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ABSTRACT: Since detection of familial hyperaldosteronism type I (glucocorticoid-suppressible hyperaldosteronism) allows specific treatment of hypertension with dexamethasone, we compared clinical, biochemical and genetic approaches to detection.
We studied 22 affected patients, 21 from a single, large family and an additional adopted male. Plasma aldosterone, plasma renin activity and urinary 18-oxo-cortisol were measured by radioimmunoassay. The hybrid gene was demonstrated using either Southern blotting or a long polymerase chain reaction technique.
Thirteen out of 22 (59%) patients with familial hyperaldosteronism type I, but only four out of 12 (33%) under 20 years of age, were hypertensive. Plasma potassium and aldosterone were each normal in 20 out of 22 (91%), and unhelpful in diagnosis. Plasma renin activity, the aldosterone: plasma renin activity ratio and 18-oxo-cortisol were more sensitive, being abnormal in 20 out of 22 (91%), 19 out of 22 (86%) and 20 out of 20 (100%) patients, respectively. Aldosterone was unresponsive (<50% rise) to 2 h of upright posture following overnight recumbency in 15 out of 15 (100%) patients studied, and to angiotensin II infusion (2 ng/kg per min for 1 h) in 14 out of 14 patients (100%). Whereas all the abovementioned abnormalities are also characteristic of angiotensin II-unresponsive aldosterone-producing adenoma, marked aldosterone suppression following 4 days of dexamethasone (0.5 mg every 6 h) was sensitive and specific for familial hyperaldosteronism type I (n = 11). The hybrid gene was detectable in peripheral blood leucocyte DNA in all 22 affected patients by Southern blotting, and by a faster, long polymerase chain reaction method developed in our laboratory, both methods requiring only a single blood collection.
Should studies in other families confirm its universal applicability, long polymerase chain reaction should prove to be the most practical means of detecting familial hyperaldosteronism type I in laboratories equipped with this technique.
Journal of Hypertension 12/1995; 13(12 Pt 2):1610-3. · 4.02 Impact Factor
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ABSTRACT: Previous studies have shown a significant association between allelic frequencies at the ANP gene locus and aldosterone responsiveness to angiotensin in aldosterone-producing adenoma (APA). We searched for any gross insertions or deletions in the ANP gene in APA and any associations between allelic frequencies at the Hpa II and Sca I RFLP sites within the ANP gene and angiotensin-responsive and unresponsive APA and normal subjects. We also searched for possible point mutations in the promoter region of the ANP gene (-595 to transcription start site) in peripheral blood and tumor DNA from 59 patients with APA and in peripheral blood DNA from 39 normal subjects by polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) analysis. No large alterations in the ANP gene were observed, and no difference in allelic frequencies at the RFLP sites were seen between the two tumor subtypes, angiotensin-responsive and angiotensin-unresponsive APA, or between the APA group and normal subjects. SSCP analysis, however, did reveal mutations in the promoter region of the ANP gene (-375 to -595) in both peripheral blood and tumor DNA from 8 of 59 (14%) patients with APA, compared with only one of 39 normal controls (2.6%). This study suggests that alterations in the proximal promoter region of the ANP gene in APA may be important in the regulation of ANP transcription and may be involved in the underlying pathophysiology of aldosterone-producing adenoma in at least some patients.
Biochemical and Biophysical Research Communications 11/1995; 215(1):172-8. · 2.48 Impact Factor
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ABSTRACT: We investigated renal and peripheral forearm extraction of atrial natriuretic peptide in patients with primary aldosteronism to determine whether alterations in extraction may contribute to the elevated levels of circulating atrial natriuretic peptide observed in primary aldosteronism. We obtained simultaneous venous blood samples from the left renal vein and a peripheral vein and from the radial artery in 28 patients with primary aldosteronism and 10 patients with essential hypertension. Renal extraction of atrial natriuretic peptide was significantly (P < .001) reduced (40 +/- 2%) in primary aldosteronism compared with essential hypertensive patients (62 +/- 3%). Peripheral forearm extraction was also reduced (P < .01) in primary aldosteronism compared with essential hypertensive patients (24 +/- 3% versus 38 +/- 4%). These findings are consistent with widespread downregulation of atrial natriuretic peptide receptors in primary aldosteronism. Consistent with reports that marked reduction in glomerular filtration rate is required before the renal extraction of atrial natriuretic peptide is reduced, no significant relationship between renal extraction of atrial natriuretic peptide and plasma creatinine was seen in primary aldosteronism or essential hypertension. Although the major regulators of atrial natriuretic peptide secretion in primary aldosteronism are presumably alterations in arterial blood pressure and plasma volume, reduced renal and peripheral extraction of atrial natriuretic peptide in primary aldosteronism may also contribute significantly to the elevated circulating levels observed.
Hypertension 11/1995; 26(4):624-7. · 6.21 Impact Factor
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ABSTRACT: The effects on blood pressure (BP) and heart rate (HR), at rest and during bicycle exercise, of the vascular selective calcium antagonist felodipine, the cardio-selective beta-blocker metoprolol, and of the two drugs in combination, were assessed in a double-blind, three-way cross-over study comprising 23 patients with essential, mild to moderate hypertension. All three treatment regimens were given to each patient in randomised order for 4 weeks after a 4 week placebo run-in period. Felodipine 10-20 mg daily, metoprolol 100-200 mg daily and the combination of felodipine 10-20 mg plus metoprolol 100 mg daily were all effective antihypertensive treatments both at rest and during exercise. The two drugs seemed to have additive effects and the effect on BP of the combination was greater than that of either drug given as monotherapy. The mean sitting BP was 148/103 mmHg at randomisation, after 4 weeks of placebo treatment, and 134/88, 134/94 and 121/84 mmHg, respectively, after 4 weeks' treatment with felodipine, metoprolol and the combination. Maximal exercise capacity was similar irrespective of treatment regimen, and the normal response to exercise BP and HR was maintained during all active treatments. Changes observed in volume regulatory hormones (PRA, aldosterone and ANP) were consistent with a direct tubular natriuretic-diuretic effect of felodipine and of beta-blocker attenuated release of renin. All treatment regimens were well tolerated and adverse events reported were usually mild and transient.
Blood Pressure 10/1995; 4(5):300-6. · 1.43 Impact Factor
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ABSTRACT: In Familial Hyperaldosteronism Type I (FH-I, glucocorticoid-suppressible hyperaldosteronism), a curable form of hypertension inherited in an autosomal dominant fashion, the underlying genetic defect is a "hybrid gene" in which 11 beta-hydroxylase gene regulatory elements are fused to the coding region of the aldosterone synthase gene. The detection of this hybrid gene by Southern blotting is time consuming and involves the use of radioactive isotopes. We describe a new, long polymerase chain reaction-based method for detecting the hybrid gene which greatly reduces the time required to obtain a result, avoids exposure of laboratory workers to radioactive materials, and will thereby facilitate the screening of patients for the presence of FH-I.
Biochemical and Biophysical Research Communications 03/1995; 207(2):565-71. · 2.48 Impact Factor
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ABSTRACT: Primary aldosteronism is an important, potentially curable, form of hypertension. We examined the possible association between restriction fragment length polymorphisms in the atrial natriuretic peptide (ANP) gene and responsiveness of aldosterone to angiotensin II in 59 patients with primary aldosteronism due to aldosterone-producing adenoma (APA). Significant differences in the allelic frequencies of the BglI, TaqI and XhoI polymorphic sites at the ANP gene locus (chromosome 1; 1p36) between angiotensin II-unresponsive and angiotensin II-responsive tumors were observed. Variation in the ANP gene between the two groups may result in altered expression of ANP within the adrenal gland, and may contribute to the biochemical regulation of aldosterone production of these two subgroups of patients with APA.
Biochemical and Biophysical Research Communications 12/1994; 204(3):1312-7. · 2.48 Impact Factor
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ABSTRACT: 1. In 1991 we described a familial variety of primary hyperaldosteronism which was not glucocorticoid-suppressible and was associated with adenoma formation, and called it familial hyperaldosteronism type II (FH-II) in order to distinguish it from the glucocorticoid-suppressible variety described in 1966, familial hyperaldosteronism type I (FH-I). 2. In 1992 the genetic basis of FH-I was clarified by description of a hybrid gene. 3. Primary aldosteronism due to bilateral adrenocortical hyperplasia or to aldosterone-producing tumour can be part of the multiple endocrine neoplasia type I syndrome (MEN I), in which loss of heterozygosity has been described on chromosome 11q13. Loss of heterozygosity at the MEN I locus was found in five of 26 aldosterone-producing tumours from our series (by Japanese collaborators). These included two with adrenal cancer and two with FH-II. 4. We recently described an association of aldosterone responsiveness of aldosterone-producing adenomas with renin gene restriction fragment length polymorphisms, suggesting a possible role for renin genotype and intra-adrenal renin gene expression in the development and biochemical expression of some aldosterone-producing tumours. 5. We found abnormal karyotypes in 13 of 32 benign aldosterone-producing adenomas.
Clinical and Experimental Pharmacology and Physiology 12/1994; 21(11):915-8. · 1.85 Impact Factor
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ABSTRACT: 1. This study sought to assess the incidence of primary aldosteronism in 199 hypertensives who were normokalaemic and in whom the question of primary aldosteronism had never been raised. 2. The screening test applied was the aldosterone to renin ratio in plasma, which was raised in 40 and normal in 159 patients. A second ratio was normal in 14 of these 40. 3. Twenty-two patients with two further raised ratios required fludrocortisone suppression testing. This has been completed in 17, and failure to suppress led to a diagnosis of primary aldosteronism in all. 4. A dexamethasone suppression test (DST) excluded ACTH-dependent hyperaldosteronism and laterality of aldosterone production was determined by adrenal vein sampling. 5. Unilaterality in five patients led to adrenalectomy in four and spironolactone in one. Bilaterality in six patients led to spironolactone. 6. This study so far provides a proven (minimum) incidence for primary aldosteronism of 8.5%, a probable incidence of 12.0% (including two raised ratios) and a possible (maximum) incidence of 13.0% (leaving out those with second ratio normal). Exclusion of hypokalaemic hypertensives will lead to an underestimation of the true incidence of primary aldosteronism. 7. Based on this and other evidence, it is estimated that the incidence of primary aldosteronism in the 'essential hypertensive' population is between 5 and 15%, and is probably around 10%.
Clinical and Experimental Pharmacology and Physiology 05/1994; 21(4):315-8. · 1.85 Impact Factor
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ABSTRACT: 1. Normokalaemic primary aldosteronism (PA) masquerades as 'essential hypertension', and 50% of patients with aldosterone-producing adenoma (APA) are normokalaemic at presentation to this unit. 2. Angiotensin-responsive (AII-R) APA is as common as angiotensin-unresponsive (AII-U) APA, and requires adrenal venous sampling for differentiation from bilateral adrenal hyperplasia (BAH). 3. From 1981 to 1992, 55 patients with APA underwent unilateral adrenalectomy and were followed up for at least 12 months postoperatively. Hypertension was cured in 55% and improved in the remainder. 4. Cure rate was lower (P < 0.001) in males (11/32, 34%) vs females (19/23, 83%), lower (P < 0.005) in patients over 45 years of age (13/33, 39%) vs those 45 years or younger (17/22, 77%), lower (P < 0.05) in AII-R APA (11/28, 39%) vs AII-U APA (19/27, 70%) and tended to be lower (not significant) in normokalaemic APA (7/17, 41%) vs hypokalaemic APA (23/38, 61%). 5. A higher proportion (P <0.001) of AII-R APA patients were males (23/28, 82%) vs AII-U APA (9/27, 33%), and a higher proportion were from the older age group AII-U APA 13/27, 48%; P < 0.05). Females with AII-U APA who were hypokalaemic had a very high cure rate (16/17, 94%). 6. Since unilateral adrenalectomy cures or improves blood pressure in normokalaemic and AII-R as well as in hypokalaemic and AII-U patients, all hypertensives should be screened for PA, and AII-R APA differentiated from BAH in proven PA.
Clinical and Experimental Pharmacology and Physiology 05/1994; 21(4):319-22. · 1.85 Impact Factor
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ABSTRACT: 1. Elevated peripheral atrial natriuretic peptide (ANP) levels were observed in 12 patients with unilateral renal artery stenosis (U-RAS). 2. Renal extraction of ANP was higher across the affected than the unaffected kidney in U-RAS, provided the glomerular filtration rate in the affected kidney was not severely reduced (> 12 mL/min). As ANP is a high clearance compound, reduced flow on the affected side may result in increased renal extraction of ANP. 3. When glomerular filtration rate (GFR) in the affected kidney was severely reduced (< 12 mL/min), renal extraction of ANP was also reduced, possibly contributing to increased circulating ANP levels in this subgroup. 4. Overall, renal extraction of ANP was inversely correlated to peripheral ANP levels in patients with U-RAS. This might be explained by progressive sodium retention as GFR falls leading to volume expansion and increased ANP secretion.
Clinical and Experimental Pharmacology and Physiology 04/1994; 21(3):211-4. · 1.85 Impact Factor
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ABSTRACT: 1. Two patients with adrenaline-only secreting phaeochromocytomas and primary aldosteronism were studied. 2. Urinary adrenaline levels were raised and plasma adrenaline was not suppressed normally following administration of clonidine. Plasma aldosterone to plasma renin activity ratios were repeatedly elevated. 3. Both had large intra-adrenal phaeochromocytomas visible on computerized tomography (CT) scanning. Surrounding adrenal cortical tissue contained an adenoma in one and nodular hyperplasia in the other. 4. Following removal of the adrenal gland containing the phaeochromocytoma, plasma and urinary adrenaline levels, and plasma aldosterone to plasma renin activity ratios returned to normal. 5. Adrenaline-only secreting phaeochromocytomas and primary aldosteronism have been rarely diagnosed even as separate entities, but reliable screening tests are now available. 6. Simultaneous presence of these two conditions of hormone excess is probably a chance occurrence. Alternatively, there may be a genetic predisposition to endocrine dysplasia, or an interaction between the contiguous medullary and cortical tissues, particularly after the normal architecture has been disturbed by an enlarging phaeochromocytoma.
Clinical and Experimental Pharmacology and Physiology 04/1994; 21(3):219-22. · 1.85 Impact Factor
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ABSTRACT: 1. Aldosterone levels in patients with unilateral aldosterone-producing adenomas may be responsive or unresponsive to the renin-angiotensin system, with the former often previously misdiagnosed as bilateral adrenal hyperplasia. 2. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals. 3. We compared the frequency of four renin gene polymorphisms in peripheral blood DNA from the two subgroups and found significant associations between BglI, TaqI and HinfI restriction fragment length polymorphisms (RFLP) and aldosterone responsiveness. 4. Allelic variation in the constitutive renin gene was associated with a specific cause of hypertension.
Clinical and Experimental Pharmacology and Physiology 04/1994; 21(3):215-8. · 1.85 Impact Factor
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Journal of hypertension. Supplement: official journal of the International Society of Hypertension 01/1994; 11(5):S302-3.
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Journal of hypertension. Supplement: official journal of the International Society of Hypertension 01/1994; 11(5):S222-3.
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Journal of hypertension. Supplement: official journal of the International Society of Hypertension 01/1994; 11(5):S310-1.
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ABSTRACT: Aldosterone-producing adenomas may be responsive or unresponsive to the renin-angiotensin system. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals. We compared the frequency of two renin gene polymorphisms in peripheral blood DNA from the two subgroups and found a significant association (allele frequency X2 = 7.67, p < 0.006) between BglI polymorphism and aldosterone responsiveness. This may be a significant determinant of the biochemical behaviour of these tumours.
Biochemical and Biophysical Research Communications 11/1993; 197(1):197-201. · 2.48 Impact Factor
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ABSTRACT: The responses of renin, aldosterone, and blood pressure to ACTH suppression with dexamethasone in a 61-yr-old man with glucocorticoid-suppressible hyperaldosteronism were modified by coexistent atheromatous renal artery stenosis (RAS). The apparent responsiveness of aldosterone to angiotensin-II resulting from RAS has implications for the regulation of steroidogenesis in this condition. After successful surgical correction of the RAS, the response changed and resembled that seen in two younger males (one his son) with uncomplicated glucocorticoid-suppressible hyperaldosteronism.
Journal of Clinical Endocrinology & Metabolism 10/1993; 77(3):800-4. · 6.50 Impact Factor
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ABSTRACT: Because familial hyperaldosteronism type II (FH-II) includes tumor formation, we examined the karyotypes of benign adrenocortical aldosterone-producing adenomas (APAs), including those from patients with FH-II. Cell culture was successful in 12 of 14 tumors removed, two of which were from patients with FH-II. Five of the 12 tumors cultured (one from a patient with FH-II) had abnormal karyotypes. All were from male patients, and loss of the Y chromosome was observed in each. One showed loss of chromosome 19, and another showed an unbalanced t(6;7) producing partial trisomy 7q. Oncogenes are present at these breakpoints, and loss of the Y chromosome and monosomy 19 have previously been reported in neoplasia. This is the first report of cytogenetic abnormalities in benign adrenocortical tumors.
Cancer Genetics and Cytogenetics 08/1993; 68(1):78-81. · 1.39 Impact Factor
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ABSTRACT: 1. In vitro short-term production of cortisol by dispersed tumour and non-tumourous adrenal cortical cells was measured with and without added angiotensin II (AII) or adrenocorticotrophin (ACTH) in adrenals removed from five patients with primary aldosteronism. 2. Aldosterone-producing adenomas (APA) were classified as angiotensin responsive (AII-R) or angiotensin unresponsive (AII-U) based on pre-operative behaviour in vivo. 3. Cortisol was produced by both tumour and cortex in vitro without stimulation, and significantly more cortisol was generated by the cortex. 4. Addition of AII significantly increased cortisol production by both tumour and cortex to an equal extent. 5. Addition of ACTH also significantly increased cortisol production by both tumour and cortex, but tumours were more responsive than cortex. The response to ACTH exceeded the response to angiotensin in both tumour and cortex. 6. There was no obvious difference between AII-R and AII-U APA in terms of cortisol production.
Clinical and Experimental Pharmacology and Physiology 06/1993; 20(5):292-5. · 1.85 Impact Factor
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ABSTRACT: 1. Six (12%) out of 52 respondents to newspaper advertisements for antihypertensive drug trials had elevated aldosterone to renin ratio, confirmed by repeated measurement. 2. Failure to suppress aldosterone with fludrocortisone acetate administration and oral salt loading confirmed the presence of primary aldosteronism in all six patients. 3. Two of the six patients have already had aldosterone-producing adenomas removed, one has commenced spironolactone, and one has an adrenal mass on computerized tomography but investigation is incomplete. 4. None of the six patients with primary aldosteronism had unprovoked hypokalaemia. 5. Plasma aldosterone levels did not distinguish those patients with subsequently proven primary aldosteronism from the others. Plasma renin activity (PRA) was a better discriminator, but not as good as the aldosterone to renin ratio. 6. The incidence of primary aldosteronism is probably much higher than the 1% currently quoted in texts, with earlier, normokalaemic forms accounting for the majority of cases.
Clinical and Experimental Pharmacology and Physiology 06/1993; 20(5):296-8. · 1.85 Impact Factor
