Adrenal Flashcards
What are primary causes of adrenal insufficiency?
Addison’s disease (most common)
CAH
Infection
1. TB
2. Histoplasmosis
3. HIV
Hemorrhagic infarction
Metastatic disease
1. Breast
2. Lung
Drugs (inhibit cortisol synthesis)
1. Etomidate
2. Ketoconazole/fluconazole
What are secondary causes of adrenal insufficiency?
Exogenous steroid exposure (most common, decreased ACTH w/ adrenal atrophy)
Sheehan’s syndrome
Pituitary tumor s/p resection
How do you diagnose Addison’s disease?
- Morning serum cortisol concentration (< 3 mcg/dL) & ACTH
- Short ACTH stimulation test (high vs low dose) - cortisol will fail to rise in primary adrenal insufficency; will be >2x in 30min if 2º
What is Addison’s disease and what is the prevalence of concomitant autoimmune disease? POI?
Autoimmune process that destroys adrenal cortex
- 53% have another autoimmune disease
- 20% have pOI
How do you diagnose CAH?
-17-OHP (8am in follicular phase) >800 ng/dL (neonates > 3500 ng/dL)
< 200 ng/dL excludes diagnosis (<100 in neonates)
200-800 ng/dL indeterminate (per UTD >200 is virtually diagnostic)
-If indeterminate, perform High-dose ACTH stimulation test:
Phlebotomy ~ 1 hour post 1 ug/m2 (or 250 mcg) ACTH; >1500 ng/dL = diagnostic
Describe pattern of 17-OHP secretion?
17-OH P has diurnal pattern – peak in AM and nadir late in day
How do you treat CAH initially?
-Classical: Glucocorticoids (hydrocortisone) + mineralocorticoids (fludrocortisone)
-Potential for GnRH agonist to avoid/delay precocious puberty
-Monitoring:
*17-OHP between 400 and 1200 ng/dL
Bone density, serum 17 OHP, androstendione, testosterone
*Plasma-renin levels for MC treatment
How do you manage CAH long term in adults?
Transition to PM long-acting glucocorticoids (dex – most potent, prednisone – mid potent)
How do you treat NCCAH
- Children: Glucocorticoids if premature puberty/accelerated growth (hydrocortisone 10-15 mg/m2)
- Women: OCPs for hirsutism/acne +/- anti-androgens
Describe presentation of Sheehan’s syndrome?
Failed lactation, secondary amenorrhea, loss of sexual hair
Common chronic s/sx of adrenal insufficiency?
acute?
Acute: shock, abd pain, fever
Nausea/vomiting, weakness, hypoglycemia, hypotension (rare in 2’ & 3’)
If PRIMARY - buccal hyperpigmentation (95%) (from increased ACTH and increase MSH as byproduct of POMC)
How do you diagnose Cushing’s Syndrome?
(One of three tests)
1. 24-hour urine free cortisol excretion (measured twice)
2. Late night salivary cortisol level (measured twice)
3. 1mg (high dose) overnight dexamethasone suppression test (best test in patient with hirsutism)
*Take dexamethasone between 11pm-12am, measure serum cortisol at 8am
*False positive in women on OCPs (E2 leads to increased CBG) and obesity
What are the different etiologies of Cushing’s Syndrome?
Iatrogenic / glucocorticoid therapy (most common)
Cushing’s Disease (pituitary ACTH-secreting adenoma)
Ectopic CRH or ACTH by bronchial carcinoids / small cell lung ca
Cortisol-secreting adrenal tumors
How do you determine if the cause of Cushing’s Syndrome is ACTH independent or dependent?
-Measure serum ACTH (normal circadian rhythm is lost so can be measured anytime)
<5 pg/mL (low) = ACTH independent (adrenal tumor) -> CT A/P
>20pg/mL (high) = ACTH dependent (ACTH adenoma, ectopic ACTH secretion)
What is the most common cause of secondary Cushing’’s Syndrome?
Cushing’s Disease
What is the most common cause of primary Cushing’’s Syndrome?
Iatrogenic
(*only one without hyperandrogenism)
Describe the role of CRH stim test in identifying the cause of Cushing’s Syndrome?
- Pituitary (responds to CRH)
- Ectopic (does not response to CRH) ACTH secretion
Describe the role of high dose dexamethasone suppression test in identifying the cause of Cushing’s Syndrome?
High dose dexamethasone suppresses pituitary ACTH (i.e. CRH bronchiole tumor)
High dose dexamethasone does not suppress ectopic ACTH (i.e. small cell lung tumor)
Describe the role of petrosal venous sinus catheterization in identifying the cause of Cushing’s Syndrome?
risks?
Measure differential in ACTH concentration b/w petrosal venous sinus & peripheral vein w/ 10 min of CRH administration
Higher in the petrosal venous sinus (brain) if pituitary tumor, lower in the brain if ectopic ACTH secreting tumor
Risks of CVA, PE/DVT, cranial nerve palsy
Describe treatment approach for Cushing’s syndrome?
- Address underlying cause (transsphenoidal surgery (70% success), lung tumor resection, adrenalectomy)
- If surgery contraindicated or persistent/recurrent following surgery:
- Adrenal enzyme inhibitors = 1st line (i.e. ketoconazole -> metyrapone)
- Inhibits the first step in cortisol biosynthesis (side-chain cleavage) and, to a lesser extent, the conversion of 11-deoxycortisol to cortisol
- Even more potent inhibitor of C17-20 desmolase, decreasing androstenedione and testosterone production
- Also inhibits ACTH secretion in vitro at therapeutic doses by impairing corticotroph adenylate cyclase activation
- Adrenolytic agents (i.e. mitotane)
- If pituitary tumor, consider cabergoline or somatostatin-analog
Describe clinical presentation of iatrogenic Cushing’s Syndrome?
Glaucoma
Cataracts
Osteonecrosis
Pseudotumor cerebri
Pancreatitis
Panniculitis
Describe clinical presentation shared by Cushing’s Syndrome?
Central obesity
Psychiatric
Poor wound healing
Osteoporosis
Glucose intolerance
HPA supp.
Describe clinical presentation of endogenous Cushing’s Syndrome?
HTN
Hirsutism / acne
Striae
Menstrual abn
Impotence
Cervical fat pad / buffalo hum
Round face
Androgens in women – Serum concentration (highest to lowest)
i. DHEAS
ii. DHEA
iii. Androstenedione
iv. Testosterone
v. DHT
Enzyme deficiencies associated w/ salt-wasting (and the 2 not)
i. 21-hydroxylase (low aldosterone/cortisol, high androgens)
ii. 11β-hydroxylase (low aldosterone/cortisol, high androgens)
iii. 3β-hydroxysteroid dehydrogenase (low aldosterone/cortisol/androgens) (Some masculinization of 46XX fetus (High DHEA can convert to Test); Amb genitalia of 46XY (Low test, Low DHT) )
iv. Aldosterone synthase (low aldosterone, high cortisol/androgens)
v. StAR (steroid acute-regulatory protein)
vi. Lipoid
NOT
i. 17α-hydroxylase (high deoxycorticosterone – low aldosterone)
ii. 17,20-lyase (normal deoxycorticosterone – normal aldosterone, normal cortisol
How is 11B-hydroxylase deficiency different from the others?
HTN / HYPERnatremia / HYPOkalemia
Since some mineralcorticoid action, but can rarely still get salt-wasting
17α- hydroxylase and its effect on ACTH, mineralcorticoids, renin, aldosterone
Increased ACTH & mineralcorticoids
Decreased renin & aldosterone (due to volume expansion/HTN form increased mineralcorticoids)
Ovulation induction in a patient with 17α-hydroxylase deficiency?
(Will only work if the patient has some residual 17α-hydroxylase activity)
- Glucocorticoid replacement to decrease P4 levels & improve BP
- Continuous transdermal E3 and then add P4 on days 15-25
- Then stimulate w/ FSH, add incremental E2 for EMS (follicle will develop on its own mostly)
RAAS system mechanism
- Low blood pressure → kidneys secrete renin
- Renin then converts angiotensinogen (from the liver) → angiotensin I
- Angiotensin I → angiotensin II by the enzyme angiotensin converting enzyme from the lungs
Effects of Angiotensin II
- Blood vessel constriction
- Stimulates the synthesis of aldosterone from the adrenal cortex
- Aldosterone causes reabsorption of sodium/water from the kidneys
- Stimulates vasopressin secretion from posterior pituitary
- Vasopressin increases water reabsorption from kidney
- Moderate peripheral vasoconstriction
Treatment of prenatal CAH (for mom & fetus)
Mom: Hydrocortisone (not metabolized by placenta, no risk of fetal HPA suppression)
Fetus: If high risk, start Dex asap (before 9w) to decrease androgen production in fetus. If male (or unaffected female), can stop when CVS results
Inheritance of CAH
AR
CAH most common / least common in what population?
Most: Eskimo/French/Mediterranean
Least: AA’s/Chinese
Autoimmune disorder with a deficit of thyroid/adrenal hormones – which hormone would you replace 1st and 2nd
MC → GC → Thyroid (otherwise can precipitate adrenal insuff.)
How does metyrapone work?
If using to dx, what hormone are you checking?
What can it treat?
inhibits 11B-hydroxylase blocker - blocks cortisol synthesis
Checking ACTH to determine primary/secondary adrenal insuff.
Can treat Cushing’s syndrome
Most potent GC receptor inhibitor
RU-486 (mifepristone)
What causes a false positive dexamethasone suppression test?
Estrogen (i.e. OCP)
Difference b/w low and high dose dex suppression test
LDDST used for initial cushing’s syndrome as a screening or a confirmatory test
HDDST - is used in ACTH-dependent Cushing syndrome, to help distinguish pituitary (i.e., Cushing disease) from an ectopic source of ACTH overproduction.
principle behind the high-dose test is that overproduction of ACTH in Cushing disease (but not ectopic tumors) can undergo partial or full suppression by high doses of dexamethasone
