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primary hyperaldosteronism (Conn's syndrome)

Etiology: 1) aldosterone-producing adenoma (50-90% of cases) a) generally unilateral b) rarely malignant 2) bilateral adrenal hyperplasia (idiopathic form) a) glucocorticoid-remediable hyperaldosteronism - 11-beta hydroxysteroid dehydrogenase deficiency b) idiopathic form Epidemiology: 1) female:male ratio 2:1 2) occurs most commonly ages 30-50 3) incidence as high as 1% of hypertensive patients [2] 4) underdiagnosed in patients with resistant hypertension & chronic kidney disease [11] Pathology: - aldosterone secreting adrenal adenoma vs adrenal hyperplasia - hyposecretion of renin - hypersecretion of aldosterone Genetics: - family history Clinical manifestations: - treatment-resistant hypertension* [8] - unprovoked hypokalemia - muscle cramping - nocturia - thirst [4] * diastolic hypertension without edema Laboratory: 1) indications for testing a) untreated hypertension with sustained blood pressure (BP) > 150/100 mm Hg b) resistant hypertension (> 140/90 mm Hg) with 3-drug therapy including a diuretic c) hypertension & an adrenal incidentaloma d) hypertension & hypokalemia (spontaneous or diuretic-induced) e) hypertension & 1st degree relative with primary hyperaldosteronism f) hypertension & family history of hypertension < 40 years of age 2) initial screening consists of midmorning ambulatory (seated) plasma renin + plasma aldosterone in a normovolemic, normokalemic patient - discontinue spironolactone or eplerenone 6 weeks prior to testing [4] - screening positive (strongly suggestive) if plasma aldosterone > 15 ng/dL* & plasma aldosterone/renin activity ratio > 20 [4] - or plasma aldosterone/renin activity ratio > 23 ng/dL / ng/mL/hr (positive) [4] > 23 ng/dL / ng/mL/hr sensitivity of 97%, specificity of 94% > 67 ng/dL / ng/mL/hr sensitivity of 100% ^ ^ | | aldosterone renin -> angiotensin-1 3) plasma renin in a patient taking ACE inhibitor or ARB a) a low plasma renin is a positive screening test [4] b) a high plasma renin rules out hyperaldosteronism [4] 4) serum K+, unprovoked hypokalemia (> 50%); almost 50% without hypokalemia [4] 5) suppressed plasma renin* that fails to increase during volume depletion (upright posture, sodium depletion) 6) elevated plasma aldosterone* that does not suppress appropriately with volume expansion (salt loading) 7) 24-hour urine aldosterone cutoff of 12 ug (gold standard for diagnosis) [7] * plasma levels of aldosterone variable * 38% of patients with at least 1 level < 15 ng/dL, 14% with at least 1 level < 10 ng/dL [9] Special laboratory: - adrenal vein sampling prior to surgery to confirm source of aldosterone secretion & lateralization when imaging shows adrenal adenoma [4] - even when imaging fails to show adrenal adenoma, some patient have unilateral adrenal hyperplasa, thus adrenal vein sampling still indicated [12] Radiology: - CT or MRI of adrenals* * after laboratory confirmation of autonomous hyperaldosteronism Management: 1) adrenalectomy for aldosterone-secreting adenoma - medical management (aldosterone antagonist) may be non-inferior to adrenalectomy [11] 2) aldosterone antagonists for adrenal hyperplasia a) spironolactone 25-100 mg every 8 hours (drug of choice) b) eplerenone (off label use, less gynecomastia) 3) potassium-sparing diuretics second line a) triamterene b) amiloride 4) not sensitive to dexamethasone 5) referral to a specialty center for patients with elevated plasma aldosterone/renin activity ratio & plasma aldosterone or for patients who do not respond to empirical trials of aldosterone antagonists [2] 6) see hyperaldosteronism

Interactions

disease interactions

General

chronic endocrine disease hyperaldosteronism

Properties

THERAPY: spironolactone

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 1995
  2. Douma S et al Prevalence of primary hyperaldosteronism in resistant hypertension: A retrospective observational study. Lancet 2008 Jun 7; 371:1921 PMID: 18539224 http://dx.doi.org/10.1016/S0140-6736(08)60834-X
  3. Funder JW et al Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008 Sep;93(9):3266-81 PMID: 18552288
  4. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  5. Rossi GP, Bernini G, Caliumi C et al A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006 Dec 5;48(11):2293-300 PMID: 17161262
  6. Rossi GP, Auchus RJ, Brown M An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension. 2014 Jan;63(1):151-60. Epub 2013 Nov 11. PMID: 24218436
  7. Brown JM, Siddiqui M, Calhoun DA et al. The unrecognized prevalence of primary aldosteronism: A cross-sectional study. Ann Intern Med 2020 May 26; [e-pub]. PMID: 32449886 https://www.acpjournals.org/doi/10.7326/M20-0065 - Funder JW. Primary aldosteronism: At the tipping point. Ann Intern Med 2020 May 26; [e-pub]. PMID: 32449882 https://www.acpjournals.org/doi/10.7326/M20-1758
  8. Cohen JB, Cohen DL, Herman DS et al. Testing for primary aldosteronism and mineralocorticoid receptor antagonist use among U.S. veterans: A retrospective cohort study. Ann Intern Med 2020 Dec 29 PMID: 33370170 https://www.acpjournals.org/doi/10.7326/M20-4873
  9. Maciel AAW et al. Intra-individual variability of serum aldosterone and implications for primary aldosteronism screening. J Clin Endocrinol Metab 2023 May; 108:1143 PMID: 36413507 https://academic.oup.com/jcem/article-abstract/108/5/1143/6840305
  10. Dogra P, Bancos I, Young WF Jr Primary Aldosteronism: A Pragmatic Approach to Diagnosis and Management. Mayo Clinic Proceedings. 2023. 98(8):P1207-1215. August https://www.mayoclinicproceedings.org/article/S0025-6196(23)00239-2/fulltext
  11. Cohen DL et al. Primary aldosteronism in chronic kidney disease: Blood pressure control and kidney and cardiovascular outcomes after surgical versus medical management. Hypertension 2023 Oct; 80:2187. PMID: 37593884 https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.123.21474
  12. NEJM Knowledge+