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J. A. Haley Veterans Hospital Tampa, Florida 33612
Address correspondence to: Arunabha Ganguly, M.D., J. A. Haley Veterans Hospital, Research Service (151), Building 2, Room 208, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612.
To the editor:
In the May issue of the JCEM, Fardella et al. (1) report the prevalence of primary aldosteronism in their hypertensive population as 9.5%. That figure may be too high for the general hypertensive population. Their studies have been conducted on patients recruited from a university outpatient clinic. I do not believe this population can be considered as representative of an unselected hypertensive population (or population at large) and, therefore, the prevalence estimate made is likely to be biased and skewed upward. This may have been the case for the figure given by Gordon as well (as cited). Investigation of a large number of hypertensive patients in one of my previous institutions (2) revealed a similarly high estimate and that population of hypertensives also was not unselected. In the hypertensive population at large (completely unselected), the incidence must be lower, although it is not precisely known.
There are other issues related to this study. What is the gold standard for the definitive diagnosis of primary aldosteronism? Is it the aldosterone level, the pathology, or the effect of treatment on the hypertension or all of them? The ratio of PA/PRA may be adequate for screening, but not for diagnosis. This is also evident in the study of these authors. The fludrocortisone suppression test has not been as widely used in the past as other methods, and the abnormal suppression level of plasma aldosterone with this test has been higher in the past studies than that used by these authors. Previously, we and others have used saline-suppressed plasma aldosterone level or urinary aldosterone level after sodium loading (along with stimulated plasma renin level) for the definitive biochemical diagnosis of primary aldosteronism. The DOCA suppression test with urinary aldosterone measurement has been used with success (3). The current fludrocortisone test may not have the equivalency with the other tests mentioned. Has there been a good comparative study of the fludrocortisone test using plasma aldosterone with the other methods in a good number of hypertensive patients?
It is surprising that all patients diagnosed to have definite primary aldosteronism in this study, had normal serum potassium. Usually, a minority of patients with primary aldosteronism in most series are normokalemic, although patients with glucocorticoid-suppressible aldosteronism (GSH) are often normokalemic and patients with idiopathic aldosteronism tend to have normokalemia more often than those with aldosteronoma. It was also surprising that plasma aldosterone was suppressed after 2 days of dexamethasone treatment in so many patients who did not have GSH. In this regard, use of direct plasma aldosterone measurement with a commercial kit can be the problem. Although the assays with the kit is generally reasonable for clinical purposes, they are not wholly reliable for specificity and this type of investigations. Because dexamethasone lowers most adrenal steroid hormones in the blood, the lowering of serum "aldosterone" may actually be an indicator of relative nonspecificity of the assay rather than true lowering of serum aldosterone. Dexamethasone does reduce serum aldosterone (measured by highly specific assays) transiently in non-GSH patients with primary aldosteronism, but the aldosterone promptly goes up, usually on the second day on the dexamethasone (4). In a few patients perhaps, it may remain low a little longer. We had earlier recommended at least 3 days of dexamethasone suppression for the aldosterone measurements for the diagnosis of GSH.
It has been recognized for sometime that aldosterone secretion is not normally suppressible by salt loading in a segment of hypertensive population, irrespective of their renin status (5). The significance of this finding has remained unclear. Is it an indication of mild hyperaldosteronism in these patients? Which variety is it—primary, secondary, or tertiary? Imaging or pathological data are also fraught with problems because of the high incidence of nonspecific adrenal abnormalities in the hypertensive population (incidentaloma or adrenal hyperplasia), basis of which also had been elusive. Thus, we are left in a quandary with quite a few unresolved, but important questions relating to the definitive diagnosis of primary aldosteronism. Clearly, there is a gray zone between patients with essential hypertension and primary aldosteronism and the diagnostic criteria for the latter are somewhat arbitrary. We have to decide which group each of the patients in the gray zone belongs to. If these patients in the gray zone are in a state of early primary aldosteronism, their progression to florid form of the disease has not been demonstrated, as far as I know. The authors may have characterized some of the patients in this group as subjects with primary aldosteronism.
There is no doubt that hypokalemia can no longer be considered as a requisite for the diagnosis of primary aldosteronism. PRA probably should be suppressed in all untreated patients. The key question then is the height of the plasma aldosterone at which to label such a hypertensive patient to have primary aldosteronism. But, then, we have to be sure that the modality (e.g. suppression) and methodology (e.g. aldosterone assay) used to determine the plasma aldosterone level to be abnormally high, are reliable. Otherwise we may be diluting the criteria for the diagnosis. Basically, we have to decide if the aldosterone level in a given patient with hypertension (in the low renin state) is producing a supraphysiologic effect. The situation may be analogous to primary hyperparathyroidism in which serum PTH level is not suppressed in the face of high serum calcium or to subclinical hyperthyroidism in which serum TSH is suppressed in the face of normal serum T4 and T3 levels. The original definition of "primary" aldosteronism by Jerome Conn (6) was not only the demonstration of high aldosterone level and low PRA, but also cure or improvement of the hypertension after removal of the offending adrenal. Obviously, such criteria can no longer be applied, because of the diversity of the etiology for this entity now. What will then be the definitive and uniform criteria for the diagnosis of "primary" aldosteronism today?
Received November 12, 2000.
References
This article has been cited by other articles:
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  L. Mosso, C. Carvajal, A. Gonzalez, A. Barraza, F. Avila, J. Montero, A. Huete, A. Gederlini, and C. E. Fardella Primary Aldosteronism and Hypertensive Disease Hypertension, August 1, 2003; 42(2): 161 - 165. [Abstract] [Full Text] [PDF]
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