0CARDIOLOGY IN Original Article REVIEW
Volume 12, Number 1 January/February 2004
From the Division of Endocrinology, Diabetes & Hypertension, Brigham & Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
Reprints: Graham T. McMahon, MB, BCh, Division of Endocrinology, Diabetes & Hypertension, Brigham & Women's Hospital, 221 Longwood Ave., RFB 2, Boston, MA 02115. E-mail: gmcmahon@partners.org
Copyright © 2003 by Lippincott Williams & Wilkins
ISSN: 1061-5377/04/1201-0044
DOI: 10.1097/01.crd.0000096417
Glucocorticoid-Remediable Aldosteronism
Graham T. McMahon, MB, BCh, MRCPI, and Robert G. Dluhy, MD
Abstract
Glucocorticoid remediable aldosteronism (GRA) appears to be the most common monogenic form of human hypertension. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the zona fasciculata of the adrenal gland under the control of adrenocorticotropin (ACTH). Affected individuals are typically hypertensive, often with onset in youth, and demonstrate refractoriness to standard antihypertensives such as angiotensin-converting enzyme inhibitors and ^-blockers. GRA subjects are normokalemic but often develop hypokalemia when treated with a potassium-wasting diuretic. Analysis of affected kindreds has demonstrated a high prevalence of early cerebral hemorrhage, largely as a result of aneurysms. Identification of affected individuals should allow direct neurovascular screening and targeted antihypertensive therapy.
Key Words: glucocorticoid-remediable aldosteron-ism, dexamethasone-suppressible hyperaldoste-ronism, monogenic hypertension, hyperaldosteronism
(Cardiology in Review 2004;12:44-48)
In 1966, Sutherland et al.1 described a father and son with an autosomal-dominant hypokalemic hypertensive syndrome. These and subsequent patients2 had typical biochemical features of primary hyperaldoste-ronism, including hypertension, suppressed plasma renin activity, and hypokalemia. However, their cases differed from others with hyperaldosteronism because their hypertension and hyperaldosteronism were reversed by the administration of the glucocorticoid dexamethasone. The molecular basis of this disorder, which was known earlier as dexa-methasone-suppressible hyperaldosteronism, and more recently as glucocorticoid-remedi-able aldosteronism (GRA), is now fully understood. GRA has now been reported worldwide, and it appears to be the most common monogenic form of human hypertension.
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PATHOPHYSIOLOGY
Adrenal steroid hormones are synthesized in different zones of the cortex: aldosterone in the zona glomerulosa, cortisol in the zona fasciculata, and androgens/estro-gens in the zona reticularis. The first 3 enzymatic steps of aldosterone biosynthesis (cholesterol to progesterone) are identical to those required for the biosynthesis of cortisol. However, the synthesis of cortisol requires 17-hydroxylation of pregnenolone by 17-hydroxylase (CYP17), which is expressed only in the zona fasciculata and is regulated by adrenocorticotropin (ACTH). Aldosterone synthase 18-hydroxylates corticosterone and is solely expressed in the zona glomerulosa under the regulation of angiotensin II.
Aldosterone regulates circulating potassium concentrations as well as intravascular volume through receptors in the distal tubules and cortical-collecting ducts of the kidney, where it acts to increase sodium resorption and increase potassium excretion.3 Primary hyperaldosteronism resulting from autonomous production of aldosterone results in volume expansion, hypertension, and often hypokalemia. The renin-angiotensin system is suppressed by the volume-expanded state resulting in the characteristically increased plasma aldosterone (PA) to plasma renin activity (PRA) ratio. The majority of patients with primary aldosteronism have either a unilateral aldosterone-producing adenoma or bilateral idiopathic hyperplasia.
In GRA, aldosterone secretion is positively and solely regulated by adrenocortico-tropic hormone (ACTH) that normally regulates cortisol secretion. As a result, sodium is retained and the renin-angiotensin system is suppressed.
Glucocorticoid-Remediable Aldosteronism CARDIOLOGY IN
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11(3-hydroxylase
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
The aldosterone synthase gene (CYP11B2) shares 95% homology with steroid 11 ^-hydroxylase (CYP11B1), which regulates the production of cortisol. Both genes are located in close proximity on the long arm of chromosome 8 and have identical in-tron- exon structures. Steroid 11^-hydroxy-lase, which is regulated by ACTH, is normally only expressed in the zona fasciculata of the adrenal gland, whereas aldosterone synthase is normally only expressed in the zona glomerulosa.
In all GRA kindreds, affected subjects have 2 normal copies of genes encoding al-dosterone synthase and 11 ^-hydroxylase, but they also have an abnormal gene duplication. This hybrid, or chimeric, gene combines the 5' promoter sequence of the 11 ^-hydroxylase gene fused to the more distal 3' aldoste-rone-synthase coding sequence (Fig. 1). As a result, aldosterone synthase is ectopically expressed in the cortisol-producing zone of the adrenal cortex under the regulation of ACTH. This chimeric gene results from variable, and unequal, crossing over between the 2 genes.4 The variability of the crossover site suggests that the defect arose independently in each pedigree and did not originate from a single ancestral mutation.
Genetic analysis of GRA kindreds has revealed that the disorder is inherited as an autosomal-dominant trait.5 Celtic ancestry is frequent among the reported pedigrees,6 and no cases have been reported among blacks.6
CLINICAL FEATURES
GRA is the most common monogenic cause of human hypertension. As an autosomal-dominant disorder, it appears with equal frequency in males and females. GRA is usually characterized by severe hypertension, volume expansion, and suppressed plasma renin activity.7 Unlike other etiologies of primary aldosteronism, hypokalemia in the absence of diuretic treatment is unusual.
Hypertension
GRA is characterized by moderate to severe hypertension with onset early in life.8 In a retrospective report from the GRA registry, 80% of 20 children (under the age of 18) who carried the genetic mutation had hypertension by the age of 13 years; blood pressures also correlated with siblings who shared the mutation. However, only half of the children with this diagnosis had severe hypertension (blood pressure >99th percentile for age), and 4 of 20 had normotension.8 A kindred has been described in which only
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8 of 21 affected subjects had systolic blood pressures of greater than 140 mm Hg and/or diastolic blood pressures of greater than 90 mm Hg.9 In other families,10 all affected members have been hypertensive.
Possible explanations for this incomplete penetrance of hypertension raise possibilities that include self-selected dietary salt restriction, concomitant inheritance of blood pressure-lowering genes, or decreased pen-etrance of the chimeric gene in affected families. Data from 2 GRA kindreds suggest that elevated urinary levels of the vasodilator kal-likrein could serve to protect against hyperten-sion.11 Another potential source of phenotypic variation in GRA is linkage disequilibrium with the "a" allele of the aldosterone synthase gene.12 Individuals inheriting the chimera from their mothers were noted to have significantly higher mean arterial pressure without having higher aldosterone levels, suggesting that in utero exposure to abnormal maternal mineralo-corticoid concentrations13 could upregulate
processes responsible for aldosterone
responsiveness.12
Hypokalemia
Many patients with GRA have normal potassium levels7 despite biochemical evidence for primary hyperaldosteronism. A prospective study in a large pedigree with GRA7 revealed that normokalemia was the rule unless patients had been treated with potassium-wasting diuretics. The reason why GRA subjects have normal potassium levels in the setting of hyperaldosteronism is unknown, but there does not appear to be renal impairment of the actions of aldosterone.
Hemorrhagic Stroke
In a cohort of 27 GRA pedigrees, early hemorrhagic stroke was a characteristic feature, occurring at a mean age of 32 years and associated with high mortality (61%).14 In this retrospective report, nearly half of all GRA pedigrees and 18% of all patients with GRA demonstrated early hemorrhagic events as a result of ruptured intracranial aneurysms. By contrast, there were no strokes in GRA-© 2003 Lippincott Williams & Wilkins
TABLE 1. Candidates for GRA testing_
Hypertensive individuals who:
• are members of known GRA kindreds;
• are diagnosed with primary hyperaldosteronism without demonstrable tumor;
• are young, especially children, and have suppressed plasma renin activity;
• have a family history of cerebral hemorrhage or hypertension before age 30 years;
• develop hypokalemia after treatment with a potassium-wasting diuretic; or
• have refractory hypertension.
GRA, glucocorticoid-remediable aldosteronism.
negative family members. As a result, screening with magnetic resonance imaging angiog-raphy, beginning at puberty and then every 5 years, has been recommended to detect occult intracranial aneurysms.14 A reduction in event rates after screening has not been documented.
DIAGNOSIS
Patients with GRA can have mild hypertension and are typically normokalemic7; such patients are often misdiagnosed as having "essential" hypertension. Clues pointing to a possible diagnosis of GRA include an early onset of hypertension (often in youth), a family history of early-onset hypertension or early cerebral hemorrhage, precipitation of hypokalemia when treated with potassium-wasting diuretics, and the refractoriness of the blood pressure to standard treatments (Table 1). A screening policy targeted at these features performed at 1 hypertension clinic discovered 2 index families and 4 further families containing 40 mutation-positive individuals in 1 year.15 Genetic screening of random hypertensive individuals by contrast is not efficacious.15
Like in other etiologies of primary aldo-steronism, the PA/PRA ratio in those with GRA is greater than 30, but this is not diagnostic. Hypokalemia lacks sensitivity as a screening test.716 As a result, these historical clues are the most useful in pointing to a possible diagnosis of GRA.
When the diagnosis of GRA is entertained, a number of different strategies can
Glucocorticoid-Remediable Aldosteronism
FIGURE 2. Suggested diagnostic algorithm for glucocorticoid-remediable aldosteronism. *The patient must not be taking spironolactone, eplerenone, triamterene, or amiloride. fA urinary level of 18-hydroxycortisol >10 nmol/L is diagnostic.17
be used to screen for and diagnose this disorder, including the dexamethasone suppression test, measurement of urinary 18-hydroxy/oxo-steroids,17 or direct genetic analysis (Fig. 2).
As noted previously, the zona fascicu-lata ectopically produces aldosterone under the regulation of ACTH. As a result, when 0.5 mg of the potent glucocorticoid dexametha-sone is given every 6 hours for 2 days, it suppresses aldosterone to undetectable levels (<4 ng/dL in GRA subjects).18 On the other hand, 10% of 60 patients with high aldosterone levels had a positive dexametha-sone suppression study but a negative genetic test.19
Affected patients with GRA excrete large amounts of urinary 18-hydroxycortisol and 18-oxocortisol17; these so-called "hybrid" steroids reflect the action of aldosterone synthase on cortisol in the zona fasciculata. Very low levels are produced in normal subjects, but mild elevations occur with aldosterone-producing adenomas.6
Direct screening for the chimeric gene duplication by Southern blotting is 100% sensitive and specific for diagnosing GRA and is available free of charge through the International Registry for Glucocorticoid Remediable Aldosteronism, which can be contacted at www.brighamandwomens.org/gra.
TREATMENT
Securing the correct diagnosis in these patients is critical, because nondirected antihypertensive therapies are often ineffective.8
Treatment with low-dose glucocorticoids 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 avoided; iatrogenic Cushing's syndrome and impaired linear growth in children have resulted from such overdosing.8 The therapeutic goal should be normotension, and not normalization of biochemical markers such as urinary 18-oxosteroid or serum aldoste-rone levels, because these remain elevated in the majority of those who normalize blood pressure.20 Titrating therapy to normalize laboratory values could unnecessarily increase the risk of Cushingoid side effects.20
Eplerenone and spironolactone, both type I mineralocorticoid receptor antagonists, are often effective treatment choices. Amiloride and triamterene, sodium epithelial channel antagonists, have also been used successfully. Both groups of agents block aldosterone action rather than reducing the production of this mineralocorticoid. Nondirected antihypertensives such as ß-blockers and angiotensin-converting enzyme inhibitors are less likely to be efficacious in the setting of a suppressed renin-angiotensin system.8 However, dihydro-pyridine calcium channel blockers can be useful adjunctive treatments to these diuretic agents.
CONCLUSION
GRA is the most common monogenic form of human hypertension and often masquerades as essential hypertension. Clinicians should consider the diagnosis, particularly in hypertensive children, and those with a family history of either early-onset hypertension or early cerebral hemorrhage. A dexa-
CARDIOLOGY IN REVIEW
Volume 12, Number 1 January/February 2004
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McMahon and Dluhy
methasone suppression test can be a useful screening maneuver; genetic screening and the measurement of urinary 18-oxosteroids are diagnostic. Treatment options include glucocorticoids to suppress ACTH and aldo-sterone levels, and mineralocorticoid receptor antagonists. Hypertension in GRA subjects can often be controlled with directed monotherapy.
REFERENCES
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3. White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med. 1994;331:250-258.
4. Lifton RP, Dluhy RG, Powers M, et al. A chimeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355:262-265.
5. Lifton RP, Dluhy RG, Powers M, et al. Hereditary hypertension caused by chimeric gene duplication and ectopic expression of aldosterone synthase. Nat Genet. 1992;2:66-74.
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19. Mulatero P, Veglio F, Pilon C, et al. Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexa-methasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab. 1998;83:2573-2575.
20. Stowasser M, Bachmann AW, Huggard PR, et al. Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension. J Clin Endocri-nol Metab. 2000;85:3313-3318.
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