week 3, lecture 3

Question 1

when thinking of HPA axis and endocrine pathologies how can the dysfunctions be divided into 3 categories

Answer 1

primary, secondary and tertiary

Question 2

primary dyfunction

Answer 2

in the “final” endocrine organ i.e. adrenal glands

Question 3

secondary dysfunction

Answer 3

in the pituitary gland

Question 4

tertiary dysfunction

Answer 4

in the hypothalamus

Question 5

what is hyper function in the adrenal glands?

Answer 5

▪ secondary causes are quite common
▪ Can involve increased levels of cortisol or aldosterone

• Disorders that are associated with elevated levels of androgens usually also involve decreased levels of glucocorticoids and/or mineralocorticoids

Question 6

diseases of hyper function in the adrenal glands

Answer 6

▪ Cushing’s syndrome (Hypercortisolism)
▪ Hyperaldosteronism
▪ Pheochromocytoma

Question 7

diseases of hypofunction in the adrenal glands

Answer 7

▪ Adrenocortical
insufficiency
▪Congenital adrenal hyperplasia

Question 8

what is Cushing syndrome an excess of?

Answer 8

• Disorder caused by any condition that produces an elevation in glucocorticoid levels (cortisol)

Question 9

4 common sources of excess cortisol in Cushing syndrome

Answer 9

▪ Iatrogenic (i.ed drugs/meds/ exogenous)

▪ hypothalamic-pituitary diseases associated with hypersecretion of ACTH

▪ Hypersecretion of cortisol by an adrenal adenoma, carcinoma or nodular hyperplasia

▪ Secretion of ectopic ACTH by a nonendocrine neoplasm – aka paraneoplastic syndrome

Question 10

is hyper secretion of ACTH mostly endogenous or exogenous? men or women effected more?

Answer 10

mostly women

exogenous from drugs

Question 11

what is the main cause of hyper secretion of ACTH in Cushing disease

Answer 11

pituitary gland contains an ACTH- producing microadenoma

Question 12

ectopic ACTH production - paraneoplastic syndrome (could be a cause of Cushings)

Answer 12

• Paraneoplastic syndrome

▪Main tumours are small cell lung cancer and a
renal adenocarcinoma
▪Represent about 10% of cases of endogenous Cushing syndromes
▪Usually involve rapid increases in the levels of ACTH and evolution of symptoms/signs

Question 13

primary Cushing syndrome (ACTH independent cushings)

Answer 13

▪10 to 20 % of cases of endogenous hypercorticolism are due to an adenoma in the adrenal glands themselves

• Adenomas are usually well-differentiated, more common in women, and functional (i.e. secrete cortisol)

Question 14

adrenocortical carcinom

Answer 14

-uncommon cause
-rare and aggressive tumor
* Typically large mass with excess production glucocorticoids & androgens

Question 15

Iatrogenic Cushing Syndrome

Answer 15

Exogenous administration of glucocorticoids (such as hydrocortisone, prednisone, methyl-prednisolone or dexamethasone) prescribed by a health care practitioner to treat other diseases

Question 16

what is the most common cause of Cushing syndrome

Answer 16

Iatrogenic Cushing Syndrome (exogenous drugs)

Question 17

what form of exogenous glucocorticoids must be given To develop Iatrogenic Cushing Syndrome

Answer 17

Needs to be systemically administered to cause Cushing syndrome – topical or inhaled will not cause significant increases in serum glucocorticoids

Question 18

Cushing ACTH dependent vs independent diagram

Answer 18

slide 12

Question 19

CUSHING mnemonic

Answer 19

– C - Central obesity, Cervical fat pads,
Collagen fibre weakness, Comedones (acne)
– U - Urinary free cortisol and glucose increase
– S - Striae, Suppressed immunity
– H - Hypercortisolism, Hypertension,
Hyperglycemia, Hirsutism
– I - Iatrogenic (Increased administration of corticosteroids)
– N - Noniatrogenic (Neoplasms)
– G - Glucose intolerance, impaired Growth

Question 20

other clinical features of cushings

Answer 20

-psychiatric (anxiety, depression, paranoia, depressive psychosis)
-infection
-irregular menses
-long term hypercortisolism can cause osteoporosis and subsequent fractures

Question 21

endogenous vs exogenous (iatrogenic) Cushing time course

Answer 21

endogenous- slow –> start with hypertension and weight gain
(exception: paraneoplastric can be rapid)

iatrogenic is rapid

Question 22

labs for cushing

Answer 22

24 hour free urine cortisol and low dexamethasone suppression test

▪ Often cortisol is measured as 24-hour free urine cortisol and/or serum cortisol within a low dexamethasome suppression test
* Since cortisol secretion varies so much over the course of a day, doing a 24-hour urine collection gives you a rough idea of the “average” secretion
▪ Salivary cortisol is also used sometimes as well * But there is wide diurnal variation

Question 23

dexamethasone suppression test - low dose

Answer 23

• A small dose of dexamethasone is given the night before & endogenous glucocorticoid levels are assessed the next morning
  ▪ In a healthy patient we would expect dexamethasome to inhibit the anterior pituitary gland and supress endogenous glucocorticoids.
  ▪ No suppression is indicative of Cushing syndrome

Question 24

if healthy, what are the results of dexamethasone test

Answer 24

inhibit the anterior pituitary gland and supress endogenous glucocorticoids.

no suppression=cushing

Question 25

high dose dexamethasone suppression test is used for what

Answer 25

* Used to differentiate Cushing’s disease from other causes of Cushing’s syndrome

Question 26

high dose dexamethasone suppression test suppression means what disease and no suppression means what disease

Answer 26

▪ Suppression of endogenous glucocorticoids => Cushing’s disease ▪ No suppression => ectopic ACTH-dependent

Question 27

CHART ON SLIDE 18

Answer 27

differente for Cushing labs

Question 28

can adrenocortical insufficiency be primary, secondary or tertiary and what does that mean

Answer 28

primary (adrenals) or secondary (pituitary-ACTH) * Caused by primary adrenal disease or decreased stimulation of the adrenals due to a deficiency of ACTH

Question 29

acute or chronic adrenocortical insufficiency

Answer 29

▪Those with chronic adrenal insufficiency may show signs similar to acute insufficiency if their need for steroids (stress, infection) suddenly increases ▪Acute can be iatrogenic – people being weaned off of high doses of glucocorticoids too quickly

Question 30

what are the 3 patterns of primary and secondary adrenal insuffieicieny

Answer 30

–Primary acute adrenocortical insufficiency (Adrenal crisis) –Primary chronic adrenal insufficiency (Addison Disease) –Secondary adrenocortical insufficiency

Question 31

what is Addison disease AKA

Answer 31

primary chronic adrenal insufficiency

Question 32

etiologies (causes) of primary acute adrenocortical insufficiency

Answer 32

-stress that precipitates chronic adrenocortical insufficiency -exogenous corticosteroids - adrenal hemorrhage ▪ In patients with chronic adrenocortical insufficiency precipitated by any form of stress that requires an increased in steroid output from glands incapable of responding ▪ In patients on exogenous corticosteroids * Rapid withdrawal of steroids or failure to increase steroid doses in response to acute stress may precipitate an adrenal crisis * = inability of atrophic adrenals to produce glucocorticoid hormones ▪Adrenal hemorrhage ▪ Newborns after a prolonged & difficult delivery ▪ Anticoagulant therapy ▪ Post-surgical disseminated intravascular coagulation (aka DIC) ▪ Waterhouse-Friderichsen syndrome (rare)

Question 33

clinical features of acute adrenal insufficiency

Answer 33

▪ Hemodynamic instability (inability to maintain bloodpressure, shock, severe postural hypotension) ▪ Abdominal pain, nausea, vomiting, fever ▪ Hypoglycemia and hyponatremia ▪ Decreased level of consciousness, stupor * Often exacerbated by concomitant illness and physiologic stress (shock, infection, surgery, trauma) ▪ Can occur on a background of slowly progressive chronic insufficiency

Question 34

Addison disease: Chronic primary Adrenal Insufficiency

Answer 34

▪ Uncommon disorder resulting from progressive destruction of adrenal cortex ▪ Clinical manifestations do not appear until 90% of adrenal cortex compromised

Question 35

what are the 4 main disorders that cause Addison disease/ Chronic primary Adrenal Insufficiency

Answer 35

▪ Autoimmune destruction of the adrenal cortex (60-70% in developed countries) ▪ TB (less common now, but most common cause worldwide) ▪ AIDS ▪ Sarcoidosis or malignancy (usually lung or breast metastases)

Question 36

autoimmune causes of Addison disease

Answer 36

-autoimune polyendocrine syndrome (APS) type 1 -APS type 2 -idiopathic

Question 37

APS 1 vs APS 2 (Addisons autoimmune)

Answer 37

APS1- autosomal recessive APS2- more common, no skin or dental findings

Question 38

clinical features of Addisons disease

Answer 38

* Begins insidiously- at least 90% of cortex of both glands destroyed * Initial manifestations: progressive weakness and easy fatigability * GI disturbances: anorexia, nausea, vomiting, weight loss, diarrhea * Hyperpigmentation * Loss of sodium: Hypotension, hyperkalemia, hyponatremia, volume depletion * Stress (infection, trauma, or surgery) can cause an acute adrenal crisis * Death can occur rapidly unless corticosteroid therapy begins immediately

Question 39

what is a secondary adrenocortical insuffcieicny? possible causes?

Answer 39

* Any disorder of hypothalamus and pituitary that reduces the output of ACTH → syndrome of hypoadrenalism ▪ Possible etiologies include: metastatic cancer, infection, infarction, irradiation

Question 40

how does secondary adrenocortical insuffieicny differ from primary Addisons? what steroid hormones are deficient and what is normal?

Answer 40

* With secondary disease, hyperpigmentation of primary Addison is absent * Deficient cortisol and androgen output but normal aldosterone levels (therefore no hyperkalemia, hyponatremia)

Question 41

what labs if suspect ACTH deficiency?

Answer 41

▪ Insulin tolerance test: after insulin administration cortisol & ACTH secretion should increase ▪ CRH administration should also show increased cortisol and ACTH plasma levels

Question 42

labs for adrenal insufficiency

Answer 42

▪ Often ACTH & cortisol is measured (as 24-hour free urine cortisol and/or serum morning cortisol)

Question 43

how to distinguish between primary and secondary adrenal insufficiency in labs?

Answer 43

ACTH stimulation test can be done ▪ Exogenous ACTH (cosyntropin) is given

Question 44

CHART ON SLIDE 28

Question 45

primary hyperaldosteronism --> what does chronic excess secretion of aldosterone cause (hint: Na+ and K+)

Answer 45

* Causes sodium retention and potassium excretion * Resulting in hypertension and hypokalemia

Question 46

how does hyperaldosteronism after the renin-angiotensin system?

Answer 46

autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity

Question 47

causes of primary hyperaldosteronism

Answer 47

▪Adrenocortical neoplasm: usually a solitary aldosterone secreting adenoma *--> Conn Syndrome ▪Bilateral hyperplasia of adrenals

Question 48

secondary hyperaldosteronism- why is the excess aldosterone released?

Answer 48

* Aldosterone release in response to activation of the renin-angiotensin system * Characterized by increased levels of plasma renin

Question 49

what conditions can cause secondary hyperaldosteronism?

Answer 49

–Decreased renal perfusion –Arterial hypovolemia and edema: CHF, cirrhosis, nephrotic syndrome –Pregnancy: due to estrogen induced increases in plasma renin substrate

Question 50

2 main symptoms of hyperaldosteronism

Answer 50

hypertension and hypokalemia * Hypertension: ▪ sodium retention increases total body sodium and expands the extracellular fluid * Hypokalemia: ▪ due to renal potassium wasting and can cause variety of neuromuscular manifestations

Question 51

what labs to do for hyperaldosteronism?

Answer 51

▪ Serum aldosterone & renin can be measured for an aldosterone: renin ratio (ARR)

Question 52

congenital adrenal hyperplasia

Answer 52

* Autosomal recessive defect in enzyme in cortisol synthesis pathways (to make cortisol and aldosterone)

Question 53

what is the most common deficiency enzyme in congenital adrenal hyperplasia ? what step cannot be done?

Answer 53

21-Hydroxylase progesterone cannot be converted into cortisol (or way less)

Question 54

what are the types of congenital adrenal hyperplasia

Answer 54

classic (affects newborns) non-classic (later onset) ▪Classic: affects newborns * Salt-wasting: ▪complete inactivation of 21-hydroxylase * Simple virilizing: ▪significantly reduced function of 21-hydroxylase ▪ Non-classic * Milder & later onset (late childhood/early adulthood) * Partial deficiency in 21- hydroxylase

Question 55

classic forms of congenital adrenal hyperplasia: salt wasting vs simple virilizing

Answer 55

salt wasting= complete inactivation of 21-hydrolase enzyme simple virilizing= reduced enzyme activity * Salt-wasting ▪ No synthesis of aldosterone causes hyponatremia, hyperkalemia, dehydration, hypotension, & increased renin secretion * Can be fatal if not treated ▪ Virilization of female infants * Simple virilizing ▪ Female infants often have ambiguous genitalia at birth ▪ Male infants show no abnormalities of sexual organs at birth ▪ Adult women typically experience infertility * Adult men can be fertile or experience azoospermia

Question 56

what happens to female babies with congenital adrenal hyperplasia?

Answer 56

females show male characteristics (virilization or ambiguous genitalia) because too much aldosterone, but how because progesterone is not being converted into aldosterone or cortisol??e???

Question 57

non classic/late onset congenital adrenal hyperplasia

Answer 57

▪ No abnormalities at birth, symptoms typically present at puberty ▪ In women, late-onset CAH can often mimics poly cystic ovary syndrome (PCOS) * Hirsutism, acne, menstrual irregularities, infertility ▪ Men are often asymptomatic

Question 58

what is the most common form of congenital adrenal hyperplasia?

Answer 58

late onset/non- classic

Question 59

what labs to run for congenital adrenal hyperplasia

Answer 59

17 hydroxyprogesterone (17-OHP) levels

Question 60

what cells do pheochromocytoma effect?

Answer 60

Rare tumour of chromaffin cells ▪ Most of the time secretes elevated quantities of catecholamines (NE and E)

Question 61

where are the tumors in pheochromocytoma?

Answer 61

▪ Most of the time tumours arises in the adrenal medulla (which is where chromaffin cells are) ▪ In about 10% of cases they can be malignant and will invade

Question 62

what is the main feature of pheochromocytoma?

Answer 62

hypertension -paroxysmal hypertension * enormous acute increases in blood pressure, often precipitated by stress or even posture changes * Large changes in blood pressure can result in cerebrovascular accidents, heart failure, and eventual hypertrophy of the heart -surgical excision to treat

Question 63

which conditions have increased levels of cortisol

Answer 63

▪ Cushing disease, Cushing syndrome ▪ Stress (physiologic or psychologic) ▪ Hyperthyroidism (increased cortisol to meet needs of metabolism)

Question 64

which conditions have decreased levels of cortisol

Answer 64

▪ Congenital adrenal hyperplasia ▪ Addison disease ▪ Hypopituitarism, hypothyroidism

Question 65

what does dexamethasone work on

Answer 65

inhibits ACTH at anterior pituitary