Adrenal Cortico Hypo- and Hyperfunction

Question 1

What are the general (widespread) symptoms of Cushing syndrome?

Answer 1

Obesity due to hyperphagia and insulin resistance

HTN due to Na retention

Question 2

What are the skin symptoms of Cushing syndrome?

Answer 2

plethora, striae and bruising due to skin thinning

hirsutism and acne due to androgen excess

Question 3

What are the MSK symptoms of Cushing syndrome?

Answer 3

osteopenia due to increased bone resorption

weakness due to catabolic effects of cortisol on muscle

Question 4

What are the gonadol symptoms of Cushing syndrome?

Answer 4

menstrual disorders and impotence, decreased libio due to inhibition of GnRH, LH and FSH

Question 5

What are the pediatric symptoms of Cushing syndrome?

Answer 5

growth retardation due to GH inhibition

Question 6

What are the metabolic symptoms of Cushing syndrome?

Answer 6

diabetes due to insulin resistance (20%)

polyuria (30%) due to suppression of AVP

kidney stones (50%) due to increased calcium, uric acid, and oxalate and decreased citrate

Question 7

One of the first derangements that occurs in Cushing’s syndrome is _________.

Answer 7

failure to achieve a normal late-night circadian nadir. I.e. the cortisol does not come down around midnight like it should

Question 8

How is Cushing’s diagnosed?

Answer 8

measure of the following:

24 hr urine free cortisol

late-night salivary cortisol

1-mg overnight dexamethasone suppression test (cortisol should be less than 1.8 (5) mcg/dL when measured in the morning)

Question 9

There are high false-positive rates for the overnight DST in what pts.?

Answer 9

50% of women taking oral contraceptive pills because of increased cortisol binding globulin (CBG) levels

Question 10

What is a standard two-day 2mg low dexamethasone suppression test?

Answer 10

consists of administering 0.5mg dexa every 6 hrs for 8 doses, and measurement of serum cortisol either 2 or 6 hrs after the last dose. The same criteria for normal suppression (less than 1.8 (5) mcg/dl) used for the 1mg dex test are used

Question 11

Once Cushing Syndrome has been diagnosed, how can Cushing disease be determined as the cause?

Answer 11

First measure plasma ACTH and if its normal or elevated, its abnormal and you have ACTH-dependent Cushing syndrome

Then MRI the pituitary and if its abnormal, the Dx is made

Question 12

Once Cushing Syndrome has been diagnosed, how can ectopic ACTH be determined as the cause?

Answer 12

First measure plasma ACTH and if its normal or elevated, its abnormal and you have ACTH-dependent Cushing syndrome

Then get a pituitary MRI and if normal do a bilateral petrosal sinus sampling for ACTH with CRH administration and if there is no pituitary gradient for ACTH, the diagnosis is ectopic ACTH but if there is, the cause is Cushing disease

Question 13

Once Cushing Syndrome has been diagnosed, how can adrenal source be determined as the cause?

Answer 13

Measure plasma ACTH and it will be low (then get an adrenal CT)

Question 14

How would Cushing’s be treated?

Answer 14

remove either the pituitary or the adrenals

Question 15

What is one lab way to differentiate primary and secondary adrenal insufficiency?

Answer 15

In primary all three hormone lines (cortisol, aldosterone, and andogrens) will be effected while in secondary probably only the cortisol and androgens will be because aldosterone is under other control

Question 16

How is adrenal insufficiency diagnosed?

Answer 16

ACTH stimulation test in which a basline sample for cortisol is drawn, a bolus injection of 250mcg ACTH is given, and cortisol is chest at 30 and 60 min.

Cut off for an adequate peak serum cortisol is 18mcg/dl

Question 17

Describe congential adrenal hyperplasia

Answer 17

AR disorder caused by defects in the cholesterol hormon pathways that is usually discovered at birth and is characterized by a hyperplastic adrenal cortex

NOTE: Nonclassic CAH can manifest in adolescence or even adulthood

Question 18

Defective ______ enzyme (hint: mediates conversion of 17-hydroxyprogesterone to 11-deoxycortisol) accounts for more than 95% of CAH cases

Answer 18

21-hydroxylase (mutation of the CYP21A2 gene)

Question 19

In terms of androgen production, DHEA can be converted to androstenedione (so can 17-hydroxyprogesterone). What happens to androstenedione?

Answer 19

Oxidoreductase converts it to testosterone which is then extra-adrenally converted to dhydrotestosterone (DHT) via 5a-reductase (target of the ‘steride drugs)

Question 20

High (3500+ng/dL) serum levels of what enzyme would be diagnostic of 21-hydroxylase deficiency? How does it present in girls as neonates? Males?

Answer 20

17-hydroxyprogesterone

Girls as neonates present with: ambiguous genitalia, clitoral enlargement, a common urethral-vaginal orifice, and may present with a salt-losing adrenal crisis at 1-2 weeks of age

NOTE: Internal female reproductive organs (uterus and ovaries) are normal

Males present with salt-losing adrenal crises or as toddlers with signs of early puberty but typically dont show signs of CHA< although phallic enlargement and scrotal hyperpigmentation is sometimes present

Question 21

What causes nonclassical CAH?

Answer 21

Same pathophys invovled BUT enzymatic activity is only reduced (20-50%) but sufficient to maintain normal glucocorticoid and mineralcorticoid production, at the expense of excessive androgen production

Salt wasting is absent and affected females do not ambiguous genitalia

Question 22

What symptoms might someone with nonclassical CAH present with?

Answer 22

premature pubarche

acne

accelerate bone age

hirsutism and menstrual irregularities in women

Although most men with the nonclassical form are though to have normal teticular function and fertility, some do present with testicular adrenal rests (benign tumors) and infertility

Question 23

How is NCCAH diagnosed in women?

Answer 23

basal 17-hydroxyprogesterone greater than 200 ng/dl and confirmed with a high-dose ACTH stimulation test (gold standard).

In NCCAH, the response to ATCH is exaggerated, leading to a serum 17-hydroxyprogesterone value exceeding 1500ng/dl

Question 24

What are some common causes of primary aldosteronism?

Answer 24

-bilateral idiopathic hyperaldosteronism (60-70%)

Unilateral aldosterone producing adenomas (30-40%)

familial hyperald types I, II, and III

pur aldosterone-producing adrenocortical carcinomas anc ectopic aldosterone-secreting tumors

Question 25

What is familial hyperald type I?

Answer 25

glucocorticoid-remediable aldosteronism (GRA)

Question 26

What is familial hyperald type III?

Answer 26

germline mutations in the KCNJ5 K+ channel

Question 27

What are the clinical features of hyperaldosteronism?

Answer 27

HTN, hypokalemia, and metabolic alkalosis

mild hypernatremia, hypomagnesemia

muscle weakness and CV risks

Question 28

How is primary hyperald diagnoed?

Answer 28

simultaneously measure morning ald and renin levels. In most pts. with hyperalp, the plasma ald level exceeds 15ng/dl, but the plasma renin activtiy is very low or undetectable

A ratio of plasma ald: plasma renin greater than 30 has a 90% sensitivity and specificity for diagnosis (but a ratio of 20-30 is also highly suggestive, especially when the plasma ald is greater than 15ng/dL)

Question 29

What should you do if you give a PAC/PRA to a pt. with HTN and hypokalemia and PRA AND PAC are elevated and the ratio=~10?

Answer 29

investigate for causes of secondary hyperald such as:
renovascular HTN, diuretic overuse, renin-secreting tumor, malignant HTN, or coarctation of the aorta

Question 30

What should you do if you give a PAC/PRA to a pt. with HTN and hypokalemia and PRA is down, PAC is elevated, the ratio=~20+, and PAC is over 15ng/dL?

Answer 30

suggests primary hyperald

Question 31

What should you do if you give a PAC/PRA to a pt. with HTN and hypokalemia and PRA AND PAC are both decreased?

Answer 31

Investigate for:

Congenital adrenal hyperplasia

exogenous mineralcorticoid use

Cushing syndrome

11B-HSD deficiency

Liddle’s syndrome

Question 32

After the biochemical diagnosis of primary hyperald is confirmed, what is done?

Answer 32

CT of the adrenal gland. It can show either a solitary adrenal adenoma or diffuse bilateral adrenal hyperplasia

Question 33

How is primary hyperald caused by a solitary ald-secreting adenoma treated?

Answer 33

adrenalectomy

Question 34

How is primary hyperald caused by bilateral adrenal hyperplasia treated?

Answer 34

use of a nonselective (spironolactone) or more selective (eplernone) aldosterone blocking agent

Question 35

What causes 17,20 lyase deficiency?

Answer 35

mutation on 10q24.3

Question 36

How does 17,20 lyase deficiency present?

Answer 36

sexual infantilism, HTN, and cortisol deficiency

Question 37

What causes 17a-hydroxylase deficiency and how does it present?

Answer 37

CYP17 mutation causing ambiguous genitalia in males