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 hypertension. As a result of chimeric sterone in the zona glomerulosa, cortisol in gene duplication, aldosterone 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 hypokalemia when treated with a potassium-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 renin–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 primary aldosteronism 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 hyperplasia. 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 adrenal gland, 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- adrenal cortex under the regulation of ACTH. tension by the age of 13 years; blood 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 (blood pressure 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