44 CARDIOLOGY IN Original Article REVIEW Volume 12, Number 1 January/February 2004

Glucocorticoid-Remediable Aldosteronism

Graham T. McMahon, MB, BCh, MRCPI, and Robert G. Dluhy, MD

Abstract PATHOPHYSIOLOGY Glucocorticoid remediable aldosteronism (GRA) Adrenal steroid hormones are synthe- appears to be the most common monogenic form sized in different zones of the cortex: aldo- of human . As a result of chimeric sterone in the zona glomerulosa, in gene duplication, is ectopically syn- thesized in the zona fasciculata of the adrenal the zona fasciculata, and androgens/estro- gland under the control of adrenocorticotropin gens in the zona reticularis. The first 3 enzy- (ACTH). Affected individuals are typically hyper- matic steps of aldosterone biosynthesis (cho- tensive, often with onset in youth, and demon- strate refractoriness to standard antihypertensives lesterol to progesterone) are identical to such as angiotensin-converting enzyme inhibitors those required for the biosynthesis of corti- and ␤-blockers. GRA subjects are normokalemic sol. However, the synthesis of cortisol re- but often develop when treated with a -wasting diuretic. Analysis of affected quires 17-hydroxylation of pregnenolone by kindreds has demonstrated a high prevalence of 17-hydroxylase (CYP17), which is expressed early cerebral hemorrhage, largely as a result of only in the zona fasciculata and is regulated aneurysms. Identification of affected individuals should allow direct neurovascular screening and by adrenocorticotropin (ACTH). Aldosterone targeted antihypertensive therapy. synthase 18-hydroxylates corticosterone and is solely expressed in the zona glomerulosa Key Words: glucocorticoid-remediable aldosteron- ism, dexamethasone-suppressible hyperaldoste- under the regulation of angiotensin II. ronism, monogenic hypertension, Aldosterone regulates circulating potas- hyperaldosteronism sium concentrations as well as intravascular (Cardiology in Review 2004;12:44–48) volume through receptors in the distal tubules and cortical-collecting ducts of the kidney, where it acts to increase sodium resorption n 1966, Sutherland et al.1 described a father and increase potassium excretion.3 Primary and son with an autosomal-dominant hy- I hyperaldosteronism resulting from autono- pokalemic hypertensive syndrome. These and subsequent patients2 had typical bio- mous production of aldosterone results in chemical features of primary hyperaldoste- volume expansion, hypertension, and often ronism, including hypertension, suppressed hypokalemia. The –angiotensin system plasma renin activity, and hypokalemia. How- is suppressed by the volume-expanded state resulting in the characteristically increased From the Division of Endocrinol- ever, their cases differed from others with ogy, Diabetes & Hypertension, hyperaldosteronism because their hyperten- plasma aldosterone (PA) to plasma renin ac- Brigham & Women’s Hospital, tivity (PRA) ratio. The majority of patients and Harvard Medical School, sion and hyperaldosteronism were reversed Boston, Massachusetts. by the administration of the glucocorticoid with have either a uni- Reprints: Graham T. McMahon, dexamethasone. The molecular basis of this lateral aldosterone-producing adenoma or bi- MB, BCh, Division of Endocri- lateral idiopathic . nology, Diabetes & Hyperten- disorder, which was known earlier as dexa- sion, Brigham & Women’s Hos- methasone-suppressible hyperaldosteronism, In GRA, aldosterone secretion is posi- pital, 221 Longwood Ave., RFB and more recently as glucocorticoid-remedi- tively and solely regulated by adrenocortico- 2, Boston, MA 02115. E-mail: [email protected] able aldosteronism (GRA), is now fully under- tropic hormone (ACTH) that normally regu- Copyright © 2003 by stood. GRA has now been reported world- lates cortisol secretion. As a result, sodium is Lippincott Williams & Wilkins wide, and it appears to be the most common retained and the renin–angiotensin system is ISSN: 1061-5377/04/1201-0044 monogenic form of human hypertension. suppressed. DOI: 10.1097/01.crd.0000096417.42861.ce Glucocorticoid-Remediable Aldosteronism CARDIOLOGY IN 45 REVIEW Volume 12, Number 1 January/February 2004

FIGURE 1. Chimeric gene duplication in glucocorticoid-remediable aldosteronism. The adrenocorticotropin-responsive promoter of 11␤-hydroxylase and the coding sequence of aldosterone synthase are fused. Adapted from reference 4, with permission.

GENETICS Genetic analysis of GRA kindreds has The aldosterone synthase gene revealed that the disorder is inherited as an (CYP11B2) shares 95% homology with ste- autosomal-dominant trait.5 Celtic ancestry is roid 11␤-hydroxylase (CYP11B1), which reg- frequent among the reported pedigrees,6 and ulates the production of cortisol. Both genes no cases have been reported among blacks.6 are located in close proximity on the long arm of chromosome 8 and have identical in- CLINICAL FEATURES ␤ tron–exon structures. Steroid 11 -hydroxy- GRA is the most common monogenic lase, which is regulated by ACTH, is normally cause of human hypertension. As an autoso- only expressed in the zona fasciculata of the mal-dominant disorder, it appears with equal , whereas aldosterone synthase frequency in males and females. GRA is usu- is normally only expressed in the zona ally characterized by severe hypertension, glomerulosa. volume expansion, and suppressed plasma In all GRA kindreds, affected subjects renin activity.7 Unlike other etiologies of pri- have 2 normal copies of genes encoding al- mary aldosteronism, hypokalemia in the ab- ␤ dosterone synthase and 11 -hydroxylase, but sence of diuretic treatment is unusual. they also have an abnormal gene duplication. This hybrid, or chimeric, gene combines the Hypertension 5Ј promoter sequence of the 11␤-hydroxy- GRA is characterized by moderate to lase gene fused to the more distal 3Ј aldoste- severe hypertension with onset early in life.8 rone–synthase coding sequence (Fig. 1). As a In a retrospective report from the GRA regis- result, aldosterone synthase is ectopically ex- try, 80% of 20 children (under the age of 18) pressed in the cortisol-producing zone of the who carried the genetic mutation had hyper- under the regulation of ACTH. tension by the age of 13 years; pres- This chimeric gene results from variable, and sures also correlated with siblings who unequal, crossing over between the 2 genes.4 shared the mutation. However, only half of The variability of the crossover site suggests the children with this diagnosis had severe that the defect arose independently in each hypertension ( Ͼ99th percen- pedigree and did not originate from a single tile for age), and 4 of 20 had normotension.8 ancestral mutation. A kindred has been described in which only 46 CARDIOLOGY IN McMahon and Dluhy REVIEW Volume 12, Number 1 January/February 2004

8 of 21 affected subjects had systolic blood TABLE 1. Candidates for GRA testing pressures of greater than 140 mm Hg and/or Hypertensive individuals who: diastolic blood pressures of greater than 90 • are members of known GRA kindreds; 9 10 mm Hg. In other families, all affected • are diagnosed with primary hyperaldosteronism members have been hypertensive. without demonstrable tumor; • Possible explanations for this incom- are young, especially children, and have suppressed plasma renin activity; plete penetrance of hypertension raise possi- • have a family history of cerebral hemorrhage bilities that include self-selected dietary salt or hypertension before age 30 years; • restriction, concomitant inheritance of blood develop hypokalemia after treatment with a potassium-wasting diuretic; or pressure-lowering genes, or decreased pen- • have refractory hypertension. etrance of the chimeric gene in affected fami- GRA, glucocorticoid-remediable aldosteronism. lies. Data from 2 GRA kindreds suggest that elevated urinary levels of the vasodilator kal- likrein could serve to protect against hyperten- negative family members. As a result, screen- sion.11 Another potential source of phenotypic ing with magnetic resonance imaging angiog- variation in GRA is linkage disequilibrium with raphy, beginning at puberty and then every 5 the “a” allele of the aldosterone synthase years, has been recommended to detect oc- 14 gene.12 Individuals inheriting the chimera from cult intracranial aneurysms. A reduction in their mothers were noted to have significantly event rates after screening has not been higher mean arterial pressure without having documented. higher aldosterone levels, suggesting that in utero exposure to abnormal maternal mineralo- DIAGNOSIS corticoid concentrations13 could upregulate Patients with GRA can have mild hyper- processes responsible for aldosterone tension and are typically normokalemic7; responsiveness.12 such patients are often misdiagnosed as hav- ing “essential” hypertension. Clues pointing Hypokalemia to a possible diagnosis of GRA include an Many patients with GRA have normal early onset of hypertension (often in youth), potassium levels7 despite biochemical evi- a family history of early-onset hypertension dence for primary hyperaldosteronism. A or early cerebral hemorrhage, precipitation prospective study in a large pedigree with of hypokalemia when treated with potassi- GRA7 revealed that normokalemia was the um-wasting diuretics, and the refractoriness rule unless patients had been treated with of the blood pressure to standard treatments potassium-wasting diuretics. The reason why (Table 1). A screening policy targeted at GRA subjects have normal potassium levels these features performed at 1 hypertension in the setting of hyperaldosteronism is un- clinic discovered 2 index families and 4 fur- known, but there does not appear to be renal ther families containing 40 mutation-positive impairment of the actions of aldosterone. individuals in 1 year.15 Genetic screening of random hypertensive individuals by contrast Hemorrhagic Stroke is not efficacious.15 In a cohort of 27 GRA pedigrees, early Like in other etiologies of primary aldo- hemorrhagic stroke was a characteristic fea- steronism, the PA/PRA ratio in those with ture, occurring at a mean age of 32 years and GRA is greater than 30, but this is not diag- associated with high mortality (61%).14 In nostic. Hypokalemia lacks sensitivity as a this retrospective report, nearly half of all screening test.7,16 As a result, these historical GRA pedigrees and 18% of all patients with clues are the most useful in pointing to a GRA demonstrated early hemorrhagic events possible diagnosis of GRA. as a result of ruptured intracranial aneurysms. When the diagnosis of GRA is enter- By contrast, there were no strokes in GRA- tained, a number of different strategies can © 2003 Lippincott Williams & Wilkins Glucocorticoid-Remediable Aldosteronism CARDIOLOGY IN 47 REVIEW Volume 12, Number 1 January/February 2004

TREATMENT Securing the correct diagnosis in these patients is critical, because nondirected anti- hypertensive therapies are often ineffective.8 Treatment with low-dose glucocorti- coids is effective18 by providing feedback suppression of pituitary ACTH release, which suppresses the abnormal regulation of aldo- sterone secretion. Typical dosing in adults include 0.125 to 0.25 mg of dexamethasone, or 2.5 to 5 mg of prednisolone daily, often administered at bedtime. However, overtreat- ment with exogenous steroids must be avoid- FIGURE 2. Suggested diagnostic algorithm for ed; iatrogenic Cushing’s syndrome and im- glucocorticoid-remediable aldosteronism. *The paired linear growth in children have patient must not be taking , resulted from such overdosing.8 The thera- , triamterene, or amiloride. †A urinary level of 18-hydroxycortisol Ͼ10 nmol/L peutic goal should be normotension, and not is diagnostic.17 normalization of biochemical markers such as urinary 18-oxosteroid or serum aldoste- be used to screen for and diagnose this disor- rone levels, because these remain elevated in der, including the dexamethasone suppression the majority of those who normalize blood test, measurement of urinary 18-hydroxy/oxo- pressure.20 Titrating therapy to normalize 17 steroids, or direct genetic analysis (Fig. 2). laboratory values could unnecessarily in- As noted previously, the zona fascicu- crease the risk of Cushingoid side effects.20 lata ectopically produces aldosterone under Eplerenone and spironolactone, both the regulation of ACTH. As a result, when 0.5 type I receptor antagonists, mg of the potent glucocorticoid dexametha- are often effective treatment choices. Amilo- sone is given every 6 hours for 2 days, it ride and triamterene, sodium epithelial channel suppresses aldosterone to undetectable lev- antagonists, have also been used successfully. Ͻ 18 els ( 4 ng/dL in GRA subjects). On the Both groups of agents block aldosterone action other hand, 10% of 60 patients with high rather than reducing the production of this aldosterone levels had a positive dexametha- mineralocorticoid. Nondirected antihyperten- sone suppression study but a negative ge- sives such as ␤-blockers and angiotensin- 19 netic test. converting enzyme inhibitors are less likely to Affected patients with GRA excrete be efficacious in the setting of a suppressed large amounts of urinary 18-hydroxycortisol renin–angiotensin system.8 However, dihydro- 17 and 18-oxocortisol ; these so-called “hybrid” pyridine calcium channel blockers can be use- steroids reflect the action of aldosterone syn- ful adjunctive treatments to these diuretic thase on cortisol in the zona fasciculata. Very agents. low levels are produced in normal subjects, but mild elevations occur with aldosterone- producing adenomas.6 CONCLUSION Direct screening for the chimeric gene GRA is the most common monogenic duplication by Southern blotting is 100% sen- form of human hypertension and often mas- sitive and specific for diagnosing GRA and is querades as essential hypertension. Clini- available free of charge through the Interna- cians should consider the diagnosis, particu- tional Registry for Glucocorticoid Remedia- larly in hypertensive children, and those with ble Aldosteronism, which can be contacted a family history of either early-onset hyper- at www.brighamandwomens.org/gra. tension or early cerebral hemorrhage. A dexa- 48 CARDIOLOGY IN McMahon and Dluhy REVIEW Volume 12, Number 1 January/February 2004

methasone suppression test can be a useful 10. O’Mahony S, Burns A, Murnaghan DJ. Dexametha- sone-suppressible hyperaldosteronism: a large new screening maneuver; genetic screening and kindred. J Hum Hypertens. 1989;3:255–258. the measurement of urinary 18-oxosteroids 11. Dluhy RG, Lifton RP. Glucocorticoid-remediable are diagnostic. Treatment options include aldosteronism (GRA): diagnosis, variability of phe- glucocorticoids to suppress ACTH and aldo- notype and regulation of potassium homeostasis. Steroids. 1995;60:48–51. sterone levels, and mineralocorticoid recep- 12. Jamieson A, Slutsker L, Inglis GC, et al. Glucocorti- tor antagonists. Hypertension in GRA sub- coid-suppressible hyperaldosteronism: effects of jects can often be controlled with directed crossover site and parental origin of chimaeric gene on phenotypic expression. Clin Sci. monotherapy. 1995;88:563–570. 13. Wyckoff JA, Seely EW, Hurwitz S, et al. Glucocorti- REFERENCES coid-remediable aldosteronism and pregnancy. Hy- 1. Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, pertension. 2000;35:668. increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can 14. Litchfield WR, Anderson BF, Ruedigger JW, et al. Med Assoc J. 1966;95:1109–1119. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hyper- 2. New MI, Peterson RE. A new form of congenital tension. 1998;31(part 2):445–450. adrenal hyperplasia. J Clin Endocrinol Metab. 1967;27:300–305. 15. Gates LJ, Benjamin N, Haites NE, et al. Is random screening of value in detecting glucocorticoid-re- 3. White PC. Disorders of aldosterone biosynthesis mediable aldosteronism within a hypertensive pop- and action. N Engl J Med. 1994;331:250–258. ulation? J Hum Hypertens. 2001;15:173–176. 4. Lifton RP, Dluhy RG, Powers M, et al. A chimeric 11 beta-hydroxylase/aldosterone synthase gene 16. Litchfield WR, Coolidge C, Silva P, et al. Impaired causes glucocorticoid-remediable aldosteronism potassium-stimulated aldosterone production: a and human hypertension. Nature. possible explanation for normokalemic glucocorti- 1992;355:262–265. coid-remediable aldosteronism. J Clin Endocrinol Metab. 1997;82:1507–1510. 5. Lifton RP, Dluhy RG, Powers M, et al. Hereditary hypertension caused by chimeric gene duplication 17. Mosso L, Gomez-Sanchez CE, Foecking MF, et al. and ectopic expression of aldosterone synthase. Serum 18-hydroxycortisol in primary aldosteron- Nat Genet. 1992;2:66–74. ism, hypertension, and normotensives. Hyperten- sion. 2001;38(part 2):688–691. 6. Dluhy RG, Lifton RP. Glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 18. Litchfield WR, New MI, Coolidge C, et al. Evalua- 1999;84:4341–4344. tion of the dexamethasone suppression test for the 7. Rich GM, Ulick S, Cook S, et al. Glucocorticoid- diagnosis of glucocorticoid remediable aldosteron- remediable aldosteronism in a large kindred: clini- ism. J Clin Endocrinol Metab. cal spectrum and diagnosis using a characteristic 1997;82:3570–3573. biochemical phenotype. Ann Intern Med. 19. Mulatero P, Veglio F, Pilon C, et al. Diagnosis of 1992;116:813–820. glucocorticoid-remediable aldosteronism in pri- 8. Dluhy RG, Anderson B, Harlin B, et al. Glucocorti- mary aldosteronism: aldosterone response to dexa- coid-remediable aldosteronism is associated with methasone and long polymerase chain reaction for severe hypertension in early childhood. J Pediatr. chimeric gene. J Clin Endocrinol Metab. 2001;138:715–720. 1998;83:2573–2575. 9. Mulatero P, Morra Di Cella S, Williams A, et al. 20. Stowasser M, Bachmann AW, Huggard PR, et al. Glucocorticoid remediable aldosteronism: low Treatment of familial hyperaldosteronism type I: morbidity and mortality in a four-generation Italian only partial suppression of adrenocorticotropin pedigree. J Clin Endocrinol Metab. required to correct hypertension. J Clin Endocri- 2002;87:3187–3191. nol Metab. 2000;85:3313–3318.

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