CME Review Article #18 0021-972X/2001/1104-0263 The Endocrinologist Copyright © 2001 by Lippincott Williams & Wilkins CHIEF EDITOR’S NOTE: This article is the 18th of 36 that will be published in 2001 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned appear following the Table of Contents. Glucocorticoid-Remediable Aldosteronism Robert G. Dluhy, M.D.* Glucocorticoid-remediable aldosteronism (GRA) eralocorticoid-excess state. GRA is caused by a represents a rare, heriditary form of primary aldos- chimeric gene duplication that results from unequal teronism which is inherited in an autosomal domi- crossing over between the highly homologous 11␤- nant fashion. GRA is characterized by early onset hydroxylase (CYP11B1) and aldosterone synthase of moderate-to-severe hypertension and suppressed (CYP11B2) genes. The chimeric gene represents a plasma renin activity. The family history is often fusion of the 5'adrenocorticotropin-responsive reg- positive for a history of early hemorrhagic stroke. ulatory region of the 11␤-hydroxylase gene and the However, the clinical and biochemical features that 3' coding sequence of the aldosterone synthase define mineralcorticoid excess states, such as hy- gene. This results in ectopic expression of aldos- pokalemia, are not consistently present in GRA. terone synthase activity in the zona fasciculata, the Accordingly, recognition of this syndrome can be zone of the adrenal gland that normally secretes difficult. In GRA, aldosterone secretion is solely cortisol. This mutation explains the physiology and regulated by adrenocorticotropin. As a result, the genetics of GRA and provides the basis for a simple administration of exogenous glucocorticoids will direct genetic test for this disorder. ■ suppress the hypothalamic-pituitary axis and sup- press aldosterone levels, thereby relieving the min- The Endocrinologist 2001; 11: 263–268 Learning Objectives: suppressible hyperaldosteronism (more recently renamed • Identify the demographic, pathophysiologic, and glucocorticoid-remediable aldosteronism (GRA), or familial genetic features of glucocorticoid-remediable al- hyperaldosteronism type I). GRA was found to have an au- dosteronism (GRA), emphasizing those that dis- tosomal dominant pattern of inheritance, and earlier physi- tinguish it from other forms of aldosteronism. ologic studies revealed that plasma renin activity (PRA) was • Recall the phenotypic expression of GRA and the suppressed and aldosterone secretion was solely regulated by best way to diagnose it. adrenocorticotrophic hormone (ACTH). • Describe and contrast options for treating GRA. Historical Background Prevalence n 1966, Sutherland and Laidlaw described a syn- GRA is considered a rare cause of primary aldostero- drome of hypertension, hyperaldosteronism, nism with an estimated incidence of 1% to 3% of cases. I and hypokalemia that was found in a family and However, the diagnosis of a new case of GRA can yield a ❦ was reversed by exogenous glucocorticoid ther- large number of affected individuals in a family if the pedi- apy [1]. The disorder was called dexamethasone- gree is expanded and at-risk individuals are tested. Cases of GRA have been reported worldwide. Many Professor of Medicine, Harvard Medical School, Associate Director, Endocrine Hypertension Division, Brigham and Women’s Hospital, Boston, Massachusetts. affected families in North America are of Celtic ancestry; Address correspondence to: Robert G. Dluhy, M.D., Brigham and Women’s no known cases are reported among blacks. Unlike other Hospital, 221 Longwood Avenue, Boston, MA 02115. etiologies of primary aldosteronism, which are usually diag- *The author has disclosed that he has no significant relationships with or financial nosed in the third to fifth decades of life, GRA is present interest in any commercial companies that pertain to this educational activity. from birth onward, occurring equally among males and fe- 263 Glucocorticoid-Remediable Aldosteronism males. Co-investigators at Harvard Medical School in Boston, Massachusetts and Yale University School of Med- icine in New Haven, Connecticut who published the ini- tial discovery of the mutation causing GRA (see below) have established an International Registry for GRA. Free genetic screening is provided (telephone number: 800–722-5520 ext. 28481 or www.partners.org/bwh/gra) and the clinical characteristics of affected pedigrees have been recorded in an effort to characterize the GRA pheno- type (see below). Pathophysiology Figure 1. Steroidogenesis in the normal adrenal cortex and in the glu- cocorticoid-remediable aldosteronism (GRA) adrenal. A. The biosyn- Aldosterone production in normal subjects is regu- thetic pathway of aldosterone in the normal zona glomerulosa. B. In the lated by the renin-angiotensin system and potassium. Thus, normal zona fasciculata cortisol is the normal end product; in the GRA adrenal cortisol is the further 18-oxygenated to the compounds, 18- aldosterone secretion is normally positively regulated by hydroxycortisol (18-OH-F) and 18-oxocortisol (18-OXO-F). These angiotensin II (Ang II) and by potassium balance, with compounds are a unique biochemical phenotype to diagnose GRA. (Re- high levels stimulating and low levels reducing aldosterone printed with permission: Rich GM, Ulick S, Cook S, et al.: Glucocorti- coid-remediable aldosteronism in a large kindred: clinical spectrum and secretion. In normal subjects, ACTH transiently stimulates diagnosis using a characteristic biochemical phenotype. Ann Intern Med aldosterone secretion but a continuous, prolonged ACTH 1992; 116: 813–20.) infusion (over 24–48 hours) leads to a return of aldosterone levels to baseline. In contrast, in GRA aldosterone secre- Clinical Phenotype tion is solely regulated by ACTH with GRA subjects show- Blood Pressure ing an exaggerated response to infused ACTH and a failure to exhibit the expected normal decline after continuous New index cases of GRA continue to be discovered, ACTH administration [2]. In GRA, the renin-angiotensin most commonly in hypertensive children. As a result, a pos- system is suppressed and there is an absence of the normal sible diagnosis of GRA should be considered in all hyper- potassium-induced increase in aldosterone secretion [3]. It tensive children, especially those with suppressed PRA. A is likely that this dysregulation of aldosterone secretion recent study of 20 children with GRA underscores the im- solely by a hormone (ACTH) that is not sensitive to portance of considering the diagnosis of GRA in the setting sodium balance results in this mineralocorticoid excess of severe hypertension [5]. Fifty percent (8 of 16) of the state. As a corollary of the sole regulation of aldosterone by GRA children in this study were classified as having severe ACTH in GRA, the administration of exogenous gluco- hypertension (Ͼ99th centile for age and sex) (Fig. 2); the corticoids will suppress the hypothalamic-pituitary axis, presence of severe diastolic and systolic hypertension to- suppress aldosterone levels, reactivate suppressed PRA lev- gether particularly called for an evaluation for GRA. The els and reverse this mineralocorticoid excess state [1]. diagnosis of hypertension in childhood or adolescence is of- The adrenal cortex in GRA also produces large quan- ten delayed, which may reflect the failure of clinicians to ap- tities of novel 18-oxygenated cortisol compounds (18- preciate the normative blood pressure levels in these patient oxocortisol [18-OXO-F]; 18-hydroxycortisol [18-OH-F]) groups (blood pressure classification in children and adoles- [4] (Fig. 1). These so-called “hybrid” steroids share struc- cents requires reference to sex- and age-specific blood pres- tural features of both the cortisol-producing zona fascicu- sure centile nomograms) [6]. Thus the blood pressure levels lata and the aldosterone-producing zona glomerulosa (that in GRA-affected children are typically lower than values is, these compounds are both 17 and 18 oxidized). GRA is used to define hypertension in adults, but are usually higher easily distinguished from aldosterone-producing adenoma than age- or sex-matched controls. (APA), the only other condition in which there is over- Hypertension associated with GRA across all age production of 18-OXO-F and 18-OH-F, because the levels groups is often refractory to conventional antihyperten- of these compounds are 20 to 30 times higher than normal sive agents. In addition, the blood pressure in GRA- in GRA compared with only modest elevations in APA. It affected subjects within and between pedigrees is often is not clear whether 18-OXO-F and 18-OH-F possess highly variable; some affected individuals are normoten- sodium-retaining properties and contribute to the pheno- sive, whereas others have only mild hypertension. This typic variability of this mineralocorticoid excess state. variability in blood pressure levels in GRA may relate to 264 Volume 11, Number 4 Glucocorticoid-Remediable Aldosteronism Hemorrhagic Stroke A retrospective review of 27 pedigrees with geneti- cally proven GRA has documented an increased preva- lence of early cerebrovascular complications, primarily cerebral hemorrhage, which is associated with high mor- tality (61%) [8]. In this study, cerebrovascular complica- tions were present in 48% of all GRA pedigrees and 18% of all GRA patients, and the mean age at the time of stroke was 32 years. As a result, a prominent history of early he- morrhagic stroke in a family is also a clue