Flashcards in Adrenal Deck (46):
What three layers make up the adrenal cortex?
sex steroids: progesterone, androgens, estrogen precursors
What is the primary mineralcorticoid and what does it do?
Na and K homeostasis
What is the most important glucocorticoid and what does it regulate?
cardiovascular, metabolic, immunologic, homeostatic
What are the primary sex steroids?
What are hte primary catecholamines secreted from the adrenal cortex?
What stimulates the movement of cholesterol into the mitochondria where CYP enzymes
38 year old female presents to the emergency room saying her heart keeps “racing”
• Patient also reports that she is sweating profusely and has a severe headache
• Patient is monitored in the ED
– Frequent paroxysms of tachycardia with episodic hypertension exceeding 180/100 mm Hg
What is in the differential diagnosis for paroxysmal HTN?
• 2 – 8 cases/million people annually
• Only 1/300 patients evaluated for pheo end up with a confirmed diagnosis
– Labile hypertension – Panic disorder
• When cause remains unknown
What is the classic triad of symptoms in patients with a pheochromocytoma?
• Sustained or paroxysmal hypertension
• Generalized sweating
• Due to the generic nature of these symptoms and the rarity of pheos, only 1 in 300 patients evaluated for pheo end up with a confirmed diagnosis
What laboratory tests should be ordered to confirm a diagnosis of pheochromocytoma?
– Plasma free fractionated metanephrines
• Specificity felt to be lower than urine tests (thus more false positives)
What are metanephrines and why are they elevated in pheochromocytoma?
• Pheos are catecholamine‐ secreting tumors that arise from the adrenal medulla
• NE and Epi are metabolized to normetanephrine and metanephrine intratumorally
– Pheos contain high level of COMT
• Metanephrines spill into plasma and are excreted in excess in urine
Why is measurement of urine metanephrines preferred over measurement of plasma or urine catecholamines?
Intratumoral metabolism of catecholamines occurs continuously and independently of catecholamine release
– Consistently elevated level of metanephrines
• Catecholamine release may occur intermittently or at low
• Supported by studies that show elevated metanephrines change negligibly during paroxysms, while catecholamine levels change dramatically during paroxysms
• Additionally, metanephrine levels have been shown to correlate with tumor size whereas catecholamine levels do not
• That being said, 24 hour urine catecholamine measurement is part of the diagnostic algorithm because a 24 hour collection removes some of the element of variability that would be seen in a one time plasma measurement
Why are urine homovanillic acid (HVA) and vanillylmandelic acid (VMA) measured for diagnosis of neuroblastoma, and not metanephrines, since it is also a catecholamine‐secreting tumor?
• Neuroblastomas originate from sympathetic ganglion cells
– Contain MAO but not COMT
• Produce norepinephrine and dopamine
– Lack PNMT so no epi
• Intratumoral inactivation of NE and dopamine leads to HVA and VMA accumulation
Why aren’t urine HVA and VMA used for the diagnosis or monitoring of pheochromocytoma?
• Dopamine‐producing pheos rare so HVA not elevated
• Pheos do contain MAO but at lower levels than COMT
• DHPG and MHPG are produced by pheos and converted to VMA
• However, the increase in VMA levels is obscured by the baseline production of VMA from metabolism of sympathetic nerve norepinephrine, thus making VMA an insensitive marker of pheos
• 78 year old man presents to an outside hospital with hematuria and urinary retention
￼• Transferred to UMMC with urosepsis
• Physical exam:
– Height 5’2”
– Scrotal sac empty with no palpable testes
CT scan of abdomen & pelvis
• Enlarged uterus with large fibroid obstructing the bladder
• 3.8 cm cyst in the left adnexa possibly arising from an ovary
• Bilaterally enlarged adrenal glands
Elevated ACTH, 17-Hydrogxyprogest, androstendione, DHEAS
What is the most likely diagnosis in this case?
Congenital Adrenal Hyperplasia
What enzyme is most likely defective in this case?
• 21 hydroxylase deficiency accounts for > 95% of congenital adrenal hyperplasia cases
• 1 in 10,000 to 18,000 live births
21 hydroxylase def leads ot the accumulation of...
17 hydroxy progesterone
Everything is shunted to the androgen biosynthetic pathway that is unaffected by the block (there is decreased/NO cortisol production)
What is the effect of exccess androgens?
prenatal masculinization (ambiguous genitailia) in females and postnatal virilization in both sexes
Is this case most likely due to partial or complete deficiency of 21‐hydroxylase?
Simple virilizing (our case):
– Mild form, only partial deficiency
– Increase in ACTH is able to keep cortisol at NORMAL LEVELS
– 17‐OHP in excess causes mild salt‐losing leads to up‐regulation of aldosterone
– Aldosterone may actually be INCREASED in these patients
What are the clinical and laboratory differences in patients with partial or complete 21‐hydroxylase deficiency?
– Severe form, complete deficiency
– Increase in ACTH has no effect on enzyme since it is non‐ functional
– LOW/NO aldosterone and cortisol
– Dehydration due to salt wasting
A baby girl is born at 38 1/7 weeks with ambiguous genitalia.
17‐hydroxyprogesterone: 32,710 ng/dL (<630)
Testosterone: 1449 ng/dL (20‐80) Plasma renin: 74.25 ng/ml/60 min (2.0‐35.0)
How confident are you in the diagnosis? What test(s) should be ordered next?
• Very high 17‐hydroxyprogesterone is
diagnostic for 21‐hydroxylase deficiency
• Virtually all affected patients present with
levels > 3500 ng/dl
– Diagnosis considered “highly probable” if > 10,000 ng/dL
• Order sodium and potassium!! – Want to avoid an adrenal crisis
What are the electrolyte abnormalities that can occur in classic congenital adrenal hyperplasia (21‐hydroxylase deficiency)?
• Hyponatremic, hypochloremic, hyperkalemic acidosis
• Due to aldosterone deficiency
What’s considered the gold standard for diagnosing congenital adrenal hyperplasia?
ACTH (cosyntropin) stimulation test
What is the second most common cause of CAH and what laboratory findings would be expected?
11‐beta hydroxylase deficiency
How do you diagnose 11‐beta hydroxylase deficiency?
elevated 11‐beta hydroxylase levels
How is 11‐beta hydroxylase deficiency similar to 21 hydroxylase def?
Ambiguous genitalia in females due to androgen
How does 11‐beta hydroxylase deficiency differ from 21 hydroxylase def?
– Hypertension due to 11‐deoxycortisone’s action as a mineralocorticoid
– Results in low renin which may result in hypokalemia
30 year old female presents with complaints of weight gain
• Patient also complains of fatigue, moodiness, and says she is having relatively new issues with facial hair
– Hirsutism noted
– BP: 180/110
– Bilateral pedal edema
What are the common signs and symptoms of hypercortisolism (Cushing’s syndrome)?
Why do patients with Cushing’s syndrome become hypertensive?
• Cortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor (MR)
• 11‐hydroxysteroid dehydrogenase type 2 normally inactivates cortisol preventing its action at the MR
• With cortisol excess, enzyme is overwhelmed and excess cortisol activates MR leading to Na retention and hypertension
What three tests are recommended options to screen for Cushing’s syndrome?
1. 24 hour urinary cortisol
– 2 measurements to confirm diagnosis
– Serum ACTH and cortisol are secreted in discrete bursts so measurement not helpful
– Measured at bedtime or between 2300 and 0000 h
– 2 measurements to confirm diagnosis
3. Overnightlowdosedexamethasonesuppression test
– Administer dexamethasone between 2300 and 0000 h
– Measure serum cortisol between 800 and 900 h
What is in the differential diagnosis for Cushing’s syndome?
ACTH dep Cushings syndrome (cushings disease, ectopic ACTH syondrome, ectopic CRH syndrome)
ACTH indep Cushings Syndrome (adrenal adenoma/carcinoma, micro/macronodular hyperplasia)
Pseudo Cushings syndrome (MDD, alcoholism)
How is the low dose dexamethasone test performed and interpreted?
Dexamethasone INHIBITS pit ACTH secretion
LOW DOSE: overnight screening (1 mg dose)
- can perform a 2 day test w/ 2 mg dose
- Cushings syndrome pts will generally NOT suppress cortisol below 1.8-2 mcg/dL
- however sutdies have shown that there are some cushings that DO suppress so anohter test must be used to confirm the diagnosis
What is the high dose dexamethasone suppression test, and what is it used for clinically?
-- OVernight or 2 days (8 mg doses)
– Used to differentiate Cushing’s disease from Cushing’s syndrome
– ACTH secretion in Cushing’s disease is only relatively resistant to dex suppression
– ThereforeinCushing’sdiseaseitwillNOTsuppressatlowdosebutWILL suppress at high dose
• Cushing’s disease (pit adenoma) patients will generally suppress to < 5.0 mcg/dL serum cortisol
• Normal patients will suppress to undetectable cortisol levels
– Incontrast,mostnonpituitarytumorswillnotsuppresswitheitherlowor high dose
Why is dexamethasone used in the suppression test and not other steroids?
• Measurement of cortisol is unaffected by dexamethasone
• Several other steroids cross‐react with cortisol assays and would give falsely elevated cortisol results
• Can measure serum dexamethasone when performing suppression tests
– Verify compliance
– Verify adequate blood levels obtained from dose
Once Cushing’s syndrome has been confirmed, how do you establish the cause?
• Measurementof ACTH on 2 separate days recommended due to episodic nature of secretion
• CRH = corticotropin releasing hormone test
• IPSS = inferior petrosal sinus sampling
12 year old girl presents for outpatient follow‐up after a recent hospitalization for severe vomiting requiring rehydration
– Diagnosed with celiac disease at age 8
– Total of 3 hospitalizations for vomiting in the last 16 months – History of anxiety and depression
– Severe irritability, hypersomnia
– Stomachaches, dizziness, anorexia with significant weight loss – Severe fatigue
– Muscle and joint pain
What are the common signs and symptoms of chronic adrenal insufficiency (Addison’s disease)?
weakness, tiredness, fatigue
What findings are helpful for distinguishing primary adrenal insufficiency from secondary or tertiary adrenal insufficiency?
• Hyperpigmentation secondary to elevated ACTH
– Seen in primary adrenal insufficiency (not secondary or tertiary)
– Due to increased pro‐opiomelanocortin, a prohormone that is cleaved to biologically active ACTH, MSH, and others
– Elevated MSH leads to increased melanin synthesis
– Most conspicuous in areas exposed to light or friction
– Will fade with adequate therapy
• Mineralocorticoid deficiency not present in secondary/tertiary adrenal insufficiency
– Aldosterone preserved, and can be stimulated by intact renin‐angiotensin system
– As a result, will not see hyponatremic hyperkalemic hypotension
What are the causes of adrenal insufficiency in children?
Primary (CAH, abnormal adrenal deve, autoimmunity, infection, drugs)
What laboratory tests are used to establish a diagnosis of adrenal insufficiency?
First step: measure a random 8 am serum cortisol and ACTH
Second step: ACTH stimulation test
– Measure serum cortisol at baseline and 30 and 60 minutes after IV injection of cosyntropin (synthetic ACTH)
– Normal response is considered a minimum serum cortisol value of 18‐20 mcg/dL before or after ACTH injection
Third step: test to evaluate hte underlying cause
Our patient had the following results:
Serum cortisol: < 0.3 mcg/dL (5‐25) Serum ACTH: 2069 pg/mL (≤ 46 pg/mL)
ACTH stimulation test:
Baseline, 30 min and 60 min serum cortisol: < 0.3 mcg/dL (5‐25)
Does she have primary, secondary or
tertiary adrenal insufficiency? What
additional tests should be performed?
Primary adrenal insufficiency
How do you evaluate for pimary adrenal insufficiency?
– Measure anti‐adrenal antibodies
– If CAH is suspected measure adrenal androgens
• Unlikely in this case given later age of presentation and lack of virilization
– If negative, screen for TB, adrenoleukodystrophy, adrenomyeloneuropathy, adrenal hypoplasia congenita
What is autoimmune adrenal insufficiency?
found with high anti-21-hydroxylase antibodies present
– In adults, accounts for 70‐90% of adrenal
– In the 1800s when Addison’s disease was first described, bilateral adrenal destruction by TB was most common cause
– Anti‐21‐hydroxylase is present in serum of 86% of affected patients
In patients diagnosed with autoimmune
adrenal insufficiency, what other clinical issues should the physician be concerned about?
50‐65 % of patients with autoimmune adrenal insufficiency have one or more other autoimmune endocrine disorders
– Combination of autoimmune adrenal insufficiency and other autoimmune endocrine disorders known as polyglandular autoimmune syndromes types I and II
– If you recall, the patient has a known diagnosis of celiac disease which is associated with autoantibodies
• Patients with celiac disease had an 11x increased risk for adrenal insufficiency in a Swedish study