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In Familial Hyperaldosteronism Type I, Hybrid Gene-Induced Aldosterone Production Dominates That Induced by Wild-Type Genes¹

Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane, 4120, Australia

Address all correspondence and requests for reprints to: Professor Richard D. Gordon, Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane, Australia 4120.

	Abstract

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We compared the aldosterone-producing potency of the angiotensin II-sensitive wild-type aldosterone synthase genes and the ACTH-sensitive hybrid 11ß-hydroxylase/aldosterone synthase gene by examining aldosterone, PRA, and cortisol day-curves (2-hourly levels over 24 h) in patients with familial hyperaldosteronism type I, before and during long-term (0.8–13.5 yr) glucocorticoid treatment. In 8 untreated patients, PRA levels were usually suppressed, and aldosterone correlated strongly with cortisol (r = 0.69–0.99). Fourteen studies were performed on 10 patients receiving glucocorticoid treatment that corrected hypertension, hypokalemia, and PRA suppression in all. ACTH was markedly and continuously suppressed in 6 studies, 3 of which demonstrated strong correlations between aldosterone and PRA (r = 0.77–0.92). ACTH was only partially suppressed in the remaining 8 studies; aldosterone correlated strongly: 1) with cortisol alone in 5 (r = 0.71–0.98); 2) with cortisol (r = 0.90) and PRA (r = 0.74) in one; 3) with PRA only in one (r = 0.80); and 4) with neither PRA nor cortisol in one. Unless ACTH is markedly and continuously suppressed, aldosterone is more responsive to ACTH than to renin/angiotensin II, despite the latter being unsuppressed. This is consistent with the hybrid gene being more powerfully expressed than the wild-type aldosterone synthase genes in familial hyperaldosteronism type I.

	Introduction

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IN FAMILIAL hyperaldosteronism type I (FH-I, glucocorticoid-suppressible hyperaldosteronism), aldosterone production is primarily regulated by ACTH, rather than by renin-angiotensin II (AII) (1, 2, 3, 4). Hence, in FH-I, plasma aldosterone fails to rise normally or falls during 2 h of upright posture, after overnight recumbency or during a midmorning AII infusion, because ACTH falls at this time of day as part of its normal circadian rhythm (3, 5, 6), and aldosterone is profoundly suppressed for several days by dexamethasone (0.5 mg, 6 hourly) (4, 6), unlike the transient suppression seen normally and in patients with other forms of primary aldosteronism (7, 8). The underlying molecular defect is a hybrid gene composed of 5' regulatory sequences of CYP11B1 (encoding 11ß-hydroxylase, which primarily catalyzes the final step in cortisol production, regulated by ACTH) and 3' coding sequences of CYP11B2 (encoding aldosterone synthase, which catalyzes aldosterone production, regulated mainly by the renin/AII system) (9, 10). The gene product has aldosterone synthase activity (11, 12), but its expression is regulated by ACTH instead of renin/AII.

Most patients with FH-I have very low levels of PRA, with raised aldosterone/PRA ratios consistent with primary aldosteronism (13). The wild-type aldosterone synthase genes, which are predominantly driven by renin/AII, therefore, are probably in a state of chronic suppression in FH-I, which presumably accounts for the failure of aldosterone levels to rise in response to upright posture or AII infusion in these patients. These biochemical features, together with the sensitivity of aldosterone production to ACTH, suggest that, at least in untreated FH-I, the hybrid gene dominates over the wild-type genes as the primary determinant of aldosterone production.

When patients with FH-I commence treatment with glucocorticoids, aldosterone falls to very low levels; and, with the ensuing release from sodium/volume expansion, blood pressure progressively falls, and renin becomes unsuppressed (2, 6). Presumably, the wild-type aldosterone synthase genes are also released from chronic suppression, because the rise in renin levels is associated with a return of aldosterone levels towards normal, and with the emergence of aldosterone responsiveness to upright posture and AII infusion (2). We sought to determine whether the hybrid gene possesses a greater capacity to induce aldosterone production than the wild-type aldosterone synthase genes, not only in the untreated state (when the wild-type genes are chronically suppressed) but even when they are released from chronic suppression during long term glucocorticoid treatment. We therefore examined aldosterone, cortisol, and PRA day-curves and sought correlations between aldosterone and cortisol (as an indication of hybrid gene expression) and between aldosterone and PRA (as an indication of wild-type gene expression) in patients with FH-I, both before and after commencement of long-term glucocorticoid treatment.

	Materials and Methods

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Diagnosis of FH-I

The study population consisted of 18 patients (10 males and 8 females, age range: 10–78 yr, derived from 3 families) with FH-I. In all patients, the diagnosis was confirmed by demonstrating the presence of the hybrid gene in peripheral blood leucocyte DNA using a long-PCR-based method recently developed in our laboratory (13, 14).

Day-curve study design

Day-curve studies were performed either before (Group 1) or at least 0.8 yr after (Group 2) commencement of glucocorticoid treatment. Although five of the Group 1 patients are also now receiving glucocorticoids, posttreatment day-curve studies in this group have not been included in the current analysis because the duration of follow-up since commencement of treatment remains relatively short (less than 0.8 yr). In the Group 2 patients, only posttreatment day-curves were available for analysis, because glucocorticoid treatment had already been initiated in these patients at the time the day-curve studies were designed.

For each day-curve study, patients were admitted at 0800 h to the Hypertension Unit. A cannula was then inserted into a forearm vein in the cubital fossa for blood sampling. Dietary sodium was uncontrolled; and, based on 24-h urinary sodium levels, ranged from 0.6 to 4.0 mmol/kg BW per day (mean ± SD 1.7 ± 0.7 mmol/kg·day). Hence, comparisons focussed, in the main, on patterns of hormone response, rather than absolute levels. Patients remained recumbent from midnight until 0800 h. Posture was unrestricted for other times of the day. In the Group 2 patients, glucocorticoid doses were given at 0700 h for once-daily regimens, and at 0700 h and 1700 h for twice-daily regimens. Blood (15 mL) was collected every 2 h for 24 h (from 1000 h to 1000 h) for measurement of plasma aldosterone, PRA, and plasma cortisol. Immediately after each collection, the blood was centrifuged and the plasma component snap frozen on dry ice and stored at -20 C pending assay.

Other biochemical analyses

In all Group 1 and Group 2 patients, levels of plasma potassium, plasma aldosterone, PRA, and aldosterone/PRA ratios were measured in blood collected midmorning (after at least 2 h of upright posture, before the commencement of glucocorticoid treatment) and compared with ranges established in our laboratory for normal subjects studied under similar conditions. In addition, in the Group 2 patients, the effects of glucocorticoid treatment on these measurements were assessed by comparing them with levels measured in blood collected at 1000 h during the most recent posttreatment day-curve study performed on each patient in this group.

Levels of 18-oxo-cortisol (corrected for creatinine excretion) were measured in a 24-h urine collection obtained before commencement of glucocorticoid treatment.

Assays

Plasma aldosterone was measured by RIA (Coat-A-Count ¹²⁵I-Aldosterone RIA Kit, Diagnostic Products Corporation, Los Angeles, CA), in a modification of the method of Mayes et al. (15), with intra- and interassay coefficients of variation of 4.0% and 6.0%, respectively, and a sensitivity range of 69–3300 pmol/L. PRA was measured by RIA (Gamma Coat [¹²⁵I] Plasma Renin Activity RIA Kit, Incstar Corporation, Stillwater, MN) of generated angiotensin I in a modification of the method of Haber et al. (16), with intra- and interassay coefficients of variation of 4.3% and 7.2%, respectively, and a sensitivity range of 1.3–257.2 pmol/L·min. Plasma cortisol was measured by RIA using a commercial kit (Quanticoat ¹²⁵I-Cortisol RIA Kit, Kallestad Diagnostics, Chaska, MN), with intra- and interassay coefficients of variation of 4.5% and 9.6% respectively, and a sensitivity range of 28–1517 nmol/L. Urinary 18-oxo-cortisol levels were determined by RIA using a method previously described (17).

Data analysis

For the comparisons of pre- and posttreatment plasma potassium, plasma aldosterone and PRA levels and aldosterone/PRA ratios in Group 2 patients (n = 10), medians were compared by Wilcoxon’s matched-paired test, with significance defined as P < 0.05 using two-sided P values. For each day-curve study, Spearman rank correlation coefficients were determined for correlations between aldosterone and cortisol levels as a reflection of ACTH-dominated aldosterone regulation, and between aldosterone and PRA levels as a reflection of AII-dominated regulation of aldosterone.

	Results

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Midmorning upright plasma potassium, aldosterone and PRA, and urinary 18-oxo-cortisol levels

Before commencement of glucocorticoid treatment, at the time of the midmorning upright blood collections, three normotensive patients (patients 1, 2, and 4) and three patients only recently found to be hypertensive (patients 6, 14, and 18) had not previously received antihypertensive medications of any type. In three further patients (patients 3, 5, and 9), antihypertensive medications had been withdrawn at least 1 week before blood collection. The remaining nine patients (patients 7, 8, 10–13, and 15–17) were receiving preparations of metoprolol, labetalol, verapamil, felodipine, hydralazine, fosinopril, or lisinopril (either singly or in combination). In the eight patients who had previously received diuretic treatment, diuretics were ceased for 1 week (patient 9), 2 weeks (patient 10), or at least 4 weeks (patients 3, 5, 8, 11, 12, and 16) before blood collection.

Before commencement of glucocorticoid treatment, 5 of the 18 patients were hypokalemic. Midmorning upright plasma aldosterone levels were normal in all (Table 1). PRA levels were suppressed in 16 patients, normal in 1 [patient 11, a 64-yr-old male with concommitant renal artery stenosis, who has been previously reported in detail (6)], and high-normal in one (patient 4, a 39-yr-old female). Patient 4 had never been hypertensive nor received other antihypertensive medications, and demonstrated no evidence of marked dietary salt restriction (urinary sodium excretion: 1.8 nmol/kg·day) or past or current use of diuretics to explain the high-normal PRA level. The aldosterone/PRA ratio was elevated in all but 5 patients, including the two with unsuppressed PRA and 3 others (patients 3, 8, and 12) who had previously been on diuretics. Urinary levels of 18-oxo-cortisol were elevated in all 17 patients in whom it was measured, including those with normal aldosterone/PRA ratios.

Day-curve studies

Eight patients underwent day-curve studies before receiving glucocorticoid treatment (Group 1, Table 2). In all eight, aldosterone correlated strongly with cortisol (r = 0.69–0.99) but not with PRA levels (r = -0.42–0.39, Fig. 1).

View larger version (27K): [in this window] [in a new window]   Figure 1. Plasma aldosterone, PRA, and plasma cortisol day-curves in patient 1, who had not yet received glucocorticoid treatment.

Six of the 14 day-curve studies performed on patients receiving long-term glucocorticoid treatment demonstrated marked, continuous cortisol suppression, with at least 12 of the 13 day-curve plasma cortisol levels for each study being undetectable by RIA (Group 2 (a), Table 2; and Fig. 2). During all six day-curve studies, midmorning (1000 h) upright levels of plasma potassium (range 3.7–4.2 mmol/L) and plasma aldosterone (range 236–566 pmol/L) were within the normal ranges (3.5–5.0 mmol/L and 140-1100 pmol/L for plasma potassium and aldosterone, respectively). The corresponding midmorning upright PRA levels (range 52.7–171.0 pmol/L·min) were elevated above the normal range (13–50 pmol/L·min) and the aldosterone/PRA ratios (range 1.4–6.5) below normal during all 6 studies. Correlations between day-curve aldosterone and PRA levels were strong in 3 of these studies (r = 0.77–0.92) and weak in the remaining three (0.20–0.34). The marked degree of cortisol suppression precluded correlation analysis between aldosterone and cortisol levels for these 6 day-curve studies.

View larger version (28K): [in this window] [in a new window]   Figure 2. Plasma aldosterone, PRA, and plasma cortisol day-curves in patient 10, in whom glucocorticoid treatment (dexamethasone: 0.5 mg mane, 0.25 mg nocte) was associated with marked, continuous suppression of cortisol levels.

View larger version (29K): [in this window] [in a new window]   Figure 3. Plasma aldosterone, PRA, and plasma cortisol day-curves in patient 15, in whom glucocorticoid treatment (dexamethasone: 0.5 mg mane) was associated with partial suppression of cortisol levels.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Lifton et al. (9, 10) have suggested that patients with FH-I have one copy of the hybrid gene but, as well, two copies each of the wild-type aldosterone synthase and wild-type 11ß-hydroxylase genes. This would make them capable of an aldosterone response to AII but, in the untreated state, the wild-type aldosterone synthase genes are presumably dormant because of life-long suppression of AII by the sodium-volume expansion of excessive, ACTH-driven aldosterone. In the current study, the seven individuals with FH-I who had not yet received glucocorticoids, and whose PRA levels were suppressed, demonstrated close correlations of plasma aldosterone with cortisol day-curve levels, consistent with aldosterone production being regulated primarily by ACTH (rather than by renin/AII) and, thus, with dominance of the hybrid gene over the suppressed wild-type genes in the induction of aldosterone biosynthesis. Unexpectedly, this relationship also was evident in an untreated 39-yr-old normotensive subject with FH-I, whose PRA levels were consistently in the high/normal range and who, therefore, might have been expected to demonstrate stronger correlation of aldosterone with PRA levels than with cortisol levels. There was no history of diuretic use or evidence of dietary salt restriction (urinary sodium excretion: 1.8 mmol/kg·day) to explain this subject’s higher PRA and normal blood pressure. The fact that urinary 18-oxo-cortisol levels were elevated argues against nonexpression of the hybrid gene (17). Aldosterone/PRA ratios were low, suggesting a defect in renin/AII-regulated aldosterone biosynthesis. Whatever the explanation for the constellation of findings in this individual, the results of the day-curve study suggest that, as in the other untreated subjects, the hybrid gene was dominant over the wild-type genes, in terms of inducing aldosterone production, despite high-normal renin/AII levels.

In all treated subjects, long-term glucocorticoid administration corrected hypertension and hypokalemia, when present, and released PRA from suppression. In the subjects in whom treatment resulted in marked, continuous suppression of cortisol levels, and presumably of ACTH-driven aldosterone production, the demonstration of plasma aldosterone levels in the midnormal range was consistent with recovery of the chronically suppressed wild-type genes, now driven by PRA. Furthermore, three of the six day-curves undertaken on these subjects exhibited close correlations between aldosterone and PRA levels.

In those patients to whom glucocorticoids were administered in quantities sufficient to allow release of PRA levels from suppression (at least to within, and sometimes above, the normal range) but without causing marked, continuous suppression of ACTH it was possible to study and compare aldosterone production induced concurrently by both the wild-type and hybrid genes, because the primary regulator for each (renin/AII and ACTH, respectively) was functionally operative. Aldosterone levels in this situation usually correlated strongly with cortisol rather than with PRA levels, consistent with aldosterone production being predominantly regulated by ACTH.

Hence, unless ACTH is markedly and continuously suppressed, aldosterone production in FH-I is usually regulated by ACTH, rather than by renin/AII, not only when renin/AII levels are chronically suppressed (as in untreated FH-I), but even after long periods of unsuppressed renin/AII activity (as in treated FH-I). These findings suggest that the hybrid gene dominates over the wild-type aldosterone synthase genes in its capacity to induce aldosterone synthesis.

In FH-I, excessive production of 18-hydroxy- and 18-oxo-cortisol is thought to result from the aberrant expression of aldosterone synthase activity in zona fasciculata, where cortisol is available as a substrate and is thereby converted into these so-called hybrid steroids (9, 10, 17, 30). Expression of the hybrid gene throughout all adrenal cortical layers in FH-I has been demonstrated by way of in situ hybridization analysis in nontumorous adrenal tissue removed from a patient with FH-I (31). The greater aldosterone-producing capacity of the hybrid gene over the wild-type aldosterone synthase genes, therefore, may relate to its more ubiquitous expression and, presumably, to its capacity to generate aldosterone throughout the entire adrenal cortex, whereas expression of the wild-type genes is restricted to zona glomerulosa.

In patients on long-term treatment with glucocorticoids, PRA levels were elevated and aldosterone/PRA ratios were usually low, consistent with impaired wild-type gene-induced aldosterone biosynthesis. Most of these treated patients also have demonstrated failure of plasma aldosterone to respond to AII infusion (32). In patients with primary aldosteronism caused by an adenoma, who exhibit severely suppressed levels of PRA, despite the capacity of the contralateral adrenal cortex to eventually respond to AII after removal of the adenoma, failure of response is seen immediately after removal and persists for a variable period (33, 34). However, the fact that AII-regulated, presumably wild-type gene-induced aldosterone production in FH-I remained impaired in our subjects (even after up to 13.5 yr of continuous glucocorticoid treatment) suggests a more chronic, possibly permanent, abnormality in FH-I patients. Given that such long periods of glucocorticoid treatment and correction of hyperaldosteronism should have been sufficient to render our patients potassium replete, it is unlikely that a state of potassium deficiency could have accounted for this chronic impairment in wild-type gene-induced aldosterone biosynthesis. In none of the day-curve samples collected from any of our treated patients, were plasma potassium levels below the normal range. Given that ACTH is a known aldosterone secretogogue, it is possible that the impairment of wild-type gene-induced aldosterone production may have been caused by a nonspecific effect of glucocorticoid administration on aldosterone biosynthesis. Hamilton et al. (35), however, reported no change in levels of plasma aldosterone and PRA after long-term dexamethasone administration in essential hypertensives, compared with those measured basally. Conceivably, inheritance of the hybrid gene could, in some way, result in defective function of other genes, such as the closely situated wild-type aldosterone synthase gene, involved in AII-regulated aldosterone production. Recent reports (36, 37) of altered 11ß-hydroxylase activity, in patients with FH-I, raise the possibility that the function of the 11ß-hydroxylase gene might also be compromised in these patients, somehow by virtue of its close proximity to the hybrid gene. Whatever the explanation for the impairment in AII-regulated aldosterone production exhibited by our patients with treated FH-I, such impairment could have contributed to the tendency for hybrid gene-induced aldosterone production in these individuals to dominate that induced by the wild-type genes.

	Footnotes

 
¹ This work was supported by the Department of Veterans’ Affairs and the National Heart Foundation of Australia.

Received December 2, 1996.

Revised June 2, 1997.

Accepted July 21, 1997.

	References

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