Hyperaldosteronism/Pheochromocytoma Flashcards
Describe the mechanism of the Renin-Angiotensin-Aldosterone-System:
- Begins as the liver releases angiotensinogen
- Decreases in blood pressure is sensed in the glomerulus and trigger release of renin from the juxtaglomerular cells
- Renin is an enzyme that catalyzes the cleavage of the decapeptide angiotensin I from angiotensinogen (a.k.a. renin substrate)
-
Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE)
- ACE is primarily found in most vascular endothelia
How does angiotensin II increase blood pressure?
- Vasoconstriction
- Increases aldosterone release from the zona glomerulosa of the adrenal cortex
- What are the increases aldosterone secretion?
- What are the effects of aldosterone?
-
Increased by other stimuli:
- potassium (hyperkalemia) and acutely by ACTH.
-
Causes increased sodium (and hence water) reabsorption in the renal tubules.
- increases vascular volume
- increases blood pressure
Negative Feedback of RAAS:
- Direct
- Indirect
-
Direct
- Ang II directly inhibits renin release
-
Indirect
- ↑ Ang II and aldosterone ⇒ ↑ blood volume and pressure ⇒ ↓ stimulation of renin release
Where does aldosterone act?
Aldosterone works in the distal convoluted tubule and affects sodium/potassium channels
- What does aldosterone cause reabsorption of?
- How is the ion balance maintained?
- What is the overall effect?
- Aldosterone causes increased reabsorption of sodium from the tubules, thereby causing increased sodium retention in the body
- In order to maintain ionic balance, potassium and hydrogen are secreted into the tubule in place of sodium
- This process leads to overall fluid retention and increased blood volume
What is the consequence of excess aldosterone?
- net loss of potassium ⇒ hypokalemia
- metabolic alkalosis
What drug classes affect the RAAS?
- Direct renin inhibitors
- ACE inhibitors
- Angiotensin receptor blockers (ARB)
- Mineralocorticoid receptor antagonist
Give examples of RAAS drugs:
- Direct renin inhibitors
- Aliskiren
- ACE inhibitors
- Lisinopril, enalapril, and captopril
- Angiotensin receptor blockers (ARB)
- Losartan, candesartan, and irbesartan
- Mineralocorticoid receptor antagonist
- Spironolactone and eplerenone
Primary Hyperaldosteronism:
- Where is the problem?
- What is different about aldosterone secretion compared to normal?
- What happens as aldosterone levels increase?
- In primary hyperaldosteronism, the adrenal gland(s) secrete excessive amounts of aldosterone
- either an adenoma on one adrenal or both adrenals that have undergone hyperplasia
- Secretion is autonomous and is not under the normal regulation from renin and angiotensin II
- As aldosterone levels increase,
- indirect negative feedback causes decreases in renin production
- downstream decreases in angiotensin
When should testing for primary aldosteronism be considered?
- HTN and hyperkalemia
- Resistant HTN (3 drugs and poor BP control)
- Adrenal incidentaloma and HTN
- Onset of HTN at a young age (< 30 y)
- Severe HTN (≥ 160 mmHG systolic or ≥ 100 mmHg diastolic)
- Whenever considering secondary HTN
What should be obtained in patients suspected of having primary hyperaldosteronism?
plasma aldosterone:renin activity ratio
Plasma aldosterone:renin activity ratio
- Normal
- In patients with primary hyperaldosteronism
-
Normal
-
ratio should be < 20
- aldosterone < 20 ng/dL
- renin activity 1-4 ng/mL/hour (depending on sodium intake)
-
ratio should be < 20
-
In subjects with primary hyperaldosteronism
-
ratio > 20 or 30
- ↑ aldosterone level (> 12 ng/dL)
- ↓ plasma renin activity (< 1 ng/mL/hour)
-
ratio > 20 or 30
- What is the best scan to determine PHA?
- When should this scan be done?
- Once a diagnosis of PHA is confirmed, what else must be determined?
-
CT scan is the best when trying to determine PHA (may be hard to see anatomic structures)
- only should be done after a confirmed biochemical diagnosis
- Once the diagnosis of primary hyperaldosteronism has been secured, it is necessary to determine if this is from a unilateral or bilateral adrenal source
What is expected from an AVS if the PHA is from a unilateral source?
- Aldosterone levels from the affected adrenal gland will be quite elevated
- Importantly, the contralateral adrenal venous blood should have an aldosterone level that is quite low
- even lower than the inferior vena cava
-
High aldosterone levels ⇒ suppression of renin
- Causes the adrenal gland without autonomous production to produce low levels of aldosterone
What is expected from an AVS if the PHA is from a **bilateral **source?
aldosterone levels in adrenal venous blood are elevated bilaterally and there is no gradient between the right or left adrenal
Causes of Primary Hyperaldosteronism:
- Aldosterone-secreting adrenocortical adenoma
- Bilateral hyperplasia of zona glomerulosa
Causes of Secondary Hyperaldosteronism:
- Renal ischemia
-
Decreased intravascular volume
- Congestive heart failure
- Chronic diuretic or laxative use
- Hypoproteinemic states (cirrhosis, nephrotic syndrome)
-
Sodium-wasting disorders
- Chronic renal failure
- Secondary hyperaldosteronism is the result of ….
- What patient population is particularly vunerable?
- …. excess aldosterone production in response to increased RAAS activity
- It occurs in patients with renal artery stenosis, where renal perfusion pressure is decreased
What is the **important differential **between primary and secondary hyperaldosteronism?
- Primary hyperaldosteronism ⇒ ↓ renin levels
- Secondary hyperaldosteronism ⇒ ↑ renin levels
- appropriate physiologic stimualtion
- A definitive unilateral tumor by CT or MRI in a young person can be treated with _________ ___________
- In most cases (no unilateral adrenal nodule, bilateral adrenal nodules, or patients >40 years of age), ___ is necessary
- A definitive unilateral tumor by CT or MRI in a young person can be treated with laparoscopic adrenalectomy
- In most cases (no unilateral adrenal nodule, bilateral adrenal nodules, or patients >40 years of age), AVS is necessary
If aldosterone production is unilateral, _________ ____________ is the preferred approach
If aldosterone production is unilateral, laparoscopic adrenalectomy is the preferred approach
- medical management is also appropriate in many patients
If aldosterone production is bilateral, _______ ___________ is used
If aldosterone production is bilateral, medical management is used
What medical management is used for PHA?
Mineralocorticoid receptor antagonists
- spironolactone and eplerenone
- competitive receptor antagonists
- By blocking aldosterone actions
- decrease sodium and water retention
- increase serum potassium levels
What else can affect the mineralocorticoid receptor (2)?
- Type 1 apparent mineralocorticoid excess (AME)
- Liddle Syndrome
How is cortisol normally handled?
- Cortisol is a potent mineralocorticoid and bind to the mineralocorticoid receptor with an affinity similar to aldosterone
- In the normal state, cortisol is in much greater plasma concentrations
- If cortisol is not “deactivated” in the kidney, its high relative concentration would negate aldosterone regulation of the mineralocorticoid receptor
- The mineralocorticoid receptor in the kidney is protected by 11-HSD2 which rapidly converts cortisol to cortisone
- which lacks potent mineralocorticoid activity
What is the pathophysiology of AME?
- result of impaired activity of the microsomal enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11- HSD2)
- High levels of cortisol accumulate in the kidney
- activate the mineralocorticoid receptor and create a physiological picture similar to aldosterone excess
What can be consumed and causes a deficiency in 11-HSD2?
glycyrrhizic acid (licorice root and chewing tobacco)
The clinical phenotype of patients with AME includes:
- **low aldosterone **
- normal plasma cortisol levels
- hypertension
- hypokalemia
- metabolic alkalosis
- low renin activity
Liddle’s syndrome is caused by mutations in the ….
amiloride-sensitive epithelial sodium channel (ENaC)
What is the clinical picture of Liddle Syndrome?
- low renin and aldosterone levels
- increased sodium reabsorption
- potassium wasting
- hypertension
- hypokalemia
How is Liddle Syndrome treated?
amiloride and triamterene (K+ sparing diuretics)
Describe the pathway for catecholamine synthesis:
Drugs with adrenergic effects:
- Phenylephrine
- Albuterol
-
Phenylephrine
- α agonist
- causes vasoconstriction and raises blood pressure
- **Albuterol **
- **β2 agonist **
- causes bronchodilation and the ability to increase ventilation
- used for asthma and bronchoconstriction
- Where is norepinephrine mainly secreted from?
- Where is epinephrine mainly secreted from?
- What is the reason behind this?
- Sympathetic postganglionic nerve fibers ⇒ mainly norepinephrine
-
Adrenal medullary (chromaffin) cells ⇒ mainly epinephrine
- adrenal medulla is bathed in high cortisol
concentration produced by the adrenal cortex - cortisol induces the expression of PNMT
- adrenal medulla is bathed in high cortisol
Catecholamine Effects:
- **Heart **
- **Blood vessels **
- Pancreas (β cells)
- **Heart **
- Increased heart rate
- Tachycardia ⇒ Palpitations
- Tachyarrhythmia ⇒ Angina pectoris
- Increased contractility
- Increased myocardial O2 consumption ⇒ Angina pectoris
- Myocarditis ⇒ Congestive heart failure
- Cardiomyopathy
- Increased heart rate
- **Blood vessels **
- Arteriolar constriction
- Hypertension ⇒ Headache, Congestive heart failure, Angina pectoris
- Venoconstriction
- Decreased plasma volume ⇒ Dizziness,
Orthostatic hypotension, Circulatory collapse
- Decreased plasma volume ⇒ Dizziness,
- Arteriolar constriction
-
Pancreas (β cells)
- Suppression of insulin release
- Carbohydrate intolerance ⇒ Hyperglycemia, Glucosuria
- Suppression of insulin release
What are the classic symptoms of pheochromocytomas?
- hypertension (90%)
- headaches (80%)
- diaphoresis (70%)
- palpitations (60%)
Pheochromocytomas vs. Paragangliomas
- Definition?
- Main catecholamine secreted?
-
Pheochromocytomas
- tumors of the chromaffin cells of the adrenal medulla
- secrete excessive amounts of both **epinephrine and norepinephrine **
-
Paragangliomas
- tumors that arise from extra-adrenal ganglia of the sympathetic nervous system.
- paragangliomas and metastases of pheochromocytomas generally secrete primarily norepinephrine
Testing for pheochromocytoma:
- What is the main test in a 24hr urine sample?
- What is the main test for the plasma?
- What are the main imaging studies used?
- 24hr urine sample
- catecholamines
-
Plasma
- metanephrines
-
Imaging studies
- CT
- MRI
When should imaging be done when there is a suspected pheochromocytoma?
After confirmatory biochemical diagnosis!
Diagnosis of pheochromocytoma is made through the demonstration of catecholamine excess via 2 tests, ….
plasma free metanephrines & urinary catecholamines
Secretion of large amounts of catecholamines from secretory vesicles causes a ________ _____ and can lead to __________ _____
Secretion of large amounts of catecholamines from these secretory vesicles causes a paroxysmal event and can lead to hypertensive crisis
- due to excessive metanephrines in the plasma
What is the best imaging test for a pheochromocytoma?
CT scan of the abdomen/adrenal glands
- What is the only curative therapy for pheochromocytoma?
- Why can this be potentially dangerous?
only curative therapy is surgical removal of the tumor
- Unilateral adrenalectomy
- During surgical removal of a pheochromocytoma the manipulation of the tumor can cause __release of excessive amounts of catecholamines
- This surge in catecholamines can cause profound vasoconstriction and resultant hypertensive emergency
What should be done for patients prior to surgery for a pheochromocytoma?
patients should be treated with alpha-adrenergic blockers
- catecholamine induced vasoconstriction is prevented
- What is the α blocker of choice?
- What else can potentially be given along with it?
- When should this second drug be given?
-
Phenoxybenzamine
-
nonselective α blocker
- long half-life of about 24hours
- does not block the synthesis of catecholamines
- synthesis of catecholamines and metanephrines tends to increase during α blockade
-
nonselective α blocker
- A β1 blocker might also be needed
- Therapy with alpha blockers tends to increase the heart rate
- **Given after appropriate alpha blockade is achieved **
- Otherwise, it can cause a paradoxical worsening of hypertension
Besides anti-adrenergics, what else should be done prior to surgery for pheochromocytoma?
make sure the patient is well-hydrated
