Term
| What are the major anatomical regions and functions of the adrenal glands? |
|
Definition
1) Outer Cortex (80%)- Mesoderm
- Yellow-organge from high lipid content
- Steroid synthesis from cholesterol
2) Inner medulla (20%)- Neuroectoderm
- Dark red due to sinusoidal blood supply
- Catecholamine synthesis from tyrosine. |
|
|
Term
| What are the 3 types of secretory cells of the adrenal cortex? |
|
Definition
1) Glomerulosa cells (Zona glomerulosa)
- Outermost (5%) cells that produce Aldosterone
- Under RAAS regulation
2) Fasciculata cells (Zona fasciculata)
- Middle/largest zone (80%) production of CORTISOL
- Regulated by ACTH
3) Reticularis cells (Zona reticularis)
- Innermost cortex region (15%)
- Site of androgen production (Androstenedione and Dehydroepiandrosterone/DHEA)
- Regulated by ACTH with extra-adrenal conversion to estrogen and testosterone |
|
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Term
| Describe the vascular supply of the adrenal glands. |
|
Definition
1) Rich arterial supply from branches of the Aorta, Renal and Inf. Phrenic arteries
- High basal flow, with increased flow from cortex to medulla during stress (ACTH).
2) Adrenal central vein (smooth muscle bundles) is exposed to catecholamines from medulla during stress, causing venoconstriciton and increased intra-adrenal pressure during stress. |
|
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Term
A patient on aspirin who was in a car accident presents with acute hypotension and adrenal insufficiency.
What happened? |
|
Definition
Spontaneous massive bilateral hemorrhage of adrenal glands (Adrenal apoplexy) (Bleeding predisposition with severe stress)
Central adrenal vein is exposed to medullary catecholamines during stress, which causes venoconstriction and increased intra-adrenal pressure that can cause hemorrhage. |
|
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Term
| Describe the embryonic development of Adrenal cortex. |
|
Definition
Mesodermal origin.
In mid-gestation, outer "definitive" zone of cortex (10%) is destined to become adult cortex, while large inner "fetal zone" (90%) is destined regress.
- Zona glomerulosa (aldosterone) and fasciculata (cortisol) become fully developed by 1-3 years (partially at 1 year)
- Zona reticularis (sex hormone precursors) is not partially developed until 1 year and not fully until puberty. |
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Term
| The fetal HPA axis is established by week 8 of gestation. How do the fetal adrenal cortex and placenta regulate cortisol and androgen levels in the fetus? |
|
Definition
1) Adrenal 2beta-hydroxysteroid DH activity type 2 (HSD3b2)
- Expressed in "definitive" outer cortex ONLY
- Conversion of cholesterol to cortisol and biosynthesis of aldosterone and androstenedione (fetal zone can ONLY make DHEA)
- Expression of cortisol during 8-12 weeks prevents fetal ACTH and therefore prevents fetal zone DHEA production, protecting genetic female embryo's undifferentiated genitalia from exposure.
2) Placenta HSD11b2
- Inactivates cortisol (to cortisone)
- High during 1st trimester (prevents fetal exposure)
- Maternal cortisol is dominant source during 2nd trimester (75%)
- Lower again (25%) during 3rd trimester
3) Placental aromatase
- Converts androgenic to esterogenic steroids (DHEA from fetal adrenal to estrogen estriol)
- Limits fetal female exposure to DHEA
- Minor protective mechanism during 1st trimester |
|
|
Term
How do HSD3b2 and HSD11b2 levels fluctuate during the 1st 3 trimesters of fetal development?
How is this fluctuation protective the fetal female? |
|
Definition
1) 1st trimester
- HSD3b2 and HSD11b2 are high
- Fetal cortisol production inhibits ACTH-dependent DHEA production in fetal zone and prevents exposure of undifferentiated female genetalia to androgen
- High HSD11b2 inhibits maternal cortisol and prevents it from crossing placenta
2) 2nd trimester
- Both enzymes decline (less fetal cortisol and more maternal cortisol)
3) 3rd trimester
- HSD32b increases and 75% of cortisol is derived from fetus again.
HSD3b2 (adrenal) makes Cortisol, Aldosterone and Androstenedione and is expressed in "definitive" outer cortex ONLY (fetal zone makes DHEA ONLY)
HSD11b2 (placental) inactivates Cortisol |
|
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Term
| Describe the basics of steroid biosynthesis. |
|
Definition
Produced as needed- NOT stored
1) Cholesterol cleaved to C21 4 ringed structure
- C21: progesterone, glucocorticoids and mineralcorticoids
- C19: Androgenic
- C18: Estrogenic
2) Adrenal gland makes all steroids, while gonads produce all EXCEPT cortisol and aldosterone, which require 11b-Hydroxylase |
|
|
Term
| How is cortisol transported in the plasma? |
|
Definition
Free plasma cortisol levels do not change, but CBG levels do (this is why nephrotic syndrome or estrogen administration do not manifest as low or high cortisol symptoms, respectively).
1) 90% binds high affinity, low capacity (Cortisol binding globulin/Transcortin)
2) 10% binds low affinity, high capacity (Albumin) |
|
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Term
| What clinical manifestations related to cortisol deficiency might a patient with nephrotic syndrome have? |
|
Definition
Low CGB levels, but plasma levels DO NOT CHANGE.
NO symptoms. |
|
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Term
| How are adrenal androgens converted to estrogen and testosterone? |
|
Definition
Steroid hormones are hepatically metabolized and excreted in urine.
1) Adrostenedione is converted to estrogens by P450 aromatase expressed in fat cells
- fat people have high estrogen levels!
2) Androstenedione is converted to Testosterone via HSD17b3, which can be converted to estradiol by CYP19 |
|
|
Term
| How is adrenal secretion of cortisol from the zona fasciculata regulated? |
|
Definition
HPA axis negative feedback
1) Stimulated by ACTH (stimulated by pulsatile release of CRH in PVN of hypothalamus that peaks at 8am) binding to adrenal cortex
**typical cortisol levels decline during the day**
**65% of daily adrenal secretion of cortisol (15 mg/day) occurs between 6am and 2pm, so give 2/3 of replacement in morning**
2) CRH also stimulated by acute/chronic stress, exercise, cold exposure, hypotension, trauma and hypoglycemia |
|
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Term
| What are the acute and chronic actions of ACTH on the adrenal gland? |
|
Definition
1) Acute increases occur via cAMP
- Increased blood flow
- Increased cholesterol (generation of pregnelolon)
- Increased cortisol (2-5 min)
2) Chronic occurs via CRE on genes
- Increased adrenal mass
- Increased synthesis of steroidogenic enzymes
- Increased LDL receptors. |
|
|
Term
| What are the basic genomic and non-genomic actions of glucocorticoids like cortisol? |
|
Definition
Diffuse through plasma membrane, bind cytoplasmic receptor (Glucocorticoid/Type 2) and translocate to nucleus.
**potency correlates with affinity for type 2 receptor (example, dexamethasone >>> aldosterone for type 2)**
1) Genomic (hours to days)
- Major: GR complex binds Glucocorticoid response elements (GRE) and alter transcription
- Secondary: Bind transcription factors in cytoplasm preventing or enhancing expression of their genomic actions (binds NF-KB and prevents inflammation)
2) Non-genomic (minutes)
- Plasma membrane alterations (restoring BP in hypotensive patients with adrenal insufficiency) |
|
|
Term
True or False:
Binding affinity of steroid hormones to type 1 Mineralcorticoid receptors correlates with cellular potency. |
|
Definition
False: This is ONLY true to type 2 glucocorticoid receptors (Dexamethasone vs. aldosterone).
Cortisol and aldosterone bind type 1 receptors with the same affinity, but aldosterone is >400x more potent mineralcorticoid action.
Type 1 receptors are restricted in their distribution, while Type 2 receptors are everywhere! |
|
|
Term
Which of the following is NOT a known action of glucocorticoids?
1) Maintain/Raise blood glucose
2) Protein loss from muscle
3) Chronic central fat accumulation
4) Decrease glucose delivery to brain
5) Osteopenia
6) Suppressed GI absorption of calcium |
|
Definition
| 4: This is not characteristic |
|
|
Term
| Describe the basics of Aldosterone biosynthesis. |
|
Definition
1) Both glomerulosa and fasciculata possess enzymatic capacity to produce Deoxycorticosterone (DOC) from Cholesterol
2) Only glomerulosa posses Aldo synthase (CYP11b2), which is required for the final 3 steps of converting DOC to aldosterone
- Final step regulated by Ang-II (vs. ACTH for cortisol in fasciulata) |
|
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Term
| What is the major biological action of aldosterone? |
|
Definition
Acts on principal cell of cortical collecting duct, as well as colon and salivary glands, binding Type 1 cytosolic receptors.
1) Increases ENaC residence and mRNA expression in apical membrane of tubule, by suppressing rate of recycling
- Increased sodium reabsorption, potassium/hydrogen excretion
2) Increases basolateral Na/K ATPase
- Increased sodium reabsorption to blood stream and expansion of extracellular envrionment. |
|
|
Term
Why does the kidney response to aldosterone preferentially to cortisol despite the fact that Type 1 receptors exhibit the same affinity to both and cortisol is 100-fold more prevalent?
What does this have to do with licorice consumption? |
|
Definition
1) 11b-hydroxysteroid DH type 2 (HSD11b2) in distal nephron inactivates cortisol to cortisone (<1% affinity)
2) High levels of glycyrrhizic acid, an HSD11b2 inhibitor, can cause mineralocorticoid excess syndrome!
Also can be caused by cortisol over-production or defective HSD11b2 |
|
|
Term
| Describe the regulation of Aldosterone secretion from the adrenal cortex. |
|
Definition
ACTH is IRRELEVANT
1) RAAS (Ang-II)
- In response to low blood volume and/or pressure, renin is released to maintain renal perfusion
- Ang-II acts as vasoconstrictor and direct stimulus to zona glomerulosa of adrenal cortex.
2) High extracellular potassium levels
- Act directly on glomerulosa cells as independent stimulator |
|
|
Term
| What might the effect of ectopic ACTH production be on aldosterone secretion? |
|
Definition
NOTHING CHRONICALLY
Acute ACTH can have a transient effect by stimulating the first step in steroid hormone biosynthesis. |
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Term
| Why might a patient with CHF present with hypokalemia? |
|
Definition
Hyperaldosteronism due to RAAS to restore BP (Common in CHF, Cirrhosis with ascites and Renal artery stenosis)
This is physiological, vs. pathological (would have low renin, because high BP from decreased sodium excretion would inhibit renin) |
|
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Term
| How can you most easily distinguish secondary hyperaldosteronism from primary forms? |
|
Definition
Primary (hypertension, hypokalemia and metabolic acidosis) will have LOW RENIN (renal sodium retention sensed by macula densa)
Secondary will have HIGH RENIN (CHF, cirrhosis, renal artery stenosis) |
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|
Term
Patient presents with hypertension, hypokalemia, metabolic acidosis and no edema.
What is going on and what complications are you concerned about? |
|
Definition
1) Sounds like primary hyperaldosteronism (low renin)
- Patients without cirrhosis, CHF or arterial stenosis DO NOT have edema because of "mineralcorticoid escape" from ANP
2) Low cellular potassium causes
- Glucose intolerance
- Nephrogenic DI
- Weakness or paralysis |
|
|
Term
| What are the 2 major subgroups of primary hyperaldosteronism? |
|
Definition
Renin-indendent adrenal secretion with hypertension, hypokalemia and metabolic acidosis. Usually in <20 or >60 with htn refractory to antihypertensives.
1) Aldosterone-producing Adenoma (ADA)
- benign tumor in one adrenal gland
- cured by resection with anti-hypertensives
2) Idiopathic hyperaldosteronism
- Bilateral hyperplasia of zona glomerulosa
- Treated medically with Spironolactone and anti-hypertensives
- Second line agents include eplerenone, amiloride and triamterene |
|
|
Term
| How can primary hyperaldosteronism be diagnosed? |
|
Definition
High PAC:PRA ratio
1) Plasma aldosterone concentration (immunoassay) is high
2) Plasma renin activity (enzymatic assay) is low
- If both are increased, it is consistent with SECONDARY hyperaldosteronism
- If both are decreased, it is consistent with non-aldosterone mediated mineralocorticoid excess or mimetic syndrome (high cortisol or licorice intoxication) |
|
|
Term
A 19 year old presents with evidence of hypertension and hypokalemia. You run a plasma aldosterone concentration immunoassay and a renin-activity assay.
What do each of the following indicate diagnostically?
1) High PAC, Low PRA and High PAC:PRA ratio
2) High PAC, High PRA and Normal PAC:PRA ratio
3) Low PAC, Low PRA and Normal PAC:PRA ratio |
|
Definition
1) Primary hyperaldosteronism
- Aldosterone producing adenoma (surgical) or Idiopathic (medical treat)
OR low-renin essential hypertension
2) Secondary hyperaldosteronism
- CHF, Cirrhosis, Renal artery stenosis, Diuretics, Renin-producing tumor
3) Non-aldosterone mineralcorticoid excess syndrome
- High cortisol, low HSD11b2 (from licorice or other) |
|
|
Term
| How can you distinguish between primary hyperaldosteronism and essential hypertension (low-renin) in a patient with a high PAC and a low PRA? |
|
Definition
Aldosterone Suppression Tests (since PAC:PRA alone has poor PPV)
To confirm PHA, you must demonstrate non-physiologic adrenal aldosterone secretion with aldosterone suppression.
If PHA is present, order CT or MRI in young patients to look for APA vs. idiopathic PHA. If older, use adrenal venous sampling of aldosterone to distinguish unilaeral from bilateral (idiopathic)
1) Chronic volume expansion (CHronic oral sodium loading with measurement of 24h urinary excretion)
2) Acute volume expansion (IV saline with measurement of plasma Aldosterone)
3) Acute Ang-II inhibition with Ace-inhibitor (should see drop in plasma aldosterone) |
|
|
Term
| How can you clinically distinguish between ADA PHA and idiopathic PHA? |
|
Definition
Demonstrate PHA with elevated PAC:PRA and an abnormal aldosterone suppression test.
If PHA is present,
1) order CT or MRI in young patients to look for APA vs. idiopathic PHA.
2) If older, use adrenal venous sampling of aldosterone to distinguish unilaeral from bilateral (idiopathic) |
|
|
Term
Which of the following is NOT a classic clinical manifestation of chronic aldosterone deficiency or resistance?
1) Hyperkalemia with cardiac depolarization changes
2) Anion Gap metabolic acidosis
3) Negative sodium balance with volume contraction
4) Type IV renal tubular acidosis |
|
Definition
2- Aldosterone resistance/deficiency involves a Hyperchloremic metabolic acidosis (also called "Type IV RTA), because of impaired K/H exchange for Na in distal nephron.
Excess potassium leads to impaired production/excretion of ammonia, resulting in acidosis.
Hyperkalemia (cardiac repolarizarization issues), Negative sodium balance and Type IV RTA fit. |
|
|
Term
| What is Addison's disease? |
|
Definition
Chronic bilateral adrenal insufficiency with hypoaldosteronism and hypocortisolism and hypoadrogenism presenting with weakness and orthostatic hypotension (primary insufficiency)
Can be Primary (Autoimmune, infectious, infiltrative, bilateral hemorrhage, surgery) or Secondary (Hypopituitarism with lack of ACTH or HPA suppression)
Patients have hyperkalemia, hyperchloremic MA and chronic volume contraction due to deficient sodium reabsorption. |
|
|
Term
| What is the pathophysiology of the most common acquired form of isolated aldosterone deficiency not due to medications? |
|
Definition
Hyporeninemic Hypoaldosteronism associated with diabetic nephropathy
- Defective intrarenal conversion of prorenin to renin, with NO increase in PRA or PAC in response to salt deprivation.
- Hyperkalemia WITHOUT volume contraction (as opposed to Addison's disease) or advanced renal failure in adults. |
|
|
Term
Which of the following drugs DOES NOT cause drug-induced aldosterone deficiency/resistance?
1) Spironolactone
2) Loop diuretic
3) Cyclosporine
4) Ace inhibitors
5) NSAIDs
6) Amiloride
7) Beta blocker |
|
Definition
2- These drugs inhibit Na,K, 2Cl channels in TAL.
1) Inhibit aldosterone receptor (Increase PAC and PRA)
3 & 4) Inhibit synthesis/secretion (Decrease PAC and increase PRA)
5) Suppress renin release (Decrease PAC and PRA)
6) ENaC blocker interferes with renal action (High PAC and PRA)
7) Supreses renin release (Decrease PAC and PRA) |
|
|
Term
| What is the biggest clinical concern associated with aldosterone deficiency/resistance? |
|
Definition
Hyperkalemia- fix with potassium wasting diuretic (Furosemide), restriction and/or fludrocortisone (synthetic mineralocorticoid )
1) Cardiac re-polarization defect
2) Asystolic cardiac arrest |
|
|
Term
| How can you reduce hyperkalemia in isolated deficiency/resistance of aldosterone? |
|
Definition
1) Remove offending drug (Spironolactone, Ace inhibitors, B blockers, cyclosporine, Amiloride, Triamterene, NSAIDS)
2) Restrict K+ intake
3) K+ wasting diuretic (Furosemide)
4) Synthetic mineralocorticoid (Fludracortisone) |
|
|
Term
| Describe the underlying pathophysiology of the most common cause of primary adrenal insufficiency. |
|
Definition
Autoimmune Adrenalitis most common cause of Addison's
- anti 21-hydroxylase (cortisol and aldosterone synthesis) antibodies produce adrenal fibrosis and atrophy with lymphocytic infiltration
- 50% of cases have 1 or more other autoimmune conditions (2 types of polyglandular autoimmune syndrome)
1) Type 1
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
- AR mutation in autoimmune regulator (AIRE) on chromosome 21 presenting in childhood with a) hypoparathyroidism and b) chronic mucocutaneous candidiasis due to defective T-cell mediated anti-fungal immunity (Th17 with IL-17 and IL-22)
2) Type 2 (Schmidt's Syndrome)
- More common than type 1 with primary adrenal insufficiency in patients 20-40
- Graves (hyper) or Hashimoto (hypo), Pernicious anemia and/or Diabetes type 1 |
|
|
Term
| What form of Addison's disease is associated with AR mutations in the AIRE gene? |
|
Definition
Autoimmune Adrenalitis: Type 1 polyglandular autoimmune syndrome type 1 (APECED)
1) Primary hypoparathyroidism and chronic mucocutaneous candidiasis before age 10
2) Autoimmune adrenalitis between 10-15 (vs. 20-40 in type 2 Schmidt's) |
|
|
Term
| What are the major infectious causes of Addison's disease? |
|
Definition
1) TB- world issue
2) HIV/AIDS- US issue
- CMV and mycobacterium avium-intracellare infections |
|
|
Term
| What are the most common associations with Adrenal apoplexy? |
|
Definition
Bilateral massive spontaneous hemorrhage from increased intra-adrenal pressure (more arterial flow and venoconstriction from catecholamines)
Need severe stress + predisposition to bleeding or thrombosis
1) Bleeding
- Aspirin, Thienopyridine
- DIC with sepsis (bacterial)- also called "Waterhouse-Fridericksen Syndrome"
2) Thrombosis
- DIC (also), TP, anti-coagulatn drugs, antiphospholipid syndrome |
|
|
Term
| What is Waterhouse-Fridericksen Syndrome? |
|
Definition
| Bacterial sepsis with DIC causing Adrenal Apoplexy (bilateral hemorrhage) |
|
|
Term
| What are the major Congenital Adrenal Hyperplasia (CAH) syndromes? |
|
Definition
AR disorders of steroid biosynthesis (mos commonly reduced/absent activity of 21 hyroxylase (CYP21A2) producing primary adrenal insufficiency (Addison's) because of steroid hormone excesses and deficiencies.
1) Reduced adrenal production of cortisol leads to secondary increase in ACTH
2) ACTH leads to increased steroid hormones proximal to blockage and decreased hormones distal to the block |
|
|
Term
| Why might a male present with pseudohermaphroditism with adrenal insufficiency? |
|
Definition
Congenital Adrenal Hyperplasia Syndrome from deficient 21 hydroxylase (CYP21A2): no cortisol or aldosterone.
1) Lack of cortisol leads to increased ACTH
2) Buildup of androgen precursors that cannot be converted to cortisol or aldosterone |
|
|
Term
Which form of congenital adrenal hyperplasia leading to Addison's disease is associated with each of the following?
1) Hypertension and hypokalemia with male psuedohermaphrodism
2) Hypertension and hypokalemia due to excess DOC
3) Hypertension, hypokalemia and hypogonadism in males AND females |
|
Definition
All are AR
1) 21-hydroxylase deficiency MOST COMMON
2) 11b-hydroxylase deficiency
3) 17a-hydroxylase/17,20 lyase deficiency |
|
|
Term
| What drugs are known to induce primary adrenal insufficiency? |
|
Definition
| Etomidate (anesthetic) and Ketoconazole (Anti-fungal) |
|
|
Term
| What is Adrenoleukodystrophy? |
|
Definition
X-linked recessive cause of primary chronic adrenal insufficiency (10%).
Defective beta oxidation of fatty acids leading to accumulation of very long chain FA in serum with accumulation of lipid moieties in membrane or cells of brain and adrenal cortex
See neurologic dysfunction (progressive) and primary adrenal insufficiency (no aldosterone or cortisol) |
|
|
Term
| What is the most common causes of secondary adrenal insufficiency? |
|
Definition
HPA suppression from chronic glucocorticoids (withdrawal effects)
Patients who have either received 80mg cortisol per day for >3 weeks or who have clinical manifestations of Cushing's.
1) Destruction of fasciculata and reticularis with sparing of glomerulosa (Aldosterone)
2) Recovery takes 1 year and capacity of hypothalamus to secrete CRH and pituitary to secrete ACTH returns before fasciulata function of adrenal gland does. |
|
|
Term
| Why is the zona glomerulosa spared in Glucocorticoid-mediated HPA suppression (secondary cause of Addison's)? |
|
Definition
It is ACTH independent! Aldosterone is spared.
Fasciculata and Reticularis depend on ACTH and take 1 year or more to recover (ACTH and CRH come back before fasciulata does) |
|
|
Term
| Which neoplastic diseases commonly cause secondary adrenal insufficiency? |
|
Definition
1) Primary pituitary tumors (prevent ACTH release occurs late)
- MOST COMMON is Pituitary macroadenoma (75% overall)
2) Craniopharyngromas (and other hypothalamic tumors that prevent CRH release) |
|
|
Term
What are the most common causes of secondary adrenal insufficiency in each of the following categories?
1) HPA suppression
2) Neoplastic
3) Inflammatory disease
4) Acute |
|
Definition
1) Glucocorticoids
- ACTH and CRH suppression and withdrawal
- Recover after a year or more
2) Pituitary macroadenoma- Late ACTH loss
3) Autoimmune hypophysitis- Early ACTH loss
- common in young post-partum women who have taken humanized antibodies
4) Postpartum pituitary necrosis (Sheehan's Syndrome), Sudden hemorrhage (Pituitary apoplexy), Head trauma
- Maintain normal response to exogenous ACTH for several weeks |
|
|
Term
Which of the following is not a common cause of secondary adrenal insufficiency?
1) Pituitary macroadenoma
2) Glucocorticoid over-use
3) Autoimmune hypophysitis
4) Adrenoleukodystrophy
5) Pituitary apoplexy |
|
Definition
4- This is a cause of PRIMARY Addison's
X-linked recessive disorder with defective beta oxidation of fatty acids
High concentrations of long-chain fatty acids form lipid moietites in cell membranes of brain and adrenal cortex, leading to progressive neurological disease and adrenal insufficiency. |
|
|
Term
| What is the most important cause for alarm in primary and secondary adrenal insufficiency? |
|
Definition
Deficient CORTISOL producing hypotension that is unresponsive to pressors or volume expansion is biggest worry
1) Hypotension: See low systemic resistance with high or normal CO (like septic shock)
2) Hypoglycemia (impaired hepatic gluconeogenesis),
3) Hyponatremia (SIADH from cortisol) |
|
|
Term
| What diagnosis should always be considered in a patient with unexplained hypotension, hypoglycemia and/or hyponatremia? |
|
Definition
| Adrenal Insufficiency (lack of cortisol) |
|
|
Term
| How can secondary causes of adrenal insufficiency be distinguished from chronic primary causes clinically? |
|
Definition
Both have hypotension, hypoglycemia (hepatic gluconeogenesis issue) and hyponatremia (SIADH) due to low cortisol.
**In primary form, lack of aldosterone also contributes to volume contraction and hyponatremia**
Chronic Primary ONLY
- Hyperpigmentation (chronic ACTH induction of melanin)
- Hyperkalemia (Lack of aldosterone)
- Hyperchloremic acidosis (Type IV RTA)
- Salt craving |
|
|
Term
| What is "Adrenal Crisis" and how does it present clinically? |
|
Definition
Adrenal insufficiency with Cardiovascular collapse that is often precipitated by severe intercurrent illness or stress.
1) Hypotension (<90/60) unresponsive or partially responsive to volume expansion or pressors (catecholamine)
2) Multiple organ underperfusion
3) Fever/Abd pain/Hypoglycemia/Confusion |
|
|
Term
| How is Adrenal insufficiency diagnosed? |
|
Definition
1) Can measure 8am cortisol
2) Confirm with Rapid ACTH stimulation test to assess reserve capacity of adrenal cortex to secrete cortisol.
- NO response with elevated ACTH is primary and small response with low ACTH is secondary
3) If adrenal crisis is suspected (hypotension that is unresponsive with multiple organ hypoperfusion), TREAT immediately with stress doses of IV glucocorticoid replacement and 0.9% NaCl |
|
|
Term
What are the principles of glucocorticoid replacement for adrenal insufficiency?
How should it be adjusted in pregnancy?
What about with congenital adrenal hyperplasia (CAH)? |
|
Definition
Diagnosed with morning cortisol level and confirmed with ACTH stimulation test.
1) When short-acting hydrocortisone/cortisol is used, give 2/3 in morning and 1/3 in late afternoon to approximate diurnal pattern
- Single daily dose of prednisone/dexa is sufficient.
2) Requirements increase 25% during pregnancy because of increased VOD of cortisol, increased plasma CBG levels and increased HPA axis activity.
- Use HYDROCORTISONE and not dexamethasone
3) CAH has chronically elevated plasma ACTH levels, which must be suppressed with longer-acting glucocorticoids (Prednisone, Dexa) to prevent over-stimulation with androgens. |
|
|
Term
True or False:
Hydrocortisone is the preferred treatment for adrenal insufficiency during pregnancy. |
|
Definition
True: Short-acting agent that does not harm fetus.
This is different than in other adults, with CAH, for example, who benefit from long-acting prednisone or dexamethasone |
|
|
Term
True or False:
Patients with secondary adrenal insufficiency do not require Mineralocorticoid replacement |
|
Definition
True! Only primary Addison's disease has damage to zona glomerulosa, which is NOT sensitive to ACTH.
Addison's patients do get replacement as a precautionary measure and to prevent salt craving (Fludrocortisone monitored by renin levels)
**Fludrocortisone is not useful for immediate treatment** |
|
|
Term
| Why might you prescribe a patient Fludrocortisone? |
|
Definition
| Synthetic mineralocorticoid used as a safety measure in primary Addison's adrenal insufficiency for aldosterone. |
|
|
Term
| How should patients with suspected adrenal crisis be treated? |
|
Definition
| Unresponsive hypotension with multi-organ hypoperfusion requires immediate IV glucocorticoid replacement and 0.9% NaCl to correct hypotension. |
|
|
Term
Which of the following is NOT a classic feature of Cushing's syndrome?
1) Moon faces
2) Central obesity
3) Nausea/vomitting
4) Hypertension
5) Diabetes
6) Osteoporosis |
|
Definition
Overproduction of Cortisol presenting with central obesity, new onset, refractory hypertension and diabetes.
3: Nausea and vomiting are not classically associated with Cushing's
Signs and Symtpoms
- Central obesity
- Hypertension/edema/hypokalemia
- Hirsutism/amenorrhea/acne
- Ecchymoses
- Proximal myopathy
- Diabetes mellitus
- Osteoporis |
|
|
Term
| What are the 3 primary etiologies of spontaneous Cushing's syndrome? |
|
Definition
Overproduction of cortisol due to loss of negative feedback on HPA axis
**Most common cause is corticosteroid use**
1) Pituitary tumor (75%)
- microadenoma that secretes ACTH semi-autonomously
2) Adrenal tumor (5%)
- Usually benign
3) Ectopic ACTH- or CRH-secreting tumor (20%)
- Small cell lung cancer or Carcinoid |
|
|
Term
| Why do patients with cortisol-secreting tumors get diabetes? |
|
Definition
Cushing's syndrome is associated with insulin-resistance (80%) and frank Diabetes mellitus (20%).
Cortisol inhibits insulin action on glucose metabolism, favoring gluconeogenesis and preventing utilization by muscle and fat cells. |
|
|
Term
Explain why patients with Cushing syndrome get each of the following.
1) Diabetes
2) Purple cutaneous striae and muscle weakness
3) Osteoporosis
4) Hypertension
5) Infection/Mycoses
6) Psychological disturbance |
|
Definition
1) Cortisol-mediated inhibition of insulin action on glucose (gluconeogenesis occurs)
2) Cortisol increases proteolysis in muscle (weakness) and skin (striae)
3) Cortisol increases calcium excertion- look for fractures
4) Increased sensitization to catecholamines, or mineralosteroid action of cortisol at high levels
5) Suppression of immune system (Inflammatory cytokines and antibodies decrease)
6) Decreases CNS threshold for seizures |
|
|
Term
| What clinical testing is employed to definitely diagnose Cushing's syndrome and to asess adrenal cortical function? |
|
Definition
1) Screening tests
- 24h urine free cortisol (2 or more): adrenal production)
- 1mg Dex suppression test (HPA sensitivity)
- Late night salivary cortisol (2 or more)
2) Suspicious results (Pseudo expected)
- 2 day low dose Dex suppression
3) If Cushing's is detected, measure plasma ACTH
- if high, it is ACTH-dependent (Pituitary microadenoma or Ectopic ACTH secretion)
- If low, suspect order Adrenal CT (Adrenal tumor)
Static Measures
- Plasma cortisol (8-25)
- Urinary free cortisol (20-100)
- Plasma ACTH
Dynamic Measures
- Stimulation (of pituitary or adrenal reserve) with ACTH or CRH
- Suppression (PA axis) with Dexamethasone. |
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Term
What do each of the following laboratory values indicate about a patient with new-onset, refractory hypertension, diabetes and hypokalemia?
1) Elevated free urinary cortisol on two 24 collections
2) Low overnight Dexamethasone suppression test
3) Elevated late night salivary cortisol |
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Definition
1) Excess production
2) Abnormal HPA feedback
3) Lack of normal circadian rythm |
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Term
| What is the "high dose Dexamethasone test" and how is it generally used? |
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Definition
1) Differentiate pituitary microadenoma etiology from other causes
2) Failure of high dose suppression or urinary or serum cortisol is evidence AGAINST pituitary microadenoma, since these tumors are "semi-autonomous"
Abnormal high dose dexamethasone test suggests ectopic ACTH secretion or primary adrenal tumor. |
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Term
How is CRH stimulation used diagnostically in a patient with suspected Cushing's (hypertension, new onset diabetes, central obesity, hypokalemia, ect)?
What is the role of "petrosal sampling"? |
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Definition
1) Distinguish between pituitary microadenoma tumors and ectopic ACTH-producing tumors.
Most ACTH- secreting pituitary tumors are hyper-responsive to CRH relative to normal pituitary, but most ectopic producers do NOT respond.
Response >35% indicates pituitary tumor, vs. <35% for ectopic production.
2) Sampling from petrosal venous blood allows you to localize "pituitary production"
- Gradient of > 3:1 (petrosal:peripheral) ACTH suggests pituitary tumor.
- Gradient <3:1 suggests ectopic producer. |
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Term
Diagnose the cause of cushing's syndrome based upon the provided laboratory parameters.
1) Elevated plasma ACTH, 25% suppression of ACTH with high dose dexmethasone, normal pituitary MRI and negative petrosal sampling with CRH.
2) Slightly elevated plasma ACTH with 75% suppression with high dose dexamethasone. Normal adrenal CT with positive petrosal sampling with CRH.
3) Decreased plasma ACTH with 20% suppression with high dose dexa. Negative petrosal sampling with CRH. |
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Definition
1) Ectopic ACTH or CRH-producing tumor
- Negative petrosal sampling, pituitary MRI and 25% suppression argues against pituitary cause
- Elevated plasma ACTH argues against adrenal tumor
2) Pituitary microadenoma
- normal/elevated ACTH with normal adrenal CT argues against adrenal tumor
- >50% suppression with dexa argues against ectopic production
3) Adrenal Adenoma/Carcinoma
- Low ACTH rules out ectopic production
- <50% suppression and negative petrosal sampling rules out pituitary microadenoma. |
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Term
| Why must patients with Cushing's disease be treated and how would you go about it? |
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Definition
1) High risk of thromboembolic disease, atherosclerosis, opportunistic infections and cerebrovascular disease
- Hypertension, obesity and immunosuppression.
2) Treat
- Pituitary: Transphenoidal resection (60-90% cure) with post-operative glucocorticoid replacement
- Adrenal: Unilateral adrenalectomy (100%) with 6-12 months of transient adrenal suppression
- Ectopic: CT/MRI for bronchial or thymic carcinoid tumor (Surgery unless significant metastasis) |
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Term
| How can patients with persistent hypercortisolism following surgery for pituitary microadenoma producing Cushings be treated medically? |
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Definition
Up to 85% will improve eventually, but may need long-term treatment.
1) Agents that block cortisol synthesis early in pathway (Ketoconazole and aminoglutethimide)
2) 11-b hydroxylase inhibitor (Metyrapone)
3) Cortisol receptor blocker (Mifepristone)
- good for diabetic patients
4) ACTH secretion suppression (Paireotide and cabergoline) |
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Term
| What is the sympathoadrenal system? |
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Definition
Adrenal medulla + Sympathetic nervous system, both of which are derived from neural ectoderm (vs. cortex, which comes from mesoderm)
- Chromaffin (90% in medull anad 10% in symp ganglia) cells produce endogenous catecholamines (Epinephrine, Norepinephrine, Dopamine) |
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Term
| How do chromaffin cells in the adrenal medulla differ from those in the sympathetic ganglia? |
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Definition
1) They have no post-synaptic fibers
2) Express PNMT, for the conversion of Norepinephrine to Epinephrine (final step in catecholamine synthesis).
**Exception is Organ of Zukerkandl (symp plexus at bifurcation of aorta), which also expresses PMNT** |
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Term
| What kind of extra-adrenal tumor can synthesize epinephrine? |
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Definition
Only organ outside adrenal gland that has PMNT is organ of Zukerkandl at bifurcation of aorta.
Usually persists only until 3 years of age, but can sometimes persist and give rise to Phochrocytomas. |
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Term
| What are the basic steps and enzymes involved in catecholamine synthesis? |
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Definition
Derived from Tyrosine (diet or liver conversion from phenalalynine)
1) Tyrosine is converted to L-Dopa by Tyrosine Hydroxylase (RLS)
2) L-DOPA converted to dopamine by Aromatic L-amino acid decarboxylase and transported into chromaffin granules in the adrenal medulla
3) Within granules, Dopamine is converted to NE by Dopamine beta-Hydroxylase
4) In chromaffin cells, NE diffuses back into cytoplasm where it is converted to Epi by PNMT with SAM as methyl donor. |
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Term
| How are catecholamines released from chromaffin cells of the adrenal medulla? |
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Definition
Released with hypotension, fever, stress, cold exposure, hypoglycemia, exercise, ect.
1) Sympathetic pre-ganglionic cells release ACh
2) Calcium-mediated granule and catecholamine release by exocytosis. |
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Term
| How are catecholamines metabolized? |
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Definition
COMT, MAO and Aldehyde dehydrogenase, occurring in adrenal, liver and kidney
1) COMT
- NE to normetanephrine
- Epi to metanephrine
2) MAO and AD
- Converts them to Vanillylmandelic acid (VMA) |
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Term
| What is the difference between a "Pheochromocytoma" and a "Paraganglioma"? |
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Definition
Catecholamine secreting tumors that cause Hypertension (usually sustained, but can be paroxysmal, which is hallmark of disease), Headache, Excess sweating, Palpitations and Posturar Hypotension.
1) Pheos are functional and derived from adrenal gland.
- rare but cause immediate, life threatening HTN that can be cured surgically
2) PGLs may arise from symp or parasymp ganglia and 95% are non-functional |
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Term
| What is the clinical "hallmark" of a Pheochromocytoma? |
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Definition
AD genetic syndrome with Paroxysmal hypertension episodes (really only occur 25-40% of the time).
Also see headache, sweating, palpitations and postural hypotension. |
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Term
| What conditions are commonly confused for Pheochromocytoma? |
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Definition
1) CV- Labile hypertension, paroxysmal tachycardia, acute pulmonary edema
2) Psychoneurological- Anxiety attacks with hyperventilation
3) Factitious ingestion of sympathomimetics |
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Term
Which of the following familial genetic syndromes is NOT associated with Pheochromocytoma?
1) Multiple endocrine neoplasia type 2A (MEN 2A)
2) Factor V Leiden mutations (Factor V)
3) Von Hippel Lindau Disease (VHL)
4) Neurofibromatosis (NF) Type 1
5) Succinate DH gene family syndromes
6) Multiple endocrine neoplasia type 2B (MEN2B) |
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Definition
Pheochromocytoas are AD inheritance, as do these familial syndromes
2- This is mutation in site of protein C binding to cleave Factor V that produces thrombosis.
- MEN 2A and 2B are associated with RET proto-oncogene mutations
- VHL is associated with mutations in VHL on chromosome 3 (no HIF-1A suppression)
- NF-1 is associated with NF1 gene mutations (tumor suppressor), care-au-lait spots.
- Succinate DH syndromes are germ-lin mutations that encode SDH enzyme subunits. |
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Term
| What are the major indications for screening/diagnosis of Pheochromocytoma? |
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Definition
1) Screening
- Hypertension (sustained or paroxysmal)
- BP lability periods
- Recurrent attacks with a pheo in normotensive adult
- Associated familial disorders
2) Diagnosis
- Measurement of FRACTIONED catecholamine metabolites (Metanephrines: metanephrine and normetanephrine)
- Elevated levels are highly sensitive/specific, with metanephrine being specific for Pheos, with exception of tumor from Organ of Zukerkandl |
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Term
| What is the utility of a clonidine suppression test? |
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Definition
Good specificity for Pheochromocytomas.
If clonidine suppression is absent, it is specific
Suppression testing, pharmacological measures and imaging are generally NOT indicated, since biochemical tests are so useful at detecting metabolites (exception is familial syndromes). |
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Term
| What are the treatment options for Pheochromocytoma? |
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Definition
Surgery is choice (for metastasis, try I-MIBG)
1) Pre-operative Hypertension with alpha-blocker (Phenoxybenzamine, Prazosin) 7 days prior.
- may combine with Calcium channel locker and/or Metyrosine (comp inhibitor or tyrosine hydroxylase)
2) Pre-operative volume expansion with oral NaCl loading or IV normal saline to prevent post-op hypotension. |
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Term
| Why might you give a patient who will be undergoing surgery for Pheochromocytoma an alpha blocker and IV normal saline prior to surgery? |
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Definition
| Prevent hypertension and post-operative hypotension, respectively (start the alpha blocker 7 days prior) |
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