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Original Studies |
Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (W.R.L., C.C., R.G.D.), Boston, Massachusetts 02115; the Department of Medicine, New York Hospital and Cornell Medical Center (M.I.N.), New York, New York 10021; and the Departments of Medicine and Genetics, Boyer Center for Molecular Medicine (R.P.L.), Yale University School of Medicine, New Haven, Connecticut 06510
Address all correspondence and requests for reprints to: Dr. W. Reid Litchfield, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 221 Longwood Ave RFB-2, Boston, Massachusetts 02115.
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Abstract |
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We conclued that a post-DST aldosterone level below 4 ng/dL will correctly diagnose GRA patients with high sensitivity and specificity. Suppression compared to baseline can be misleading, as evidenced by the results in APA patients and referred subjects who genetically screened negative.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Retrospective review of the records of patients that had been genetically screened for GRA by the International Registry for Glucocorticoid-Remediable Aldosteronism revealed 24 individuals that had prior DST with baseline and post-DST plasma aldosterone levels. These patients were referred for genetic testing based on the clinical setting, family history, or results of DST (3, 4). Twelve subjects tested positive (GRA+), and 12 tested negative (GRA-).
The results of DST in these patients were compared to results in patients with primary hyperaldosteronism reported previously [15 patients with aldosterone-producing adenomas (APA) (5, 6) and 4 patients with idiopathic hyperaldosteronism (IHA) (7)]. APA patients were diagnosed on the basis of biochemical testing alone (n = 2) or biochemical testing and adrenal venous sampling (n = 5), surgery (n = 6), or adrenal venography (n = 2). IHA was diagnosed on the basis of biochemical findings and adrenal scintigraphy (n = 3) or postmortem examination (n = 1). Genetic testing was not performed in these historical controls.
Genetic testing
Total genomic DNA was extracted from 10–20 mL peripheral venous blood as previously described (8). The chimeric 11ß-hydroxylase/aldosterone synthase gene was identified using a previously reported Southern blotting technique (4). Genetic testing was performed without prior knowledge of the response to DST.
DST
Most subjects underwent low dose DST based on that originally described by Liddle et al. (9, 10). Dexamethasone (0.75–2.0 mg/day) was administered orally for at least 2 days. Plasma aldosterone was measured before and after the DST.
Statistical analysis
The two patient groups were compared using an unpaired
t test with an 
level of 0.05. Results are expressed as
the mean ± SEM. Sensitivity, specificity, positive
predictive value, and negative predictive value were calculated for DST
using genetic testing as the definitive test. Baseline and post-DST
aldosterone levels and percent suppression of aldosterone were compared
in these patient groups.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The GRA+ subjects (n = 12) were similar to the
GRA- subjects (n = 12) with respect to gender,
systolic blood pressure, diastolic blood pressure, baseline serum
aldosterone, and PRA (Table 1
).
GRA+ and GRA- subjects differed significantly
with respect to age (mean age, 21.2 ± 3.6 and 36.4 ± 4.2
yr, respectively; P = 0.02). The median plasma
aldosterone/PRA ratio for both groups was 141.5, consistent with a
diagnosis of primary aldosteronism where the ratio usually exceeds 30
(11).
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). Although all subjects had aldosterone measured during the DST, pre- and post-DST cortisol levels were measured in only 7 of 12 GRA+ patients and in 3 of 12 GRA- patients. Post-DST cortisol levels indicated that the dexamethasone dose was sufficient to suppress cortisol levels to less than 5 ng/dL in these subjects (data not shown). Of those subjects without post-DST cortisol measurements, all had been given dexamethasone at doses that have been previously shown to suppress morning cortisol levels in normal subjects.
Baseline aldosterone levels tended to be higher, but were not
significantly different, in the GRA- compared to the
GRA+ group (54.2 ± 13.9 vs. 26.0 ±
3.6 ng/dL, respectively; P = 0.06; Fig. 1A). However, post-DST aldosterone levels
were significantly lower in GRA+ patients compared to
GRA- subjects (2.4 ± 0.44 and 22.0 ± 5.5 ng/dL,
respectively; P < 0.002). In addition, the percent
suppression of aldosterone vs baseline was significantly
greater in GRA+ subjects (88 ± 3% vs.
54 ± 4%; P < 0.0001; Fig. 1B).
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Historical subjects with primary aldosteronism (5, 6, 7)
Compared to our study subjects, the historical patients had been
given a greater mean dose of dexamethasone (2.1 ± 0.2 mg/day;
P = 0.02) and a shorter mean duration of treatment
(2.2 ± 0.1 days; P < 0.01). DST in 15 APA
patients resulted in mean baseline plasma aldosterone levels (50.0
± 7.3 ng/dL) declining to 23.1 ± 5.2 ng/dL (49 ± 9%
suppression). Basal and post-DST plasma aldosterone levels and percent
suppression of plasma aldosterone in APA patients were significantly
different from those in GRA+ subjects (P values
0.01, 0.02, and 0.001, respectively), but not from those in
GRA- subjects (Fig. 2).
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summarizes the results of DST in
all 4 patient groups.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study represents a retrospective review of patients referred for genetic testing to the International Registry for Glucocorticoid-Remediable Aldosteronism. Of 24 subjects with pre- and post-DST aldosterone measurements (12 GRA positive and 12 GRA negative), the DST proved to be accurate in correctly diagnosing GRA if the proper suppression criteria were applied. Cut-offs based on absolute aldosterone levels (<4 ng/dL) or percent suppression of aldosterone (>80%) were equally effective in correctly diagnosing GRA, with only 1 subject that was GRA+ being misclassified. This subject’s plasma aldosterone level fell from 14.3 to 6.4 ng/dL (55% suppression) after the administration of 0.5 mg dexamethasone every 6 h for 3 days. However, treatment compliance could not be confirmed because cortisol was not measured post-DST. This underscores the importance of measuring both aldosterone and cortisol concurrently when performing DST to ensure that noncompliance with dexamethasone administration does not result in a false negative test.
In considering the differential diagnosis of GRA, there
are a number of mineralocorticoid excess states in which the
elevation in blood pressure may be glucocorticoid responsive (1).
These include congenital and acquired 11ß-hydroxysteroid
dehydrogenase deficiency as well as congenital adrenal hyperplasia due
to 11ß-hydroxylase or 17-hydroxylase deficiency. Although lowering
blood pressure with DST in these syndromes is similar to that seen in
GRA, these low renin syndromes can be distinguished because the
mineralocorticoid excess state is caused by a steroid other than
aldosterone (e.g. cortisone in 11ß-hydroxysteroid
deficiency). However, DST in patients with the more common etiologies
of primary aldosteronism, such as APA and IHA, could cause
confusion, because dexamethasone-induced suppression of aldosterone
is a well documented and often not appreciated finding in APA (5, 6, 7, 21, 22, 23).
As the final diagnosis was unknown in our subjects who genetically screened negative for GRA, we reviewed the literature for the plasma aldosterone response to DST in patients with primary aldosteronism. When the above DST diagnostic criteria were applied to 15 patients with APA (5, 6), the post-DST aldosterone level was more accurate than the percent suppression in correctly classifying these patients as GRA-; 14 of 15 APA subjects had post-DST aldosterone levels above 4 ng/dL. On the other hand, one third of the APA patients had more than 80% suppression of aldosterone levels post-DST (5, 6). Thus, even though APA patients often show clear-cut dexamethasone suppressibility of aldosterone, the post-DST aldosterone level is usually higher than those seen in GRA patients.
Thus, DST can be used to correctly diagnose almost all patients with GRA if appropriate post-DST aldosterone criteria are applied. We believe that DST is best accomplished by administering 0.5 mg dexamethasone, orally, every 6 h for 2 days; concurrent measurement of cortisol with aldosterone is recommended to document adequate suppression of ACTH. Longer duration of DST (>1 week), as has been performed by some investigators (20, 25), is not recommended because this may result in reactivation of the renin-angiotensin system in GRA patients, possibly yielding false negative results. Although a cut-off of more than 80% suppression of aldosterone after DST would clearly have misclassified some patients with APA, a post-DST aldosterone level less than 4 ng/dL was seen in less than 7% of APA patients. Thus, there was overlap in the post-DST aldosterone levels in the GRA+ and APA groups. As the DST cannot definitively distinguish APA from GRA+, direct genetic testing still appears to be the definitive confirmatory test (100% sensitivity and 100% specificity). This is underscored by a report of autonomous aldosterone production with failure to suppress after DST in an established GRA family (24).
When should the DST be administered? GRA is rare and has a low prevalence, even among patients with biochemical primary hyperaldosteronism. It is, therefore, important to stress that the routine use of the DST as part of the initial diagnostic evaluation of patients with primary hyperaldosteronism is inappropriate. Rather, we propose that the DST be used in patients with biochemical primary hyperaldosteronism, who have a suggestive clinical history (i.e. early-onset hypertension in the proband and in first degree relatives) and negative computed tomography imaging of the adrenals. Finally, a positive DST should not displace the primacy of direct genetic testing in the diagnosis of GRA.
The fall in aldosterone to nearly undetectable levels after DST in GRA is expected and reflects the sole control of aldosterone by ACTH in this disorder. The significant suppression of aldosterone levels after DST in APA reflects the well recognized regulation of aldosterone by ACTH in this disorder (16, 17, 24, 25, 26). However, autonomous production of aldosterone by the neoplasm 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 dexamethasone-suppressible hyperaldosteronism for the disorder that he biochemically characterized by the measurement of unique steroid metabolites (6). These data underscore his penetrating contributions and insights.
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Footnotes |
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Received May 9, 1997.
Accepted July 17, 1997.
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References |
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, P < 0.0001.