Glucocorticoid-Remediable Aldosteronism

Robert G. Dluhy and Richard P. Lifton

Harvard Medical School, Endocrine Hypertension Division, Brigham and Women’s Hospital (R.G.D.), Boston, Massachusetts 02115; and Department of Genetics, Internal Medicine, and Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06519

Address correspondence and requests for reprints to: Robert G. Dluhy, Endocrine-Hypertension Division, Brigham and Women’s Hospital, Ambulatory Clinic Center, 221 Longwood Avenue, Boston, Massachusetts 02115.


    Introduction
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 Introduction
 Pathophysiology
 Phenotype
 Genotype
 Diagnosis
 Treatment
 References
 
Sutherland et al. (1) described a new hypokalemic hypertensive syndrome in a father and son in 1966. Thirty years later, the genetic basis of this disorder is completely understood. In that description, aldosterone secretion was solely regulated by ACTH, and the syndrome was reversed by exogenous glucocorticoid therapy. A similar syndrome was subsequently reported by New and Peterson (2) 1 yr later. Glucocorticoid-remediable aldosteronism (GRA), alternatively called dexamethasone-suppressible hyperaldosteronism (DSH) or familial hyperaldosteronism type I, a mineralocorticoid-excess state characterized by low PRA, is now a well-established subset of primary aldosteronism. The early literature described patients with GRA as fitting the classical description of a mineralocorticoid-excess state, including hypertension, hyporeninemia, and "spontaneous" hypokalemia. However, recent evidence suggests that the full expression of the classic mineralocorticoid phenotype, such as hypokalemia, is seen in only a minority of GRA patients.

Cases of GRA have been reported worldwide. Many affected families in North America are of Celtic ancestry; no known cases are reported among blacks. Unlike other etiologies of primary aldosteronism, which occur with increased frequency in women and are usually diagnosed in the 3rd to 5th decades of life, hyperaldosteronism in GRA is evident from birth onward. GRA is inherited as an autosomal dominant trait, occurring equally among men and women.


    Pathophysiology
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 Introduction
 Pathophysiology
 Phenotype
 Genotype
 Diagnosis
 Treatment
 References
 
Under normal conditions, aldosterone production is regulated by the renin-angiotensin system and potassium balance. In GRA, aldosterone secretion is positively and solely regulated by ACTH, the renin-angiotensin system is suppressed, and there is an absence of the normal potassium-induced increase in aldosterone secretion. This dysregulation of aldosterone secretion solely by a hormone that is not sensitive to sodium balance explains the autonomy of aldosterone production, resulting in a chronic mineralocorticoid excess state. The regulation of aldosterone by ACTH in GRA also results in a circadian pattern of aldosterone production that parallels that of cortisol. In addition, the administration of exogenous glucocorticoids that suppress ACTH secretion result in the suppression of aldosterone levels and a reversal of this mineralocorticoid excess state (thus, the appellation DSH or GRA).

In GRA there is acute exaggerated aldosterone responsiveness to ACTH and a failure to show the normal decline following chronic continuous ACTH infusion. The normal regulation of aldosterone by angiotensin II (Ang II) is absent in GRA, as evidenced by the failure of aldosterone to respond to upright posture as well as to infused Ang II. However, aldosterone responsiveness to Ang II can be restored by chronic therapy with exogenous glucocorticoids. Thus, glucocorticoid treatment reverses the volume expansion associated with GRA, leading to reactivation of the suppressed renin-angiotensin system and restoration of function of the previously suppressed zona glomerulosa.

The adrenal cortex in GRA produces large quantities of 18-oxygenated cortisol compounds, 18-oxocortisol (18-oxo-F), and 18-hydroxycortisol (18-OH-F), so-called hybrid steroids because they possess enzymatic features of both zona glomerulosa and zona fasciculata steroids (that is, exhibiting aldosterone and 17-hyroxylase activities, respectively) (3). Elevated levels of these compounds in a timed 24-h urine collection provides a highly sensitive and specific test to diagnose GRA. GRA is easily distinguished from the aldosterone-producing adenoma (APA; the only other condition in which there is overproduction of 18-oxo-F and 18-OH-F) because the levels of these compounds are 20 to 30 times higher than normal in GRA compared to only modest elevations in APA. It is not clear whether 18-oxo-F and 18-OH-F possess sodium-retaining properties and contribute to the phenotypic variability of this disorder. In addition, reduced 11ß-hydroxylase activity in association with elevated levels of the mineralocorticoid 11-deoxycorticosterone have been reported in untreated individuals with GRA.


    Phenotype
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 Introduction
 Pathophysiology
 Phenotype
 Genotype
 Diagnosis
 Treatment
 References
 
Blood pressure

GRA is usually characterized by moderate to severe hypertension with onset early in life. The diagnosis of hypertension in childhood or adolescence may be delayed due to failure of some clinicians to appreciate the normative blood pressure levels in these patient groups. Thus, the blood pressure levels in GRA-affected children are usually greater than the percentile of age- and sex-matched controls.

Hypertension associated with GRA is often difficult to control with conventional antihypertensive agents. In addition, the blood pressure in GRA-affected subjects within and between pedigrees is often highly variable; while most are severely hypertensive, some affected individuals are normotensive whereas others have only mild hypertension. This variability in blood pressure levels in GRA may relate to other hereditary factors that regulate blood pressure or environmental factors such as variation in dietary sodium intake. Thus, the family history in GRA does not invariably reveal a history of severe hypertension in first-degree relatives of affected subjects.

Hemorrhagic stroke

Early, often fatal, cerebrovascular complications in GRA patients were sporadically reported by earlier investigators. Establishment of a registry and a retrospective review of 27 GRA pedigrees has documented an increased prevalence of early cerebrovascular complications, primarily cerebral hemorrhage, which is associated with high mortality (61%) (4). Complications were noted in 48% of all GRA pedigrees and 18% of all GRA patients. The mean age at the time of the initial event was 32 yr, and the underlying mechanism was intracranial aneurysm. Accordingly, screening of asymptomatic GRA patients with magnetic resonance angiography is recommended, beginning at puberty and every 5 yr thereafter (similar to the recommendations for patients with adult polycystic kidney disease, where there is a similar frequency of aneurysm).

Potassium levels

Normokalemia in GRA-affected patients was first described by Grim and Weinberger (4A ), but it was believed to be uncommon. A prospective study by Rich et al. (5) revealed that affected patients in a large GRA pedigree were normokalemic unless they had been treated with potassium-wasting diuretics. Other investigators screening at-risk relatives in GRA families have corroborated this finding. Thus, serum potassium lacks sensitivity as a screening test for this mineralocorticoid-excess state. The mechanism(s) for the absence of hypokalemia in GRA are unknown, but there does not seem to be an impairment in renal responsiveness to potassium loading or florinef administration.


    Genotype
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 Introduction
 Pathophysiology
 Phenotype
 Genotype
 Diagnosis
 Treatment
 References
 
GRA is inherited as an autosomal dominant trait that follows classic Mendelian genetics. Lifton et al. (6) was the first to show in a large pedigree that GRA is caused by a chimeric gene duplication that results from unequal crossing over between the highly hormologous 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. Located in close proximity to each other on chromosome 8, CYP11B1 and CYP11B2 share more than 90% bp homology. The chimeric gene represents a fusion of the 5' adrenocorticotropin-responsive promotor region of the 11ß-hydroxylase gene and the 3' coding sequences of the aldosterone synthase gene. This gene duplication results in ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata. As a result, aldosterone and the novel steroids 18-OH-F and 18 oxo-F are produced ectopically in the zona fasciculata under the regulation of adrenocorticotropin from cortisol and cortisol steroid precursors.

In 11 additional GRA pedigrees all subjects proved to have chimeric gene duplications, but in these subjects a minimum of eight independent mutations with five different sites of crossing over were identified (7). Crossover breakpoints ranged from intron 2 to intron 4 of the genes, in all cases fusing 5' 11ß-hydroxylase sequences to more distal aldosterone synthase sequences. Confirmation of the presence of such chimeric gene mutations was subsequently reported in another study of four additional patients from unrelated GRA pedigrees by Pascoe et al. (8).

DNA sequence analyses of the chimeric genes from unrelated pedigrees indicate that the sites of fusion are variable, but in all cases are upstream of exon 5, suggesting that encoded amino acids in exon 5 of aldosterone synthase are essential for aldosterone synthase enzymatic function. Expression of various chimeric gene constructs in vitro has demonstrated that when these genes are fused after exon 3 the expressed product retains aldosterone synthase enzymatic activity, whereas when the fusion is after exon 5 aldosterone synthase enzymatic activity is undetectable. Transfection studies with complementary DNA encoding hybrids between the highly homologous 11ß-hydroxylase and aldosterone synthase enzymes have shown that two amino acid changes, Ser288Gly and Val320Ala, can convert 11ß-hydroxylase into an efficient aldosterone-producing enzyme (9). These results suggest that a gene conversion involving exons 5 and 6, in which these residues are encoded, could cause a novel form of GRA. However, to date, no conversions of the CYP11B1 gene expected to cause GRA (involving exons 4, 5, and 6 from CYP11B2) have been found in a sample of low renin hypertensive patients, patients with primary aldosteronism, and 90 normotensive individuals (10).

Jamieson et al. (11) have also reported that the chimeric gene causing GRA was in strong linkage disequilibrium with the "a" allele of the aldosterone synthase gene, pointing to a possible role for this allele in the development of the chimeric gene. Individuals inheriting the chimera from their mothers also had significantly higher basal mean arterial pressure and basal aldosterone levels compared with individuals with a paternal source of the chimeric gene. The authors speculated that chronic exposure of the developing fetus to high mineralocorticoid levels could alter the expression of the genes that regulate aldosterone synthesis. However, they were not able to show a difference in basal plasma aldosterone concentrations between affected and unaffected GRA siblings to support this hypothesis, but the numbers of normal siblings studied was small.


    Diagnosis
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 Introduction
 Pathophysiology
 Phenotype
 Genotype
 Diagnosis
 Treatment
 References
 
GRA can masquerade as essential hypertension because most affected subjects are normokalemic and their blood pressures can range from mildly to severely elevated (5). Many patients are refractory to conventional antihypertensive agents but may become hypokalemic if potassium-wasting diuretics are administered. However, a careful medical history can be revealing. The diagnosis of GRA should be considered in a patient with hypertension of early onset (especially children) or a history of early onset hypertension in first-degree relatives. Another clue is a prominent family history of mortality or morbidity from early hemorrhagic stroke.

Patients with GRA have abnormal plasma aldosterone (PA) PRA ratios (>30). PRA will be suppressed unless mineralocorticoid antagonists (such as spironolactone or amiloride) have been used as therapeutic agents. Therefore, nonsuppressed PRA levels in the absence of such therapies strongly argues against a diagnosis of GRA. However, the presence of a suppressed PRA level is nonspecific, with up to 20% of essential hypertensive patients having a PRA level of less than 2 ng/mL · h. Aldosterone blood levels or urinary aldosterone excretion rates are usually normal or mildly elevated, but the levels may be inappropriate for the intake of sodium since production is solely regulated by ACTH.

The diagnosis of GRA is supported by dexamethasone suppression testing (DST). Although most patients show a significant improvement in blood pressure levels following DST, PA levels or aldosterone excretion rates have been the primary end points of this test. A fall in aldosterone to nearly undetectable levels after low-dose DST (0.5 mg dexamethasone orally every 6 h over 2–4 days) in GRA is expected and reflects the sole control of aldosterone by ACTH in this disorder. A recent study concluded that a post-DST PA below 4 ng/dL will correctly diagnose GRA patients with high sensitivity and specificity (12). Test length variability can be a cause of misinterpretation because DST of short duration can result in false positive results, whereas longer duration tests may yield false negative results as aldosterone levels return to the normal range subsequent to reactivation of the renin-angiotensin system. Significant suppression of aldosterone levels after DST also occurs in APA patients reflecting the well-recognized regulation of aldosterone by ACTH in this disorder. However, autonomous production of aldosterone in APA accounts for the failure of aldosterone levels to fall to very low or nearly undetectable levels. It was with these observations in mind that the late Dr. Stanley Ulick favored the term GRA over DSH for the disorder that he biochemically characterized by the measurement of unique steroid metabolites (3).

Urinary excretion of the 18-oxygenated cortisol corresponds 18-OH-F and 18-oxo-F are markedly elevated in GRA and provide a sensitive and highly specific test to diagnose this disorder. However, measurement of urinary 18-OH-F and 18-oxo-F necessitates a 24-h collection, but, more importantly, the assay is usually not available to most practicing clinicians.

The above reasons, combined with the inconvenience of DST, support the use of direct genetic testing for the chimeric gene to diagnose GRA. Currently available biochemical testing, such as DST and/or 24-h urine collections are also difficult to perform in children. Genetic testing is 100% sensitive and specific to diagnose GRA and requires only a single blood collection for leucocyte DNA assessment. After DNA extraction the hybrid or chimeric gene can be detected by the Southern blot approach [developed by Lifton et al. (6)], or more recently by the long-PCR-based approach (13). The advantage of the long-PCR method is that it is considerably faster and cheaper than Southern blotting.


    Treatment
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 Introduction
 Pathophysiology
 Phenotype
 Genotype
 Diagnosis
 Treatment
 References
 
The gratifying reduction in blood pressure in response to directed monotherapy (see below) underscores the importance of making the diagnosis of GRA. In addition, because GRA is a volume-expanded mineralocorticoid excess state, a sodium-restricted diet (<2 g/day) is also recommended in conjunction with pharmacotherapy because it will minimize potassium wasting and may lower blood pressure. To date, randomized studies have not been performed that compare various pharmacological treatment regimens in GRA.

Glucocorticoid suppression

Suppression of the hypothalamic-pituitary-adrenal axis does not always result in normalization of blood pressure in GRA. This may relate to the duration of hypertension, end-organ injury from poorly treated hypertension, concomitant essential hypertension, or, rarely, autonomous production of aldosterone in patients with longstanding GRA. Of great importance is the potential toxicity (Cushing’s syndrome) associated with excessive doses of suppressive glucocorticoids, especially in children. If glucocorticoids treatment is initiated, the smallest effective dose of shorter-acting agents such as prednisone or hydrocortisone should be used; steroid dosing should also be related to body surface area (8 to 10 mg hydrocortisone per m2/day). Target blood pressure in children should be guided by age-specific blood pressure percentiles. Children should be followed by physicians who have experience in administering glucocorticoid therapy; linear growth should be monitored with a stadiometer to detect any slowing as a result of overtreatment. Another side effect of glucocorticoid suppression is hypoaldosteronism with salt wasting, hypotension, and hyperkalemia immediately after treatment is initiated. This occurs because aldosterone levels fall to nearly undetectable levels and the zona glomerulosa remains acutely hypofunctional as a result of chronic suppression of the renin-angiotensin system.

Mineralocorticoid antagonism

Spironolactone, a competitive antagonist of aldosterone for the mineralocorticoid receptor, is often very effective as monotherapy in treating GRA patients. Adult patients should be started with 50 mg twice daily with meals, with subsequent upward titration to 400 mg/day until blood pressure is controlled. Potassium-wasting diuretics (12.5–25 mg hydrochlorothiazide or 20–40 mg furosemide) may be added in an attempt to further achieve sodium depletion; close monitoring of serum potassium is important if these diuretics are used. Spironolactone also has antiandrogenic actions with chronic usage commonly resulting in erectile dysfunction, decreased libido, and gynecomastia in adult men; menstrual irregularities are seen in women. Gastrointestinal symptoms such as nausea may be ameliorated if the drug is taken with food. Amiloride blocks the aldosterone-regulated sodium epithelial channel in the distal nephron and is an alternative to spironolactone treatment. Like spironolactone, it usually restores normokalemia in subjects with low serum potassium, but may require the addition of other diuretics or antihypertensive agents to normalize blood pressure. Divided dosing should be used starting at 5 mg twice daily, with a maximum dose of 15 mg twice daily.

Triamterene, an alternative treatment to amiloride, also acts to inhibit the distal nephron sodium epithelial channel. A divided-dosing regimen should be used with maximum doses not to exceed 300 mg/day. Adverse effects of this drug include rash and abnormalities of liver enzymes.

Dihydropyridine calcium channel blockers

The extended-release formulation of the dihydropyridine calcium channel blocker nifedipine has also been advocated in the medical management of primary aldosteronism because this agent has also been shown to inhibit aldosterone biosynthesis in vitro. However, the antihypertensive response to nifedipine as monotherapy in various etiologies of primary aldosteronism has been generally disappointing. However, the antihypertensive response to dihydropyridine calcium channel blockers, such as amlodipine and nifedipine, can be gratifying in patients with GRA (Dluhy R.G., unpublished data), but these medications should be viewed as second-line agents.

Received August 3, 1999.

Accepted October 8, 1999.


    References
 Top
 Introduction
 Pathophysiology
 Phenotype
 Genotype
 Diagnosis
 Treatment
 References
 

  1. Sutherland DJ, Ruse JL, Laidlaw JC. 1966 Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 95:1109–1119.[Medline]
  2. New MI, Peterson RE. 1967 A new form of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 27:300–305.[Medline]
  3. Ulick S, Chan CK, Gill JR Jr, et al. 1990 Defective fasciculata zone function as the mechanism of glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 71:1151–1157.[Abstract]
  4. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG. 1998 Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension. 31:445–450.[Abstract/Free Full Text]
  5. Grim CE, Weinberger MH. 1980 Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism. Pediatrics. 65:597–604.
  6. Rich GM, Ulick S, Cook S, Wang JZ, Lifton RP, Dluhy RG. 1992 Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype. Ann Intern Med. 116:813–820.[Medline]
  7. Lifton RP, Dluhy RG, Powers M, et al. 1992 A chimeric 11 ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 355:262–265.[CrossRef][Medline]
  8. Lifton RP, Dluhy RG, Powers M, et al. 1993 Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet. 2:66–74.
  9. Pascoe L, Curnow KM, Slutsker L, et al. 1992 Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA. 89:8327–8331.[Abstract]
  10. Curnow KM, Mulatero P, Emeric-Blanchouin N, Aupetit-Faisant B, Corvol P, Pascoe L. 1997 The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme. Nat Struct Biol. 4:32–35.[Medline]
  11. Mulatero P, Curnow KM, Aupetit-Faisant B, et al. 1998 Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. J Clin Endocrinol Metab. 83:3996–4001.[Abstract/Free Full Text]
  12. Jamieson A, Slutsker L, Inglis GC, Fraser R, White PC, Connell JM. 1995 Glucocorticoid-suppressible hyperaldosteronism: effects of crossover site and parental origin of chimaeric gene on phenotypic expression. Clin Sci (Colch). 88:563–570.[Medline]
  13. Litchfield WR, New MI, Coolidge C, Lifton RP, Dluhy RG. 1997 Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 82:3570–3573.[Abstract/Free Full Text]
  14. Stowasser M, Gartside MG, Gordon RD. 1997 A PCR-based method of screening individuals of all ages, from neonates to the elderly, for familial hyperaldosteronism type I. Aust NZ J Med. 27:685–690.[Medline]




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