week 3, lecture 3 Flashcards
when thinking of HPA axis and endocrine pathologies how can the dysfunctions be divided into 3 categories
primary, secondary and tertiary
primary dyfunction
in the “final” endocrine organ i.e. adrenal glands
secondary dysfunction
in the pituitary gland
tertiary dysfunction
in the hypothalamus
what is hyper function in the adrenal glands?
▪ 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
diseases of hyper function in the adrenal glands
▪ Cushing’s syndrome (Hypercortisolism)
▪ Hyperaldosteronism
▪ Pheochromocytoma
diseases of hypofunction in the adrenal glands
▪ Adrenocortical
insufficiency
▪Congenital adrenal hyperplasia
what is Cushing syndrome an excess of?
- Disorder caused by any condition that produces an elevation in glucocorticoid levels (cortisol)
4 common sources of excess cortisol in Cushing syndrome
▪ 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
is hyper secretion of ACTH mostly endogenous or exogenous? men or women effected more?
mostly women
exogenous from drugs
what is the main cause of hyper secretion of ACTH in Cushing disease
pituitary gland contains an ACTH- producing microadenoma
ectopic ACTH production - paraneoplastic syndrome (could be a cause of Cushings)
- 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
primary Cushing syndrome (ACTH independent cushings)
▪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)
adrenocortical carcinom
-uncommon cause
-rare and aggressive tumor
* Typically large mass with excess production glucocorticoids & androgens
Iatrogenic Cushing Syndrome
Exogenous administration of glucocorticoids (such as hydrocortisone, prednisone, methyl-prednisolone or dexamethasone) prescribed by a health care practitioner to treat other diseases
what is the most common cause of Cushing syndrome
Iatrogenic Cushing Syndrome (exogenous drugs)
what form of exogenous glucocorticoids must be given To develop Iatrogenic Cushing Syndrome
Needs to be systemically administered to cause Cushing syndrome – topical or inhaled will not cause significant increases in serum glucocorticoids
Cushing ACTH dependent vs independent diagram
slide 12
CUSHING mnemonic
– 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
other clinical features of cushings
-psychiatric (anxiety, depression, paranoia, depressive psychosis)
-infection
-irregular menses
-long term hypercortisolism can cause osteoporosis and subsequent fractures
endogenous vs exogenous (iatrogenic) Cushing time course
endogenous- slow –> start with hypertension and weight gain
(exception: paraneoplastric can be rapid)
iatrogenic is rapid
labs for cushing
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
dexamethasone suppression test - low dose
- 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
if healthy, what are the results of dexamethasone test
inhibit the anterior pituitary gland and supress endogenous glucocorticoids.
no suppression=cushing
high dose dexamethasone suppression test is used for what
- Used to differentiate Cushing’s disease from other causes of Cushing’s syndrome
high dose dexamethasone suppression test
suppression means what disease and no suppression means what disease
▪ Suppression of endogenous glucocorticoids => Cushing’s disease
▪ No suppression => ectopic ACTH-dependent
CHART ON SLIDE 18
differente for Cushing labs
can adrenocortical insufficiency be primary, secondary or tertiary
and what does that mean
primary (adrenals) or secondary (pituitary-ACTH)
- Caused by primary adrenal disease or decreased stimulation of the adrenals due to a deficiency of ACTH
acute or chronic adrenocortical insufficiency
▪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
what are the 3 patterns of primary and secondary adrenal insuffieicieny
–Primary acute adrenocortical insufficiency (Adrenal crisis)
–Primary chronic adrenal insufficiency (Addison Disease)
–Secondary adrenocortical insufficiency
what is Addison disease AKA
primary chronic adrenal insufficiency
etiologies (causes) of primary acute adrenocortical insufficiency
-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)
clinical features of acute adrenal insufficiency
▪ 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
Addison disease: Chronic primary Adrenal Insufficiency
▪ Uncommon disorder resulting from progressive destruction of
adrenal cortex
▪ Clinical manifestations do not appear until 90% of adrenal cortex compromised
what are the 4 main disorders that cause Addison disease/ Chronic primary Adrenal Insufficiency
▪ 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)
autoimmune causes of Addison disease
-autoimune polyendocrine syndrome (APS) type 1
-APS type 2
-idiopathic
APS 1 vs APS 2 (Addisons autoimmune)
APS1- autosomal recessive
APS2- more common, no skin or dental findings
clinical features of Addisons disease
- 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
what is a secondary adrenocortical insuffcieicny? possible causes?
- Any disorder of hypothalamus and pituitary that reduces the output of ACTH → syndrome of hypoadrenalism
▪ Possible etiologies include: metastatic cancer, infection, infarction, irradiation
how does secondary adrenocortical insuffieicny differ from primary Addisons? what steroid hormones are deficient and what is normal?
- With secondary disease, hyperpigmentation of primary Addison is absent
- Deficient cortisol and androgen output but normal aldosterone levels (therefore no hyperkalemia, hyponatremia)
what labs if suspect ACTH deficiency?
▪ Insulin tolerance test: after insulin administration cortisol &
ACTH secretion should increase
▪ CRH administration should also show increased cortisol and ACTH plasma levels
labs for adrenal insufficiency
▪ Often ACTH & cortisol is measured (as 24-hour free urine
cortisol and/or serum morning cortisol)
how to distinguish between primary and secondary adrenal insufficiency in labs?
ACTH stimulation test can be done
▪ Exogenous ACTH (cosyntropin) is given
CHART ON SLIDE 28
primary hyperaldosteronism –> what does chronic excess secretion of aldosterone cause (hint: Na+ and K+)
- Causes sodium retention and potassium excretion
- Resulting in hypertension and hypokalemia
how does hyperaldosteronism after the renin-angiotensin system?
autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity
causes of primary hyperaldosteronism
▪Adrenocortical neoplasm: usually a solitary aldosterone secreting adenoma
*–> Conn Syndrome
▪Bilateral hyperplasia of adrenals
secondary hyperaldosteronism- why is the excess aldosterone released?
- Aldosterone release in response to activation of the renin-angiotensin system
- Characterized by increased levels of plasma renin
what conditions can cause secondary hyperaldosteronism?
–Decreased renal perfusion
–Arterial hypovolemia and edema: CHF, cirrhosis, nephrotic syndrome
–Pregnancy: due to estrogen induced increases in plasma renin substrate
2 main symptoms of hyperaldosteronism
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
what labs to do for hyperaldosteronism?
▪ Serum aldosterone & renin can be measured for an
aldosterone: renin ratio (ARR)
congenital adrenal hyperplasia
- Autosomal recessive defect in enzyme in cortisol synthesis pathways (to make cortisol and aldosterone)
what is the most common deficiency enzyme in congenital adrenal hyperplasia ? what step cannot be done?
21-Hydroxylase
progesterone cannot be converted into cortisol (or way less)
what are the types of congenital adrenal hyperplasia
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
classic forms of congenital adrenal hyperplasia: salt wasting vs simple virilizing
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
what happens to female babies with congenital adrenal hyperplasia?
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???
non classic/late onset congenital adrenal hyperplasia
▪ 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
what is the most common form of congenital adrenal hyperplasia?
late onset/non- classic
what labs to run for congenital adrenal hyperplasia
17 hydroxyprogesterone (17-OHP) levels
what cells do pheochromocytoma effect?
Rare tumour of chromaffin cells
▪ Most of the time secretes elevated quantities of catecholamines (NE and E)
where are the tumors in pheochromocytoma?
▪ 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
what is the main feature of pheochromocytoma?
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
which conditions have increased levels of cortisol
▪ Cushing disease, Cushing syndrome
▪ Stress (physiologic or psychologic)
▪ Hyperthyroidism (increased cortisol to meet needs of metabolism)
which conditions have decreased levels of cortisol
▪ Congenital adrenal hyperplasia
▪ Addison disease
▪ Hypopituitarism, hypothyroidism
what does dexamethasone work on
inhibits ACTH at anterior pituitary
