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Pathophysiology and diagnosis of primary aldosteronism
Biomed & Pharmacother 2000 ; 54 Suppl 1 : 118-23 © 2000 t~ditions scientifiques et m6dicales Elsevier SAS. All rights reserved
Mini review
Pathophysiology and diagnosis of primary aldosteronism H. Suzuki Department of Nephrolog), Saitama Medical School, Moroyama-machi, lruma-gun, Saitama, Japan Summary - The pathophysiology of primary aldosteronism still remains unknown. In mRNA and protein levels, overexpression of aldosterone synthase (P-450aldo) is recognized, although abnormalities and defects of DNA and its upper stream have not been detected. Several candidate genes responsible for pathogenesis of primary aldosteronism, such as renin, angiotensin receptor type II, etc., have been proposed, but no decisive genes have been found. A relatively reliable screening for hyperaldosteronism is a determination of the ratio of the plasma aldosterone level to the plasma renin activity. For differentiating several types of aldosteronisms, the simplest test is the response of plasma aldosterone to two hours in an upright posture: plasma aldosterone rises in most patients with idiopathic hyperaldosteronism. In contrast, in cases of autonomous aldosterone-producing tumor, most patients show no response or even a decrease in plasma aldosterone concentration. The size and location of the aldosterone-producing adenoma are determined by using computed tomography. @ 2000 l~ditions scientifiques et m~dicales Elsevier SAS adenoma / aldosterone synthase / aldosteronism / CYPllB1 / hyperplasia
INTRODUCTION
Primary aldosteronism is characterized by hypertension, hypokalemia, reduced plasma renin activity, and increased plasma aldosterone levels [1]. Aldosterone s e c r e t i o n in p r i m a r y a l d o s t e r o n i s m is p a r t i a l l y autonomous, and is not suppressed by volume expansion or sodium loading, while the most important regulators are the renin-angiotensin system and potassium in the normal adrenal glands [2]. In most cases of primary aldosteronism, aldosterone secretion is influenced by corticotropins and is unresponsive to angiotensin II [2]. In addition, abnormal aldosterone response is observed in postural changes. However, some cases' responses to small increases in the p l a s m a level of angiotensin II and to postural testing have been found [3]. Thus, there are at least two functionally and histologically different types of aldosteronoma: a corticotropin-responsive (and renin-unresponsive) type and a renin-responsive type. P A T H O G E N E S I S OF A L D O S T E R O N I S M
The pathogenesis of aldosterone-producing adenoma still remains unknown, like other endocrine tumors. Previously, Shibata et al. demonstrated the overexpression of P-450aldo, which was characterized as aldosterone synthase cytochrome P-450, in the mitochondria
of the tumor portion of aldosterone-producing adenoma [4]. Ogo et al. reported that steroidogenic P-450mRNAs are found in the adrenocortical adenoma from patients with primary aldosteronism and suggested that the overproduction of aldosterone in aldosterone-producing adenoma resulted from increased expression of P-4501 lb m R N A [5]. From these findings, overexpression of P-450aldo may contribute to the development of aldosterone-producing tumor. However, it is unresolved why overexpression of P-450aldo is introduced in the tumor portion of primary aldosteronism. Genetic studies
Glucocorticoid-remediable aldosteronism In familial hyperaldosteronism type 1 (FH-1) (glucocorticoid-suppressible hyperaldosteronism), aldosterone production is primarily regulated by ACTH. Most patients have raised aldosterone/PRA ratios consistent with primary aldosteronism. This genetic mutation explains the biochemical features of FH-1 [6]: 11 [3-hydroxylase, the enzyme that catalyses the last step in cortical synthesis, and aldosterone synthase, the enzyme that catalyses the last step in aldosterone synthases; 1 l[~-hydroxylase in the zona fasciculata, and aldosterone synthase converts corticosterone to aldosterone through 1 l[3-hydroxylation, 18-hydroxylation, and oxidation. These enzymes are encoded by two
Pathophysiologyand diagnosis of primaryaldosteronism genes, CYP 11B 1 and CYP 121B2, located in tandem on chromosome 8. Despite the similarity in the coding sequences of 1 l l]-hydroxylase and aldosterone synthase (> 95%), their 5' sequences differ, which allows regulation of 11 ~l-hydroxylase by corticotropin through cyclic AMP and aldosterone synthase by angiotensin II through intracellular calcium, to establish functional zonation of the adrenal cortex. In glucocortical-suppressible hyperaldosteronism a hybrid gene is formed at meiosis from unequal crossover of the CYP11B 1 and CYP11B2 genes, and this hybrid contains proximal components of C Y P l l B 1 and distal components of CYP11B2. Provided that the breakpoint of the hybrid gene is in exon IV or further towards the 5' end of the CYP11B1 gene, the product of the gene can synthesis aldosterone but is controlled by corticotropin [7]. Therefore, these patients are biochemically unique in having markedly increased levels of 18-oyocortisol and 18-hydroxycortisol.
Non-glucocorticoid-suppressible primary aldosteronims Pascoe et al. [8] have reported that FH1 chimeric genetranfected cells possess aldosterone synthase activity. They studied a French pedigree with seven affected individuals in which two affected individuals also have adrenal tumors and two others have micronodular adrenal hyperplasia. One of the adrenal tumors and the surrounding adrenal tissue has been removed. The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex. Beuschlein et al. [9] investigated the mutational spectrum of the CYP21B gene and the messenger RNA expression of P450c21 in six aldosterone-producing tumors, seven cortisol-producing adenomas, two nonfunctional incidentally detected adenomas, and four adrenal carcinomas. They found a somatic, heterozygous microdeletion in exon 3 of one aldosterone-producing tumor. The P450c21 gene expression correlated with the clinical phenotype of the tumor, with low P450c21 messenger RNA expression in nonfunctional adenomas (18.8%, 1.5%) compared with high P450c21 expression in aldosterone- and cortisol-producing adenomas (84 + 8% and 101 -+ 4%, respectively, vs normal adrenal, 100 _+ 10%). The prevalence of heterozygous germline mutations in the CYP21B gene was higher in patients with adrenocortical tumors (11%) than in the general European population (2%). However, they questioned the pathophysio-
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logical significance of these findings because of the low number of subjects. The same group reported that DAX- 1 may be one of the factors influencing the steroid biosynthesis of adrenocortical tumors [ 10]. They found low or absent DAX-1 expression in aldosteroneproducing tumors (35 -+ 11% vs. normal adrenals:100 _+17%). In contrast to DAX- 1, StAR mRNA expression did not show significant variations between groups. Gordon et al. [11] reported some preliminary observations on the renin [ 12, 13], angiotensin II type 1 receptor [ 14], atrial natriuretic peptide [ 15] and P53 gene [ 16] in both tumor and constitutive DNA in both the angiotensin-responsive and -unresponsive types of primary aldosteronism. In tumor DNA, the renin gene was overexpressed in the tumors in angiotensin-responsive aldosteronism compared with angiotensin-unresponsive aldosteronism or normal adrenals. In addition, no alterations in exon 1 were found by PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) analysis. Mutations in eight of 59 patients with aldosterone-producing adenoma but only in one of 39 control patients were found in the promotor region of atrial natriuretic peptide gene from tumor DNA. The p53 protein, an important determinant in human cancer, regulates the growth of cells in culture [17]. Mutations of the p53 tumor suppressor gene are among the most frequent molecular events in human oncogenesis and are found in both sporadic and familial cancers [18]. Lin et al. [ 19] demonstrated that using a PCR-SSCP study, five of six pheochromocytoma tissues and 11 of 15 adrenocortical adenomas (two with Cushing's syndrome and 13 with primary aldosteronism) had an apparent electrophoretic mobility shift between the tumor and its paired adjacent normal adrenal tissue. From these data it has been previously suggested that the p53 gene mutation may play a role in the tumorigenesis of benign and functional human adrenal tumors, although it remains unclear at present. G-proteins involved in signal transduction are heterotrimers consisting of t~-, ~-, and T-subunits that bind guanine nucleotide and interact with specific receptors and effectors [20]. G-protein activation normally requires the interaction of the inactive GDP-bound heterotrimer with a ligand-occupied receptor, resulting in the exhange of GTP for GDP and dissociation of the aunit [21]. Mutations in the a-unit of Gs, the adenylyl cylase-stimulating protein, have been described in GHsecreting pituitary adenomas [22]. These mutations caused an amino acid exchange at the highly conserved codons Arg201 and Gln227, resulting in a constitutive activation of Gstx by inhibition of endogenous GTPase activity. These putative oncogenic mutations, which
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were called Gsp, were found in 40% of GH-producing tumors and 4% of thyroid tumors [23, 24]. Point mutations at similar codons of a different G-protein, codons 179 and 205 of Gi~2, were reported in adrenocortical neoplasms, suggesting a potential role of mutated Gic~2 in the tumorigenesis of adrenocortical masses [23]. Contrary to this report, Reincke et al. found no mutations at codons 201,227 and 179, 205 of Gsa and Gic~2 respectively, in the tumors studied. Therefore they concluded that oncogenic point mutations in the stimulatory and inhibitory c~-chain of G-proteins do not appear to be present at high frequency in adrenal neoplasmas [25]. Reincke et al. [26] postulated the constitutive activating point mutations of the ACTH receptor gene, a member of the G-protein-coupled receptor superfamily. However, these were not present in hormone-secreting adrenal tumors. Further, they studied the LOH (loss of heterozygosity) in adrenal tumors. LOH was not found in adrenal tumors. Northern blot analysis demonstrated reduced expression of ACTH receptor messenger RNA in the tumors with LOH of the ACTH receptor gene, suggesting functional significance at the transcriptional level. From these observations, LOH of the ACTH receptor gene is possibly involved in adrenal tumorigenesis, contributing to cellular dedifferentiation in adenomas and carcinomas. In addition to these mutations of tumor DNA, LOH is considered to be one of the candidates in association with MEN (multiple endocrine neoplasia) 1 as described in ACTH receptor gene. MEN 1 is an autosomal, dominantly inherited disorder characterized by neoplastic hyperfunction of two or more endocine tissues. The most frequent endocrinopathies are represented by hyperparathyroidism, pancreatic and anterior pituitary neoplasms. Moreover, adrenocortical and thyroid tumors, carcinoids, lipomas, and pinealomas are observed more frequently in MEN 1 patients than in the normal population [27]. Beckers et al. [28] reported LOH of the MEN 1 locus in primary aldosteronism in a member of a family with MEN 1. Other investigators sought LOH at the MEN 1 locus in paired aldosteroneproducing tumor and peripheral blood DNA, using six RFLPs (restriction fragment length polymorphism). Five of 11 informative tumors showed LOH at one or more loci, and two of these were from patients with FHII. Moreover, using four microsatellite markers to target the MEN 1 locus in 64 paired aldosterone-producing tumor and peripheral blood DNA samples, ten of them were found to have LOH for one or more markers. These findings suggest that there is a close association with MEN 1 genetic lesion in at least some aldosterone-producing tumors [29].
Genetic analysis of aldosterone synthase Patients with aldosterone synthase deficiency, an autosomal recessive disorder, may have potentially fatal electrolyte abnormalities as neonates or a variable degree of hyponatremia and hyperkalemia combined with poor growth in childhood, but they usually have no symptoms as adults [30, 31 ]. There are two forms of this deficiency, which differ only in the relative concentrations in serum. In type l deficiency, 18-fiydroxycorticosterone concentrations are normal or decreased, whereas in type II deficiency they are elevated. Both deficiencies are caused by mutations in the aldosterone synthase gene (CYP11B2) [32, 33]. One mutationcausing type I deficiency is associated with no aldosterone synthase activity, whereas mutations causing type II deficiency are associated with an aldosterone synthase that retains l l[3-hydroxylase but not 18-oxidase activity. Hampf et al. [34] investigated the known promoter region of the aldosterone synthase gene in six patients with the diagnosis of idiopathic hyperaldosteronism in order to elucidate a possibly changed promoter activity through mutations. They amplified the 2.2 kb promoter region and 13 polymorphic sites were found. One was within a predicted CRE and another previously decribed polymorphic site was located in a putative SF-1 binding site. All alleles which were found in patients were also found in controls. From these observations, it is unlikely that the promotor of the aldosterone synthase is responsible for the molecular basis of an aldosterone-producing tumor. On the other hand, Takeda et al. [35] compared activity of aldosterone synthase and expression of aldosterone synthase mRNA in mononulcear leukocytes from patients with idiopathic hyperaldosteronism and with aldosterone-producing adenoma or normal. From these studies, they found that both aldosterone synthase activity and CYPI 1B2 mRNA expression were greater in patients with idiopathic hyperaldosteronism, suggesting the pathogenic role of regulator factors of the aldosterone synthase in patients with idiopathic hyperaldosteronism. In spite of this extensive research for the molecular basis of primary aldosteronism, the causative gene still remains undiscovered. D I A G N O S I S tables I and II) The diagnosis of primary aldosteronism was suspected if patients presented with one or more of the following conditions: l) refractory hypertension; 2) spontaneous hypokalemia; or 3) difficulty maintaining normal serum
Pathophysiology and diagnosis of primary aldosteronism Table I. Aldosterone-renin ratio: predicted effects of diet and certain medications. Modified from Gordon, RD (J Endocrinol Invest 1995 ; 18). (a) Diet
1 Dietary salt restriction 2 Dietary salt loading
possible false negative possible false positive
(b) Medication
1 Beta-adrenoceptor blockers 2 Calcium channel blockers 3 Angiotensin-converting-enzyme inhibitors 4 Angiotensin receptor blockers 5 Aldosterone competitive inhibitor 6 Other diuretics 7 Alpha-adrenergic blockers 8 Vasodilators
probable false positive possible false negative less likely false negative possible false negative highly likely false negative possible false negative possibly no effect possibly no effect
Table II. Guidline for diagnosis for primary aldosteronism. Diagnostic Criteria
a. Symptoms Muscle weakness General fatigue Polyuria during night b. Clinical findings Hypertension c. Blood chemistry Hypokalemia Metabolic alkalosis Low renin Elevated plasma and urinary concentration of aldosterone Elevated plasma concentration of aldosterone in the adrenal venous blood in the tumor side d. Radiological findings Tumor staining in inferior vena cavography Adenoma in computed tomography Positive in adrenal scintigraphy e. Differential diagnosis Idiopathic hyperaldosteronism Glucocorticoid responsive aldosteronism Pseudoaldosteronism Liddle's syndrome potassium levels while receiving potassium supplementation [36]. A relatively reliable screening for hyperaldosteronims is a determination of the ratio of the plasma aldosterone level to the plasma renin activity [2, 36-42]. Definitive biochemical diagnosis of hyperaldosteronism can be made by inhibitor and stimulatory aldosterone and renin secretion by physiologic maneuvers of sodium loading and sodium depletion, respectively. A high rate of urinary aldosterone excretion while a high sodium diet is maintained or a high plasma aldosterone level after intravenous infusion of normal saline. Urinary aldosterone excretion of less than 14 mg in 24 hours after sodium loading rules out primary aldos-
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teronism. In addition, a plasma aldosterone level of less than 8.5 ng/dL at the end of saline infusion rules out all types of primary aldosteronism. A high oral intake of sodium can increase blood pressure and accentuate hypokalemia. Correcting hypokalemia before a highsodium diet is initiated or saline infusion is administered is helpful. Differential diagnosis Once the biochemical diagnosis of aldosteronism has been established, the case can be determined by a variety of tests and techniques. Mainly, two maneuvers can be employed: the orthostatic test and the response to angiotensin II infusion. The simplest test is the response of plasma aldosterone to two hours of upright posture. Plasma aldosterone rises in most patients with idiopathic hyperaldosteronism. In contrast, in cases of autonomous aldosterone-producing tumors, most patients showed no response or even a decrease in plasma aldosterone concentration [43]. However, 20 to 25% of patients with an autonomous aldosterone-producing tumor showed an unexpected rise in plasma aldosterone concentration after upright posture [44-46]. Moreover, the even rarer form of primary adrenal hyperplasia described by Ganguly et al. [47] and Irony et al. [48] presents with no significant change or drop in plasma aldosterone in the upright posture. Circadian rhythm of plasma aldosterone is observed in patients with autonomous aldosterone-producing tumors whereas in patients with idiopathic hyperaldosteronism this rhythm is partially lost [49, 50]. This test is carried out by measuring plasma aldosterone together with cortisol at 0800, 1000, 1200, and 1600 h when there is a clear-cut fall in plasma aldosterone during the day or no change at all. As the final precursor in the synthesis of aldosterone produced principally in the zona glomerulosa, 18-hydroxycorticosterone(18OHB) was found to be markedly elevated (exceeding 1 mg/L) in patients with autonomous aldosterone-producing tumors at 0800 h after overnight recumbence [51 ]. Altough available in only a few centers, the determination of other corticosteroids, such as 18-hydroxycortisol, 18-oxocortisol, or 19-nordeoxycorticosterone appears useful in detecting forms of aldosteronism curable by unilateral adrenalectomy [52-541. The size and location of the aldosterone-producing adenoma are determined by using computed tomography (CT). The usual size of tumor is approximately 1.8 cm in diameter; if a large adrenal tumor more than 3 cm in diameter is found, the possibility that the patient
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has adrenal carcinoma should be raised. At the present state of the technique, magnetic resonance imaging d o e s n o t s e e m to o f f e r a n y a d v a n t a g e o v e r C T s c a n n i n g . Sampling of adrenal venous blood, preferably with c o r t i c o t r o p h i n s t i m u l a t i o n , is c a r r i e d out. M e a s u r e m e n t o f c o r t i s o l as w e l l as a l d o s t e r o n e in t h e a d r e n a l v e n o u s e f f l u e n t a n d in t h e s a m p l e f r o m t h e i n f e r i o r v e n a c a v a is critical f o r e v a l u t i n g t h e a c c u r a c y a n d s u c c e s s o f a d r e n a l v e n o u s s a m p l i n g [40]. Finally, it s h o u l d also b e r e m e m b e r e d that t h e b l o o d - p r e s s u r e r e s p o n s e to s p i r o n o l a c t o n e t r e a t m e n t b e f o r e s u r g e r y c a n b e a p r e d i c t o r o f surgical o u t c o m e in p a t i e n t s w i t h a l d o s t e r o n o m a , but n o t in t h o s e w i t h i d i o p a t h i c a l d o s t e r o n i s m [55]. In s u m m a r y , in p r i m a r y a l d o s t e r o n i s m , e x c e s s i v e p r o d u c t i o n o f a l d o s t e r o n e s y n t h a s e s e e m s to b e o n e o f t h e causes of adrenal tumors. However, the precise genetic mechanisms of this disease remain unknown. From the view of the differential diagnosis, the concomittant determination of serum aldosterone and plasma renin a c t i v i t y r e p r e s e n t s t h e first s i m p l e s c r e e n i n g test.
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11 Gordon R. Primary aldosteronism: a new understanding. Clin Exp Hypertens 1997 ; 19 : 857-70. 12 Klemm S, Ballantine D, Gordon R, Tunny T, Stowasser M. The renin gene and aldosterone-producing adenomas. Kidney Int 1994 ; 46 : 1591-3. 13 Klemm S, Pinet F, Riousal-Caroff N, Tunny T, Blake K, Ballantine D, et al. Detection of renin mRNA by polymerase chain reaction in aldosterone-producing adenomas. J Hypertens 1993 ; l l Suppl 5 : $302-3. 14 Klemm S, Ballantine D, Tunny T, Stowasser M, Gordon R. PCR-SSCP analysis of the promoter region of the renin gene in patients with aldosterone-producing adenomas. Clin Exper Pharmacol Physiol 1995 ; 23 : 584-6. 15 Tunny T, Jonsson J, Klemm S, Ballantine D, Stowasser M, Gordon R. Association of restriction fragment length polymorphism at the atrial natriuretic peptide gene locus with aldosterone responsiveness to angiotensin in aldosterone-producing adenoma. Biochm Biophys Res Comm 1994 ; 204 : 1312-7. 16 Ballantine D, Klemm S, Tunny T, Stowasser M, Gordon R. PCR-SSCP analysis of the p53 gene in turnouts of the adrenal gland. Clin Exper Pharmacol Physiol 1996 ; 23 : 582-3. 17 Levine A, Momand J, Finlay C. The p53 tumor suppressor gene. Nature 1991 ; 351 : 453-6. 18 Prosser J, Thompson A, Cranston G, Evans H. Evidence that p53 behaves as a tumour suppressor gene in sporadic breast tumours. Oncogene 1990 ; 5 : 1573-9. 19 Lin SR, Lee YJ, Tsai JH. Mutations of the p53 gene in human functional adrenal neoplasms. J Clin Endocrinol Metab 1994 ; 78 : 483-91. 20 Simon M, Strathmann M, Gautum N. Diversity of G-proteins in signal transduction. Science 1991 ; 252 : 802-8. 21 Bourne H, Sanders D, McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 1990 ; 348 : 152-3. 22 Landis C, Masters S, Spada A, Pace A, Bourne H, Vallar L. GTAase inhibiting mutations activate the a chain of Gs and stimulate adenylyl cyclase in human pituitary turnouts. Nature 1989 ; 340 : 692-6. 23 Lyons J, Landis C, Harsh G, et al. Two G protein oncogenes in human endocrine tumors. Science 1990 ; 249 : 655-9. 24 Suarez H, du Villard J, Caillou B, Schlumberger M, Parmentier C, Monier R. Gsp mutations in human thyroid tumors. Oncogene 1991 ; 6 : 677-9. 25 Reincke M, Karl M, Travis W, Chrousos G. No evidence for oncogenic mutations in guanine nucleotide-binding proteins of human adrenocortical neoplasms. J Clin Endocrinol Metab 1993 ; 77 : 1419-22. 26 Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos G, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis. J Clin Endocrin Metab 1997 ; 82 : 3054-8. 27 Brandi M, Marx S, Aurbach G, Fitzpatrick L. Familial multiple endocrine neoplasia type 1: a new look at pathophysiology. Endocr Rev 1987 ; 8 : 391-405. 28 Beckers A, Abs R, Willems P, van der Auwea B, Kovacs K, Reznik MS. Aldosterone-secreting adrenal adenoma as part of multiple endocrine neoplasia type 1 (MEN-l): loss of heterozygosity for polymorphic chromosome 11 de-oxyribonucleic acid markers, including the MEN-I locus. J Clin Endocrinol Metab 1992 ; 75 : 564. 29 lidaA, Blake K, Tunny T, Klemm S, Stowasser M, Hayward N, et al. Allelic losses on chromsome band 1lq13 in aldosterone producing adrenal tumors. Genes Chrom Canc 1995 ; 12 : 73-5. 30 Rosler A. The natural history of salt-wasting disorders of adrenal and renal origin. J Clin Endocrinol Metab 1984 ; 59 : 689-700.
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31 Ulick S, Wang J, Morton D. The biochemical phenotypes of two inborn errors in the biosynthesis of aldosterone. J Clin Endocrinol Metab 1992 ; 74 : 15-20. 32 MitsuuchiY, Kawamoto T, Miyahara K, Toda K, Imura H, Gordon R, et al. Congentially defective aldosterone biosynthesis in human: inactivation of the P-450c18 gene (CYP11B2) due to nucelotide deletion in CMO I deficient patients. Biochem Biophys Res Commun 1993 ; 190 : 864-9. 33 Pascoe L, Curnow K, Slutsker L, Rosler A, White P. Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc Natl Acad Sci USA 1992 ; 89 : 4996-5000. 34 Hampf M, Widimsky J, Bernhardt R. Aldosterone synthase gene in patients suffering from hyperaldosteronism. Endocr Res 1998 ; 24 : 877-80. 35 Takeda Y, Furukawa K, Inaba S, Miyamori I, Mabuchi H. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab 1999 ; 84 : 1633-7. 36 Brabo E, Tarazi R, Dustan H, et. al. The changing clinical spectrum of primary aldosteronism. Am J Med 1983 ; 74 : 641-51. 37 Stewart P. Mineralocorticoid hypertension. Lancet 1999 ; 353 : 1341-7. 38 Blumenfeld J, Darracuff E, Vaughan J. Diagnosis and treatment of primary aldosteronism. World J Urol 1999 ; 17 : 15-21. 39 Gordon R. Primary aldosteronism. J Endocrinol Invest 1995 ; 18 : 495-511, 40 Weinberger M, Grim C, Hollifield J. Primary aldosteronism: diagnosis, localization, and treatment. Ann Intern Med 1979 ; 90 : 386-95. 41 Vallotton M. Primary aldosteronism. Part II: differential diagnosis of primary hyperaldosteronism and pseudoaldosteronism. Clin Endocrinol 1996 ; 45 : 53-60. 42 Young W J, Hogan M, Klee G, Grant C, van Heerden J. Primary aldosteronism: diagnosis and treatment. Mayo Clin Proc 1990 ; 65 : 96-110. 43 Ganguly A, Melada G, Luetscher J, Dowdy A. Control of plasma aldosterone in primary aldosteronism: distinction between adenoma and hyperplasia. J Clin Endocrinol Metab 1973 ; 37 : 765-75.
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44 Tunny T, Gordon R, Klemm S, Cohn D. Histological and biochemical distinctiveness of atypical aldosterone-producing adenomas responsive to upright posture and angiotensin. Clin Endocrinol (Oxf) 1991 ; 34 : 363-9. 45 Mantero F, Armanini D, Boscaro M, Carpene G, Fallo F, Opocher G, et al. Steroids and hypertension. J Steroids Biochem Mol Biol 1991 ; 40 : 35-44. 46 F e l t y n o w s k i T, I g n a t o w s k a - S w i t a l s k a H, Wocial B, Lewandowski J, Chodakowska J, Januszewicz W. Postural stimulation test in patients with aldosterone producing adenomas. Clin Endocrinol (Oxf) 1994 ; 41 : 309-14. 47 Ganguly A, Zager P, Luetscher J. Primary aldosteronism due to unilateral adrenal hyperplasia. J Clin Endocrinol Metab 1980 ; 51 : 1190-4. 48 Irony I, Kater C, Biglieri E, Shackleton C. Correctable subsets of primary aldosteronism. Primary adrenal hyperplasia and renin responsive adenoma. Am J Hypertens 1990 ; 3 : 576-82. 49 Vetter H, Berger M, Armbruster H, Siegenthaler W, Werning C, Vetter W. Episodic secretion of aldosterone in primary aldosteronism: relationship to cortisol. Clin Endocrinol 1974 ; 3 : 41-8. 50 Kem D, Weinberger M, Gomez-Sanchez C, Kramer N, Lerman R, Furuyama S, et al. Circadian rhythm of plasma aldosterone concentration in patients with pirmary aldosteronism. J Clin Invest 1973 ; 52 : 2272-7. 51 Biglieri E, Schambelan M, Hirai J, Chang B, Brust N. The significance of elevated levels of plasma 18-hydroxycorticosterone in patients with primary aldosteronism. J Clin Endocrinol Metab 1979 ; 49 : 87-91. 52 Takeda Y, Miyamori I. 19-Noraldosterone, a new mineralocorticoid. Endocr J 1994 ; 41 : 483-9. 53 Ulick S, Blumenfeld J, Atlas S, Wang J, Vaughan EJ. The unique steroidogensis of the aldosteronoma in the differential diagnosis of primary aldosteronism. J Clin Endocrinol Metab 1993 ; 76 : 873-8. 54 Griffing G, Dale S, Holbrokk M, Melby J. 19-nor-deoxycorticosterone excretion in primary aldosteronism and low renin hypertension. J Clin Endocrinol Metab 1983 ; 56 : 218-21. 55 Saruta T, Suzuki H, Takita T, Saito I, Murai M, Tazaki H. Preoperative evaluation of the prognosis of hypertension in primary aldosteronism owing to adenoma. Acta Endocrinol (Copenh) 1987 ; 116 : 229-34.
Mini review
Pathophysiology and diagnosis of primary aldosteronism H. Suzuki Department of Nephrolog), Saitama Medical School, Moroyama-machi, lruma-gun, Saitama, Japan Summary - The pathophysiology of primary aldosteronism still remains unknown. In mRNA and protein levels, overexpression of aldosterone synthase (P-450aldo) is recognized, although abnormalities and defects of DNA and its upper stream have not been detected. Several candidate genes responsible for pathogenesis of primary aldosteronism, such as renin, angiotensin receptor type II, etc., have been proposed, but no decisive genes have been found. A relatively reliable screening for hyperaldosteronism is a determination of the ratio of the plasma aldosterone level to the plasma renin activity. For differentiating several types of aldosteronisms, the simplest test is the response of plasma aldosterone to two hours in an upright posture: plasma aldosterone rises in most patients with idiopathic hyperaldosteronism. In contrast, in cases of autonomous aldosterone-producing tumor, most patients show no response or even a decrease in plasma aldosterone concentration. The size and location of the aldosterone-producing adenoma are determined by using computed tomography. @ 2000 l~ditions scientifiques et m~dicales Elsevier SAS adenoma / aldosterone synthase / aldosteronism / CYPllB1 / hyperplasia
INTRODUCTION
Primary aldosteronism is characterized by hypertension, hypokalemia, reduced plasma renin activity, and increased plasma aldosterone levels [1]. Aldosterone s e c r e t i o n in p r i m a r y a l d o s t e r o n i s m is p a r t i a l l y autonomous, and is not suppressed by volume expansion or sodium loading, while the most important regulators are the renin-angiotensin system and potassium in the normal adrenal glands [2]. In most cases of primary aldosteronism, aldosterone secretion is influenced by corticotropins and is unresponsive to angiotensin II [2]. In addition, abnormal aldosterone response is observed in postural changes. However, some cases' responses to small increases in the p l a s m a level of angiotensin II and to postural testing have been found [3]. Thus, there are at least two functionally and histologically different types of aldosteronoma: a corticotropin-responsive (and renin-unresponsive) type and a renin-responsive type. P A T H O G E N E S I S OF A L D O S T E R O N I S M
The pathogenesis of aldosterone-producing adenoma still remains unknown, like other endocrine tumors. Previously, Shibata et al. demonstrated the overexpression of P-450aldo, which was characterized as aldosterone synthase cytochrome P-450, in the mitochondria
of the tumor portion of aldosterone-producing adenoma [4]. Ogo et al. reported that steroidogenic P-450mRNAs are found in the adrenocortical adenoma from patients with primary aldosteronism and suggested that the overproduction of aldosterone in aldosterone-producing adenoma resulted from increased expression of P-4501 lb m R N A [5]. From these findings, overexpression of P-450aldo may contribute to the development of aldosterone-producing tumor. However, it is unresolved why overexpression of P-450aldo is introduced in the tumor portion of primary aldosteronism. Genetic studies
Glucocorticoid-remediable aldosteronism In familial hyperaldosteronism type 1 (FH-1) (glucocorticoid-suppressible hyperaldosteronism), aldosterone production is primarily regulated by ACTH. Most patients have raised aldosterone/PRA ratios consistent with primary aldosteronism. This genetic mutation explains the biochemical features of FH-1 [6]: 11 [3-hydroxylase, the enzyme that catalyses the last step in cortical synthesis, and aldosterone synthase, the enzyme that catalyses the last step in aldosterone synthases; 1 l[~-hydroxylase in the zona fasciculata, and aldosterone synthase converts corticosterone to aldosterone through 1 l[3-hydroxylation, 18-hydroxylation, and oxidation. These enzymes are encoded by two
Pathophysiologyand diagnosis of primaryaldosteronism genes, CYP 11B 1 and CYP 121B2, located in tandem on chromosome 8. Despite the similarity in the coding sequences of 1 l l]-hydroxylase and aldosterone synthase (> 95%), their 5' sequences differ, which allows regulation of 11 ~l-hydroxylase by corticotropin through cyclic AMP and aldosterone synthase by angiotensin II through intracellular calcium, to establish functional zonation of the adrenal cortex. In glucocortical-suppressible hyperaldosteronism a hybrid gene is formed at meiosis from unequal crossover of the CYP11B 1 and CYP11B2 genes, and this hybrid contains proximal components of C Y P l l B 1 and distal components of CYP11B2. Provided that the breakpoint of the hybrid gene is in exon IV or further towards the 5' end of the CYP11B1 gene, the product of the gene can synthesis aldosterone but is controlled by corticotropin [7]. Therefore, these patients are biochemically unique in having markedly increased levels of 18-oyocortisol and 18-hydroxycortisol.
Non-glucocorticoid-suppressible primary aldosteronims Pascoe et al. [8] have reported that FH1 chimeric genetranfected cells possess aldosterone synthase activity. They studied a French pedigree with seven affected individuals in which two affected individuals also have adrenal tumors and two others have micronodular adrenal hyperplasia. One of the adrenal tumors and the surrounding adrenal tissue has been removed. The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex. Beuschlein et al. [9] investigated the mutational spectrum of the CYP21B gene and the messenger RNA expression of P450c21 in six aldosterone-producing tumors, seven cortisol-producing adenomas, two nonfunctional incidentally detected adenomas, and four adrenal carcinomas. They found a somatic, heterozygous microdeletion in exon 3 of one aldosterone-producing tumor. The P450c21 gene expression correlated with the clinical phenotype of the tumor, with low P450c21 messenger RNA expression in nonfunctional adenomas (18.8%, 1.5%) compared with high P450c21 expression in aldosterone- and cortisol-producing adenomas (84 + 8% and 101 -+ 4%, respectively, vs normal adrenal, 100 _+ 10%). The prevalence of heterozygous germline mutations in the CYP21B gene was higher in patients with adrenocortical tumors (11%) than in the general European population (2%). However, they questioned the pathophysio-
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logical significance of these findings because of the low number of subjects. The same group reported that DAX- 1 may be one of the factors influencing the steroid biosynthesis of adrenocortical tumors [ 10]. They found low or absent DAX-1 expression in aldosteroneproducing tumors (35 -+ 11% vs. normal adrenals:100 _+17%). In contrast to DAX- 1, StAR mRNA expression did not show significant variations between groups. Gordon et al. [11] reported some preliminary observations on the renin [ 12, 13], angiotensin II type 1 receptor [ 14], atrial natriuretic peptide [ 15] and P53 gene [ 16] in both tumor and constitutive DNA in both the angiotensin-responsive and -unresponsive types of primary aldosteronism. In tumor DNA, the renin gene was overexpressed in the tumors in angiotensin-responsive aldosteronism compared with angiotensin-unresponsive aldosteronism or normal adrenals. In addition, no alterations in exon 1 were found by PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) analysis. Mutations in eight of 59 patients with aldosterone-producing adenoma but only in one of 39 control patients were found in the promotor region of atrial natriuretic peptide gene from tumor DNA. The p53 protein, an important determinant in human cancer, regulates the growth of cells in culture [17]. Mutations of the p53 tumor suppressor gene are among the most frequent molecular events in human oncogenesis and are found in both sporadic and familial cancers [18]. Lin et al. [ 19] demonstrated that using a PCR-SSCP study, five of six pheochromocytoma tissues and 11 of 15 adrenocortical adenomas (two with Cushing's syndrome and 13 with primary aldosteronism) had an apparent electrophoretic mobility shift between the tumor and its paired adjacent normal adrenal tissue. From these data it has been previously suggested that the p53 gene mutation may play a role in the tumorigenesis of benign and functional human adrenal tumors, although it remains unclear at present. G-proteins involved in signal transduction are heterotrimers consisting of t~-, ~-, and T-subunits that bind guanine nucleotide and interact with specific receptors and effectors [20]. G-protein activation normally requires the interaction of the inactive GDP-bound heterotrimer with a ligand-occupied receptor, resulting in the exhange of GTP for GDP and dissociation of the aunit [21]. Mutations in the a-unit of Gs, the adenylyl cylase-stimulating protein, have been described in GHsecreting pituitary adenomas [22]. These mutations caused an amino acid exchange at the highly conserved codons Arg201 and Gln227, resulting in a constitutive activation of Gstx by inhibition of endogenous GTPase activity. These putative oncogenic mutations, which
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were called Gsp, were found in 40% of GH-producing tumors and 4% of thyroid tumors [23, 24]. Point mutations at similar codons of a different G-protein, codons 179 and 205 of Gi~2, were reported in adrenocortical neoplasms, suggesting a potential role of mutated Gic~2 in the tumorigenesis of adrenocortical masses [23]. Contrary to this report, Reincke et al. found no mutations at codons 201,227 and 179, 205 of Gsa and Gic~2 respectively, in the tumors studied. Therefore they concluded that oncogenic point mutations in the stimulatory and inhibitory c~-chain of G-proteins do not appear to be present at high frequency in adrenal neoplasmas [25]. Reincke et al. [26] postulated the constitutive activating point mutations of the ACTH receptor gene, a member of the G-protein-coupled receptor superfamily. However, these were not present in hormone-secreting adrenal tumors. Further, they studied the LOH (loss of heterozygosity) in adrenal tumors. LOH was not found in adrenal tumors. Northern blot analysis demonstrated reduced expression of ACTH receptor messenger RNA in the tumors with LOH of the ACTH receptor gene, suggesting functional significance at the transcriptional level. From these observations, LOH of the ACTH receptor gene is possibly involved in adrenal tumorigenesis, contributing to cellular dedifferentiation in adenomas and carcinomas. In addition to these mutations of tumor DNA, LOH is considered to be one of the candidates in association with MEN (multiple endocrine neoplasia) 1 as described in ACTH receptor gene. MEN 1 is an autosomal, dominantly inherited disorder characterized by neoplastic hyperfunction of two or more endocine tissues. The most frequent endocrinopathies are represented by hyperparathyroidism, pancreatic and anterior pituitary neoplasms. Moreover, adrenocortical and thyroid tumors, carcinoids, lipomas, and pinealomas are observed more frequently in MEN 1 patients than in the normal population [27]. Beckers et al. [28] reported LOH of the MEN 1 locus in primary aldosteronism in a member of a family with MEN 1. Other investigators sought LOH at the MEN 1 locus in paired aldosteroneproducing tumor and peripheral blood DNA, using six RFLPs (restriction fragment length polymorphism). Five of 11 informative tumors showed LOH at one or more loci, and two of these were from patients with FHII. Moreover, using four microsatellite markers to target the MEN 1 locus in 64 paired aldosterone-producing tumor and peripheral blood DNA samples, ten of them were found to have LOH for one or more markers. These findings suggest that there is a close association with MEN 1 genetic lesion in at least some aldosterone-producing tumors [29].
Genetic analysis of aldosterone synthase Patients with aldosterone synthase deficiency, an autosomal recessive disorder, may have potentially fatal electrolyte abnormalities as neonates or a variable degree of hyponatremia and hyperkalemia combined with poor growth in childhood, but they usually have no symptoms as adults [30, 31 ]. There are two forms of this deficiency, which differ only in the relative concentrations in serum. In type l deficiency, 18-fiydroxycorticosterone concentrations are normal or decreased, whereas in type II deficiency they are elevated. Both deficiencies are caused by mutations in the aldosterone synthase gene (CYP11B2) [32, 33]. One mutationcausing type I deficiency is associated with no aldosterone synthase activity, whereas mutations causing type II deficiency are associated with an aldosterone synthase that retains l l[3-hydroxylase but not 18-oxidase activity. Hampf et al. [34] investigated the known promoter region of the aldosterone synthase gene in six patients with the diagnosis of idiopathic hyperaldosteronism in order to elucidate a possibly changed promoter activity through mutations. They amplified the 2.2 kb promoter region and 13 polymorphic sites were found. One was within a predicted CRE and another previously decribed polymorphic site was located in a putative SF-1 binding site. All alleles which were found in patients were also found in controls. From these observations, it is unlikely that the promotor of the aldosterone synthase is responsible for the molecular basis of an aldosterone-producing tumor. On the other hand, Takeda et al. [35] compared activity of aldosterone synthase and expression of aldosterone synthase mRNA in mononulcear leukocytes from patients with idiopathic hyperaldosteronism and with aldosterone-producing adenoma or normal. From these studies, they found that both aldosterone synthase activity and CYPI 1B2 mRNA expression were greater in patients with idiopathic hyperaldosteronism, suggesting the pathogenic role of regulator factors of the aldosterone synthase in patients with idiopathic hyperaldosteronism. In spite of this extensive research for the molecular basis of primary aldosteronism, the causative gene still remains undiscovered. D I A G N O S I S tables I and II) The diagnosis of primary aldosteronism was suspected if patients presented with one or more of the following conditions: l) refractory hypertension; 2) spontaneous hypokalemia; or 3) difficulty maintaining normal serum
Pathophysiology and diagnosis of primary aldosteronism Table I. Aldosterone-renin ratio: predicted effects of diet and certain medications. Modified from Gordon, RD (J Endocrinol Invest 1995 ; 18). (a) Diet
1 Dietary salt restriction 2 Dietary salt loading
possible false negative possible false positive
(b) Medication
1 Beta-adrenoceptor blockers 2 Calcium channel blockers 3 Angiotensin-converting-enzyme inhibitors 4 Angiotensin receptor blockers 5 Aldosterone competitive inhibitor 6 Other diuretics 7 Alpha-adrenergic blockers 8 Vasodilators
probable false positive possible false negative less likely false negative possible false negative highly likely false negative possible false negative possibly no effect possibly no effect
Table II. Guidline for diagnosis for primary aldosteronism. Diagnostic Criteria
a. Symptoms Muscle weakness General fatigue Polyuria during night b. Clinical findings Hypertension c. Blood chemistry Hypokalemia Metabolic alkalosis Low renin Elevated plasma and urinary concentration of aldosterone Elevated plasma concentration of aldosterone in the adrenal venous blood in the tumor side d. Radiological findings Tumor staining in inferior vena cavography Adenoma in computed tomography Positive in adrenal scintigraphy e. Differential diagnosis Idiopathic hyperaldosteronism Glucocorticoid responsive aldosteronism Pseudoaldosteronism Liddle's syndrome potassium levels while receiving potassium supplementation [36]. A relatively reliable screening for hyperaldosteronims is a determination of the ratio of the plasma aldosterone level to the plasma renin activity [2, 36-42]. Definitive biochemical diagnosis of hyperaldosteronism can be made by inhibitor and stimulatory aldosterone and renin secretion by physiologic maneuvers of sodium loading and sodium depletion, respectively. A high rate of urinary aldosterone excretion while a high sodium diet is maintained or a high plasma aldosterone level after intravenous infusion of normal saline. Urinary aldosterone excretion of less than 14 mg in 24 hours after sodium loading rules out primary aldos-
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teronism. In addition, a plasma aldosterone level of less than 8.5 ng/dL at the end of saline infusion rules out all types of primary aldosteronism. A high oral intake of sodium can increase blood pressure and accentuate hypokalemia. Correcting hypokalemia before a highsodium diet is initiated or saline infusion is administered is helpful. Differential diagnosis Once the biochemical diagnosis of aldosteronism has been established, the case can be determined by a variety of tests and techniques. Mainly, two maneuvers can be employed: the orthostatic test and the response to angiotensin II infusion. The simplest test is the response of plasma aldosterone to two hours of upright posture. Plasma aldosterone rises in most patients with idiopathic hyperaldosteronism. In contrast, in cases of autonomous aldosterone-producing tumors, most patients showed no response or even a decrease in plasma aldosterone concentration [43]. However, 20 to 25% of patients with an autonomous aldosterone-producing tumor showed an unexpected rise in plasma aldosterone concentration after upright posture [44-46]. Moreover, the even rarer form of primary adrenal hyperplasia described by Ganguly et al. [47] and Irony et al. [48] presents with no significant change or drop in plasma aldosterone in the upright posture. Circadian rhythm of plasma aldosterone is observed in patients with autonomous aldosterone-producing tumors whereas in patients with idiopathic hyperaldosteronism this rhythm is partially lost [49, 50]. This test is carried out by measuring plasma aldosterone together with cortisol at 0800, 1000, 1200, and 1600 h when there is a clear-cut fall in plasma aldosterone during the day or no change at all. As the final precursor in the synthesis of aldosterone produced principally in the zona glomerulosa, 18-hydroxycorticosterone(18OHB) was found to be markedly elevated (exceeding 1 mg/L) in patients with autonomous aldosterone-producing tumors at 0800 h after overnight recumbence [51 ]. Altough available in only a few centers, the determination of other corticosteroids, such as 18-hydroxycortisol, 18-oxocortisol, or 19-nordeoxycorticosterone appears useful in detecting forms of aldosteronism curable by unilateral adrenalectomy [52-541. The size and location of the aldosterone-producing adenoma are determined by using computed tomography (CT). The usual size of tumor is approximately 1.8 cm in diameter; if a large adrenal tumor more than 3 cm in diameter is found, the possibility that the patient
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has adrenal carcinoma should be raised. At the present state of the technique, magnetic resonance imaging d o e s n o t s e e m to o f f e r a n y a d v a n t a g e o v e r C T s c a n n i n g . Sampling of adrenal venous blood, preferably with c o r t i c o t r o p h i n s t i m u l a t i o n , is c a r r i e d out. M e a s u r e m e n t o f c o r t i s o l as w e l l as a l d o s t e r o n e in t h e a d r e n a l v e n o u s e f f l u e n t a n d in t h e s a m p l e f r o m t h e i n f e r i o r v e n a c a v a is critical f o r e v a l u t i n g t h e a c c u r a c y a n d s u c c e s s o f a d r e n a l v e n o u s s a m p l i n g [40]. Finally, it s h o u l d also b e r e m e m b e r e d that t h e b l o o d - p r e s s u r e r e s p o n s e to s p i r o n o l a c t o n e t r e a t m e n t b e f o r e s u r g e r y c a n b e a p r e d i c t o r o f surgical o u t c o m e in p a t i e n t s w i t h a l d o s t e r o n o m a , but n o t in t h o s e w i t h i d i o p a t h i c a l d o s t e r o n i s m [55]. In s u m m a r y , in p r i m a r y a l d o s t e r o n i s m , e x c e s s i v e p r o d u c t i o n o f a l d o s t e r o n e s y n t h a s e s e e m s to b e o n e o f t h e causes of adrenal tumors. However, the precise genetic mechanisms of this disease remain unknown. From the view of the differential diagnosis, the concomittant determination of serum aldosterone and plasma renin a c t i v i t y r e p r e s e n t s t h e first s i m p l e s c r e e n i n g test.
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