Aldosteronism

Aldosteronism is a syndrome caused by excessive and inappropriate aldosterone production and is the most common form of endocrine hypertension.

Epidemiology

Prevalence – 5-15% of random hypertensive patients
Age – 30s-40s
Sex – M<F, 1:2

Etiologies

Unilateral or bilateral cortical nodular hyperplasia
Aldosterone-producing tumor (Conn syndrome)
Adrenal carcinoma (rare in the general population)

Genetics

Three forms of familial hyperaldosteronism (FH)
- FHI – unequal recombination between CYP11B1 and CYP11B2
- FHII – linkage in 7922 region; nonglucocorticoid remediable
- FHIII – aggressive form; medication resistant

Pathophysiology

Hypersecretion of aldosterone increases the reabsorption of sodium for potassium and hydrogen by the renal distal tubule
- Excess sodium reabsorption leads to hypertension
- Progressive depletion of potassium and hydrogen leads to hypokalemia and metabolic alkalosis
Classification
- Primary – excessive aldosterone secretion by the adrenal glands
- Secondary – renin-mediated secretion
  - Seen in congestive heart failure, nephritic syndrome, cirrhosis, renal artery hypertension, severe arteriolar nephrosclerosis, rare renin-secreting tumors

Clinical Presentation

Constitutional – weakness, fatigue
Renal – polyuria, proteinuria, renal failure
Cardiac – hypertension, cardiac hypertrophy
Edema – rarely exists

Treatment

Often involves surgical excision if tumor present
Aldosterone antagonists (spironolactone) may be successful therapy

Indications for Testing

Suggested by persistent hypokalemia and hypertension in patients with normal sodium intake, absence of edema and not currently receiving diuretics (from electrolyte testing)
- Hypokalemia – often severe, although patients may have normokalemia, particularly if already taking potassium-sparing diuretics
- Impaired urinary concentration
- Metabolic alkalosis
- Hypomagnesemia (if hypokalemia is severe)
- Hypernatremia is rare
Family history of early onset hypertension or cardiovascular accident (≤40 years of age)
Drug-resistant hypertension (≥3 drugs necessary to control blood pressure)
Patients may only present with hypertension and be normokalemic

Laboratory Testing

Initial testing – upright aldosterone/renin activity ratio (ARR) or direct renin ratio
- Best assessed in the morning
- Hypokalemia should be corrected prior to testing

Confirmation testing

Confirmation Testing*	Procedure	Positive Interpretation
Oral saline load	200 mmol/dL Na/day x 3 days KCl supplementation	Urine aldosterone >10 μg/24 hr Urine Na >200 mmol/24 hr
Fludrocortisone suppression test	Fludrocortisone x 4 days KCl, NaCl supplementation	Plasma aldosterone ≥6 ng/dL, normal serum potassium, urine Na >3 mmol/kg/day, 10 am cortisol <8 am
Intravenous saline load	2 L 0.9% NaCl infused over 4 hours	Plasma aldosterone >10 ng/dL (grey zone 5-10 ng/dL)
Captopril challenge	Captopril 25-50 mg orally after sitting	Post-captopril ARR >30-50 ng/dL or post captopril aldosterone >8.5-15 ng/dL
Furosemide upright posture**	40 mg IV furosemide with upright sampling after 2 hours	Plasma renin activity <1 ng/dL
Losartan test**	50 mg losartan with sampling after 2 or 4 hours in upright position	2 hours: ARR >35; aldosterone >10 ng/dL 4 hours: ARR >40
Endocrine society guidelines (2008) have no evidence that one test is preferred over another *Not currently recommended due to lack of adequate trials proving high sensitivity/specificity

Imaging Studies

Adrenal CT or MRI to screen for tumor if testing confirms aldosteronism
- MRI offers no diagnostic advantage over CT
  - Nonfunctional adrenal “incidentalomas” appear identical on imaging to functional tumors
  - Normal, micronodularity or bilateral masses on imaging
    - Refer to bilateral AVS below
  - Unilateral hypodense nodule >1 cm but <4 cm on imaging
    - >40 years – bilateral AVS (see below)
    - <40 years – APA or primary adrenal hyperplasia (PAH); unilateral laparoscopic adrenalectomy
  - Unilateral mass ≥ 4 cm on imaging – likely adrenal carcinoma
Bilateral AVS
- Indicated in all patients where surgical treatment is considered
- May be useful if scans are negative and high suspicion remains or patient >40 years with unilateral hypodense nodule >1 cm but <4 cm
- Blood samples collected simultaneously from adrenal veins and the inferior vena cava
  - Concurrent serum cortisol sampling to rule out dilution at site of right adrenal vein
  - Lateralization present – APA or PAH; unilateral laparoscopic adrenalectomy
  - No lateralization – consider genetic testing for GRA

Differential Diagnosis

Essential hypertension
Cushing syndrome
Obstructive sleep apnea
Pheochromocytoma
Liddle syndrome
Excessive licorice ingestion
Renal artery stenosis
Aortic coarctation

Endocrine Society Clinical Practice Guidelines (2008)
- Screening test should be performed in all patients with
  - Resistant hypertension
  - Stage 2 (>160-179/100-109 mmHs) or stage 3 (>180/110 mmHs) hypertension with
    - Spontaneous or diuretic-induced hypokalemia
    - Family history of early onset hypertension
    - Cardiovascular accident at young age (<40)
  - First-degree relatives with known disease
- AAR most reliable as initial screen
  - Direct renin test as screen not recommended
  - Remove any drugs 2-6 weeks before test that can interfere with test results
    - α receptors do not affect ARR
    - If necessary, secondary agent can be used – nondihydropyridine calcium channel blocker (eg, Verapamil)
- ARR increase is not diagnostic – proceed with confirmatory testing

Tests generally appear in the order most useful for common clinical situations

Test name: Aldosterone/Renin Activity Ratio

ARUP #: 0070073

Methodology: Quantitative Radioimmunoassay/Calculation

Use:

Diagnose and screen for primary hyperaldosteronism

Monitor effectiveness of treatment

Test name: Aldosterone & Renin, Direct with Ratio

ARUP #: 2002582

Methodology: Quantitative Radioimmunoassay/Quantitative Immunoradiometric Assay/Calculation

Use:

Diagnose primary hyperaldosteronism or hypoaldosteronism

Test name: Aldosterone 60 Minute

ARUP #: 0070017

Methodology: Quantitative Radioimmunoassay

Use:

Diagnose primary hyperaldosteronism; use in suppression on loading tests

Limitations:

Hypokalemia should be corrected before testing

Test name: Electrolyte Panel

ARUP #: 0020410

Methodology: Quantitative Ion-Selective Electrode/Enzymatic

Use:

Initial screen identifying electrolyte abnormalities associated with disease

Monitor disease

Panel includes anion gap, carbon dioxide; chloride; potassium; and sodium

Additional Tests Available

Test name: Renin Activity

ARUP #: 0070105

Methodology: Quantitative Radioimmunoassay

Comments:

Test name: Electrolytes, Urine

ARUP #: 0020498

Methodology: Quantitative Ion-Selective Electrode

Comments:

Monitor disease

Test name: Potassium, Plasma or Serum

ARUP #: 0020002

Methodology: Quantitative Ion-Selective Electrode

Comments:

Monitor disease

Test name: Aldosterone, Urine

ARUP #: 0070480

Methodology: Quantitative Radioimmunoassay

Comments:

Test name: Aldosterone 30 Minute

ARUP #: 0070016

Methodology: Quantitative Radioimmunoassay

Comments:

Test name: Renin, Direct

ARUP #: 2001575

Methodology: Quantitative Immunoradiometric Assay

Comments:

Detect hyper- or hypoaldosteronism

Do not use for patients treated with cathepsin B

Guidelines

Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF Jr, Montori VM. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008; 93 (9) :3266-3281.PubMed

General

ARUP Institute for Clinical and Experimental Pathology®

Malabanan, A.O., Meikle, A.W., Swenson, L., Bope, E.T., and Blackwell, E.K. Suspected Hyperaldosteronism. In Choose the Right Tests: Endocrine Disorders. Columbus, Ohio: Anadem Publishing, 2004. pp. 20-22.

Comprehensive Review: June 2011
Last Update: June 2011

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