fasciculata and zona reticularis, this protein is regulated by ACTH to move cholesterol into the mitochondria

Answer 13

STAR

Question 14

in the zona _____, cholesterol is transported into the mitochondria in an ACTH-independent process

Answer 14

glomerulosa

Question 15

name two causes of secondary adrenal insufficiency

Answer 15

hypopituitarism (ie, from either hypothalamic or pituitary disease)

chronic suppression of the pituitary-adrenal axis (ie, from prolonged corticosteroid therapy)

Question 16

With primary adrenal insufficiency, are the following measurements low, normal, or high?

• Cortisol: _____
• Aldosterone:_____
• ACTH:_____
• Na+:______
• K+:_______

Answer 16

Cortisol: low

Aldosterone: low

ACTH: high

Na+: low

K+: high

With primary adrenal insufficiency, both adrenal glands are gone so we’ve lost cortisol, aldosterone and DHEA (which can be made in ovaries/testicles). Because aldosterone is gone, we’re not able to reabsorb Na+ and dump K+.

*she says this is really important to understand

Question 17

With secondary adrenal insufficiency, are the following measurements low, normal, or high?

• Cortisol: _____
• Aldosterone:_____
• ACTH:_____
• Na+_____
• K+______

Answer 17

Cortisol: low

Aldosterone: normal

ACTH: low

Na+: slightly low

K+: normal

With secondary adrenal insufficiency, cortisol and DHEA or lost but aldosterone is normal because it is being regulated by renin on the side. K+ is fine because aldosterone is fine. Na+ is only slight low because cortisol also has a tonic inhibitory effect on anti-diuretic hormone, so when you lose cortisol, the ADH effect on the kidney becomes potentiated (a little bit has a more potent effect).

*she says this is very important to understand

Question 18

Why is hypoglycemia and eosionphilia seen in both forms of adrenal insufficiency?

Answer 18

Because cortisol normally increases gluconeogenesis and decreases insulin sensitivty. So loss of cortisol increases insulin sensitivity leading to low blood sugar.

Cortisol also normally has an apoptotic effect on eosinophils. So loss of cortisol leads to more eosinophils surviving, resulting in eosinophilia.

Question 19

Are there in general more clinical signs/symptoms associated with primary or secondary adrenal insufficiency?

Answer 19

primary

Question 20

Why is hyperpigmentation associated with primary renal insufficiency?

Answer 20

Because remember - in primary renal insufficiency ACTH is high. This stimulates melanocyte production. Patients with primary renal insufficiency often present with darker skin, espeically in areas of high friction (elbows, knees, women’s bra strap lines, mucous membranes in the mouth, etc).

Question 21

Why is hypotension associated with primary renal insufficiency but not really in secondary?

Answer 21

Because with primary renal insufficiency, you have both low cortisol AND low aldosterone, which means you dump Na+ and water. Because aldosterone is normal in secondary renal insufficiency, you don’t really see this effect - if you do, it’s only slight, and it would be due to loss of tonic effect of cortisol on the vasculature.

Question 22

What happens if you give injectable ACTH to a person with primary renal insufficiency? Secondary renal insufficiency?

Answer 22

primary renal insufficiency: nothing. the adrenal glands are non-functional and cannot make cortisol, even with a boost of ACTH.

secondary renal insufficiency: cortisol levels will rise a little bit, because the adrenal gland is still somewhat functional, but overall levels of cortisol will still be low because the glands are atrophic from lack of production

Question 23

What is the treatment for a person with primary renal insufficiency? Secondary renal insufficiency?

Answer 23

primary renal insufficiency: glucocorticoid AND mineralocorticoid, since the patient makes neither cortisol nor aldosterone

common glucocorticoids: prednisone or hydrocortisone; common mineralocorticoid: fludrocortisone

secondary renal insufficiency: glucocorticoid only. aldosterone levels are normal so they don’t need a mineralocorticoid.

Question 24

A 59-year-old woman with history of craniotomy and brain radiation for a right cavernous meningioma presents with fatigue, orthostatic dizziness, diffuse aches and low appetite. Her menstrual periods stopped after radiation. Her weight has been stable. She has no nausea, vomiting, or abdominal pain.

Physical exam reveals: Pulse 70; BP 118/58; Weight 54.4 k g; BMI 22.64; Mucus membranes moist, no hyperpigmentation; Abdomen soft and nontender.

What is the likely diagnosis?

A. Cushing’s syndrome

B. Primary aldosteronism

C. Primary adrenal insufficiency

D. Secondary adrenal insufficiency

Answer 24

D. Secondary adrenal insufficiency. The patient’s history reveals she had radiation for a cavernous meningioma (next to the pituitary gland) and also that her menses stopped afterwards (indicates lack of LH/FSH production and points to pituitary problem also)

Question 25

• A 59-year-old woman with history of craniotomy and brain radiation for a right cavernous meningioma presents with fatigue, orthostatic dizziness, diffuse aches and low appetite. Her menstrual periods stopped after radiation. Her weight has been stable. She has no nausea, vomiting, or abdominal pain.*
• Physical exam reveals: Pulse 70; BP 118/58; Weight 54.4 k g; BMI 22.64; Mucus membranes moist, no hyperpigmentation; Abdomen soft and nontender.*
• What is the likely diagnosis?* Secondary adrenal insufficiency

What set of lab values would you expect in this person? (Normal ranges - Cortisol: 4.3-22.4, ACTH: 6- 58, Na: 135-145, K: 3.5-5.0)

A. Cortisol 0.3, ACTH 120, Na 130, K 5.5

B. Cortisol 0.3, ACTH 2, Na 130, K 5.5

C. Cortisol 2.3, ACTH 2, Na 132, K 4.2

Answer 25

C

Question 26

condition in which you are born with a missing enzyme in the steroidogenesis pathways

Answer 26

congenital adrenal hyperplasia (CAH)

most common (>90% of cases): 21 hydroxylase deficiency

less common: 11-beta hydroxylase deficiency

Question 27

low cortisol production with increased ACTH, low aldosterone, and elevated androgens are the result of which form of CAH?

Answer 27

21-hydroxylase deficiency

Question 28

what is the difference between classic and non-classic form of CAH?

Answer 28

classic: more severe, presents in infancy, girls have ambiguous genitalia

non-classic: not as severe, presents later in life, normal cortisol and aldosterone, high androgens

she said to pay attention to this!

Question 29

In classical CAH, what is the difference between the classical salt-losing and non salt-losing forms?

Answer 29

classical salt-losing: complete enzyme deficiency, cannot be overcome by ACTH and renin, dehydration/hyponatremia/ hyperkalemia (low aldosterone & cortisol), failure to thrive (low cortisol & aldosterone)

classical non salt-losing: not complete enzyme deficiency, may become, normal cortisol, normal aldosterone, high androgens

she said to pay attention to this!

Question 30

How do females and males generally present with non classical CAH?

Answer 30

Females: hirsutism and menstrual irregularity in adolescence or young adulthood

Males: usually asymptomatic

less commonly both may present with early pubarche or sexual precocity in school age

Question 31

The general picture of this deficiency is low cortisol, elevated DOC, and elevated androgens; children often present with high blood pressure and hypokalemia (because DOC binds to aldosterone receptor and does everything aldosterone does)

Answer 31

CAH with 11-beta hydroxylase deficiency; level of severity depends on whether there is complete or partial blockage of this enzyme, just as in the 21 hydroxylase deficiency

Question 32

this steroid precursor is upstream of both 21 and 11-beta hyrdoxylase, and is what is measured in the newborn screening to determine and enzyme deficiency

Answer 32

17alpha-hydroxyprogesterone (17OHP)

Question 33

If 17alpha-hydroxyprogesterone (17OHP) is too high in a newborn, what is the next precursor that would be measured?

Answer 33

DOC. This will tell us if it is 21 (indicated by low DOC) or 11-beta hydroxylase deficiency (indicated by high DOC)

Question 34

What is the treatment for CAH?

Answer 34

Give them all what’s missing - glucocorticoids to suppress ACTH and replenish cortisol. If it is the salt-losing variety, they would also receive a mineralocorticoid to replenish aldosterone (fludocortisone).

Question 35

Ms Smith is a 27 year old woman who, for the last 3 months has had severe worsening fatigue, nausea, abdominal pain, joint and muscle aches, and a 15 pound unexplained weight loss. On exam, she looks thin and tired. Her mucous membranes are dry with a few dark spots on the inside of her cheeks. Her skin is dark on the elbows, knees and knuckles. Her pulse when sitting is 87 with a blood pressure of 115/72. Standing, her pulse is 115 and her blood pressure is 90/52. Which laboratory abnormalities is Ms Smith most likely to have:

Normal range: (Sodium (Na): 135- 145, potassium (K): normal 3.5-5.0, cortisol: 6.2-19.4 in am and 3.0-11.9 in pm, ACTH: 7-69.)

A. Na 127, K 5.3, cortisol 0.2, ACTH 200

B. Na 127, K 5.3, cortisol 0.2, ACTH 4

C. Na 133, K 3.9, cortisol 1.9, ACTH 4

D. Na 139, K 3.9, cortisol 1.9, ACTH 200

Answer 35

A. This is primary renal insufficiency. You have both low cortisol AND low aldosterone, which means you dump Na+ and water. ACTH is over-produced in an attempt to raise cortisol (stimulate melanocytes too, causing hyperpigmentation).