Mark W. Ball, MD
Arthur L. Burnett, II, MD, MBA, FACS
BASICS
DESCRIPTION
• Primary hyperaldosteronism or Conn syndrome is characterized by HTN, hypokalemia, hypernatremia, alkalosis, and suppressed renin, due to excess production of aldosterone.
• It classically refers to an aldosterone-producing adenoma (APA) of the adrenal gland that is usually small (<3 cm), unilateral, and renin-unresponsive.
• APA subtype of primary hyperaldosteronism accounts for 30–60% of primary hyperaldosteronism.
• Secondary hyperaldosteronism is usually related to HTN and/or edematous state disorders such as CHF, cirrhosis, and nephrotic syndrome.
• Pseudohypoaldosteronism can be due to ingestion of large amounts of licorice or Liddle syndrome
EPIDEMIOLOGY
Incidence
Incidence data is lacking.
Prevalence
• 5–13% of hypertensive population (recent increased prevalence of primary aldosteronism due to improved diagnostic testing)
• Peak incidence during 4th and 5th decades
• 20% primary aldosteronism in resistant hypertensives (elevated BP despite 3 antihypertensive medications)
• Adrenal adenoma is more common in women.
RISK FACTORS
No known risk factors for primary hyperaldosteronism
Genetics
• Hereditary pattern for more common APAs unclear
• A rare form of autosomal dominant primary hyperaldosteronism is glucocorticoid-remediable aldosteronism (GRA).
• Gene for aldosterone synthase (CYP11B2) recently identified
PATHOPHYSIOLOGY
• The biochemical hallmark of the disease is increased aldosterone after sodium (Na) loading and low plasma renin activity (PRA) during Na depletion
• Autonomous aldosterone secretion leads to inappropriate Na and water reabsorption from the cortical collecting tubule:
– Electrical gradient created favors secretion of potassium (K), resulting in hypokalemia.
– Extracellular fluid volume (ECF) volume causes mild hypertension (HTN).
• Renal escape limits Na retention and prevents significant edema:
– Occurs after ∼1.5 kg of extracellular fluid (ECF) is absorbed, or a weight gain of ∼3 kg.
– Spontaneous diuresis then occurs, lowering the ECF.
– Increased Atrial natriuretic peptide (ANP), decreased thiazide-sensitive Na-Cl cotransporter, and pressure natriuresis are factors that may contribute to renal escape.
ASSOCIATED CONDITIONS
• Adrenal cancer (rare)
• Essential HTN
GENERAL PREVENTION
N/A
DIAGNOSIS
HISTORY
• HTN, often refractory to medical therapy
– Headaches secondary to HTN
• Symptomatic hypokalemia:
– Muscle cramps, paresthesias, tetany, nocturia, polyuria
PHYSICAL EXAM
• No specific findings
• Mild-to-moderate HTN, not usually distinguishable from essential HTN
• Malignant HTN rare
• Lack of edema
DIAGNOSTIC TESTS & INTERPRETATION
• Consider screening the following patients (1):
– Hypertensive and hypokalemic:
HTN with K <3 highly suspicious of an aldosterone-producing adenoma (APA).
Hypokalemia is thought to be a late manifestation of aldosterone excess.
If patient is on restricted Na diet, severe hypokalemia often absent; only test patients if adequately salt loaded.
Hypokalemia can be induced with oral Na loading.
20% of patients with hyperaldosteronism are normokalemic; more often seen in adrenal hyperplasia.
– Inappropriate kaliuresis on initiation of diuretic
– HTN resistant to multidrug treatment
– Family history of early HTN or stroke
– Adrenal incidentaloma
• Diagnosis may be difficult in those with normal serum K levels and those being treated with antihypertensives or diuretics
Lab
• Hypernatremia, hypokalemia, metabolic alkalosis, impaired glucose tolerance
• Plasma renin activity (PRA) low in primary hyperaldosteronism; if plasma renin >1, diagnosis unlikely
• Screening: Plasma aldosterone concentration (PAC)/plasma renin activity (PRA) in the upright position; obtain when K is corrected. Positive if:
– PAC/PRA >20 with PAC ≥15 ng/dL OR
– PAC/PRA >40 with PRA >0.2 ng/mL/h
– Diuretics, ACE inhibitors, ARBs can falsely elevate PRA.
• Confirmatory studies:
– Na-loading test with:
Saline infusion: PAC at baseline and 4 hr (positive test PAC >10 ng/dL)
Oral Na: 24-hr urine Na and aldosterone on days 3 and 4 (positive if aldosterone <12 mg/d) and (Na >200 mmol/d)
Fludrocortisone suppression
• All confirmatory tests should be used with care in patients with compromised left ventricular cardiac function.
Imaging
• CT with thin cuts through the adrenals is the preferred noninvasive test:
– Used to identify surgically curable disease and differentiate the subtypes once primary aldosteronism is confirmed
– aldosterone-producing adenomas (APA’s) usually uniform, round, and hypodense with Hounsfield unit ≤10
– 6% probability of identifying an adrenal mass on CT
– Lacks overall accuracy to distinguish between unilateral and bilateral disease:
Bypass adrenal vein sampling only if clear adrenal mass (>1 cm) is identified in the younger patient (<40) with highly suspicious biochemical findings
• MRI is not more sensitive than CT
• Adrenal scintigraphy using Iodine-131-6-iodomethyl-19-nor-cholesterol is rarely available in US, cumbersome to perform, and depends heavily on the size of the adenoma.
Diagnostic Procedures/Surgery
• Adrenal vein sampling (AVS) for aldosterone is the gold standard in localizing the site of excess production:
– Aldosterone and cortisol samples obtained from peripheral veins, IVC, right and left adrenal veins after corticotrophin infusion
– 44% of patients with bilateral renal masses had a unilateral source of aldosterone secretion.
– Cure also reported after adrenalectomy in patients with AVS-proven unilaterality despite normal adrenals on CT scan.
• Postural tests, historically used to distinguish adenoma from bilateral hyperplasia have become less useful with the discovery of angiotensin-responsive APAs.
Pathologic Findings
• Solitary, well-demarcated mass with the typical mottled yellow color of adrenal cortex
• Without diffuse thickening of the zona glomerulosa or hyperplastic nodules
• May compress the nonneoplastic uninvolved adrenal gland
• Histopathology: Foamy lipid-laden clear cells, in sheets or nests
DIFFERENTIAL DIAGNOSIS
• Other causes of HTN. In Cushing disease, aldosterone and renin will both be low. In renal artery stenosis, there will be high renin and high aldosterone.
• Other causes of HTN and hypokalemia, such as:
– Overingestion of licorice
– Use of chewing tobacco
– Hyperdeoxycorticosterones
• Other subtypes of primary hyperaldosteronism:
– Bilateral adrenal hyperplasia: Idiopathic
– GRA due to aldosterone-producing, renin-responsive adenoma. Familial hyperaldosteronism type I, autosomal dominant
– Familial occurrence of APA or bilateral idiopathic hyperplasia or both
– Adrenal cancer producing aldosterone: Extremely rare
• Liddle syndrome: Autosomal dominant disorder. Mimics hyperaldosteronism and involves problems with excess resorption of Na and loss of K.
TREATMENT
GENERAL MEASURES
• Treatment selected based on etiology of hyperaldosteronism
• Control HTN
MEDICATION
First Line (2)
• Mineralocorticoid receptor antagonist used in those with bilateral adrenal hyperplasia and unilateral hyperplasia or APA who are not surgical candidates:
– Spironolactone: Limited due to affinity for androgen and progesterone receptors. Can cause gynecomastia, sexual dysfunction, menstrual irregularities
– Eplerenone: No active metabolites, shorter half-life than spironolactone, 50–75% as potent as spironolactone but less adverse effects
• Thiazide diuretics, ACE inhibitors, calcium channel antagonists, angiotensin blockers
Second Line
Amiloride, an epithelial Na channel blocker and K-sparing diuretic, may also be used, especially if spironolactone or eplerenone are intolerable. More often used in conjunction with the above.
SURGERY/OTHER PROCEDURES
• Unilateral adrenalectomy is indicated in patients with hyperaldosteronism due to an adenoma.
• HTN is cured or improved significantly in up to 90% of such cases. Usually takes 3–6 mo to see an effect.
• Adequate control of BP (see “Medications”) for several weeks and correction of metabolic abnormalities should be done before surgery.
• Obtain PAC after surgery to confirm cure
• Monitor K closely postoperatively
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
Emerging therapies include developing drugs that inhibit actions of aldosterone synthase enzyme, encoded on the CYP11B2 gene
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Patients with primary hyperaldosteronism have higher rates of prior stroke (12.9% vs. 3.4%) compared to those with essential HTN.
• Nonfatal MI (4% vs. 0.6%)
• Atrial fibrillation (7.3% vs. 0.6%)
COMPLICATIONS
• Related to HTN (left ventricular hypertrophy, coronary artery disease, heart failure, stroke, intracerebral hemorrhage, etc.)
• Related to low K (tetany, headache, arrhythmias, etc.)
FOLLOW-UP
Patient Monitoring
BP and serum electrolytes should be evaluated postoperatively and following medical therapy.
Patient Resources
Hyperaldosteronism - primary and secondary MedlinePlus. http://www.nlm.nih.gov/medlineplus/ency/article/000330.htm
REFERENCES
1. Mantero F, Mattarello MJ, Albiger NM. Detecting and treating primary aldosteronism:Primary aldosteronism. Exp Clin Endocrinol Diabetes. 2007;115:171–174.
2. Young WF Jr. Minireview: Primary aldosteronism–changing concepts in diagnosis and treatment. Endocrinology. 2003;144(6):2208–2213.
ADDITIONAL READING
• Calhoun DA. Aldosteronism and hypertension. Clin J Am Soc Nephrol. 2006;1:1039–1045.
• Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3–17.
• Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens. 2001;19(3):353–361.
• Mattsson C, Young WF Jr. Primary aldosteronism: Diagnostic and treatment strategies. Nat Clin Pract Nephrol. 2006;2(4):198–208.
• Plouin PF, Amar L, Chatellier G. Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant. 2004;19:774–777.
• Wheeler MH, Harris DA. Diagnosis and management of primary aldosteronism. World J Surg. 2003;27:627–631.
See Also (Topic, Algorithm, Media)
• Adrenal Mass
• Aldosteronism (Hyperaldosteronism, Conn Syndrome) Algorithm 
• Hypertension, Urologic Considerations
CODES
ICD9
• 255.10 Hyperaldosteronism, unspecified
• 255.12 Conn’s syndrome
• 255.14 Other secondary aldosteronism
ICD10
• E26.01 Conn’s syndrome
• E26.1 Secondary hyperaldosteronism
• E26.09 Other primary hyperaldosteronism
CLINICAL/SURGICAL PEARLS
• Hypertension (HTN) with serum K <3 meq/L is highly suspicious of an aldosterone-producing adenoma (APA).
• Treatment selection is based on etiology of hyperaldosteronism.
• Surgical excision provides excellent control of hypertension in aldosterone-producing adenoma (APA).
• Control of the adrenal vein is the most important step during adrenalectomy.