Hyperaldosteronism

Aka: Hyperaldosteronism, Aldosteronism, Conn's Disease, Conn's Syndrome, Primary Hyperaldosteronism, Secondary Hyperaldosteronism

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II. Background

  1. First described by Dr. Jerome Conn in 1955

III. Epidemiology

  1. Represents 6% of Hypertension Causes (20% with Stage 2 Hypertension)
    1. Most common cause of drug Resistant Hypertension
  2. Peak age 30-50 years
  3. More common in women

IV. Pathophysiology

  1. Inappropriate Aldosterone Hypersecretion
    1. Primary Hyperaldosteronism (See Causes below)
      1. Increased Aldosterone is initiating event
      2. Results in Sodium retention and volume increase
      3. Renin decreases
    2. Secondary Hyperaldosteronism (See Causes below)
      1. Decreased circulating volume is initiating event
      2. Results in increased renin and Aldosterone
      3. Results in Sodium retention
  2. Physiologic response to Aldosterone Excess
    1. Increased renal distal tubular Sodium reabsorption
      1. Increased total body Sodium content
      2. Increased water retention
    2. Escape phenomenon
      1. Compensatory increased atrial natriuretic factor (ANF) secretion
      2. Hypertension may not be solely volume expansion
    3. Increased Peripheral Vascular Resistance
      1. Hypokalemia: Potassium lost in distal renal tubule (Potassium wasting)
      2. Alkalosis: Ammoniagenesis
    4. Hydrogen Ion loss (avid Sodium retention)
    5. Polyuria due to decreased renal concentrating ability
    6. Plasma renin suppressed
      1. Unresponsive to intravascular volume depletion
    7. Vascular and myocardium Aldosterone receptor activation
      1. Proinflammatory and profibrotic effects with chronic Aldosterone stimulation
      2. Increases vascular complications (e.g. CVA, LVH, Proteinuria) beyond hypertensive effects
      3. Brown (2013) Nat Rev Nephrol 9(8): 459-69 [PubMed]

V. Causes

  1. Primary Hyperaldosteronism (Conn's Disease)
    1. Solitary Adrenal Adenomas (80-90%)
    2. Bilateral adrenal hyperplasia (10-20%)
      1. Idiopathic Hyperaldosteronism
      2. Accounts for 50% of cases at some referral centers
    3. Adrenal Carcinoma (rare)
    4. Unilateral Adrenal Hyperplasia (very rare)
  2. Secondary Hyperaldosteronism
    1. Hypertensive States
      1. Primary Reninism (rare renin producing tumor)
      2. Secondary reninism due to decreased renal perfusion
    2. Edematous States
      1. Cirrhosis
      2. Nephrotic Syndrome
    3. Miscellaneous causes
      1. Excessive Growth Hormone (Acromegaly)

VI. Symptoms

  1. Often Asymptomatic
  2. Frontal Headache
  3. Muscle Weakness to Flaccid Paralysis (Hypokalemia)
  4. Polyuria and Polydipsia (Carbohydrate intolerance)

VII. Signs

  1. Hypertension
    1. May be severe
    2. Rarely malignant
  2. Motor Exam with decreased Muscle Strength

VIII. Labs

  1. Serum Electrolytes
    1. Serum Potassium decreased (Hypokalemia)
      1. Hypokalemia is the most prominent feature of Hyperaldosteronism (aside from Refractory Hypertension)
      2. However, normal Potassium level does NOT exclude Hyperaldosteronism
        1. Potassium is normal in 50 to 70% of Hyperaldosteronism cases
    2. Serum Sodium increased (Mild)
    3. Metabolic Alkalosis
  2. Morning Aldosterone to Plasma Renin Activity (PRA) ratio
    1. Indicated as first diagnostic test in evaluation of Hyperaldosteronism
      1. See diagnostic protocol below
    2. Findings suggestive of Hyperaldosteronism
      1. Ratio >30 (esp if >100) suggests Hyperaldosteronism
      2. Aldosterone >15 ng/dl and plasma renin activity <1 ng/ml/h
        1. Serum Aldosterone alone may be normal in 25% of Hyperaldosteronism patients
    3. Technique
      1. Obtain 2 hours after waking and in upright position
      2. Stop Spironolactone, Eplerenone, Amiloride, Triamterene, Potassium-wasting Diuretics 4 weeks before test
      3. Consider stopping Antihypertensives and NSAIDs before test
        1. May use Verapamil XR, Hydralazine or Alpha Adrenergic Antagonist for Blood Pressure control

IX. Differential Diagnosis: Hypertension with Hypokalemia

  1. See Secondary Hypertension Causes
  2. Cushing's Disease
    1. Low Aldosterone and Low Plasma Renin
  3. Renal Artery Stenosis or other renal cause
    1. High Aldosterone and High Plasma Renin

X. Diagnosis

  1. Hyperaldosteronism Detection (see labs above)
  2. Hyperaldosteronism Screening Indications (Endocrine Society 2016)
    1. Resistant Hypertension
      1. Screen all patients
    2. Controlled Hypertension with at least 1 additional feature
      1. Adrenal Nodule
      2. Atrial Fibrillation
      3. Early Cerebrovascular AccidentFamily History
      4. First degree relative with primary Aldosteronism
      5. Hypokalemia
      6. Obstructive Sleep Apnea
  3. Testing protocol
    1. Step 1: Morning Aldosterone to Plasma Renin Activity (PRA) ratio
      1. Ratio >30: Go to Step 2
      2. Ratio <30: Hyperaldosteronism Unlikely
    2. Step 2: Plasma Renin Activity (PRA)
      1. PRA <0.6 ng/ml/h: Go to Step 3
      2. PRA 0.6 to 1 ng/ml/h: Go to Step 4 for Confirmatory Testing
      3. PRA >1 ng/ml/h: Hyperaldosteronism Unlikely
    3. Step 3: Plasma Aldosterone
      1. Aldosterone >= 30 ng/ml: Hyperaldosteronism diagnosis confirmed
      2. Aldosterone 20 to 29 ng/ml
        1. Hypokalemia (Serum Potassium <3.5 mEq/L): Hyperaldosteronism diagnosis confirmed
        2. Normokalemia (Serum Potassium >=3.5 mEq/L): Go to Step 4 for Confirmatory Testing
      3. Aldosterone 11 to 19 ng/ml: Go to Step 4 for Confirmatory Testing
      4. Aldosterone <=10 ng/dl: Hyperaldosteronism Unlikely
    4. Step 4: Confirmatory Testing
      1. Precautions
        1. Confirmatory testing is typically performed by endocrinology (as opposed to primary care)
        2. Some tests risk of exacerbating Hypertension and Hypokalemia
        3. Tests require significant time, monitoring and attention to detailed protocols
      2. Confirmatory testing options
        1. Captopril Challenge Test
          1. Administer Captopril 25 to 50 mg orally
          2. Obtain plasma Aldosterone level at 0 hours (baseline) and 2 hours after Captopril
            1. Plasma Aldosterone decrease <30% from baseline confirms Primary Hyperaldosteronism
        2. Fludrocortisone Test
          1. Patient takes Fludrocortisone 0.1 mg every 6 hours for 4 days
          2. Obtain plasma Aldosterone on day 4
            1. Plasma Aldosterone >6 ng/dl confirms Primary Hyperaldosteronism
        3. Oral Salt Loading Test
          1. Patient ingests Sodium chloride tablets (totaling 6 grams/day) for 3 consecutive days
          2. Obtain 24 hour Urine Collection on Day 3
            1. 24 Hour Urine Aldosterone >12 mcg confirms Primary Hyperaldosteronism
        4. Saline suppression
          1. Infuse Normal Saline 500 ml/hour IV for 4 hours (total of 2 L)
          2. Plasma Aldosterone > 10 ng/dl confirms Primary Hyperaldosteronism
    5. Step 5: Subtyping
      1. Distinguishes unilateral from Bilateral Hyperaldosteronism
        1. Unilateral Hyperaldosteronism is treated surgically (see below)
      2. Adrenal Vein Sampling (preferred test)
        1. Blood samples obtain from a peripheral vein and from the adrenal veins (both right and left)
        2. Accuracy is operator and lab dependent (best performed at centers performing >12/year)
      3. Adrenal CT (alternative test)
        1. Distinguishes benign adenomas from malignant lesions
        2. Three phase Adrenal CT
          1. Phase 1: Non-Contrast
          2. Phase 2: Follows IV contrast by 60 to 75 seconds
          3. Phase 3: Follows IV contrast by 15 minutes
        3. Low accuracy when compared with adrenal vein sampling (40% discordance rate)
          1. Adrenalectomy outcomes are significantly improved when guided by adrenal vein sampling
          2. Yan (2022) J Clin HYpertens 24(2): 106-15 [PubMed]
    6. References
      1. Funder (2016) J Clin Endocrinol Metab 101(5): 1889-916 [PubMed]
      2. Young (2019) J Intern Med 285(2): 126-48 [PubMed]

XI. Management

  1. Unilateral Hyperaldosteronism (Adrenal Adenoma)
    1. Surgical excision (adrenalectomy)
    2. Surgical outcomes
      1. Aldosteronism normalizes in 94% of cases
      2. Hypertension resolves in up to one third of cases
      3. Decreases cardiovascular event rate by as much as 50%
      4. Williams (2017) Lancet Diabetes Endocrinol 5(9): 689-99 [PubMed]
      5. Huang (2021) Front Endocrinol 12: 644260 [PubMed]
  2. Bilateral Hyperaldosteronism (Adrenal Hyperplasia)
    1. Dietary Sodium Restriction 1500 mg/day
    2. Mineralcorticoid receptor Antagonists
      1. Spironolactone (Aldactone)
        1. Start: 12.5 to 25 mg/day
        2. Often used as a first-Line agent due to low cost
          1. However multiple adverse effects may limit use (e.g. Gynecomastia, Erectile Dysfunction)
      2. Eplerenone (Inspra)
      3. Amiloride (Midamor)
    3. Monitoring
      1. Follow Serum Potassium and Serum Creatinine every 6 months with these agents
      2. Studies pending using PRA levels to adjust mineralcorticoid receptor Antagonist doses

XII. Complications

  1. Hyperaldosteronism is associated with chronic cardiovascular adverse effects beyond Essential Hypertension
    1. Atrial Fibrillation (Odds Ratio 3.5)
    2. Proteinuria (Odds Ratio 2.7)
    3. Cerebrovascular Accident (Odds Ratio 2.6)
    4. Left Ventricular Hypertrophy (Odds Ratio 2.3)
    5. Congestive Heart Failure (Odds Ratio 2.1)
    6. Coronary Artery Disease (Odds Ratio 1.8)
    7. Monticone (2020) J Hypertens 38(1): 3-12 [PubMed]

XIII. References

  1. Charles (2017) Am Fam Physician 96(7): 453-61 [PubMed]
  2. Mosso (2003) Hypertension 42(2): 161-5 [PubMed]
  3. Quencer (2023) Am Fam Physician 108(3): 273-7 [PubMed]

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