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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Related Studies

Ontology: Hyperaldosteronism (C0020428)

Definition (NCI) Overproduction of aldosterone by the adrenal glands, which may lead to hypokalemia and/or hypernatremia.(NICHD)
Definition (MSH) A condition caused by the overproduction of ALDOSTERONE. It is characterized by sodium retention and potassium excretion with resultant HYPERTENSION and HYPOKALEMIA.
Definition (CSP) abnormality of electrolyte function caused by excessive secretion of aldosterone by the adrenal cortex.
Concepts Disease or Syndrome (T047)
MSH D006929
ICD9 255.10, 255.1
ICD10 E26 , E26.9
SnomedCT 88213004, 190506003, 154709005, 190509005, 267484005
English Aldosteronism, Hyperaldosteronism, Hyperaldosteronism, unspecified, aldosteronism, aldosteronism (diagnosis), hyperaldosteronism, Aldosteronism NOS, Hyperaldosteronism NOS, Hyperaldosteronism [Disease/Finding], Hyperaldosteronism NOS (disorder), Aldosteronism (disorder), Aldosteronism, NOS, Hyperaldosteronism, NOS
Dutch aldosteronisme NAO, aldosteronisme, Hyperaldosteronisme, niet gespecificeerd, hyperaldosteronisme, Aldosteronisme, Aldosteronisme, hyper-, Hyperaldosteronisme
French Aldostéronisme SAI, Aldostéronisme, Hyperaldostéronisme, Hyperaldostéronisme primitif
German Aldosteronismus NNB, Hyperaldosteronismus, nicht naeher bezeichnet, Aldosteronismus, Hyperaldosteronismus
Italian Aldosteronismo NAS, Aldosteronismo, Iperaldosteronismo
Portuguese Aldosteronismo NE, Hiperaldosteronismo, Aldosteronismo
Spanish Aldosteronismo NEOM, hiperaldosteronismo, SAI (trastorno), hiperaldosteronismo, SAI, aldosteronismo con hiperplasia de la corteza suprarrenal, hiperaldosteronismo (trastorno), hiperaldosteronismo, Hiperaldosteronismo, Aldosteronismo
Japanese アルドステロン症ＮＯＳ, ｱﾙﾄﾞｽﾃﾛﾝｼｮｳ, ｱﾙﾄﾞｽﾃﾛﾝｼｮｳNOS, ｺｳｱﾙﾄﾞｽﾃﾛﾝｼｮｳ, コン症候群, アルドステロン過剰症, アルドステロン過剰, アルドステロン症, 高アルドステロン症, Conn症候群
Swedish Hyperaldosteronism
Czech aldosteronismus, hyperaldosteronismus, Aldosteronismus, Aldosteronismus NOS, Hyperaldosteronismus
Finnish Hyperaldosteronismi
Russian KONNA SINDROM, GIPERAL'DOSTERONIZM PERVICHNYI, GIPERAL'DOSTERONIZM, AL'DOSTERONIZM, АЛЬДОСТЕРОНИЗМ, ГИПЕРАЛЬДОСТЕРОНИЗМ, ГИПЕРАЛЬДОСТЕРОНИЗМ ПЕРВИЧНЫЙ, КОННА СИНДРОМ
Korean 고알도스테론증, 상세불명의 고알도스테론증
Croatian HIPERALDOSTERONIZAM
Polish Aldosteronizm, Zespół Conna, Hiperaldosteronizm pierwotny, Hiperaldosteronizm
Hungarian Hyperaldosteronismus k.m.n., Hyperaldosteronismus, Hyperaldosteronizmus
Norwegian Hyperaldosteronisme, Aldosteronisme
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Secondary hyperaldosteronism (C0271728)

Concepts Disease or Syndrome (T047)
ICD10 E26.1
SnomedCT 67805000
English Aldosteronism Secondary, secondary aldosteronism, secondary aldosteronism (diagnosis), Aldosteronism secondary, Secondary hyperaldosteronism, Secondary aldosteronism, secondary hyperaldosteronism, Secondary aldosteronism (disorder), hyperaldosteronism; secondary, secondary; hyperaldosteronism, Secondary aldosteronism, NOS
Italian Iperaldosteronismo secondario, Aldosteronismo secondario
Dutch aldosteronisme secundair, hyperaldosteronisme; secundair, secundair; hyperaldosteronisme, Secundair hyperaldosteronisme, secundair aldosteronisme
French Aldostéronisme secondaire, Hyperaldostéronisme secondaire
German Aldosteronismus sekundaer, Sekundaerer Hyperaldosteronismus, sekundaerer Aldosteronismus
Portuguese Aldosteronismo secundário, Aldesteronismo secundário
Japanese 続発性アルドステロン症, ｿﾞｸﾊﾂｾｲｱﾙﾄﾞｽﾃﾛﾝｼｮｳ
Czech Aldosteronismus sekundární, Sekundární aldosteronismus
Korean 속발성 고알도스테론증
Hungarian Másodlagos hyperaldosteronismus, Secunder hyperaldosteronismus
Spanish hiperaldosteronismo secundario (trastorno), hiperaldosteronismo secundario, Aldosteronismo secundario
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Conn Syndrome (C1384514)

Definition (NCI) An endocrine disorder characterized by excessive production of aldosterone by the adrenal glands. Causes include adrenal gland adenoma and adrenal gland hyperplasia. The overproduction of aldosterone results in sodium and water retention and hypokalemia. Patients present with high blood pressure, muscle weakness, and headache.
Definition (MSH) Primary hyperaldosteronism caused by the excess production of ALDOSTERONE by an ADENOMA of the ZONA GLOMERULOSA or CONN ADENOMA.
Definition (CSP) overproduction of aldosterone by an adrenal cortical adenoma, characterized typically by low potassium levels, underacidity of the body, muscular weakness, excess urination, excess thirst, and high blood pressure.
Concepts Disease or Syndrome (T047)
MSH D006929
ICD9 255.12
ICD10 E26.0 , E26.01
SnomedCT 258117004, 13536004, 154709005, 267484005, 190506003, 190507007
English Aldosteronism Primary, Conn Syndrome, primary hyperaldosteronism, primary aldosteronism (diagnosis), primary aldosteronism, Conn's syndrome (diagnosis), Idiopathic aldosteronism, Idiopathic hyperaldosteronism, Conns Syndrome, Conn's Syndrome, Syndrome, Conn's, conn syndrome, conn's syndrome, conns syndrome, Primary aldosteronism (disorder), Conn's syndrome, Conn syndrome, Primary aldosteronism, Primary hyperaldosteronism, Idiopathic aldosteronism (disorder), Primary hyperaldosteronism (disorder), hyperaldosteronism; primary, primary; hyperaldosteronism, Conn, Primary aldosteronism (disorder) [Ambiguous], Syndrome, Conn, Primary Hyperaldosteronism, Hyperaldosteronism, Primary
Italian Iperaldosteronismo primitivo, Sindrome di Conn
Dutch Conn-syndroom, hyperaldosteronisme; primair, primair; hyperaldosteronisme, Primair hyperaldosteronisme, primair hyperaldosteronisme
French Syndrome de conn, Syndrome de Conn, Hyperaldostéronisme primaire, Hyperaldostéronisme primaire à rénine basse
German Conn-Syndrom, Primaerer Hyperaldosteronismus, primaerer Hyperaldosteronismus
Portuguese Síndrome de Conn, Hiperaldesteronismo primário
Spanish Síndrome de Conn, aldosteronismo idiopático, aldosteronismo primario, hiperaldosteronismo idiopático (trastorno), hiperaldosteronismo idiopático, hiperaldosteronismo primario (concepto no activo), hiperaldosteronismo primario (trastorno), hiperaldosteronismo primario, síndrome de Conn, Hiperaldosteronismo primario
Japanese 原発性アルドステロン症, コーン症候群, ｺｰﾝｼｮｳｺｳｸﾞﾝ, ｹﾞﾝﾊﾟﾂｾｲｱﾙﾄﾞｽﾃﾛﾝｼｮｳ
Czech Primární hyperaldosteronismus, primární hyperaldosteronismus, Connův syndrom
Korean 원발성 고알도스테론증
Croatian CONNOV SINDROM, PRIMARNI HIPERALDOSTERONIZAM
Hungarian Conn-syndroma, Primaer hyperaldosteronismus
Derived from the NIH UMLS (Unified Medical Language System)

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