Adrenal Insufficiency and Cushings

Question 1

Adrenal Gland lie in the_______ above or medial to the upper pole of the kidneys. The adrenal cortex differentiates into three adult zones: glomerulosa (______) and fasciculata/reticularis (_____and_____)

Answer 1

retroperitoneum

aldosterone

cortisol and androgens

Question 2

The adrenal_____ is richly vascularized receiving its main arterial supply from branches of the inferior phrenic artery, the renal arteries and the aorta.

Answer 2

cortex

Question 3

What is the difference beteween the drainage of right and left adrenal glands?

Answer 3

The right adrenal vein drains directly into the posterior aspect of the vena cava and the left adrenal vein enters the left renal vein.

Question 4

What could cause bilateral adrenal hemorrhage?

Answer 4

a coagulopathy resulting in bilateral adrenal vein thrombosis.

Question 5

Steroid production from the zona fasciculata and reticularis is controlled by the pituitary hormone_____ whose secretion is regulated by the hypothalamus and central nervous system via neurotransmitters and ________ and by negative feedback.

Answer 5

ACTH

corticotroph-releasing hormone [CRH and arginine vasopressin (AVP)]

Question 6

CRH stimulates ACTH in a

Answer 6

pulsatile manner. Diurnal rhythm causes a peak before awakening and a decline as the day progresses.

Question 7

Pathologic conditions such as Cushing’s disease (an ACTH-secreting pituitary tumor) are manifested by deregulated______ secretion since the set point for negative feedback on______ is increased

Answer 7

cortisol

ACTH

Question 8

Adrenocorticotropin or ACTH is a 39 amino acid peptide hormonewhich is processed from a large precursor molecule, _________within the ACTH-secreting cells in the pituitary gland corticotroph.

Answer 8

pro-opiomelanocortin (POMC)

Question 9

The cortisol synthetic pathway requires ACTH-stimulated cholesterol import into the mitochondrion, a process initiated by the action of the __________which shuttles cholesterol from the outer to the inner mitochondrial membrane.

Answer 9

steroidogenic acute regulatory (StAR) protein,

Question 10

The majority of steroidogenic enzymes are cytochrome P450 (CYP) enzymes, which are either located in the________ (side chain cleavage enzyme, CYP11A1; 11-hydroxylase, CYP11B1; aldosterone synthase, CYP11B2) or in the_________ (17- hydroxylase, CYP17A1; 21-hydroxylase, CYP21A2)

Answer 10

mitochondrion

endoplasmic reticulum membrane

Question 11

The cholesterol side chain cleavage enzyme CYP11A1 (P450scc) generates

Answer 11

pregnenolone

Question 12

Glucocorticoid synthesis requires conversion of pregnenolone to progesterone by what enzyme

Answer 12

3-beta-hydroxysteroid dehydrogenase (3-βHSD2)

Question 13

Cortisol binds to plasma proteins on entering the circulation. At physiological concentrations, cortisol circulates in the plasma bound mainly to _______, and to a much lesser extent to albumin.

Answer 13

corticosteroid-binding globulin (CBG

Question 14

The measurement of this free cortisol can be done in

Answer 14

saliva and is independent of salivary flow rates.

used clinical application for the assessment of the hypothalamic-pituitary-adrenal axis particularly in states of suspected hypercortisolism.

Question 15

Cortisol is metabolized to biologically inert steroid cortisone by the enzyme_______ in the kidney to protect the mineralcorticoid receptor as cortisol has same affinity for that receptor as aldosterone

Answer 15

11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2).

Question 16

prodigious increases in cortisol secretion may overwhelm the intrarenal metabolism of cortisol in the kidney causing significant mineralocorticoid effects such as

Answer 16

hypertension and hypokalemia

seen in pts with Cushings

Question 17

how does the liver handle cortisone?

Answer 17

uses 11B-HSD1 takes it to cortisol

Question 18

What are the two mechanisms of action of cortisol?

Answer 18

GR Transrepression (depresses genes that work in inflammation)

GR Transactivation

Question 19

Utilization of a glucocorticoid receptor antagonist,________, has emerged as an effective therapy for the treatment of endogenous hypercortisolism

Answer 19

mifepristone

Question 20

The progesterone compound,____________ may be used to actually stimulate appetite in cancer patients and has been shown to cause suppression of ACTH and cortisol

Answer 20

megestrol acetate,

Question 21

What are the main targets and actions of clucocorticoids and consequences of hypercortisolism and hypocortisolism

Answer 21

Intermediary metabolism, calcium homeostais, other endocrine systmes, immune system, skin and CT, CV system, Na+, K+ and ECF volume and pysch

Question 22

Inadequate production of cortisol from the adrenal cortex may be caused by either a disease process in the adrenal gland :_________or due to diseases of the pituitary gland :__________ or hypothalamus __________

Answer 22

(primary adrenal insufficiency)

(secondary adrenal insufficiency)

(tertiary adrenal insufficiency)

Question 23

Secondary and tertiary cortisol deficiency are clinically and biochemically similar:____ cortisol and _________ACTH levels

(remember in states of hypocortisolism, ACTH levels should increase).

Answer 23

low

low or inappropriately normal

Question 24

Primary adrenal insufficiency differs clinically since_______ is also absent (hypotension is more common and hyperkalemia may be present).

Answer 24

aldosterone

Question 25

Plasma_____ levels are always elevated in untreated primary adrenal insufficiency.

Answer 25

ACTH

Question 26

Signs and symptoms of Adrenal Insufficiency

Answer 26

Signs and Symptoms Fatigue, malaise, lack of energy GI: nausea, vomiting, anorexiaÆwt loss HypotensionÆdizziness, orthostasis Increased skin pigmentation, salt craving (primary)

Question 27

Key lab abnormalities in adrenal insufficiency

Answer 27

Hyponatremia

Hyperkalemia (primary)

Hypercalcemia,

hypoglycemia (rare in adults)

Lymphocytosis

Question 28

What do we call it when ther is something intrinsically wrong with the adnreal gland and have elevated ACTH and CRH to activate but no Aldosterone

Answer 28

Primary adnreal insufficiency

Question 29

What are some causes of seconeary adrenal insufficiency?

Answer 29

pituitary tumor/infection/hemmorhage

decrease ACTH thus decrease in cortisol and aldosterone will be normal

ACTH has permissive and not big effect on aldosterone production in this case

Question 30

Imaging abnormality seen with adrenal insufficiency

Answer 30

Bilateral adrenal enlargement

Pituitary mass

Question 31

These drugs cause adnreal insufficiency

Adrenostatic/lytic:

Glucocorticoid receptor antagonist:

Answer 31

ketoconazole, etomidate, mitotane

mifepristone

Question 32

What concurrent Medical Problems do we see with adnreal insufficiency

Answer 32

Severe critical illness w/ hypotension, Pituitary disease, Traumatic brain injury, Brain radiation

Question 33

Genetic causes of Adrenal insufficiency

Answer 33

Congenital Adrenal Hyperplasia

Adrenoleukodystrophy (X-linked disorder w/accumulation of very long chain fatty acids in adrenal glands and the brain)

Question 34

Patient comes in with recent unintientional weight loss, posterula hypotension and HYPOnatremia, what screening do you order?

Answer 34

Get plasma cortisol level, suspicious for adrenal insufficiency

Question 35

What test can you order if you suspect adrenal insufficiency?

Answer 35

plasma cortisol or

Cosyntropin stimulation test; evals maximum adrenocortical secreatory capacity and tests for adrenal destruction or adrenal atrophy

Question 36

You can confirmed your patient has low cortisol levels, what is the next step?

Answer 36

Get pts ACTH, plasma renin and serum aldosterone levels to find out if it’s primary (elevated ACTH) or 2/3

Question 37

Your pt has low cortisol levles and high ACTH levels = Primary adrenal insufficiency, what is the next step?

Answer 37

Provide pt with Glucocorticoid AND mineralcorticoid replacement and get Adrenal Autoantibody test

Question 38

Pt tests positive for adrenal autoantibodies in what type of adrenal disease?

Answer 38

primary adrenal insufficiency

d/t autoimmune adrenaliatis–> you can still have this even if autoantibodies come back negative

Question 39

Your pt has primary adrenal insufficiency, you order autoimmune antibodies and test comes bck negative, what’s the next step?

Answer 39

Get a chest xray (+ means infiltration, infection, hemorrhage, hyperplasia)

If - can gets for long chain fatty acids for VLCFA which may be high in men with adrenoleukodystrophy

Question 40

What do we see for serum levels of cortisol, ACTH and remin in secondary adrenal insufficiency?

Answer 40

see low cortisol

low or no elevated ACTH

Question 41

What tx do you offer for patients with secondary adrenal insufficiency?

Answer 41

Glucocorticoids ONLY

Question 42

You have a pt with secondary adrenal insufficiency, what test do you need to order?

Answer 42

MRI of the pituitiary

look for hypothalamic pituitary mass

Question 43

Pt has secondary adrenal insufficiency but pituitary MRI is negative, what else could cuase this problem?

Answer 43

history of exogenous glucocorticoid tx

head trauma

isolated ACTH deficiency

Question 44

Critically or chronically ill patients may have low binding proteins (i.e., CBG), and the total cortisol concentration may be low and the “free” or biologically active cortisol may actually be normal thus how do we assess free cortisol levels?

Answer 44

Assessment of “free” cortisol can be done in saliva, plasma, or by formula calculation if the concentration of CBG is known.

Question 45

patients receiving medications (such as estrogen—e.g., oral contraceptives) will have a significant increase in_____levels that reflect an increase in CBG rather than any alteration of adrenal function.

Answer 45

total cortisol

Question 46

Measurement of __________ is sensitive marker of adrenal reserve: a normal level is very unusual in patients with any type of adrenal insufficiency

Answer 46

adrenal androgen production (i.e., DHEAS)

Question 47

Plasma ACTH is always _____ in pts with primary adrenal insufficiency and may be ______ in pts with secondary adrenal insufficiency

Answer 47

Increased! (loss of neg feedback)

low or normal (innappropriately NOT increased)

Question 48

If the peak cortisol response to ACTH is _____ or the basal morning cortisol is _____ a plasma ACTH measurement should be performed to distinguish primary from secondary adrenal insufficiency.

Answer 48

< 18 µg/dL

<5 µg/dL,

Question 49

Causes of primary adrenal insufficiency

Answer 49

Autoimmune: Autoimmune polyglandular syndromes

Malignancy :Metastatic (lung, breast, melanoma, GI) or primary adrenal lymphoma

Adrenal Hemorrhage: (bilateral) Associated with coagulopathies (anticoagulation therapy, antiphospholipid syndrome, heparin-induced thrombocytopenia) and usually due to bilateral adrenal vein thrombosis

Infectious :Tuberculosis, fungi (histoplasmosis, coccidiomycosis), HIV

Genetic: Congenital Adrenal Hyperplasia Familial glucocorticoid deficiency Adrenoleukodystrophy

Infiltrative Disorders: Amyloidosis, hemochromatosis

Drugs: Ketoconazole, metyrapone, mitotane, etomidate

Question 50

Causes of SEcondary Adrenal insufficiency

Answer 50

** (Withdrawal from) exogenous corticosteroid therapy**: dose/duration dependent, but variable from patient to patient

Pituitary/Hypothalamic Disease Especially hypophysitis [autoimmune, granulomatosis, drug-induced (ipilimumab)] may cause isolated ACTH deficiency

Question 51

What two drugs can we give for pts with adrenal insufficiency and how are they different?

Answer 51

Hydrocortisone: give 10-15mg in AM and 5-10 in the afternoon and monitor plasma ACTH, wellbeing

while

Fludrocortisone is 50-100mcg daily

*monitory electrolyte compostion and plasma renin

Question 52

What is important for pts on hydrocorisone for adnreal insufficiency when they are sick?

Answer 52

Sick day management: 3 x 3 Æ triple the dose for three days or until illness resolves

Question 53

What tx do we give for secondary adrenal insufficiency?

Answer 53

Hydrocortisone 7.5-15 mg daily in divided doses. Lower doses needed than in primary adrenal insufficiency (there is usually still some cortisol secretion from the adrenals) Mineralocorticoid replacement NOT needed

Question 54

What do pts with primary and secondary adrenal insufficiency on medication need to do for surgery?

Answer 54

Correct electrolytes, blood pressure, hydration if necessary Give hydrocortisone 100 mg IM or IV on call to OR Hydrocortisone 50 mg every 6-8 hours for 24 hours and then taper judiciously to maintenance

Question 55

evaluates maximum adrenocortical secreatory capacity and tests for adrenal destruction (primary adrenal insufficiency) or adrenal atrophy (secondary adrenal insufficiency)

Answer 55

Cosyntropin

Question 56

____ and ____ are elevated in primary AI bc of loss of cortisol and angio II negative feedback

Answer 56

Plasma ACTHand PRA