1. Armed Forces Academy of Medical Sciences
Aldosteronism
Armed Forces Academy of Medical Sciences

2. Outline Review normal physiology of RAAS system
Review normal physiology of Aldosterone
Primary hyperaldosteronism
Types
Symptoms
Diagnosis
Treatment

3. Normal Structure of Nephron
It is important to understand the normal structure and function of a nephron. Please spend a few minutes reviewing the important components of the nephron and before going to next slide make sure you understand the function of each part of the nephron.

4. Renin-Angiotensin-Aldosterone System (RAAS)
Controls water reabsorption through the manipulation of sodium reabsorption
Renin release by kidney in response to
Fluid loss
Hypotension
Low Sodium intake
Systemic Vasoconstriction
These factors are sensed by
Baroreceptors (stretch receptors)
Afferent arteriole
Cardiac and arterial baroreceptors
Macula Densa
Early Distal Convoluted Tubule
Baroreceptors sense changes in stretch of the wall (either in the afferent arteriole, the atria, or certain systemic arteries)

5. Angiotensin Converting Enzyme (ACE)
RAAS Physiology
Stimulus
Angiotensinogen
Arterial Constriction
Renin
Angiotensin II
Kidney releases renin in response to renal hypoperfusion. Renin is an enzyme which promotes Angiotensinogen (which is produced by the liver) conversion to Angiotensin I. Angiotensin I is converted to Angiotensin II by ACE, an enzyme which is found throughout the body, but primarily in the lungs. Angiotensin II causes arterial constriction and sodium retention which result in water retention and increased blood pressure.
Angiotensin I
Sodium Retention
Angiotensin Converting Enzyme (ACE)

6. RAAS Physiology Effects of Angiotensin II Increases Na Retention
Through direct stimulation of the Proximal Convoluted Tubule (PCT)
Increases Aldosterone secretion
Aldosterone increases sodium retention in corticol collecting tubule
Increased Na retention leads to increased water reabsorption
Direct systemic arterial vasoconstriction
Increased blood pressure

7. RAAS Physiology

8. Aldosterone Synthesis
Synthesized in adrenal cortex
Zona glomerulosa
Glucocorticoids (cortisol), androgens, estrogens produced in zona fasciculata and reticularis

9. Normal Mechanism of Aldosterone Action
Increase number of open sodium channels in the luminal membrane of the principal cells in the cortical collecting tubule
Increased sodium reabsorption
Removal of Na makes lumen electronegative
Potassium is secreted from the cells into the electronegative urine to even out charge
Removal of sodium makes lumen electronegative creating an electrical gradient

10. Primary Aldosteronism
Conn’s syndrome
Aldosterone-producing adenoma (30-60%)
Bilateral idiopathic Hyperaldosteronism
Unilateral adrenal hyperplasia
Bilateral macronodular adrenal hyperplasia
Familial hyperaldosteronism
Type 1
Type 2
Pure aldosterone-producing adrenocortical carcinomas
Ectopic aldosterone-secreting tumors
Types of Primary Aldosteronism. The two most common are aldosterone-producing adenoma and bilateraly idiopathic hyperaldosteronism

11. Clinical Features of Primary Aldosteronism
Hypertension
Hypokalemia
Metabolic Alkalosis
Other electrolyte abnormalities
Lack of edema

12. Clinical Features of Primary Aldosteronism: Hypertension
Frequently substantially elevated (> 160 / 100)
Generally resistant to multiple antihypertensive medications
Hypervolemia
Markedly reduces renin secretion
Persistent hypervolemia leads to increased systemic vascular resistance (SVR)
Aldosterone is potent hypertensive agent
Even high normal levels of aldosterone associated with hypertension

13. Clinical Features of Primary Aldosteronism: Hypokalemia
Increased urinary potassium wasting
Serum potassium remains stable for the short term
Aldosterone induced potassium wasting counterbalanced by potassium retaining effect of hypokalemia
Progressive hypokalemia only occurs if another factor is added
Increased aldosterone production
Initiation of diuretic medication

14. Clinical Features of Primary Aldosteronism: Hypokalemia
Patients with primary aldosteronism due to adrenal hyperplasia often do NOT have hypokalemia
Phenomenon not understood
Symptoms of hypokalemia
Mild cases are asymptomatic
Mild elevation of blood pressure
Muscle weakness, cramps, myalgias
ECG changes

15. Clinical Features of Primary Aldosteronism: Other Effects
Metabolic Alkalosis
Due to increased urinary hydrogen ion excretion as a result of aldosterone stimulating Na-H transporter
Mild Hypernatremia
Often between 143 – 147 mEq/L
Hypomagnesemia
Urinary magnesium wasting
Not well understood
Mild hypernatremia: persistent mild volume expansion resets osmostat regulating ADH secretion

16. Hyperaldosteronism and Cardiac Risk
Patients with primary hyperaldosteronism have higher risk of cardiovascular complications then patients with hypertension
Retrospective study of 124 patients with primary aldosteronism to 465 patients with essential hypertension
Two groups matched for age, gender, degree of BP elevation
Higher rates of stroke, myocardial infarction, atrial fibrillation in hyperaldosteronism group
Similar results were seen in a prospective study involving 54 patients with primary hyperaldosteronism
Journal American College Cardiology 2005; 45 (8): 1243

17. Diagnosis of Primary Hyperaldosteronism
First step is to measure Plasma Renin Activity (PRA) and Plasma Renin Concentration (PRC)
PRA and PRC levels affected by diuretic use
PRA and PRC should be LOW in primary aldosteronism
Measure the Plasma Aldosterone Concentration
Calculate PAC/PRA ratio

18. Calculating the PAC/PRA ratio
Measure levels at 0800
Test can be done while patient takes most of his antihypertensive medications
Must hold spironolactone or eplerenone
Will falsely elevated PRA
ACE inhibitor and ARBs will also affect PRA
Normal value of PAC/PRA 4-10
Primary aldosteronism average 30-50

19. Interpreting the PAC/PRA ratio
Primary Aldosteronism: PRA suppressed, PAC increased (usually > 15 ng/dL)
PAC > 20 and PAC/PRA > 30 is 90% specific for primary aldosteronism
Secondary Aldosteronism (renovascular disease): PRA and PAC increased, PAC/PRA < 10
Other (hypercoritsolism, licorice root ingestion): both PRA and PAC suppressed

20. Establishing Subtype Adrenal CT
Differentiates adenoma from hyperplasia
Normal adrenal glands does not exclude hyperplasia
Adrenal carcinoma suspected with > 4 cm adrenal mass
Left image: abdominal CT showing enlarged left adrenal gland (arrow)
Right image: abdominal MRI showing bilateral adrenal hyperplasia

21. Confirming Diagnosis Adrenal vein sampling
Interventional radiologist obtains aldosterone levels from each adrenal vein
Differentiates bilateral from unilateral disease
Indications for adrenal vein sampling
Confirm unilateral disease in anyone considering surgery
When PAC/PRA is abnormal but CT scan normal
Angiogram shows catheter placed in right renal vein via the inferior vena cava.

22. Treatment of Primary Hyperaldosteronism
Treatment or primary aldosteronism is based on whether aldosterone hypersecretion is
Unilateral
Bilateral
Goal of therapy is to prevent morbidity and mortality associated with
Hypertension
Hypokalemia
Increased cardiovascular risk

23. Treatment of Unilateral Adenoma or Hyperplasia
Surgery: Unilateral adrenalectomy
Unilateral adenoma
Unilateral hyperplasia
Partial adrenalectomy inadequate
Laparoscopic better than open
Shorter hospital stay
Less complications
Image: surgical specimen of an adrenal gland
2008 Endocrine Society Guidelines

24. Post-Op Management of Unilateral Adrenalectomy
Hypertension and hypokalemia controlled medically
Spironolactone or Eplerenone
Plasma aldosterone should be measured the day after surgery to asses for cure
Patients monitored for hyperkalemia as spironolactone, potassium supplements and anti-hypertensives are discontinued
Approximately 25% of patients are cured of their hypertension, another 60% can decrease the number or dose of antihypertensive medications

25. Medical Therapy for Unilateral Adrenal Hyperplasia or Adenoma
Surgical treatment is preferred method
Medical therapy with aldosterone antagonists is effective
50 point reduction in systolic BP
30 point reduction in diastolic BP
Increase in serum potassium of > 1.0 mEq/L
Also include low salt diet, regular exercise
No efficacy difference between spironolactone and eplerenone

26. Precautions with Spironolactone
Monitor serum potassium and creatinine frequently during first 6 weeks of therapy
Spironolactone will increase half life of digoxin
Concurrent NSAID use will blunt anti-hypertensive effects of aldactone
Patients may develop breast tenderness, decreased libido, gynecomastia

27. Treatment of Bilateral Adrenal Hyperplasia
Generally milder disease than adrenal adenoma
Less aldosterone secretion
Less severe hypertension and hypokalemia
Patients should be treated with long term aldosterone antagonist
Aldosterone or Eplerenone
May need thiazide diuretic or ACE inhibitor
Partial Adrenalectomy has been tried and failed

28. Conclusions
Primary hyperaldosteronism is one of the more common causes of hypertension
It often presents as hypertension and hypokalemia
It causes increased cardiovascular morbidity and mortality beyond it’s hypertension
There are many subtypes
Must diagnosis each subtype as treatment varies