Authors’ Response: Prevalence of Primary Aldosteronism in Unselected Hypertensive Populations—Screening and Definitive Diagnosis

Carlos E. Fardella and Lorena Mosso

Department of Endocrinology Faculty of Medicine Pontificia Universidad Católica de Chile Santiago, Chile

Address correspondence to: Carlos E. Fardella, M.D., Department Endocrinology, Faculty of Medicine, P. Universidad Católica de Chile, Marcoleta 391, Santiago, Chile. E-mail: cfardella{at}med.puc.cl

To the editor:

The prevalence of primary aldosteronism (PA) has been estimated in unselected patients with hypertension in less than 1% when the hypokalemia is used as screening. However, recent studies have demonstrated that PA may not be uncommon when determinations of serum aldosterone (SA), PRA, and the SA/PRA ratio are used in the screening and the fludrocortisone, saline infusion, or the captopril tests are used to confirm the diagnosis.

In our work, we studied 305 unselected "essential" hypertensive subjects using the screening procedure previously mentioned and the fludrocortisone test to confirm the diagnosis (1). We found 29 patients with PA and a prevalence of 9.5%, which is very similar to those reported by Lim et al. (9.2%) and Gordon et al. (8.5%) in different populations (2, 3). In the present millennium, other works have been published; three of them were performed with a similar diagnostic approach as the one used in our study (3, 4, 5). These studies (including our work) grouped 2140 unselected hypertensive subjects giving a total prevalence of PA close to 7% (range, 4.6–9.5). However, because not all subjects who screened positive underwent confirmatory studies, the prevalence of PA could be higher, probably close to 8% of all cases. These studies also found a higher frequency of idiopathic hyperaldosteronism (IHA) than the one traditionally described, being even higher or at least equal than those communicated for aldosteronoma. The hypokalemia was uncommon (16%) and probably reflects the most severe form of the disease (Table 1Go). In our study, we did not find patients with hypokalemia, probably because we only included unselected "essential" hypertensive subjects, in which a normal potassium level is currently required before to be named essential.


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Table 1. Prevalence of PA in four different populations of unselected hypertensive subjects

 
The main drawback of these studies relates to the methods used to confirm the diagnosis of PA, because it is known that the fludrocortisone, saline infusion, or captopril tests do not represent the gold standard procedures. In our work, we used the fludrocortisone test to confirm the diagnosis of PA based on the experience of Gordon and colleagues (2, 6). Their works reported the use of fludrocortisone test in more than 100 patients with PA that also underwent adrenal venous sampling that permitted the correct subclassification of PA (2, 6). In several of these patients was also carried out a saline infusion test and a [75Se]-methyl-cholesterol scanning. However, we recognize the difficulty for the establishment of a definitive biochemical diagnosis of aldosteronism. Although patients with aldosterone-producing adenoma have always autonomous aldosterone production, patients with IHA may retain some feedback suppression in the aldosterone production. In this regard, we preferred the 4-day fludrocortisone suppression test during a salt loading intake as a highly superphysiologic maneuver to inhibit aldosterone. Is probable that with this test we could have missed some IHA patients and secondarily underestimate the true prevalence of PA.

In the present, the molecular elucidation of the genetic bases of PA should be one of the most important contributions for the diagnosis of this disease. In this sense, the identification of the genetic form of glucocorticoid-remediable aldosteronism (GRA), also called familial hyperaldosteronism type I, had provided useful information for the diagnosis and treatment of affected patients. Moreover, a novel genetic locus has been recently described for a familial form of hyperaldosteronism that is not glucocorticoid-remediable, named familial hyperaldosteronism type II. This disease is currently presented as an adrenocortical hyperplasia or aldosteronoma or both and is frequently transmitted as an autosomal dominant disorder (7). Thus, it is highly probable that in the near future, the genetic test may be the gold standard tool for the correct diagnosis of some forms of PA.

In relation to the positive dexamethasone suppression test (DST) seen in some of our patients without the classical genetic for GRA, we speculate several explanations. First, we attributed it to mishandling when carrying out the test. However, Mulatero et al. (8) found a similar high frequency of false positives, even using a lower cut-off (2 ng/dl) for the aldosterone levels. We also studied whether a more prolonged DST could affect the aldosterone response performing a 5-day test that did not show differences with the shorter 2-day suppression test previously communicated (1). Moreover, we evaluated the commercial kit from Diagnostic Products Corp. (DPC; Los Angeles, CA) to measure SA concentration with an "in house" method previously described in our laboratory, and we did not find differences between both methods. The in house method is a traditional RIA, where the samples are extracted with dichloromethane and use aldosterone labeled with tritium as a tracer. This RIA was also validated for serum and urine samples with commercial controls from DPC and from the College of American Pathology, respectively. Finally, we evaluated whether other genetic alterations could exist in CYP11B genes to explain a positive DST and determine another genetic cause of GRA; the results of this work were recently submitted for publication.

We agree with Dr. Ganguly that a "gray zone" exists between patients with low renin essential hypertension and mild forms of PA. Probably, separating both entities will be easier in the future with the development of more sophisticated molecular genetic studies and more reliable and specific biochemical determinations (i.e. 18-hydroxicortisol). However, today the key issue should be the response to treatment with a specific aldosterone antagonist (i.e. spironolactone). It is our experience and the others that the treatment with a low dose of spironolactone monotherapy is enough to normalize the blood pressure or significantly to reduce the use of other antihypertensives agents in these patients (3).

Received May 15, 2001.

References

  1. Fardella CE, Mosso L, Gomez-Sanchez CE, et al. 2000 Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile and molecular biology. J Clin Endocrinol Metab 85:1863–1867[Abstract/Free Full Text]
  2. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC 1994 High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol 21:315–318[Medline]
  3. Lim PO, Dow E, Brennan G, Jung RT, MacDonald TM 2000 High prevalence of primary aldosteronism in the Tayside hypertension clinic population. J Hum Hypertens 14:311–315[CrossRef][Medline]
  4. Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young WF 2000 Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 85:2854–2859[Abstract/Free Full Text]
  5. Nishikawa T, Omura M 2000 Clinical characteristics of primary aldosteronism: its prevalence and comparative studies on various causes of primary aldosteronism in Yokohama Rosai Hospital. Biomed Pharmacother 54(Suppl 1):83s–85s
  6. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn WL, Krek AL 1991 Clinical and pathological diversity of primary aldosteronism, including a new familial variety. Clin Exp Pharmacol Physiol 18:283–286[Medline]
  7. Lafferty AR, Torpy DJ, Stowasser M, et al. 2000 A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet 37:831–835[Abstract/Free Full Text]
  8. Mulatero P, Veglio F, Pilon C, et al. 1998 Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab 83:2573–2575[Abstract/Free Full Text]