Adrenal Insufficiency, Men, Cushing's

Front 1

How does cortisol
A. modulate vascular response to beta agonists
B. effect GFR
C. effect immune system
D. maintain ionotropy of heart muscle

Back 1

Cortisol's effects:
A. modulate vascular response to beta agonists - increased expression of edrenergic receptors in smooth muscle, decreased inactivation of catecholamines
B. effect GFR - increases it
C. effect immune system - immunosuppressive and anti-inflammatory. This is why glucocorticoids are commonly used to treat inflammatory and autoimmune dz!
D. maintain ionotropy of heart muscle - by induction of cardiac Na/K ATPase

Front 2

Regarding RAA system: increased renin results in cleavage of __________ (secreted by the liver) to angiotensin I. Angiotensin I is cleaved to Angiotensin II by _________ in the lungs. Angiotensin II stimulates synthesis and secretion of _______ and also acts as a potent vasopressor. Result is increase in blood pressure due to both indirect and direct effects of AII.

Back 2

angiotensinogen,

angiotensin converting enzyme (ACE)

indirect = sodium retention in kidney due to aldosterone action
direct - vasopressor response

Front 3

Regarding adrenal insufficiency, what is the primary and secondary classification?

Back 3

Primary means there is destruction of adrenal cortex itself resulting in both glucocorticoid as well as mineralocorticoid deficiency

Secondary insufficiency is defect at the pituitary or higher (hypthalamus) level leading to atrophy of the glutocorticoid producing cells due to loss of normal trophic stimulation by ACTH.

Secondary adrenal insufficiency, therefore, results in primarily glucocorticoid and not mineralocorticoid deficiency.

Front 4

True or False:

Secondary adrenal insufficiency results in primarily glucocorticoid and not mineralocorticoid deficiency.

Back 4

TRUE

Primary adrenal insufficiency results in glucocorticoid as well as mineralocorticoid deficiency

Front 5

What are some etiologies of primary adrenal deficiency? What is most common in US? How about worldwide?

Back 5

Primary adrenal deficiency or when there is destruction of the adrenal cortex itself resulting in both glucocorticoid and mineralocorticoid deficiencies, is commonly caused by:
- in US: autoimmune. antibodies to 21-hydroxylase frequent
- worldwide: TB or other infiltrative dz
- other causes: hemorrhage, fungal infections, AIDs (though less than 5% will be symptomatic, since 80% of adrenal cortex needs to be destroyed to have clinical adrenal insufficiency), metastatic tumor (v. rare)

Front 6

What drug, used to treat Cushings, can also result in primary adrenal insufficiency?

Back 6

Ketoconazole

Front 7

What two genetic conditions can cause primary adrenal insufficiency?
A. Adrenoleukodystrophy
B. Congenital adrenal hyperplasia
C. Turner's syndrome
D. Klinefelter's syndrome
E. Prader-Willi syndrome
F. DiGeorge's syndrome

Back 7

A. Adrenoleukodystrophy: X-linked recessive disorder resulting in progressive demyelination of CNS.
B. Congenital adrenal hyperplasia: occurs as result of mutation in one of the enzymes required for cortisol and/or aldosterone biosynthesis. Usually 21-hydroxylase enzyme. B/c of the block in the biosynthesis, there is less deeback to pituitary , ,leading to increased ACTH production . Increased ACTH --> increased pregnenolone --> shunted to testosterone making pathway. Thus, female babies could present with virilization.

see back of syllabus p.278 for diagram

Front 8

Why does congenital adrenal hyperplasia cause female babies to present with virilization?

Back 8

CAH occurs due to a mutation in one of the enzymes required for cortisol and/or aldosterone biosynthesis. Most common is defect in 21-hydroxylase enzyme. Lack of negative feedback --> increased ACTH --> increased pregnenolone --> but since no cortisol or aldosterone is able to be made, shunted to testosterone pathway. Thus, high levels of testosterone present virilizes baby girl.

see back of syllabus p.278 for diagram

Front 9

Secondary adrenal insufficiency can be caused by: hypothalamic dz (lymphocytic hypophysitis, neurosarcoidosis, any infiltrative dz interrupting the connection between the hypothalamus and pituitary), pituitary dz (tumors, hemorrhage, infarction, trauma), pituitary axis suppression by exogenous glucocorticoids, chronic opiate use.

Which is the most common cause?

Back 9

pituitary axis suppression by exogenous glucocorticoids

Front 10

What is the most common cause of secondary adrenal insufficiency?

Back 10

Pituitary axis suppression by exogenous glucocorticoids

Front 11

What are the clinical manifestations of chronic primary adrenal insufficiency? (signs and symptoms and lab findings)

Back 11

SYMPTOMS: WEAKNESS AND FATIGUE AND ANOREXIA, nausea/abdominal pain, vomiting
SIGNS: WEIGHT LOSS, HYPERPIGMENTATION, HYPOTENSION, vitiligo

LAB FINDINGS: hyponatremia, hyperkalemia, anemia

Front 12

Signs and symptoms between primary and secondary adrenal insufficiency are similar except what differences with regards to the following:
A. hyperpigmentation - howso? why?
B. hyperkalemia - howso and why?
C. Hyponatremia - howso and why?

Back 12

A. primary has hyperpigmentation because of the increased ACTH, but secondary does NOT exhibit increased ACTH so ergo no hyperpigmentation
B. present has hyperkalemia due to lack of aldosterone, but secondary does not since aldosterone is present
C. hyponatremia present in both since increased ADH levels in response to hypotension

Front 13

An individual presenting with nausea vomiting, abdominal pain, shock not responsive to IV fluids or pressor agents, hypoglycemia, hyponatremia, hyperkalemia and increased BUN is suffering from:
A. primary adrenal insufficiency
B. secondary adrenal insufficiency
C. acute adrenal insufficiency (primary or secondary)

Back 13

C. acute adrenal insufficiency (primary or secondary)

Front 14

How does one determine whether a patient has adrenal insufficiency?

Back 14

1) Does adrenal insufficiency exist?
2) If yes, then primary or secondary?

Random plasma cortisol drawn at any time of the day is only suggestive if value is low in the face of stress (when it should be high). Note that normal diurnal variation occurs with cortisol. Morning cortisol level is only helpful if normal because then you don't need to do further testing. A low response would proceed to do ACTH stimulation test. Rapid high dose ACTH stimulation test is a the test of choice to adrenal insufficiency (will be abnormal result). To determine whether primary or secondary, do insulin induce hypoglycemia test.

Front 15

How does one do the ACTH stimulation test?

Back 15

Give ACTH. Then measure cortisol 60 minutes following intravenous or intramuscular injection. Normal response is measured cortisol > 20 micrograms/dL.

Front 16

What is the gold standard test for secondary adrenal insufficiency?
A. ACTH stimulation test
B. insulin-induced hypoglycemia
C. morning cortisol test
D. plasma ACTH level

Back 16

B. insulin-induced hypoglycemia

this is also useful to test the whole hypothal-pituit-adrenal axis

Front 17

What is the treatment for each:
A. Chronic primary adrenal insufficiency
B. Chronic secondary adrenal insufficiency
C. Acute adrenal insufficiency

Back 17

A. Chronic primary adrenal insufficiency - maintenance glucocorticoids (hydrocortisone or cortisone acetate) and oral mineralocorticoid (fludrocortisone) if patientsremains hypotensive or hyperkalemic on glucocorticoids alone
B. same as primary but no mineralocorticoid
C. infuse saline and glucose, draw blood to assess plasma cortisol, ACTH, electrolytes and glucose (but do not wait for results), give high dose hydrocortisone. At these high doses, hydrocortisone has both glucocorticoid as well as mineralocorticoid effects so you do not need to give fludrocortisone.

Front 18

MEN or multiple endocrine neoplasia syndromes, are characterized by ... (think v. general).

Back 18

Tumors that occur in endocrine organs. Tumors may be multifocal within one organ or across many organs in an individual or family.

Front 19

MEN1 is associated with the three P's. What are they and what are the clinical syndromes?
What is the genetics behind it?

Back 19

Parathyroid - hyperparathyroidism (elevated Ca2+, elevated PTH)
Pancreas - gastrinoma, insulinoma, gluconoma, non-secretory islet cell tumor
Pituitary - prolactinoma, acromegaly, Cushing's dz, non-secretory tumor

GENETICS: MEN1 gene, a tumor suppressor gene. Loss of function.

Front 20

MEN2 is associated with what type of cancer in all MEN2 classes?

Back 20

medullary thyroid cancer (MTC)

In MEN2A: medullary thyroid cancer, pheochromocytoma, hyperparathyroidism, cutaneous lichen amyloidosis
In MEN2B: medullary thyroid cancer, mucosal ganglioneuromas, pheochromocytoma
In FMTC: MTC in 10 or more familyi members, no pheo, HPT

Front 21

Discern which is part of MEN2A, MEN2B, and/or Familial medullary thyroid cancer.
A. cutaneous lichen amyloidosis
B. hyperparatyroidism
C. medullary thyroid cancer
D. mucosal ganglioneuromas
E. no pheochromocytoma
F. no hyperparathyroidism
G. no ganglioneuromas
H. pheochromocytoma

Back 21

In MEN2A: medullary thyroid cancer, pheochromocytoma, hyperparathyroidism, cutaneous lichen amyloidosis
In MEN2B: medullary thyroid cancer, mucosal ganglioneuromas, pheochromocytoma
In FMTC: MTC in 10 or more familyi members, no pheo, HPT

MEN2 involves the RET gene and encodes the RET protein which is a receptor tyrosine kinase. gain of function.

Front 22

True or False:
For MEN2, presymptomatic diagnosis does not affect morbidity/mortality.

Back 22

FALSE.

This statement is true for MEN1. But for MEN2, mortality has been impacted favorably by early thyroidectomy and by pheocromocytoma identification and management.

Front 23

Which autoimmune polyglandular syndrome is
A. more common
B. an autosomal recessive disorder
C. of childhood onset
D. of 20-40 y/o onset
E. can be sutosomal dominant, recessive or polygenic
F. involves the AIRE gene on chromosome21

Back 23

A. more common - APS II
B. an autosomal recessive disorder - APS I
C. of childhood onset - APS I
D. of 20-40 y/o onset - APS II
E. can be autosomal dominant, recessive or polygenic - APS II
F. involves the AIRE gene on chromosome 21 - APS I

Front 24

Which clinical features belong to APS I and/or which to APS II?
A. Autoimmune thyroid dz
B. Hypoparathyroidism
C. Mucocutaneous candidiases
D. Myasthenia gravis
E. Primary adrenal insufficiency
F. Primary hypogonadism
G. Type I DM

Back 24

A. Autoimmune thyroid dz - APS II
B. Hypoparathyroidism - BOTH
C. Mucocutaneous candidiases - APS I
D. Myasthenia gravis- APS II
E. Primary adrenal insufficiency - APSI
F. Primary hypogonadism - BOTH
G. Type I DM - BOTH

Front 25

What are the three main clinical features of APS I?
A. Autoimmune thyroid dz
B. Hypoparathyroidism
C. Mucocutaneous candidiases
D. Myasthenia gravis
E. Primary adrenal insufficiency
F. Primary hypogonadism
G. Type I DM

Back 25

B. Hypoparathyroidism
C. Mucocutaneous candidiases
E. Primary adrenal insufficiency

Front 26

What gene is responsible for APSI? APSII?

Back 26

APSI: AIRE gene on chromosome 21. It encodes nuclear protein involved in transcriptional processes.

APSII: no identified gene, only 50% of cases are familial

Front 27

What is the difference between Cushing's Syndrome and Cushing's Disease?

Back 27

Cushing's Syndrome = glucocorticoid excess of any etiology

Cushing's Disease = pituitary ACTH excess leading to adrenal stimulation and chronically elevated glucocorticoids

Front 28

Why does HTN, edema, hypokalemic alkalosis occur in Cushing's syndrome?

Back 28

Those are all conesquences of excessive mineralocorticoid-like activity that occurs due to high levels of cortisol acting on meralocorticoid receptors producing effects similar to aldosterone.

Front 29

Why does hrsutism, acne and menstrual disturbances in females, occur in Cushing's syndrome?

Back 29

These are consequences of excessive androgenic activity - due to adrenal androgens secreted in conjunction with cortisol. Cortisol also directly inhibits gonadotropin secretion at the level of the pituitary caushing amenorrhea.

Front 30

Why does amenorrhea occur with high cortisol levels?

Back 30

Cortisol directly inhibits gonadotropin secretion at the level of the pituitary causing amenorrhea.

Front 31

What is the most common cause of Cushing's syndrome?

Back 31

Exogenous glucocorticoids used in supraphysiologic doses to treat another disease such as asthma or inflammatory bowel disease.

Front 32

What are some ACTH independent causes of Cushing's syndrome? (3)

Back 32

Primary adrenal disease - autonomous adrenocorticoid secretion independent of ACTH regulation
Extopic CRH- extremely rare though
Pseudo-Cushing's Syndrome : looks like Cushing's except is resolved by treating underlying disease- usually depression, alcoholism, anorexia nervosa

Front 33

What is the diagnosis/testing algorithm for Cushing's ?

Back 33

patient must NOT be stressed. 2 different screening tests must be positive in order to make the diagnosis of hypercortisolism. (Overnight low dose dexamethasone suppression, 24 hour urine free cortisol, midnight salivary cortisol). Then, you confirm etiology (ACTH dependent or ACTH independent). Once the presence of hypercortisolism is established biochemically, the source of excess cortisol needs to be determined- do plasma ACTH level. see p.297of syllabus for whole algorithm

Front 34

If you suspect a pituitary tumor as a reason for hypercortisolism, what test can be done?
A. low dose dexamethasone suppression test
B. ACTH suppression test
C. high dose dexamethasone suppression test
D. 24 hour urine free cortisol
E. Dexamethasone-CRH test

Back 34

C. high dose dexamethasone suppression test

an overnight high dose 8mg Dexamethasone suppression test involves dexamethasone that is 10x the normal physiologic dose. if cortisol measured at next day shows inadequate suppression of cortisol- it can be due to a pituitary tumor OR ectopic ACTH. If levels are indeed suppressed adequately, then it suggests a pituitary tumor.

Front 35

Inferior petrosal sinus sampling involves venous sampling of pituitary to obtain ACTH levels. If ACTH levels from pituitary are markedly elevated in comparison to the periphery then...
A . this confirms pituitary source for ACTH
B. you can assume the patient has either a pituitary tumor or an ectopic ACTH producing source

Back 35

A . this confirms pituitary source for ACTH

Front 36

What drugs affect dexamethasone metabolism and thus can serve as diagnostic confounders for Cushing's?

Back 36

anti-convulsants like phenytoin and phenobarbital. These accelerate the metabolism of dexamethasone which can lead to false positive suppression tests. (failure to suppress)

Front 37

What are possible treatment options for hypercortisolism?

Back 37

Surgical removal of tumor
Medical therapy with drugs like ketoconazole and metyrapone
pituitary irradiation for Cushing's dz