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Biomedical subjects

Richard D Gordon

Publications and source records attributed to Richard D Gordon.

17 recordsLinked to original sources
PubMed2006

Monogenic mineralocorticoid hypertension.

Monogenic mutations leading to excessive activation of the mineralocorticoid pathway result, almost always, in suppressed renin and hypertension in adult life and sometimes in hypokalaemia and alkalosis, which can be severe. In most of these syndromes, precise molecular changes in specific steroidogenic or effector genes have been identified, permitting appreciation of (1) pathophysiology, (2) great diversity of phenotype and (3) possibility of genetic methods of diagnosis. Yet to be achieved elucidation of the genetic basis of familial hyperaldosteronism type II, the most common and clinically significant of them, will enhance detection of primary aldosteronism, currently the commonest specifically treatable and potentially curable form of hypertension. While classic, complete-phenotype presentations of monogenic forms of mineralocorticoid hypertension are rarely recognised, more subtle genetic expression causing less florid manifestations could represent a significant proportion of so-called 'essential hypertension.'

Epithelial Sodium Channels↗
PubMed2005

Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I.

OBJECTIVES: To explore whether aldosterone excess can induce adverse cardiovascular effects independently of effects on blood pressure (BP), we sought evidence of disturbed cardiovascular structure or function in normotensive individuals with primary aldosteronism. METHODS: Eight normotensive subjects with genetically proven familial hyperaldosteronism type I (FH-I) were compared with 24 age- and sex-matched normotensive controls in terms of BP, biochemical parameters, pulse wave velocity, and echocardiographic characteristics. RESULTS: Subjects with FH-I demonstrated higher serum aldosterone levels and aldosterone/renin ratios than controls, as expected. Despite having similar 24-h ambulatory BPs, subjects with FH-I demonstrated evidence of concentric remodeling with greater septal (mean +/- sd, 9.4 +/- 1.1 vs. 7.9 +/- 0.9 mm; P < 0.001), posterior wall (9.2 +/- 1.7 vs. 7.7 +/- 1.0 mm; P < 0.01), and relative wall (0.29 +/- 0.03 vs. 0.24 +/- 0.02; P < 0.001) thicknesses, and lower mitral early peak velocities (0.74 +/- 0.10 vs. 0.90 +/- 0.16 m/sec; P < 0.05), ratios of early to late peak diastolic transmitral flow velocity (1.56 +/- 0.24 vs. 2.06 +/- 0.41; P < 0.01), and myocardial early peak velocities (8.3 +/- 1.8 vs. 10.3 +/- 2.6 cm/sec; P < 0.05). There were no significant differences in pulse wave velocity or left ventricular ejection fraction, long axis strain rate, peak systolic strain, cyclic variation of integrated backscatter, or posterior wall calibrated integrated backscatter. CONCLUSIONS: Aldosterone excess is associated with increased left ventricular wall thicknesses and reduced diastolic function, even in the absence of hypertension.

Adolescent↗
PubMed2005

Primary aldosteronism--actual epidemics or false alarm?

The prevalence of "primary aldosteronism" (PAL) cannot be precisely determined at this time, given 1) lack of a universally accepted definition, and 2) normotensive as well as normokalemic phases in the evolutionary development of a disease eventually characterized by hypertension and hypokalemia. The exception is fully genetically characterised forms such as glucocorticoid-suppressible hyperaldosteronism, the true prevalence of which could be proven today by universal screening using a single blood sample, but this is neither practical nor appropriate. Controversy has arisen regarding the rareness, or otherwise, of PAL because of 1) rediscovery in the last 12 years of the normokalemic phase described by Conn, 2) application of widely available methods for measurement of aldosterone and renin to "screening", 3) variable quality of these methods, and of their application, and 4) lack of the necessary "diagnostic", in addition to "screening", tests in some studies. PAL is significantly more common than previously thought, and a very important potentially curable form of hypertension. Early diagnosis and specific treatment avoids morbidity. The current focus on increased detection is essential, and will help to resolve the question of prevalence.

Humans↗
PubMed2005

Low renin hypertensive states: perspectives, unsolved problems, future research.

Some causes of low renin hypertension are familial with known genetic bases. One of them, primary aldosteronism, is specifically treatable by mineralocorticoid receptor blockers or by surgery, and has at least two different familial varieties. These have provided insights into its natural history, with long normotensive and normokalemic phases, and variable expression within the same family. Primary aldosteronism was considered rare, but recent work beginning in 1992 suggests that it might be the most common curable cause of hypertension, worth screening for in every hypertensive. Evidence is now compelling that inappropriate aldosterone for salt status can cause not only hypertension, but vascular inflammation and end-organ damage, preventable by mineralocorticoid receptor blockade.

Cardiology↗
PubMed2005

Plasma renin and aldosterone measurements in low renin hypertensive states.

Plasma renin concentrations are extremely low, requiring high sensitivity methods to detect low renin hypertensive states. Moreover, plasma prorenin must not cryoactivate to renin to avoid falsely high values. The enzyme kinetic plasma renin activity (PRA) test has the required sensitivity, whereas direct renin assays and PRA tests with short incubation times are usually not accurate enough. Test specificity is essential for plasma aldosterone. The Nichols Advantage aldosterone assay is fast and automated but requires great attention to quality control. Here, the impact of renin on the aldosterone:renin ratio as a screening test for primary aldosteronism is reviewed. A sensitive plasma renin test is essential for the diagnosis of low renin hypertensive states and, currently, can be consistently achieved only with the PRA radioimmunoassay.

Aldosterone↗
PubMed2005

Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity.

BACKGROUND: Familial hyperaldosteronism type II (FH-II) is characterized by the familial occurrence of primary aldosteronism; unlike FH-I, it is not glucocorticoid-remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Linkage to a 5-Mbp region of chromosome 7p22 was previously reported in an Australian family with eight affected members. Mutations in the exons or intron-exon boundaries of PRKAR1B (7p22, closely related to PRKAR1A, which is mutated in Carney complex) have been excluded in this family. OBJECTIVE: To refine the region of linkage, and to seek evidence of linkage in a South American family and in three other Australian families with FH-II, using seven closely spaced markers at 7p22. METHODS: To establish phenotypes (affected, uncertain or unaffected), blood pressure, plasma aldosterone and plasma renin (activity or concentration) were measured and the aldosterone: renin ratio (ARR) calculated. Individuals with consistently increased ARR underwent fludrocortisone suppression testing. The genotypes of the five pedigrees were analysed using seven closely spaced microsatellite markers at 7p22, and two-point and multipoint logarithm of odds (LOD) scores were calculated to assess linkage with FH-II. RESULTS: The combined multipoint LOD score for three families (the original Australian, the South American and a new Australian family) showing linkage at 7p22 was highly significant at 4.61 (theta = 0) for markers D7S462 and D7S517. A newly found recombination event in the first Australian family narrowed the area of linkage by 1.8 Mbp, permitting exclusion of approximately half the candidate genes in the originally reported locus. It was not possible to demonstrate linkage at the 7p22 region in the remaining two Australian families. CONCLUSION: This study provides further evidence for linkage of FH-II to 7p22, refines the locus, and supports the notion that FH-II may be genetically heterogeneous.

Aldosterone↗
PubMed2004

Primary aldosteronism--careful investigation is essential and rewarding.

Once considered rare, primary aldosteronism (PAL) is now regarded as the commonest potentially curable and specifically treatable form of hypertension. At Greenslopes Hospital Hypertension Unit (GHHU), the decision in 1991 to screen all (and not just hypokalemic or resistant) hypertensives by aldosterone/renin ratio (ARR) testing led to a 10-fold increase in detection rate of PAL and four-fold increase in removal rate of aldosterone-producing adenomas (APAs). The GHHU/Princess Alexandra Hospital Hypertension Unit PAL series stands at 977 patients and 250 APAs removed with hypertension cured in 50-60% (remainder improved). Reliable detection requires that interfering medications are withdrawn (or their effects considered) before ARR measurement, and reliable methods (such as fludrocortisone suppression testing) to confirm PAL. Adrenal venous sampling is the only dependable way to differentiate APA from bilateral adrenal hyperplasia. Genetic testing has facilitated detection of glucocorticoid-remediable, familial PAL. Identification of mutations causing the more common familial variety described by GHHU in 1991 should further aid in detection of PAL.

Adrenal Gland Diseases↗
PubMed2004

Genomic structure of the human gene for protein kinase A regulatory subunit R1-beta (PRKAR1B) on 7p22: no evidence for mutations in familial hyperaldosteronism type II in a large affected kindred.

OBJECTIVE: Familial hyperaldosteronism type II (FH-II) is characterized by inheritance of primary aldosteronism (PAL) but, unlike FH-I, is not glucocorticoid remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Analysis of two pedigrees previously demonstrated linkage of FH-II with a locus at chromosome 7p22. We sought to determine whether mutations in the exons or intron/exon boundaries in PRKAR1B (encoding protein kinase A regulatory subunit R1-beta), which resides within the linked locus, are associated with FH-II. METHODS: Primers enabling sequencing of all exons and intron/exon boundaries were designed by BLAT search using known mRNA sequence, and comparison with an orthologous mouse gene. Sequences from four affected and two unaffected subjects from an Australian family with FH-II demonstrating linkage at 7p22 were compared with published sequences. RESULTS: A probable two-nucleotide GenBank sequence error, resulting in an amino acid change, was detected. Two of seven single nucleotide polymorphisms (SNPs) identified were in exons and five in introns. Neither exon-localized SNP resulted in an amino acid change. All intron-localized SNPs were at least 16 nucleotides from the closest intron/exon boundary and therefore unlikely to interfere with gene splicing. Importantly, none of the identified SNPs was exclusively associated with affectation status. CONCLUSIONS: Mutations in the exons or intron/exon boundaries of PRKAR1B do not appear to be responsible for FH-II in this family, but a mutation in the promoter or remaining intronic or 5' or 3' untranslated regions could be. Alternatively, a mutation within another gene residing at the 7p22 locus may be responsible.

Adult↗
PubMed2004

Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.

Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3-6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28-50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.

Aldosterone↗
PubMed2003

Primary aldosteronism.

Approaching the fiftieth year since its original description, primary aldosteronism is now thought to be the commonest potentially curable and specifically treatable form of hypertension. Correct identification of patients with primary aldosteronism requires that the effects of time of day, posture, dietary sodium intake, potassium levels and medications on levels of aldosterone and renin be carefully considered. Accurate elucidation of the subtype is essential for optimal treatment, and adrenal venous sampling is the only reliable means of differentiating aldosterone-producing adenoma from bilateral adrenal hyperplasia. With genetic testing already available for one inherited form, making more cumbersome biochemical testing for that subtype virtually obsolete and bringing about improvements in treatment approach, an intense search is underway for genetic mutations causing other, more common familial varieties of primary aldosteronism.

Adrenal Gland Neoplasms↗
PubMed2003

High rate of detection of primary aldosteronism, including surgically treatable forms, after 'non-selective' screening of hypertensive patients.

BACKGROUND: Wide testing of the aldosterone : renin ratio among hypertensive individuals has revealed primary aldosteronism to be common, with most patients normokalaemic. Some investigators, however, have reported aldosterone-producing adenoma to be rare among patients so detected. OBJECTIVE: To test the hypothesis that differences among reported studies in the rate of detection of aldosterone-producing adenoma (as opposed to bilateral adrenal hyperplasia) reflect differences in the procedures used for diagnosis of primary aldosteronism, and the methods used to identify aldosterone-producing adenomas. METHODS: In the newly established Princess Alexandra Hospital Hypertension Unit (PAHHU), we used procedures developed by Greenslopes Hospital Hypertension Unit (which reports that more than 30% of patients with primary aldosteronism have aldosterone-producing adenomas) to diagnose primary aldosteronism and determine the subtype. All patients with an increased aldosterone : renin ratio (measured after correction for hypokalaemia and while the patient was not receiving interfering medications) underwent fludrocortisone suppression testing to confirm or exclude primary aldosteronism; if they were positive, they underwent genetic testing to exclude glucocorticoid-remediable aldosteronism before adrenal venous sampling was used to differentiate lateralizing from bilateral primary aldosteronism. RESULTS: This approach allowed PAHHU to diagnose, within 2 years, 54 patients [only seven (13%) hypokalaemic] with primary aldosteronism. All tested negative for glucocorticoid-remediable aldosteronism. Aldosterone production was lateralized to one adrenal in 15 patients (31%; only six hypokalaemic) and was bilateral in 34 (69%; all normokalaemic) of 49 patients who underwent adrenal venous sampling. Among patients with lateralizing adrenal hyperplasia, computed tomography revealed an ipsilateral mass in only six and a contralateral lesion in one. Fourteen patients underwent unilateral adrenalectomy, which cured the hypertension in seven and improved it in the remainder. In patients with bilateral primary aldosteronism, hypertension responded to spironolactone (12.5-50 mg/day) or amiloride (2.5-10 mg/day). CONCLUSION: When performed with careful regard to confounding factors, measurement of the aldosterone : renin ratio in all hypertensive individuals, followed by fludrocortisone suppression testing to confirm or exclude primary aldosteronism and adrenal venous sampling to determine the subtype, can result in the detection of significant numbers of patients with specifically treatable or potentially curable hypertension.

Adenoma↗