Hyperaldosteronism Differential Diagnoses
- Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Stephen Kemp, MD, PhD more...
Delayed diagnosis of hypertension can lead to prolonged exposure to hypertension and secondary damage, as well as permanent remodeling of the blood vessels, thereby raising potential medicolegal problems. Differentiation of primary hyperaldosteronism from more common secondary causes is another area where medicolegal problems may arise, whether from failure to discontinue medications, failure to appreciate factors that may confound testing results, or failure to control blood pressure when the relevant medications are stopped.
An important condition to be considered in the differential diagnosis of primary hyperaldosteronism is congenital adrenal hyperplasia. Other problems to be considered include the following:
Apparent mineralocorticoid excess (types I and II)
Gain of function mutation of mineralocorticoid receptor
Exogenous mineralocorticoid excess
Drug-induced apparent mineralocorticoid excess
Congenital adrenal hyperplasia
11β-Hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (accounting for about 5% of all cases), with a frequency of 1 in 100,000 live births. Because conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to aldosterone are both reduced, hypersecretion of adrenocorticotropic hormone (ACTH) leads to excessive production of adrenal androgens as well as steroid hormone precursors. 11-Deoxycorticosterone has mineralocorticoid activity and can produce hypertension and sometimes hypokalemia.
The extent of virilization varies widely, ranging from newborn female infants with ambiguous genitalia to early male virilization to hirsutism and infertility in adult women.
The diagnosis should be considered in patients with features of hyperandrogenism and hypertension of the mineralocorticoid-excess type. The age at presentation correlates with the severity of the defect.
Treatment in younger children is with hydrocortisone or cortisone acetate. Those who have finished growing may be treated with dexamethasone. This treatment must be administered carefully; it may precipitate a salt-losing state, because this synthetic steroid has no mineralocorticoid activity and suppresses levels of 11-deoxycorticosterone by inhibiting ACTH release. Patients with 11β-hydroxylase deficiencies who are treated with glucocorticoids may require mineralocorticoid therapy during acute intercurrent illness.
Various mutations of the P-450c11 gene have been described. The diagnosis can be made on the basis of elevated levels of 11-deoxycorticosterone after ACTH stimulation, though basal levels are often diagnostic in affected neonates and infants. Treatment involves glucocorticoid replacement at physiologic doses.
Lyase and 17α-hydroxylase deficiencies are very rare. P-450c17 mutations produce a block in production of a single enzyme with both 17α-hydroxylase and 17,20-lyase activities.
Blockade of sex steroid production can lead to failure of female pubertal development and variable degrees of incomplete virilization with ambiguous genitalia in males. Deficient cortisol production results in ACTH hypersecretion with increased production of aldosterone precursors, including 11-deoxycorticosterone. Plasma renin activity and aldosterone are low.
Treatment involves glucocorticoid treatment similar to that employed for 11β-hydroxylase deficiencies. Males respond to testosterone in the neonatal period with phallic growth that may improve the outcome of corrective surgery. Both sexes also need pubertal induction.
Secondary hyperaldosteronism may be due to a physiologic attempt of the organism to maintain an adequate blood volume. The patient may be normotensive and edematous or may be hypertensive with no edema. Secondary hyperaldosteronism may be secondary to renal ischemia. Secondary hyperaldosteronism can be distinguished clinically and biochemically from primary hyperaldosteronism.
Syndrome of apparent mineralocorticoid excess
The syndrome of apparent mineralocorticoid excess is a rare cause of juvenile hypertension that was first described in 1979; since then, an additional 25-30 cases have been reported. Patients present with severe hypokalemia and metabolic alkalosis and suppressed plasma renin activity (PRA) and aldosterone levels. Two types of apparent mineralocorticoid excess have been described.
Type I apparent mineralocorticoid excess is characterized by impaired 11β-hydroxysteroid dehydrogenase (11β-HSD) activity with impaired conversion of cortisol to cortisone and impaired 5β-reductase activity. These patients have markedly elevated urinary ratios of cortisol, tetrahydrocortisol (THF), and allo-THF to cortisone, tetrahydrocortisone (THE), and allo-THE. Many of these patients have molecular defects of 11β-HSD type 2 (11β-HSD2).
Type II apparent mineralocorticoid excess is characterized by a decreased rate of cortisol clearance and turnover but a normal urinary THF-to-THE ratio.
Treatment of apparent mineralocorticoid excess is often difficult. A low-sodium diet in conjunction with spironolactone 1-4 mg/kg/day is often effective but may not yield long-lasting results. Patients with type II apparent mineralocorticoid excess respond to suppression of cortisol production with dexamethasone, a steroid with little mineralocorticoid activity. The problem is that dexamethasone has its significant growth-suppressing properties and therefore is not suitable for growing children.
Liddle syndrome is an autosomal dominant disorder that can partially mimic hyperaldosteronism. Patients present at a young age with hypertension and hypokalemia. Both PRA and aldosterone levels are suppressed. It is caused by mutations of the carboxy terminus of the beta-subunits or gamma-subunits of the renal epithelial sodium channel (ENaC), which result in a constitutively open channel. Treatment with the potassium-sparing diuretic triamterene or amiloride is often effective.
Gain of function mutation of mineralocorticoid receptor (MR)
An even less common autosomal-dominant cause of mineralocorticoid hypertension is associated with an activating mutation, resulting in the substitution of leucine for serine at codon 810 (S810L) in the human mineralocorticoid receptor. In this case, mineralocorticoid receptor antagonists, such as progesterone, develop agonist properties, whereas cortisone, rather than being inactive at the mineralocorticoid receptor, is actually an agonist. This gain of function mutation of the mineralocorticoid receptor results in early onset hypertension in men and gestational hypertension in women. Both spironolactone and eplerenone are not only unable to block the constitutive activity of the mutant MRS810L, but paradoxically activate this mutant receptor, exacerbating the hypertension. The patients, on the other hand, respond to amiloride acting downstream at the epithelial sodium channel.
Glucocorticoid resistance is a rare disorder that has been identified in several patients or members of kindreds. When familial, it is transmitted in both an autosomal recessive and an autosomal dominant fashion. Point mutations and microdeletions of the glucocorticoid receptor have been described.
Affected patients have an absence of cushingoid features, increased cortisol and ACTH levels (compensating for reduced glucocorticoid receptor function), and resistance to dexamethasone suppression of cortisol levels. The clinical manifestations are highly variable, though increased production of adrenal steroidogenic precursors, including deoxycorticosterone and adrenal androgens (eg, δ-4-androstenedione and dehydroepiandrostenedione), can produce hypertension in both sexes and hyperandrogenism in children and women.
Treatment consists of high-dose synthetic glucocorticoids with minimal mineralocorticoid activity (eg, dexamethasone 1-3 mg/day) to suppress plasma levels of ACTH and, ultimately, the secretion of adrenal steroids with androgenic and mineralocorticoid activity.
Drug-induced apparent mineralocorticoid excess
Some drugs can cause a clinical and biochemical picture consistent with hyperaldosteronism. Biochemically, the features of the disorder include suppression of both aldosterone and renin.
One drug that can cause this disorder is carbenoxolone, a synthetic derivative of glycyrrhizinic acid that is used to treat peptic and oral ulcers and gastroesophageal reflux. Carbenoxolone causes fluid and sodium retention and may cause hypokalemia, headaches, and myopathy. Excessive ingestion of licorice also produces a picture similar to apparent mineralocorticoid excess; the glycyrrhetinic acid in licorice blocks the enzyme 11β-HSD2 at the distal tubule, thereby giving circulating glucocorticoid access to the mineralocorticoid receptor.
Aronova A, Iii TJ, Zarnegar R. Management of hypertension in primary aldosteronism. World J Cardiol. 2014 May 26. 6(5):227-33. [Medline]. [Full Text].
Weisbrod AB, Webb RC, Mathur A, Barak S, Abraham SB, Nilubol N, et al. Adrenal histologic findings show no difference in clinical presentation and outcome in primary hyperaldosteronism. Ann Surg Oncol. 2013 Mar. 20(3):753-8. [Medline]. [Full Text].
Funder JW. The genetic basis of primary aldosteronism. Curr Hypertens Rep. 2012 Apr. 14(2):120-4. [Medline].
Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992 Jan 16. 355(6357):262-5. [Medline].
Torpy DJ, Gordon RD, Lin JP, Huggard PR, Taymans SE, Stowasser M, et al. Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene. J Clin Endocrinol Metab. 1998 Sep. 83(9):3214-8. [Medline].
Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, Lin JP, Huggard P, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet. 2000 Nov. 37(11):831-5. [Medline]. [Full Text].
Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011 Feb 11. 331(6018):768-72. [Medline]. [Full Text].
Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci U S A. 2012 Feb 14. 109(7):2533-8. [Medline]. [Full Text].
Charmandari E, Sertedaki A, Kino T, Merakou C, Hoffman DA, Hatch MM, et al. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. J Clin Endocrinol Metab. 2012 Aug. 97(8):E1532-9. [Medline]. [Full Text].
Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L, et al. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension. 2012 Mar. 59(3):592-8. [Medline].
Taguchi R, Yamada M, Nakajima Y, Satoh T, Hashimoto K, Shibusawa N, et al. Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. J Clin Endocrinol Metab. 2012 Apr. 97(4):1311-9. [Medline].
Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B, Cicala MV, et al. Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab. 2012 Aug. 97(8):E1567-72. [Medline]. [Full Text].
Azizan EA, Lam BY, Newhouse SJ, Zhou J, Kuc RE, Clarke J, et al. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. J Clin Endocrinol Metab. 2012 May. 97(5):E819-29. [Medline].
Al-Salameh A, Cohen R, Desailloud R. Overview of the genetic determinants of primary aldosteronism. Appl Clin Genet. 2014. 7:67-79. [Medline]. [Full Text].
Escher G. Hyperaldosteronism in pregnancy. Ther Adv Cardiovasc Dis. 2009 Apr. 3(2):123-32. [Medline].
Fuller PJ. Adrenal Diagnostics: An Endocrinologist's Perspective focused on Hyperaldosteronism. Clin Biochem Rev. 2013 Nov. 34(3):111-6. [Medline]. [Full Text].
Holland OB, Brown H, Kuhnert L, Fairchild C, Risk M, Gomez-Sanchez CE. Further evaluation of saline infusion for the diagnosis of primary aldosteronism. Hypertension. 1984 Sep-Oct. 6(5):717-23. [Medline].
Ignatowska-Switalska H, Chodakowska J, Januszewicz W, Feltynowski T, Adamczyk M, Lewandowski J. Evaluation of plasma aldosterone to plasma renin activity ratio in patients with primary aldosteronism. J Hum Hypertens. 1997 Jun. 11(6):373-8. [Medline].
Galati SJ, Hopkins SM, Cheesman KC, Zhuk RA, Levine AC. Primary aldosteronism: emerging trends. Trends Endocrinol Metab. 2013 Sep. 24(9):421-30. [Medline].
Guichard JL, Clark D 3rd, Calhoun DA, Ahmed MI. Aldosterone receptor antagonists: current perspectives and therapies. Vasc Health Risk Manag. 2013. 9:321-31. [Medline]. [Full Text].
Weiner ID. Endocrine and hypertensive disorders of potassium regulation: primary aldosteronism. Semin Nephrol. 2013 May. 33(3):265-76. [Medline]. [Full Text].
Harvey AM. Hyperaldosteronism: diagnosis, lateralization, and treatment. Surg Clin North Am. 2014 Jun. 94(3):643-56. [Medline].
Rossi GP, Cesari M, Cuspidi C, Maiolino G, Cicala MV, Bisogni V, et al. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension. 2013 Jul. 62(1):62-9. [Medline].
Fourkiotis V, Vonend O, Diederich S, Fischer E, Lang K, Endres S, et al. Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism. Eur J Endocrinol. 2013 Jan. 168(1):75-81. [Medline].
Kasifoglu T, Akalin A, Cansu DU, Korkmaz C. Hypokalemic paralysis due to primary hyperaldosteronism simulating Gitelman's syndrome. Saudi J Kidney Dis Transpl. 2009 Mar. 20(2):285-7. [Medline].
Künzel HE. Psychopathological symptoms in patients with primary hyperaldosteronism--possible pathways. Horm Metab Res. 2012 Mar. 44(3):202-7. [Medline].
Schmiemann G, Gebhardt K, Hummers-Pradier E, Egidi G. Prevalence of hyperaldosteronism in primary care patients with resistant hypertension. J Am Board Fam Med. 2012 Jan-Feb. 25(1):98-103. [Medline].
Kumar B, Swee M. Aldosterone-renin ratio in the assessment of primary aldosteronism. JAMA. 2014 Jul. 312(2):184-5. [Medline].
Gouli A, Kaltsas G, Tzonou A, Markou A, Androulakis II, Ragkou D, et al. High prevalence of autonomous aldosterone secretion among patients with essential hypertension. Eur J Clin Invest. 2011 Nov. 41(11):1227-36. [Medline].
Lucatello B, Benso A, Tabaro I, Capello E, Caprino MP, Marafetti L, et al. Long-term re-evaluation of primary aldosteronism after medical treatment reveals high proportion of normal mineralocorticoid secretion. Eur J Endocrinol. 2013 Apr. 168(4):525-32. [Medline].
Wu CH, Yang YW, Hu YH, Tsai YC, Kuo KL, Lin YH, et al. Comparison of 24-h urinary aldosterone level and random urinary aldosterone-to-creatinine ratio in the diagnosis of primary aldosteronism. PLoS One. 2013. 8(6):e67417. [Medline]. [Full Text].
Piaditis GP, Kaltsas GA, Androulakis II, Gouli A, Makras P, Papadogias D, et al. High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas. Clin Endocrinol (Oxf). 2009 Dec. 71(6):772-8. [Medline].
Gordon RD. Primary aldosteronism. J Endocrinol Invest. 1995 Jul-Aug. 18(7):495-511. [Medline].
Gordon RD, Stowasser M, Klemm SA, Tunny TJ. Primary aldosteronism--some genetic, morphological, and biochemical aspects of subtypes. Steroids. 1995 Jan. 60(1):35-41. [Medline].
Markou A, Pappa T, Kaltsas G, Gouli A, Mitsakis K, Tsounas P, et al. Evidence of primary aldosteronism in a predominantly female cohort of normotensive individuals: a very high odds ratio for progression into arterial hypertension. J Clin Endocrinol Metab. 2013 Apr. 98(4):1409-16. [Medline].
Papanastasiou L, Markou A, Pappa T, Gouli A, Tsounas P, Fountoulakis S, et al. Primary aldosteronism in hypertensive patients: clinical implications and target therapy. Eur J Clin Invest. 2014 Aug. 44(8):697-706. [Medline].
Mussa A, Camilla R, Monticone S, Porta F, Tessaris D, Verna F, et al. Polyuric-polydipsic syndrome in a pediatric case of non-glucocorticoid remediable familial hyperaldosteronism. Endocr J. 2012 Jun 30. 59(6):497-502. [Medline].
Rossi GP, Auchus RJ, Brown M, Lenders JW, Naruse M, Plouin PF, et al. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension. 2014 Jan. 63(1):151-60. [Medline].
Rossitto G, Regolisti G, Rossi E, Negro A, Nicoli D, Casali B, et al. Elevation of angiotensin-II type-1-receptor autoantibodies titer in primary aldosteronism as a result of aldosterone-producing adenoma. Hypertension. 2013 Feb. 61(2):526-33. [Medline].
Spyridonidis TJ, Apostolopoulos DJ. Is there a role for Nuclear Medicine in diagnosis and management of patients with primary aldosteronism?. Hell J Nucl Med. 2013 May-Aug. 16(2):134-9. [Medline].
Feldman RD. Aldosterone and blood pressure regulation: recent milestones on the long and winding road from electrocortin to KCNJ5, GPER, and beyond. Hypertension. 2014 Jan. 63(1):19-21. [Medline].
Scholl UI, Goh G, Stölting G, de Oliveira RC, Choi M, Overton JD, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013 Sep. 45(9):1050-4. [Medline]. [Full Text].
Cerny MA. Progress towards clinically useful aldosterone synthase inhibitors. Curr Top Med Chem. 2013. 13(12):1385-401. [Medline].
Uppot RN, Gervais DA. Imaging-guided adrenal tumor ablation. AJR Am J Roentgenol. 2013 Jun. 200(6):1226-33. [Medline].
Spence JD. Diagnosis of primary aldosteronism: for medical management, not just surgery. J Hypertens. 2009 Jan. 27(1):204-5; author reply 205. [Medline].
Hu YH, Wu CH, Er LK, Lin CD, Liu YB, Chueh SC, et al. Laparoendoscopic single-site adrenalectomy in patients with primary hyperaldosteronism: A prospective study with long-term follow up. Asian J Surg. 2015 Nov 25. [Medline].
Prejbisz A, Warchoł-Celińska E, Lenders J, Januszewicz A. Cardiovascular Risk in Primary Hyperaldosteronism. Horm Metab Res. 2015 Nov 17. [Medline].
Korah HE, Scholl UI. An Update on Familial Hyperaldosteronism. Horm Metab Res. 2015 Oct 7. [Medline].
|False Negative Results|
|K-wasting diuretics (Non-K-sparing diuretics, such as thiazides, induce renal potassium losses and reduce plasma potassium concentrations, leading to decreased aldosterone secretion.)||→↑||↑↑||↓|
|Angiotensin receptor blockers||↓||↑↑||↓|
|DHPs (It is a shared opinion that dihydropyridinic calcium channel blockers do not significantly affect aldosterone secretion, mainly causing an increase in PRA, which rarely gives false negatives.)||→↓||↑||↓|
|False Positive Results|
|Central alpha-2 agonists (eg, clonidine, alpha-methyldopa)||↓||↓↓||↑|
|Luteal phase of menstrual cycle||↑||PRA: Unchanged||↑|
|Antihypertensive Medications With Minimal Effect on the ARR|
|Prazosin, doxazosin, terazosin||←→|
|Renin inhibitors (Renin inhibitors raise the ARR if renin is measured as PRA [false positive] and lower it if measured as DAR concentration [false negative.])||↓||↑↓||↑↓|
|OCPs (OCPs have little effect on ARR when renin is measured as PRA. Use of immunometric measurements of DAR rather than PRA may give false positive results. Subdermal etonogestrel has no effect on ARR.)||↑||↓DAR||↑|
ARR, aldosterone-renin ratio; NSAIDs, non-steroidal anti-inflammatory drugs; K, potassium; ACE, angiotensin converting enzyme; ARBs, angiotensin II type 1 receptor blockers; DHPs, dihydropyridines; PHA-2, pseudohypoaldosteronism type 2; PRA, plasma renin activity; DAR, direct active renin; OCPs, oral contraceptive agents; SSRIs, selective serotonin reuptake inhibitors
|Spironolactone||Aldosterone antagonist||0-10 kg: 6.25 mg/dose PO q12h
11-20 kg: 12.5 mg/dose PO q12h
21-40 kg: 25 mg/dose PO q12h
>40 kg: 25 mg PO q8h
|Potassium canrenoate||Aldosterone antagonist||3-8 mg/kg IV qd; not to exceed 400 mg|
|Amiloride||Potassium-sparing diuretic||0.2 mg/kg q12h|
|Triamterene||Potassium-sparing diuretic||2 mg/kg/dose q8-24h|
|Nifedipine||Dihydropyridine calcium channel antagonist||0.25-0.5 mg/kg PO q6-8h|
|Amlodipine||Calcium channel antagonist||0.05-0.2 mg/ day PO|
|Doxazosin||Alpha1 -specific adrenergic antagonist||0.02-0.1 mg/day; not to exceed 4 mg|
|Prazosin||Alpha1 -specific adrenergic antagonist||0.005 mg/kg test dose, then 0.025-0.1 mg/kg/dose q6h; not to exceed 0.5 mg/dose|