46 results on '"Freel EM"'
Search Results
2. Studies of Adrenal Gland Volume and Aldosterone Production in Normal Volunteers.
- Author
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Freel, EM, primary, McMillan, N, additional, Ingram, M, additional, Fraser, R, additional, and Connell, JM, additional
- Published
- 2010
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3. Hypertension
- Author
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McManus, F, primary, Freel, EM, additional, and Connell, JMC, additional
- Published
- 2007
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4. Modulation of iron-regulatory protein (IRP) activity in monocytes by nitric oxide, phorbol ester and J-interferon
- Author
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Bhandari S, Freel Em, and Jeremy H. Brock
- Subjects
Iron-Sulfur Proteins ,Lipopolysaccharides ,Deferoxamine ,Nitric Oxide ,Biochemistry ,Monocytes ,Phorbol ester ,Cell Line ,Nitric oxide ,Interferon-gamma ,Mice ,chemistry.chemical_compound ,Gamma interferon ,Receptors, Transferrin ,Animals ,Homeostasis ,Humans ,Regulation of gene expression ,omega-N-Methylarginine ,Macrophages ,Iron-Regulatory Proteins ,RNA-Binding Proteins ,Kinetics ,chemistry ,Ferritins ,Tetradecanoylphorbol Acetate - Published
- 1997
5. Aldosterone status associated with insulin resistance in patients with heart failure--data from the ALOFT study.
- Author
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Freel EM, Tsorlalis IK, Lewsey JD, Latini R, Maggioni AP, Solomon S, Pitt B, Connell JM, McMurray JJ, Freel, E M, Tsorlalis, I K, Lewsey, J D, Latini, R, Maggioni, A P, Solomon, S, Pitt, B, Connell, J M C, and McMurray, J J V
- Abstract
Background: Aldosterone has a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone "escapes" from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relation between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients.Methods: 302 patients with New York Heart Association (NYHA) class II-IV heart failure on conventional therapy were randomised in the ALiskiren Observation of heart Failure Treatment study (ALOFT), designed to test the safety of a directly acting renin inhibitor. Plasma aldosterone and 24-hour urinary aldosterone excretion, as well as fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Subjects with aldosterone escape and high urinary aldosterone were identified according to previously accepted definitions.Results: 20% of subjects demonstrated aldosterone escape and 34% had high urinary aldosterone levels. At baseline, there was a positive correlation between fasting insulin and plasma (r = 0.22 p<0.01) and urinary aldosterone(r = 0.19 p<0.03). Aldosterone escape and high urinary aldosterone subjects both demonstrated higher levels of fasting insulin (p<0.008, p<0.03), HOMA-IR (p<0.06, p<0.03) and insulin-glucose ratios (p<0.006, p<0.06) when compared to low aldosterone counterparts. All associations remained significant when adjusted for potential confounders.Conclusions: This study demonstrates a novel direct relation between aldosterone status and insulin resistance in heart failure. This observation merits further study and may identify an additional mechanism that contributes to the adverse clinical outcome associated with aldosterone escape. [ABSTRACT FROM AUTHOR]- Published
- 2009
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6. Pharmacogenetics: so near and yet so far?
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Freel EM
- Published
- 2010
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7. Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium.
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Hamblin R, Fountas A, Lithgow K, Loughrey PB, Bonanos E, Shinwari SK, Mitchell K, Shah S, Grixti L, Matheou M, Isand K, McLaren DS, Surya A, Ullah HZ, Klaucane K, Jayasuriya A, Bhatti S, Mavilakandy A, Ahsan M, Mathew S, Hussein Z, Jansz T, Wunna W, MacFarlane J, Ayuk J, Abraham P, Drake WM, Gurnell M, Brooke A, Baldeweg SE, Sam AH, Martin N, Higham C, Reddy N, Levy MJ, Ahluwalia R, Newell-Price J, Vamvakopoulos J, Krishnan A, Lansdown A, Murray RD, Pal A, Bradley K, Mamoojee Y, Purewal T, Panicker J, Freel EM, Hasan F, Kumar M, Jose B, Hunter SJ, and Karavitaki N
- Subjects
- Male, Female, Humans, Adult, Middle Aged, Retrospective Studies, Cohort Studies, United Kingdom epidemiology, Pituitary Neoplasms diagnostic imaging, Pituitary Neoplasms epidemiology, Pituitary Neoplasms complications, Adenoma diagnostic imaging, Adenoma epidemiology, Hypopituitarism complications
- Abstract
Objective: The optimal approach to the surveillance of non-functioning pituitary microadenomas (micro-NFPAs) is not clearly established. Our aim was to generate evidence on the natural history of micro-NFPAs to support patient care., Design: Multi-centre, retrospective, cohort study involving 23 endocrine departments (UK NFPA consortium)., Methods: Clinical, imaging, and hormonal data of micro-NFPA cases between January, 1, 2008 and December, 21, 2021 were analysed., Results: Data for 459 patients were retrieved [median age at detection 44 years (IQR 31-57)-152 males/307 females]. Four hundred and nineteen patients had more than two magnetic resonance imagings (MRIs) [median imaging monitoring 3.5 years (IQR 1.71-6.1)]. One case developed apoplexy. Cumulative probability of micro-NFPA growth was 7.8% (95% CI, 4.9%-8.1%) and 14.5% (95% CI, 10.2%-18.8%) at 3 and 5 years, respectively, and of reduction 14.1% (95% CI, 10.4%-17.8%) and 21.3% (95% CI, 16.4%-26.2%) at 3 and 5 years, respectively. Median tumour enlargement was 2 mm (IQR 1-3) and 49% of micro-NFPAs that grew became macroadenomas (nearly all >5 mm at detection). Eight (1.9%) patients received surgery (only one had visual compromise with surgery required >3 years after micro-NFPA detection). Sex, age, and size at baseline were not predictors of enlargement/reduction. At the time of detection, 7.2%, 1.7%, and 1.5% patients had secondary hypogonadism, hypothyroidism, and hypoadrenalism, respectively. Two (0.6%) developed hypopituitarism during follow-up (after progression to macroadenoma)., Conclusions: Probability of micro-NFPA growth is low, and the development of new hypopituitarism is rare. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of tumour growth or clinical manifestations is a safe approach for micro-NFPA surveillance., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)
- Published
- 2023
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8. Management of hypertensive emergencies and urgencies: narrative review.
- Author
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Jolly H, Freel EM, and Isles C
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- Humans, Emergencies, Blood Pressure, Hypertension, Malignant, Hypertension, Acute Coronary Syndrome
- Abstract
Hypertensive emergencies are distinguished from hypertensive urgencies by the presence of clinical or laboratory target organ damage. The most common forms of target organ damage in developed countries are pulmonary oedema/heart failure, acute coronary syndrome, ischaemic and haemorrhagic stroke. In the absence of randomised trials, it is inevitable that guideline writers differ slightly regarding the speed and extent to which blood pressure should be lowered acutely. An appreciation of cerebral autoregulation is key and should underpin treatment decisions. Hypertensive emergencies, with the notable exception of uncomplicated malignant hypertension, require intravenous antihypertensive medication which is most safely given in high dependency or intensive care settings. Patients with hypertensive urgency are often treated with medications that lower their blood pressure acutely, although there is no evidence to support this practice. This article aims to review current guidelines and recommendations, and to provide user friendly management strategies for the general physician., (© The Author(s) 2021. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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9. Management of hypertensive emergencies and urgencies: narrative review.
- Author
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Jolly H, Freel EM, and Isles C
- Abstract
Hypertensive emergencies are distinguished from hypertensive urgencies by the presence of clinical or laboratory target organ damage. The most common forms of target organ damage in developed countries are pulmonary oedema/heart failure, acute coronary syndrome, ischaemic and haemorrhagic stroke. In the absence of randomised trials, it is inevitable that guideline writers differ slightly regarding the speed and extent to which blood pressure should be lowered acutely. An appreciation of cerebral autoregulation is key and should underpin treatment decisions. Hypertensive emergencies, with the notable exception of uncomplicated malignant hypertension, require intravenous antihypertensive medication which is most safely given in high dependency or intensive care settings. Patients with hypertensive urgency are often treated with medications that lower their blood pressure acutely, although there is no evidence to support this practice. This article aims to review current guidelines and recommendations, and to provide user friendly management strategies for the general physician., (© The Author(s) 2021. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
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10. Evaluating transition in Turner syndrome in the West of Scotland.
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Zahra B, Lyall H, Sastry A, Freel EM, Dominiczak AF, and Mason A
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- Adolescent, Cohort Studies, Databases, Factual, Delivery of Health Care, Endocrinologists, Female, Follow-Up Studies, Humans, Patient Compliance, Scotland epidemiology, Young Adult, Transition to Adult Care statistics & numerical data, Turner Syndrome epidemiology
- Abstract
Background: A Turner Syndrome (TS) Transition clinic, Royal Hospital for Children Glasgow (RHCG), with paediatric and adult endocrinology/gynaecology teams was established in 1998 with an aim of improving health outcomes in TS throughout the lifespan., Objective: To evaluate the success of our TS transition service, focussing on evaluating established follow-up after transfer to adult services., Methods: Girls attending the TS Transition clinic at Royal Hospital for Children Glasgow, 1998-2017, were identified. Attendance data were obtained from patient records and an electronic appointment system. We assessed good and late early attendance in our cohort of TS patients as well as established endocrine follow-up, defined as those still attending adult endocrine services 3 years after transfer. Success of TS transition was determined by the proportion of girls in established endocrine follow-up., Results: Forty-six girls (median age 18.3 yrs) were identified. Thirty-six, 36/46 girls transferred prior to 2015 and 26 of those (72%) were in established follow-up at 3 years, 22/36 girls had met with an Adult specialist prior to transfer and 14/36 had not met with an adult specialist prior to transfer. Twenty-one (80.7%) were good early attenders (p = 0.10). In the early attenders' cohort, there was no significant difference between those that had and had not met an adult specialist prior to transfer., Conclusion: A significant proportion of girls with TS are currently lost to endocrine follow-up following transfer to adult clinics. Early attendance at an adult clinic appears to predict established long-term follow-up. Strategies to improve early attendance and long-term endocrine follow-up are needed to ensure lifelong health needs are addressed., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)
- Published
- 2021
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11. Turner Syndrome.
- Author
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Freel EM and Mason A
- Subjects
- Blood Pressure, Estradiol, Female, Humans, Turner Syndrome
- Published
- 2019
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12. Non-uniform relationship between salt status and aldosterone activity in patients with chronic kidney disease.
- Author
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Taylor AHM, Rankin AJ, McQuarrie EP, Freel EM, Homer NZM, Andrew R, Jardine AG, and Mark PB
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- Adult, Aged, Angiotensin II administration & dosage, Blood Pressure drug effects, Blood Pressure physiology, Cross-Over Studies, Humans, Hypertension blood, Hypertension physiopathology, Middle Aged, Renal Insufficiency, Chronic blood, Renin-Angiotensin System drug effects, Renin-Angiotensin System physiology, Vasoconstrictor Agents administration & dosage, Young Adult, Aldosterone blood, Diet, Sodium-Restricted, Renal Insufficiency, Chronic physiopathology, Sodium Chloride, Dietary administration & dosage
- Abstract
Background: Hypertension is prevalent in chronic kidney disease (CKD). Studies suggest that reduction in dietary salt intake reduces blood pressure (BP). We studied relationships between salt intake, BP and renin-angiotensin system regulation in order to establish if it is disordered in CKD., Methods: Mechanistic crossover study of CKD patients versus non-CKD controls. Participants underwent modified saline suppression test prior to randomization to either low or high salt diet for 5 days and then crossed over to the alternate diet. Angiotensin-II stimulation testing was performed in both salt states. BP, urea and electrolytes, and plasma aldosterone concentration (PAC) were measured., Results: Twenty-seven subjects were recruited (12 CKD, 15 control). There was no difference in age and baseline BP between the groups. Following administration of intravenous saline, systolic BP increased in CKD but not controls (131 ± 16 to 139 ± 14 mmHg, P =0.016 vs 125 ± 20 to 128 ± 22 mmHg, P =0.38). Median PAC reduced from 184 (124,340) to 95 (80,167) pmol in controls ( P =0.003), but failed to suppress in CKD (230 (137,334) to 222 (147,326) pmol ( P =0.17)). Following dietary salt modification, there was no change in BP in either group. Median PAC was lower following high salt compared with low salt diet in CKD and controls. There was a comparable increase in systolic BP in response to angiotensin-II in both groups., Discussion: We demonstrate dysregulation of aldosterone in CKD in response to salt loading with intravenous saline, but not to dietary salt modification., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2018
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13. Primary Aldosteronism or Not Primary Aldosteronism: Is This Now the Question in Normotension?
- Author
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Freel EM
- Subjects
- Blood Pressure, Humans, Hypertension, Aldosterone, Hyperaldosteronism
- Published
- 2017
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14. ACTH and Polymorphisms at Steroidogenic Loci as Determinants of Aldosterone Secretion and Blood Pressure.
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MacKenzie SM, Freel EM, Connell JM, Fraser R, and Davies E
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- Adrenocorticotropic Hormone blood, Animals, Cytochrome P-450 CYP11B2 genetics, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Hypertension genetics, Hypertension metabolism, Hypertension physiopathology, Steroid 11-beta-Hydroxylase genetics, Steroid 17-alpha-Hydroxylase genetics, Adrenocorticotropic Hormone genetics, Aldosterone metabolism, Blood Pressure physiology, Polymorphism, Genetic, Quantitative Trait Loci
- Abstract
The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by data from genome-wide association studies that consistently link the CYP17A1 locus to blood pressure. In this review article, we describe common polymorphisms at three steroidogenic loci (CYP11B2, CYP11B1 and CYP17A1) that alter gene transcription efficiency and levels of key steroids, including aldosterone. However, the mechanism by which this occurs remains unclear. While the renin angiotensin system is rightly regarded as the major driver of aldosterone secretion, there is increasing evidence that the contribution of corticotropin (ACTH) is also significant. In light of this, we propose that the differential response of variant CYP11B2, CYP11B1 and CYP17A1 genes to ACTH is an important determinant of blood pressure, tending to predispose individuals with an unfavourable genotype to hypertension.
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- 2017
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15. Common Polymorphisms at the CYP17A1 Locus Associate With Steroid Phenotype: Support for Blood Pressure Genome-Wide Association Study Signals at This Locus.
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Diver LA, MacKenzie SM, Fraser R, McManus F, Freel EM, Alvarez-Madrazo S, McClure JD, Friel EC, Hanley NA, Dominiczak AF, Caulfield MJ, Munroe PB, Connell JM, and Davies E
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- Adult, Aged, Aldosterone metabolism, Alleles, Blood Pressure genetics, Cohort Studies, Female, Healthy Volunteers, Humans, Locus Control Region genetics, Male, Middle Aged, Phenotype, Reference Values, Gene Expression Regulation, Genome-Wide Association Study, Hypertension genetics, Polymorphism, Single Nucleotide genetics, Steroid 11-beta-Hydroxylase genetics, Steroid 17-alpha-Hydroxylase genetics
- Abstract
Genome-wide association studies implicate the CYP17A1 gene in human blood pressure regulation although the causative polymorphisms are as yet unknown. We sought to identify common polymorphisms likely to explain this association. We sequenced the CYP17A1 locus in 60 normotensive individuals and observed 24 previously identified single-nucleotide polymorphisms with minor allele frequency >0.05. From these, we selected, for further studies, 7 polymorphisms located ≤ 2 kb upstream of the CYP17A1 transcription start site. In vitro reporter gene assays identified 3 of these (rs138009835, rs2150927, and rs2486758) as having significant functional effects. We then analyzed the association between the 7 polymorphisms and the urinary steroid metabolites in a hypertensive cohort (n=232). Significant associations included that of rs138009835 with aldosterone metabolite excretion; rs2150927 associated with the ratio of tetrahydrodeoxycorticosterone to tetrahydrodeoxycortisol, which we used as an index of 17α-hydroxylation. Linkage analysis showed rs138009835 to be the only 1 of the 7 polymorphisms in strong linkage disequilibrium with the blood pressure-associated polymorphisms identified in the previous studies. In conclusion, we have identified, characterized, and investigated common polymorphisms at the CYP17A1 locus that have functional effects on gene transcription in vitro and associate with corticosteroid phenotype in vivo. Of these, rs138009835--which we associate with changes in aldosterone level--is in strong linkage disequilibrium with polymorphisms linked by genome-wide association studies to blood pressure regulation. This finding clearly has implications for the development of high blood pressure in a large proportion of the population and justifies further investigation of rs138009835 and its effects., (© 2016 The Authors.)
- Published
- 2016
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16. Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-meta-iodobenzylguanidine therapy in a tertiary referral centre.
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Rutherford MA, Rankin AJ, Yates TM, Mark PB, Perry CG, Reed NS, and Freel EM
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- 3-Iodobenzylguanidine adverse effects, Adolescent, Adrenal Gland Neoplasms secondary, Adult, Aged, Disease Management, Female, Genetic Testing, Humans, Male, Middle Aged, Paraganglioma metabolism, Pheochromocytoma metabolism, Radiopharmaceuticals adverse effects, Retrospective Studies, Tertiary Care Centers, Treatment Outcome, Young Adult, 3-Iodobenzylguanidine administration & dosage, Adrenal Gland Neoplasms radiotherapy, Paraganglioma radiotherapy, Pheochromocytoma radiotherapy, Radiopharmaceuticals administration & dosage
- Abstract
Background: Phaeochromocytoma (phaeo) and paraganglioma (PGL) are rare conditions, which are malignant in up to 30%. Optimal treatment is controversial, but in patients with metastatic iodine-131-meta-iodobenzylguanidine ((123)I-MIBG) avid tumours, we offer (131)I-MIBG therapy. We summarize response rates, survival and safety in a cohort of such patients treated with (131)I-MIBG in our centre from 1986 to 2012., Design/methods: Retrospective analysis of the case notes of patients with metastatic phaeo/PGL who received (131)I-MIBG was undertaken; patients underwent clinical, biochemical and radiological evaluation within 6 months of each course of (131)I-MIBG therapy., Results: Twenty-two patients (9 males) were identified, 12 with metastatic PGL and 10 with phaeo. Overall median follow-up time after first dose of (131)I-MIBG was 53 months. In total, 68 doses of (131)I-MIBG were administered; average dose was 9967 MBq (269.4 mCi). After the first dose, >50% of patients demonstrated disease stability or partial response; progressive disease was seen in 9%. A subset of patients underwent repeated treatment with the majority demonstrating partial response or stable disease. No life-threatening adverse events were reported, but three patients developed hypothyroidism and two developed ovarian failure after repeated dosing. Five-year survival after original diagnosis was 68% and median (+inter quartile range) survival from date of diagnosis was 17 years (7.6-26.4) with no difference in survival according to diagnosis (P < 0.1)., Conclusions: (131)I-MIBG is well tolerated and associates with disease stabilization or improvement in the majority of patients with metastatic phaeo/PGL. However, stronger conclusions on treatment effectiveness are limited by lack of a directly comparable 'control group' as well as an alternative 'gold standard' treatment., (© The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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17. Plasma steroid profiling and response to trophins to illustrate intra-adrenal dynamics.
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McManus F, Fraser R, Davies E, Connell JM, and Freel EM
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- Adolescent, Adult, Aged, Blood Pressure drug effects, Blood Pressure physiology, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Sodium Chloride, Dietary administration & dosage, Adrenal Cortex drug effects, Adrenal Cortex metabolism, Adrenal Cortex Hormones blood, Adrenocorticotropic Hormone administration & dosage, Angiopoietin-2 administration & dosage
- Abstract
The importance of corticosteroids in cardiovascular and other chronic disease is recognised. In addition, plasma steroid precursor-to-product ratios are useful and convenient indirect indicators of efficiency of key steroidogenic enzymes (aldosterone synthase, 11β-hydroxylase and 17α-hydroxylase). The use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has enabled measurement of numerous corticosteroid compounds simultaneously. However, normal responses to trophins and variation in salt intake are not well described. This study examined these parameters in a large group of healthy volunteers. Sixty normotensive volunteers were recruited and underwent infusion of angiotensin II (AngII) and ACTH, following low- and high-salt diet. Measurement of plasma steroids at baseline and 30 min after infusion of trophin was carried out by LC-MS. As expected, plasma mineralocorticoid levels increased in response to salt restriction and were suppressed with salt loading; ACTH infusion increased all corticosteroids, while AngII increased mineralocorticoids and suppressed glucocorticoid production. ACTH increased S:F but decreased DOC:B, thus the S:F ratio is a more appropriate index of 11β-hydroxylase efficiency. The B:F ratio increased following ACTH treatment and salt restriction. A larger proportion of plasma B than generally accepted may be derived from the zona glomerulosa and this ratio may be most informative of 17α-hydroxylase activity in salt-replete subjects. Although DOC:aldosterone, B:aldosterone and 18-hydroxyB:aldosterone should provide indices of aldosterone synthase efficiency, responses of individual compounds to trophins suggest that none of them accurately reflect this. Based on these data, aldosterone synthase activity is most accurately reflected by aldosterone concentration alone., (© 2015 Society for Endocrinology.)
- Published
- 2015
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18. Rare cause of severe hypertension in a young woman.
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Perry CG, Freel EM, O'Dwyer P, Schiffrin EL, Jennings GL, Dominiczak AF, and De Buyzere M
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- Adrenal Gland Neoplasms diagnosis, Adrenal Gland Neoplasms therapy, Combined Modality Therapy, Diagnosis, Differential, Female, Humans, Hypertension diagnosis, Hypertension physiopathology, Pheochromocytoma diagnosis, Pheochromocytoma therapy, Severity of Illness Index, Tomography, X-Ray Computed, Young Adult, Adrenal Gland Neoplasms complications, Blood Pressure physiology, Hypertension etiology, Pheochromocytoma complications
- Published
- 2015
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19. Adrenal vein sampling: is there now a consensus?
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Freel EM
- Subjects
- Consensus, Humans, Veins, Adrenal Glands blood supply, Aldosterone blood, Hyperaldosteronism diagnosis, Practice Guidelines as Topic standards
- Published
- 2015
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20. An unusual cause of mineralocorticoid hypertension.
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Freel EM, Perry CG, O'Dwyer P, Staessen JA, Jennings GL, Granger JP, De Buyzere M, and Schiffrin EL
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- Adrenal Cortex Neoplasms complications, Adrenal Cortex Neoplasms diagnosis, Adrenal Cortex Neoplasms surgery, Adrenocortical Carcinoma complications, Adrenocortical Carcinoma diagnosis, Adrenocortical Carcinoma surgery, Adult, Diagnosis, Differential, Humans, Hypertension etiology, Hypokalemia diagnosis, Hypokalemia etiology, Hypokalemia metabolism, Male, Treatment Outcome, Hypertension diagnosis, Hypertension metabolism, Mineralocorticoids metabolism
- Published
- 2014
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21. Association between urinary sodium, creatinine, albumin, and long-term survival in chronic kidney disease.
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McQuarrie EP, Traynor JP, Taylor AH, Freel EM, Fox JG, Jardine AG, and Mark PB
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- Adult, Aged, Aged, 80 and over, Albuminuria complications, Albuminuria mortality, Disease Progression, Female, Humans, Kidney physiopathology, Male, Middle Aged, Renal Insufficiency, Chronic complications, Albuminuria urine, Creatinine urine, Renal Insufficiency, Chronic mortality, Renal Insufficiency, Chronic urine, Sodium urine
- Abstract
Dietary sodium intake is associated with hypertension and cardiovascular risk in the general population. In patients with chronic kidney disease, sodium intake has been associated with progressive renal disease, but not independently of proteinuria. We studied the relationship between urinary sodium (UNa) excretion and UNa to creatinine ratio and mortality or requirement for renal replacement therapy in chronic kidney disease. Adult patients attending a renal clinic who had ≥1 24-hour UNa measurement were identified. Twenty-four-hour UNa measures were collected and UNa to creatinine ratio calculated. Time to renal replacement therapy or death was recorded. Four hundred twenty-three patients were identified with mean estimated glomerular filtration rate of 48 mL/min per 1.73 m(2). Ninety patients required renal replacement therapy and 102 patients died. Mean slope decline in estimated glomerular filtration rate was -2.8 mL/min per 1.73 m(2) per year. Median follow-up was 8.5 years. Patients who died or required renal replacement therapy had significantly higher UNa excretion and UNa to creatinine ratio, but the association with these parameters and poor outcome was not independent of renal function, age, and albuminuria. When stratified by albuminuria, UNa to creatinine ratio was a significant cumulative additional risk for mortality, even in patients with low-level albuminuria. There was no association between low UNa and risk, as observed in some studies. This study demonstrates an association between UNa excretion and mortality in chronic kidney disease, with a cumulative relationship between sodium excretion, albuminuria, and reduced survival. These data support reducing dietary sodium intake in chronic kidney disease, but additional study is required to determine the target sodium intake., (© 2014 American Heart Association, Inc.)
- Published
- 2014
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22. Response to Effect of serum chloride on mortality in hypertensive patients.
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McCallum L, Jeemon P, Hastie CE, Patel RK, Williamson C, Redzuan AM, Dawson J, Sloan W, Muir S, Morrison D, McInnes GT, Freel EM, Walters M, Dominiczak AF, Sattar N, and Padmanabhan S
- Subjects
- Female, Humans, Male, Chlorides blood, Hypertension blood, Hypertension mortality
- Published
- 2014
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23. Alterations in vascular function in primary aldosteronism: a cardiovascular magnetic resonance imaging study.
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Mark PB, Boyle S, Zimmerli LU, McQuarrie EP, Delles C, and Freel EM
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- Age Factors, Aged, Blood Pressure, Case-Control Studies, Compliance, Cross-Sectional Studies, Female, Humans, Hypertension diagnosis, Hypertension physiopathology, Male, Manometry, Middle Aged, Predictive Value of Tests, Prognosis, Pulse Wave Analysis, Risk Factors, Vascular Diseases diagnosis, Vascular Diseases physiopathology, Ventricular Function, Left, Aorta physiopathology, Hyperaldosteronism complications, Magnetic Resonance Imaging, Cine, Vascular Diseases etiology, Vascular Stiffness
- Abstract
Excess aldosterone is associated with increased cardiovascular risk. Aldosterone has a permissive effect on vascular fibrosis. Cardiovascular magnetic resonance imaging (CMR) allows study of vascular function by measuring aortic distensibility. We compared aortic distensibility in primary aldosteronism (PA), essential hypertension (EH) and normal controls and explored the relationship between aortic distensibility and pulse wave velocity (PWV). We studied PA (n=14) and EH (n=33) subjects and age-matched healthy controls (n=17) with CMR, including measurement of aortic distensibility, and measured PWV using applanation tonometry. At recruitment, PA and EH patients had similar blood pressure and left ventricular mass. Subjects with PA had significantly lower aortic distensibility and higher PWV compared with EH and healthy controls. These changes were independent of other factors associated with reduced aortic distensibility, including ageing. There was a significant relationship between increasing aortic stiffness and age in keeping with physical and vascular ageing. As expected, aortic distensibility and PWV were closely correlated. These results demonstrate that PA patients display increased arterial stiffness compared with EH, independent of vascular ageing. The implication is that aldosterone invokes functional impairment of arterial function. The long-term implications of arterial stiffening in aldosterone excess require further study.
- Published
- 2014
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24. Serum chloride is an independent predictor of mortality in hypertensive patients.
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McCallum L, Jeemon P, Hastie CE, Patel RK, Williamson C, Redzuan AM, Dawson J, Sloan W, Muir S, Morrison D, McInnes GT, Freel EM, Walters M, Dominiczak AF, Sattar N, and Padmanabhan S
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Scotland epidemiology, Sodium Chloride, Dietary, Chlorides blood, Hypertension blood, Hypertension mortality
- Abstract
Chloride (Cl-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary Cl- intake increases blood pressure, yet paradoxically, higher serum Cl- appears associated with lower mortality and cardiovascular risk. This implies that serum Cl- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12,968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl- was an independent predictor of mortality. To distinguish the effect of Cl- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+ /HCO3- and Cl- levels. Generalized estimating equation was used to determine the effect of baseline Cl- on follow-up blood pressure. The total time at risk was 19,7101 person-years. The lowest quintile of serum Cl- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+ , and HCO3- levels. The group with Na+ > 135 and Cl- > 100 had the best survival, and compared with this group, the Na+ >135 and Cl- <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.
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- 2013
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25. Assessment of the accuracy and reproducibility of adrenal volume measurements using MRI and its relationship with corticosteroid phenotype: a normal volunteer pilot study.
- Author
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Freel EM, Nicholas RS, Sudarshan T, Priba L, Gandy SJ, McMillan N, Houston JG, and Connell JM
- Subjects
- Adult, Healthy Volunteers, Humans, Male, Middle Aged, Multivariate Analysis, Observer Variation, Pilot Projects, Regression Analysis, Reproducibility of Results, Adrenal Cortex Hormones blood, Adrenal Glands anatomy & histology, Blood Pressure physiology, Magnetic Resonance Imaging methods
- Abstract
Objective: The significant role of corticosteroids in hypertension and cardiovascular disease highlights the importance of the adrenal gland in these disorders. The ability to correlate corticosteroid production with adrenal volume offers a novel research tool and intermediate phenotype in cardiovascular disease. The aim of this study was to develop and validate the use of magnetic resonance imaging (MRI) in adrenal volume assessment and investigate whether this associates with corticosteroid production., Design/methods: Twenty normotensive men underwent noncontrast 1·5T MRI scanning of adrenals, measurement of blood pressure and plasma corticosteroids. Left adrenal volume was calculated twice using standard segmentation software by four independent observers with differing levels of clinical expertise and segmentation experience. To optimize this process, adrenal 'phantoms' with known fixed volumes underwent MRI scanning and analysis by two observers., Results: Intra-observer coefficients of repeatability (CoRs) in phantoms ranged from 0·23 to 0·43 ml (interobserver CoR 0·48 ml). In the subject group, mean adrenal volumes were 3·99-5·82 ml with intra-observer CoRs 0·27-1·94 ml. Interobserver variability was 2·73 ml. Segmentation expertise was the main factor affecting variability, with experienced observers having the lowest CoRs; clinical knowledge was a factor when combined with segmentation experience. Mean adrenal volume correlated with plasma glucocorticoids (r = 0·523, P < 0·05) and aldosterone (r = 0·515, P < 0·05) for the most experienced observer only., Conclusions: Measurement of adrenal volume using MRI is challenging; most accurate volumes are achieved using a single observer with both segmentation experience and anatomical knowledge. The data also provide novel preliminary evidence that adrenal gland volume may be associated with plasma corticosteroid concentrations supporting further study of adrenal volume and steroid production across a range of blood pressures., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
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26. Urinary sodium excretion is the main determinant of mineralocorticoid excretion rates in patients with chronic kidney disease.
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McQuarrie EP, Freel EM, Mark PB, Fraser R, Connell JM, and Jardine AG
- Subjects
- Aldosterone urine, Cohort Studies, Corticosterone urine, Cross-Sectional Studies, Essential Hypertension, Female, Gas Chromatography-Mass Spectrometry, Glomerular Filtration Rate, Humans, Male, Middle Aged, Prognosis, Aldosterone analogs & derivatives, Corticosterone analogs & derivatives, Hypertension urine, Mineralocorticoids urine, Renal Insufficiency, Chronic urine, Sodium urine
- Abstract
Background: Blockade of the mineralocorticoid receptor (MR) in patients with chronic kidney disease (CKD) improves surrogate cardiovascular outcomes, such as left ventricular mass. Animal models of renal disease support a pathological role of mineralocorticoids, in the context of a high sodium intake. We aimed to assess the regulation of mineralocorticoid biosynthesis in patients with CKD., Methods: Seventy patients with CKD stages 3/4 and 30 patients with essential hypertension (EH) were recruited. Patients underwent detailed clinical phenotyping, drug history and biochemical assessment. Patients completed a 24-h urine collection for measurement of urinary tetrahydroaldosterone (THALDO) and tetrahydrocorticosterone (THDOC) excretion rates (measured using gas chromatography-mass spectrometry) and urinary electrolytes. The factors which correlated significantly with THALDO and THDOC excretion were entered into linear regression models., Results: Patients with EH and CKD were well matched with no significant differences in gender, age or weight. The mean estimated glomerular filtration rate (eGFR) in CKD patients was 38.6/min/1.73 m(2). The mean urinary excretion rates of THALDO, THDOC and 24-h urinary sodium (24-h USod) were not significantly different between CKD and EH patients. The level of renal function did not correlate with THALDO or THDOC excretion. In patients with CKD, 24-h USodium (r = 0.614, P < 0.001) and 24-h UPotassium (r = 0.538, P < 0.001) were positively correlated with THALDO excretion. On multivariate linear regression analysis, 24-h USod was the strongest independent predictor (P = 0.004) of THALDO and THDOC excretion in CKD. In patients with EH, no relationship was seen between mineralocorticoid excretion and 24-h urinary sodium excretion., Conclusions: In patients with CKD, 24-h urinary sodium excretion is the strongest positive predictor of urinary mineralocorticoid excretion. The nature of this relationship is unexpected, novel, not seen in patients with EH and may explain the association seen between high urinary sodium excretion, mineralocorticoids and poor outcomes in patients with CKD.
- Published
- 2013
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27. Aldosterone, vascular endothelial growth factor, and preeclampsia: a mystery solved?
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Delles C and Freel EM
- Subjects
- Animals, Female, Humans, Aldosterone metabolism, Pre-Eclampsia metabolism, Pregnancy metabolism, Renin-Angiotensin System physiology, Vascular Endothelial Growth Factor A metabolism
- Published
- 2013
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28. Demonstration of blood pressure-independent noninfarct myocardial fibrosis in primary aldosteronism: a cardiac magnetic resonance imaging study.
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Freel EM, Mark PB, Weir RA, McQuarrie EP, Allan K, Dargie HJ, McClure JD, Jardine AG, Davies E, and Connell JM
- Subjects
- Cardiomyopathies diagnosis, Cardiomyopathies physiopathology, Female, Fibrosis diagnosis, Fibrosis etiology, Humans, Hyperaldosteronism physiopathology, Male, Middle Aged, Blood Pressure, Cardiomyopathies etiology, Hyperaldosteronism complications, Magnetic Resonance Imaging, Cine methods, Myocardium pathology
- Abstract
Background: Primary aldosteronism (PA) is common and associates with excess cardiovascular morbidity independent of blood pressure. Exposure to aldosterone and sodium leads to cardiac fibrosis and hypertrophy in humans and animals possibly mediated by inflammation and oxidative stress. We aimed to clarify the effects of aldosterone excess on myocardial structure and composition in human subjects with PA and essential hypertension using contrast-enhanced cardiac magnetic resonance imaging as well as explore the mechanistic basis for any observed differences., Methods and Results: Twenty-seven subjects with recently diagnosed PA and 54 essential hypertension controls were recruited. Subjects underwent gadolinium-enhanced cardiac magnetic resonance; noninfarct related myocardial fibrosis was identified by a diffuse pattern of late gadolinium enhancement. Patients also underwent assessment of pulse wave velocity, measurement of circulating superoxide anion and C-reactive protein, as well as blood pressure and biochemical assessment. Subjects were well matched with no difference in severity or duration of hypertension. There was a significant increase in the frequency of noninfarct late gadolinium enhancement in PA (70%) when compared with essential hypertension subjects (13%; P<0.0001) with no difference in left ventricular mass. Pulse wave velocity, superoxide, and C-reactive protein were significantly higher in subjects with PA., Conclusions: These data illustrate that patients with PA exhibit frequent myocardial fibrosis as demonstrated by late gadolinium enhancement using cardiac magnetic resonance imaging; this finding is independent of blood pressure. This may be mediated partly through inflammation and oxidative stress. This study highlights the importance of specific targeting of aldosterone excess as well as blood pressure reduction to minimize cardiac morbidity in PA.
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- 2012
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29. Urinary free (unconjugated) metadrenalines in different hereditary forms of catecholamine-secreting phaeochromocytoma/paraganglioma.
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Davidson DF, Bradshaw N, Perry CG, Lindsay R, and Freel EM
- Subjects
- Adolescent, Adrenal Gland Neoplasms genetics, Adult, Child, Clinical Chemistry Tests, Female, Humans, Male, Middle Aged, Paraganglioma genetics, Pheochromocytoma genetics, Recurrence, Retrospective Studies, Adrenal Gland Neoplasms urine, Catecholamines urine, Metanephrine urine, Paraganglioma urine, Pheochromocytoma urine
- Abstract
Background: Catecholamine-producing neuroendocrine tumours are found in chromaffin cells of the adrenal medulla (phaeochromocytoma) or extra-adrenal paraganglia (paraganglioma), known collectively as PPGLs. In approximately a quarter or more of cases of PPGL, these rare tumours arise as a result of germline mutations of several tumour susceptibility genes. At the Crosshouse laboratory, urine tests include free metadrenalines (fMAs) (also known as free metanephrines) which demonstrate superior sensitivity over that obtained by urinary vanillyl mandelic acid, catecholamines or plasma catecholamines in the diagnosis of PPGL. This retrospective audit was to determine if urinary fMAs offered discrimination among the hereditary forms of PPGL., Methods: Retrospective biochemical and genetic data were gathered from 1997 to 2011. The identified urine specimens were those obtained at the time of first diagnosis or recurrence of PPGL. Results of catecholamines and metabolites were standardized as multiples of their respective relevant upper reference limits (URLs)., Results: Results were available for 29 affected patients (15 females and 14 males), median age 26 (range 9-63) years, comprising three mutation groups: succinate dehydrogenase subunit B or D ([SDHB/D] 16 patients), multiple endocrine neoplasia type 2 ([MEN 2] 6 patients) and von Hippel-Lindau disease ([VHL] 7 patients). The parent catecholamines exhibited increased values for noradrenaline (NA) and/or adrenaline (AD) for 25/29 (86.2%) patients. Either or both free normetadrenaline (fNMA) and fMA were elevated in 29/29 (100%) patients., Conclusions: The ratio of the multiples of URL for fMA/fNMA displayed a clearer separation of MEN 2 patients from those with SDHB/D or VHL than did the equivalent AD/NA ratio.
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- 2012
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30. Urinary corticosteroid excretion predicts left ventricular mass and proteinuria in chronic kidney disease.
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McQuarrie EP, Freel EM, Mark PB, Fraser R, Patel RK, Dargie HG, Connell JM, and Jardine AG
- Subjects
- Aged, Aldosterone urine, Biomarkers urine, Cross-Sectional Studies, Desoxycorticosterone urine, Female, Gas Chromatography-Mass Spectrometry, Humans, Hypertension complications, Hypertension urine, Hypertrophy, Left Ventricular urine, Linear Models, Magnetic Resonance Imaging, Male, Middle Aged, Multivariate Analysis, Proteinuria urine, Renal Insufficiency, Chronic urine, Sex Factors, Aldosterone analogs & derivatives, Desoxycorticosterone analogs & derivatives, Hypertrophy, Left Ventricular etiology, Proteinuria etiology, Renal Insufficiency, Chronic complications
- Abstract
Blockade of the MR (mineralocorticoid receptor) in CKD (chronic kidney disease) reduces LVMI [LV (left ventricular) mass index] and proteinuria. The MR can be activated by aldosterone, cortisol and DOC (deoxycorticosterone). The aim of the present study was to explore the influence of mineralocorticoids on LVMI and proteinuria in patients with CKD. A total of 70 patients with CKD and 30 patients with EH (essential hypertension) were recruited. Patients underwent clinical phenotyping; biochemical assessment and 24 h urinary collection for THAldo (tetrahydroaldosterone), THDOC (tetrahydrodeoxycorticosterone), cortisol metabolites (measured using GC-MS), and urinary electrolytes and protein [QP (proteinuira quantification)]. LVMI was measured using CMRI (cardiac magnetic resonance imaging). Factors that correlated significantly with LVMI and proteinuria were entered into linear regression models. In patients with CKD, significant predictors of LVMI were male gender, SBP (systolic blood pressure), QP, and THAldo and THDOC excretion. Significant independent predictors on multivariate analysis were THDOC excretion, SBP and male gender. In EH, no association was seen between THAldo or THDOC and LVMI; plasma aldosterone concentration was the only significant independent predictor. Significant univariate determinants of proteinuria in patients with CKD were THAldo, THDOC, USod (urinary sodium) and SBP. Only THAldo excretion and SBP were significant multivariate determinants. Using CMRI to determine LVMI we have demonstrated that THDOC is a novel independent predictor of LVMI in patients with CKD, differing from patients with EH. Twenty-four hour THAldo excretion is an independent determinant of proteinuria in patients with CKD. These findings emphasize the importance of MR activation in the pathogenesis of the adverse clinical phenotype in CKD.
- Published
- 2012
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31. A phaeochromocytoma occurring in a patient with Parkinson's disease on L-dopa therapy: a diagnostic challenge.
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Collier A, Ghosh S, Breckenridge A, Perry CG, Freel EM, and Davidson DF
- Subjects
- Adrenal Gland Neoplasms complications, Adrenal Gland Neoplasms urine, Antiparkinson Agents therapeutic use, Creatinine urine, Humans, Male, Metanephrine urine, Middle Aged, Normetanephrine urine, Parkinson Disease complications, Pheochromocytoma complications, Pheochromocytoma urine, Tomography, X-Ray Computed, Adrenal Gland Neoplasms diagnosis, Levodopa therapeutic use, Parkinson Disease drug therapy, Pheochromocytoma diagnosis
- Published
- 2012
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32. Disorders of blood pressure regulation-role of catecholamine biosynthesis, release, and metabolism.
- Author
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Currie G, Freel EM, Perry CG, and Dominiczak AF
- Subjects
- Adrenal Medulla metabolism, Adrenal Medulla physiopathology, Chromogranins genetics, Chromogranins metabolism, Coenzymes genetics, Coenzymes metabolism, Drug Discovery, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Polymorphism, Genetic, Therapies, Investigational, Transient Receptor Potential Channels genetics, Transient Receptor Potential Channels metabolism, Antihypertensive Agents metabolism, Antihypertensive Agents pharmacology, Blood Pressure drug effects, Blood Pressure genetics, Catecholamines biosynthesis, Catecholamines genetics, Catecholamines metabolism, Hypertension drug therapy, Hypertension genetics, Hypertension metabolism, Hypertension physiopathology, Sympathetic Fibers, Postganglionic drug effects, Sympathetic Fibers, Postganglionic metabolism, Sympathetic Fibers, Postganglionic physiopathology
- Abstract
Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.
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- 2012
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33. Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect.
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Yeap PM, Tobias ES, Mavraki E, Fletcher A, Bradshaw N, Freel EM, Cooke A, Murday VA, Davidson HR, Perry CG, and Lindsay RS
- Subjects
- Alleles, Chromosomes, Human, Pair 11, DNA Mutational Analysis, Female, Humans, Loss of Heterozygosity, Male, Pedigree, Adrenal Gland Neoplasms genetics, Germ-Line Mutation, Pheochromocytoma genetics, Succinate Dehydrogenase genetics
- Abstract
Context: Pheochromocytoma/paraganglioma occurs almost exclusively after paternal transmission of succinate dehydrogenase D (SDHD) mutations. This parent-of-origin effect has not been fully explained but is accompanied by obligate loss of the maternal copy of chromosome 11. Loss of wild-type SDHD and an additional imprinted gene (hypothesized to be H19) appears necessary for tumor formation. Two previous reports suggested tumor formation after maternal transmission of SDHD mutation, but histological and molecular characterization was unavailable., Objective: We report the first kindred in which histologically confirmed pheochromocytoma/paraganglioma occurred after maternal transmission of an SDHD mutation and investigate the molecular mechanism of tumor formation., Design: The design of the investigation was the study of a three-generation family with SDHD c.242C>T (p.Pro81Leu) mutation., Results: The index patient had a histologically confirmed pheochromocytoma and an identical SDHD germline mutation (p.Pro81Leu) to her mother (who had a glomus jugulare tumor) and paraganglioma tissue from her maternal grandfather. Tumor DNA from the index patient revealed loss of heterozygosity (LOH) at 11q23, causing loss of the wild-type paternal SDHD allele and LOH affecting maternal 11p15, including H19. These two regions of LOH were separated by a region exhibiting clearly retained heterozygosity, including SDHAF2, a recently reported paraganglioma susceptibility gene., Conclusions: Tumor formation can occur after maternal transmission of SDHD, a finding with important clinical implications for SDHD families. Tumor formation in SDHD mutation requires the loss of both the wild-type SDHD allele and maternal 11p15, leading to the predominant but now not exclusive pattern of disease inheritance after paternal SDHD transmission.
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- 2011
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34. Role of genetic variation in regulation of aldosterone biosynthesis.
- Author
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Alvarez-Madrazo S, Connell JM, and Freel EM
- Subjects
- Animals, Cardiovascular Diseases genetics, Cardiovascular Diseases metabolism, Cytochrome P-450 CYP11B2 genetics, Cytochrome P-450 CYP11B2 metabolism, Cytochrome P-450 CYP11B2 physiology, Humans, Hypertension genetics, Hypertension metabolism, Linkage Disequilibrium, Models, Biological, Polymorphism, Single Nucleotide physiology, Steroid 11-beta-Hydroxylase genetics, Steroid 11-beta-Hydroxylase metabolism, Steroid 11-beta-Hydroxylase physiology, Aldosterone biosynthesis, Genetic Variation physiology
- Abstract
Aldosterone biosynthesis is not only altered in rare mendelian disorders. Recent evidence suggests that common polymorphisms in the genes mediating the final stages of aldosterone and cortisol production (CYP11B1 and CYP11B2 respectively) are also associated with milder alterations in adrenal corticosteroid biosynthesis. These abnormalities consist of a decrease in adrenal 11β- hydroxylase activity and a subtle, life-long excess of aldosterone secretion which may lead to long-term cardiovascular risks. An interaction between the CYP11B1 and CYP11B2 genes may exist but is yet to be elucidated. This article describes the studies which highlight the importance of adrenal steroid synthesis in the development of hypertension and cardiovascular dysfunction as well as the role of common polymorphisms in adrenal synthetic genes in altering corticosteroid biosynthesis., (Copyright © 2011 S. Karger AG, Basel.)
- Published
- 2011
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35. Primary aldosteronism: an update.
- Author
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Freel EM and Connell JM
- Abstract
Primary aldosteronism (PA) is common with an estimated prevalence rate of 10% in subjects with essential hypertension and higher in those with resistant hypertension. As well as contributing to hypertension, aldosterone has detrimental effects on the heart, vasculature and kidneys as well as adverse metabolic effects leading to an excess of cardiovascular morbidity. Therefore, recognition and appropriate treatment of PA is of increasing importance. However, the diagnosis of PA and determination of subtype can be problematic. The purpose of this review is to provide an overview of the evidence supporting this increased prevalence of PA, explore the metabolic and cardiovascular consequences of aldosterone excess and discuss optimal diagnostic and therapeutic strategies of PA.
- Published
- 2010
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36. Adrenal venous sampling for catecholamines: a normal value study.
- Author
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Freel EM, Stanson AW, Thompson GB, Grant CS, Farley DR, Richards ML, and Young WF Jr
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Reference Values, Adrenal Glands blood supply, Blood Specimen Collection methods, Epinephrine blood, Norepinephrine blood
- Abstract
Context: Pheochromocytomas are rare, but potentially fatal, neoplasms. The diagnosis and localization of pheochromocytoma can be challenging, and recently there has been some debate regarding the role for adrenal venous sampling (AVS). The utility of AVS in this setting is hampered by a lack of normative value data for adrenal vein catecholamine concentrations and the reliability of lateralization ratios. We sought to address these concerns by analyzing AVS catecholamine concentrations from patients who did not have pheochromocytoma., Design/setting: Eighteen patients underwent successful AVS for evaluation of cortisol-producing adrenal masses. All had normal 24-h urinary excretion of fractionated catecholamines and metanephrines., Results: There was a wide range of catecholamine concentrations in both the right (epinephrine 389-118326 pg/ml; norepinephrine 156-11193 pg/ml) and left (epinephrine 113-9327 pg/ml; norepinephrine 229-2216 pg/ml) adrenal veins. The right adrenal vein-to-left adrenal vein epinephrine gradient was as high as 83:1 (median 2.1:1; P < 0.02). Although less striking, similar findings were also seen for norepinephrine., Conclusions: This report provides a reference range for adrenal vein catecholamine concentrations in nonpheochromocytoma patients and illustrates the wide variation in epinephrine and norepinephrine concentrations. Epinephrine and norepinephrine concentrations are statistically significantly higher in the right vs. the left adrenal vein; in the case of epinephrine, up to an 83-fold difference was found between the right and left adrenal veins. These data highlight why AVS should not be used in the investigation of adrenal pheochromocytoma.
- Published
- 2010
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37. Central mineralocorticoid receptors, sympathetic activity, and hypertension.
- Author
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McManus F, MacKenzie SM, and Freel EM
- Subjects
- Animals, Humans, Hypertension physiopathology, Sympathetic Nervous System metabolism, Blood Pressure physiology, Hypertension metabolism, Receptors, Mineralocorticoid metabolism, Sympathetic Nervous System physiopathology
- Abstract
Recent evidence highlighting the presence of cortico-steroid receptors in the central nervous system has prompted further investigation regarding their role in the pathogenesis of hypertension. The sympathetic nervous system, an important factor in the pathogenesis of hypertension, is influenced by sodium and volume status. Activation of central nervous system mineralocorticoid receptors is known to affect sympathetic activity, although the processes that underpin this phenomenon are incompletely understood. This article reviews some of the recent advances in this area, particularly mechanisms by which the mineralo-corticoid receptor maintains selectivity for its ligand within the central nervous system, its role in salt appetite, and the possibility of local production of corticosteroids. In addition, the links between central mineralocorticoid receptor activation, stress, sympathetic activity, and hypertension are discussed.
- Published
- 2009
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38. Altered corticosteroid biosynthesis in essential hypertension: A digenic phenomenon.
- Author
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Davies E, Mackenzie SM, Freel EM, Alvarez-Madrazo S, Fraser R, and Connell JM
- Subjects
- Blood Pressure physiology, Cytochrome P-450 CYP11B2 genetics, Cytochrome P-450 CYP11B2 metabolism, Humans, Polymorphism, Genetic, Steroid 11-beta-Hydroxylase metabolism, Aldosterone biosynthesis, Hypertension genetics, Hypertension metabolism
- Abstract
Aldosterone plays an important role in electrolyte and blood pressure homeostasis. Our studies have focused on the role of aldosterone in essential hypertension. We have shown that plasma aldosterone and ARR are heritable characteristics and that aldosterone concentrations in older subjects are inversely correlated with birthweight and positively correlated with blood pressure. Aldosterone levels are also associated with polymorphic variation in the CYP11B2 gene, which encodes aldosterone synthase, the enzyme responsible for aldosterone production. Interestingly, CYP11B2 polymorphisms are also associated with less efficient activity of 11beta-hydroxylase, encoded by the neighbouring, highly homologous CYP11B1 gene. We propose that a digenic effect leads to increased aldosterone production, with inefficient 11beta-hydroxylation causing a long-term increase in ACTH drive to the adrenal gland and enhanced expression of CYP11B2, thereby resulting in chronically raised aldosterone secretion in response to factors such as angiotensin II and potassium. In susceptible subjects this is likely, over many years, to result in hypertension with relative aldosterone excess.
- Published
- 2009
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39. Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic-pituitary-adrenal axis activity in hypertensive and normotensive subjects.
- Author
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Freel EM, Ingram M, Wallace AM, White A, Fraser R, Davies E, and Connell JM
- Subjects
- Adult, Case-Control Studies, Cytochrome P-450 CYP11B2 biosynthesis, Female, Genetic Variation, Humans, Male, Phenotype, Steroid 11-beta-Hydroxylase biosynthesis, Up-Regulation, Gene Expression Regulation, Enzymologic genetics, Hypertension enzymology, Hypertension genetics, Hypothalamo-Hypophyseal System enzymology, Pituitary-Adrenal System enzymology
- Abstract
Background: Aldosterone is important in the development of hypertension. We have shown that a single nucleotide polymorphism (SNP) (-344T) in the 5' regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) associates with aldosterone excess and hypertension as well as altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol). This conversion is carried out by the enzyme 11beta-hydroxylase, encoded by the adjacent gene, CYP11B1. We proposed that the effects of CYP11B2 are explained by linkage disequilibrium (LD) across the CYP11B locus. We have demonstrated high LD across this locus and identified two SNPs in the 5' UTR of CYP11B1 (-1859 G/T, -1889 A/G) that associate with reduced transcription in vitro and altered 11-hydroxylation efficiency in vivo. Accordingly, we hypothesized that the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary-adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess., Methods: To test this, we examined hypothalamic-pituitary-adrenal (HPA) axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (-344T/C) and CYP11B1 (-1859 G/T, -1889 A/G). Fifty-six subjects homozygous for CYP11B2 SNP (27 TT, 12 CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. Diurnal variation and the effects of dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions were studied., Results: Subjects with SNPs associated with reduced 11-hydroxylation efficiency (-344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P = 0.05) and an altered cortisol-ACTH relationship (decreased cortisol-ACTH ratio, P < 0.02). The same individuals also demonstrated close correlations between plasma cortisol and aldosterone (-344T CYP11B2 r = 0.508, P < 0.004; TTGG CYP11B1 r = 0.563, P < 0.003) suggesting that there was common regulation (possibly ACTH) of these hormones in genetically susceptible subjects., Conclusions: Variation in CYP11B2 and CYP11B1 associates with chronic up-regulation of the HPA axis. These novel data support the suggestion that chronic aldosterone excess, in genetically susceptible individuals, may be a consequence of increased ACTH drive to the adrenal and identify novel molecular mechanisms that may lead to the development of hypertension within the general population.
- Published
- 2008
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40. A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function.
- Author
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Connell JM, MacKenzie SM, Freel EM, Fraser R, and Davies E
- Subjects
- Animals, Humans, Hyperaldosteronism metabolism, Hypertension, Renal metabolism, Aldosterone physiology, Cardiovascular Physiological Phenomena, Hyperaldosteronism physiopathology, Hypertension, Renal physiopathology, Renin-Angiotensin System physiology
- Abstract
Up to 15% of patients with essential hypertension have inappropriate regulation of aldosterone; although only a minority have distinct adrenal tumors, recent evidence shows that mineralocorticoid receptor activation contributes to the age-related blood pressure rise and illustrates the importance of aldosterone in determining cardiovascular risk. Aldosterone also has a major role in progression and outcome of ischemic heart disease. These data highlight the need to understand better the regulation of aldosterone synthesis and its action. Aldosterone effects are mediated mainly through classical nuclear receptors that alter gene transcription. In classic epithelial target tissues, signaling mechanisms are relatively well defined. However, aldosterone has major effects in nonepithelial tissues that include increased synthesis of proinflammatory molecules and reactive oxygen species; it remains unclear how these effects are controlled and how receptor specificity is maintained. Variation in aldosterone production reflects interaction of genetic and environmental factors. Although the environmental factors are well understood, the genetic control of aldosterone synthesis is still the subject of debate. Aldosterone synthase (encoded by the CYP11B2 gene) controls conversion of deoxycorticosterone to aldosterone. Polymorphic variation in CYP11B2 is associated with increased risk of hypertension, but the molecular mechanism that accounts for this is not known. Altered 11beta-hydroxylase efficiency (conversion of deoxycortisol to cortisol) as a consequence of variation in the neighboring gene (CYP11B1) may be important in contributing to altered control of aldosterone synthesis, so that the risk of hypertension may reflect a digenic effect, a concept that is discussed further. There is evidence that a long-term increase in aldosterone production from early life is determined by an interaction of genetic and environmental factors, leading to the eventual phenotypes of aldosterone-associated hypertension and cardiovascular damage in middle age and beyond. The importance of aldosterone has generated interest in its therapeutic modulation. Disadvantages associated with spironolactone (altered libido, gynecomastia) have led to a search for alternative mineralocorticoid receptor antagonists. Of these, eplerenone has been shown to reduce cardiovascular risk after myocardial infarction. The benefits and disadvantages of this therapeutic approach are discussed.
- Published
- 2008
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41. Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study.
- Author
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Freel EM, Ingram M, Friel EC, Fraser R, Brown M, Samani NJ, Caulfield M, Munroe P, Farrall M, Webster J, Clayton D, Dominiczak AF, Davies E, and Connell JM
- Subjects
- Adrenocorticotropic Hormone metabolism, Aged, Aldosterone blood, Alleles, Cortodoxone blood, Female, Genotype, Humans, Hypertension blood, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Cytochrome P-450 CYP11B2 genetics, Hypertension genetics, Steroid 11-beta-Hydroxylase genetics
- Abstract
Background: Aldosterone is an important cardiovascular hormone; 15% of hypertensive subjects have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of the aldosterone synthase gene (CYP11B2) have focused on a single nucleotide polymorphism in the 5'promoter region (-344 C/T). In normotensive subjects, the T allele associates with raised levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for 11beta-hydroxylase, encoded by the adjacent and homologous gene, CYP11B1. We have speculated that this altered 11beta-hydroxylase efficiency leads to increased ACTH drive to the adrenal gland to maintain cortisol production and reported herein the association between the -344 C/T single nucleotide polymorphism (SNP) and adrenal steroid production in subjects with essential hypertension., Methods: The CYP11B2-344 C/T polymorphism was genotyped and urinary excretion of adrenal steroid metabolites was measured (by GCMS) in 511 unrelated hypertensives from the Medical Research Council (MRC) British Genetics of Hypertension (BRIGHT) study., Results: Thirty-five per cent of subjects were homozygous for the -344T allele whilst 16% were CC homozygotes. There was no difference in cortisol excretion rate between the two genotype groups but the index of adrenal 11beta-hydroxylation (ratio of tetrahydrodeoxycortisol/total cortisol) was significantly higher in the TT group (P < 0.005) than in the CC group. Excretion rates of the major urinary metabolite of aldosterone (tetrahydroaldosterone) correlated strongly with the ACTH-regulated steroids, cortisol (r = 0.437, P < 0.0001) and total androgen metabolites (r = 0.4, P < 0.0001) in TT but not CC subjects., Conclusions: Hypertensives homozygous for the -344 T allele of CYP11B2 demonstrate altered 11beta-hydroxylase efficiency (CYP11B1); this is consistent with the hypothesis of a genetically determined increase in adrenal ACTH drive in these subjects. The correlation between excretion of aldosterone and cortisol metabolites and suggests that, in TT subjects, ACTH exerts an important common regulatory influence on adrenal corticosteroid production in subjects with hypertension.
- Published
- 2007
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42. Endogenous corticosteroid biosynthesis in subjects after bilateral adrenalectomy.
- Author
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Freel EM, Bernhardt R, Ingram M, Wallace AM, Fraser R, Davies E, and Connell JM
- Subjects
- Adrenal Cortex Diseases metabolism, Adrenal Cortex Hormones blood, Adrenal Cortex Hormones urine, Adult, Aged, Aldosterone blood, Dexamethasone therapeutic use, Female, Gas Chromatography-Mass Spectrometry, Glucocorticoids therapeutic use, Humans, Hydrocortisone analogs & derivatives, Hydrocortisone therapeutic use, Hydrocortisone urine, Male, Middle Aged, Postoperative Period, Radioimmunoassay, Renin blood, Tetrahydrocortisol analogs & derivatives, Tetrahydrocortisol urine, Tetrahydrocortisone urine, Adrenal Cortex Diseases surgery, Adrenal Cortex Hormones biosynthesis, Adrenalectomy
- Abstract
Objective: Corticosteroids can be synthesized in extra-adrenal tissues but the contribution of this to circulating levels in humans is not known. Previous in vitro studies suggest that the 'hybrid' corticosteroid 18-oxocortisol (18-oxoF) is produced from cortisol by aldosterone synthase. We looked for evidence of extra-adrenal production of this and other corticosteroids in 10 subjects stable on long-term glucocorticoid replacement following bilateral adrenalectomy., Methods: In phase 1, patients were maintained on cortisol alone (30 mg/day), in phase 2 dexamethasone (2 mg/day), and in phase 3, both cortisol and dexamethasone. Each phase lasted 3 days., Measurements: On the last day of each phase, 24-h urine collection was performed for analysis of steroid metabolite excretion [using gas chromatography-mass spectrometry (GCMS)] and plasma aldosterone and renin were measured (by radioimmunoassay)., Results: Cortisol metabolite excretion rate [tetrahydrocortisone (THE) + tetrahydrocortisol (THF) + allotetrahydrocortisol (aTHF)] fell from 9169 nmol/24 h in phase 1 to 22 nmol/24 h in phase 2, rising to 6843 nmol/24 h in phase 3. Tetrahydroaldosterone (THAldo) excretion was readily detectable and did not alter significantly between phases (26.5, 23.5 and 28.5 nmol/24 h, respectively; P = 0.474). 18-Hydroxycortisol (18-OHF) excretion was easily detectable in phases 1 and 3 (252.5 and 212 nmol/24 h), falling in phase 2 (12 nmol/24 h). 18-oxoF excretion rates were lower but followed a similar pattern (1.62, 0.085 and 1.785 nmol/24 h in phases 1, 2 and 3, respectively)., Conclusions: Significant levels of adrenal steroids are found in adrenalectomized subjects. We speculate that this occurs at extra-adrenal sites or in residual adrenal cortex tissue in an ACTH-independent manner. Our data suggest that aldosterone synthase, acting on cortisol, is the source of 18-oxoF and 18-OHF in these subjects. Further studies of corticosteroid production within adrenalectomized subjects, looking for evidence of adrenal regrowth or residual adrenal tissue, are justified.
- Published
- 2007
- Full Text
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43. Diagnosis of adenomatous primary aldosteronism in a patient with severe hypertension.
- Author
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Freel EM and Connell JM
- Subjects
- Adrenal Glands diagnostic imaging, Adrenocortical Adenoma drug therapy, Adult, Aldosterone blood, Aldosterone therapeutic use, Algorithms, Humans, Hyperaldosteronism drug therapy, Hypertension drug therapy, Hypokalemia diagnosis, Renin blood, Tomography, X-Ray Computed, Adrenocortical Adenoma complications, Adrenocortical Adenoma diagnosis, Hyperaldosteronism complications, Hyperaldosteronism diagnosis, Hypertension complications
- Abstract
Background: A 27-year-old woman presented to her primary-care physician with severe hypertension after complaining of fatigue over the preceding months. She was otherwise asymptomatic. She was referred to a hypertension clinic and was found to be hypokalemic. She was immediately commenced on amlodipine, with atenolol added 2 weeks later. After 4 weeks of this drug therapy, her hypertension persisted and investigations to exclude secondary causes of hypertension were performed., Investigations: Aldosterone and renin levels were measured under controlled conditions and the results expressed as an aldosterone-to-renin ratio. CT of the adrenal glands was also performed., Diagnosis: Adenomatous primary aldosteronism (Conn's syndrome)., Management: The patient was initially treated with spironolactone before undergoing a laparoscopic left adrenalectomy.
- Published
- 2005
- Full Text
- View/download PDF
44. Studies on the origin of circulating 18-hydroxycortisol and 18-oxocortisol in normal human subjects.
- Author
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Freel EM, Shakerdi LA, Friel EC, Wallace AM, Davies E, Fraser R, and Connell JM
- Subjects
- Adult, Animals, CHO Cells, Cortisone urine, Cricetinae, Cytochrome P-450 CYP11B2 physiology, Dexamethasone pharmacology, Humans, Hydrocortisone urine, Male, Steroid 11-beta-Hydroxylase physiology, Transfection, Zona Fasciculata metabolism, Zona Glomerulosa metabolism, Hydrocortisone analogs & derivatives, Hydrocortisone blood
- Abstract
18-Hydroxycortisol (18-OHF) and 18-oxocortisol (18-oxoF) are derivatives of cortisol found in primary aldosteronism but whose origin and regulation in normal subjects are uncertain. 18-OHF can be synthesized by zona fasciculata 11-beta hydroxylase; 18-oxoF can only be produced by zona glomerulosa aldosterone synthase (AS). Stably transfected cell lines expressing either CYP11B1 (11beta-hydroxylase) or CYP11B2 (AS) were incubated with cortisol and other substrates over a range of concentrations. Both enzymes could synthesize 18-OHF from cortisol, but only AS could synthesize 18-oxoF. AS was more efficient than 11beta-hydroxylase at 18-hydroxylation. The apparent Michaelis-Menten constant (K(m)) of AS for cortisol was estimated to be 2.6 microm. In five patients with adrenal insufficiency maintained on hydrocortisone, urinary free cortisol and cortisone levels were high; 18-oxoF was detectable in all patients and 18-OHF in three. It is likely that the 18-oxygenated steroids were synthesized from circulating cortisol, either in the zona glomerulosa or at extraadrenal sites. In eight male volunteers, dexamethasone treatment decreased urinary excretion rates of free cortisol, cortisone, 18-OHF, and 18-oxoF, confirming dependence of 18-oxygenated steroid levels on cortisol availability. In both groups, hydrocortisone administration resulted in detectable levels of 18-OHF and raised levels of 18-oxoF. There was close correlation between 18-oxoF and cortisol excretion during hydrocortisone administration in normal subjects (r = 0.86; P < 0.001). These data show, for the first time, that 18-OHF and 18-oxoF can be synthesized from circulating cortisol. The close correlation between 18-oxoF and cortisol suggests that 18-oxoF is normally produced by the action of AS using circulating cortisol as a substrate. Although 18OHF can be synthesized using circulating cortisol as substrate, our data suggest this is normally produced in the zona fasciculata by 11beta-hydroxylase from locally available cortisol.
- Published
- 2004
- Full Text
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45. Mechanisms of hypertension: the expanding role of aldosterone.
- Author
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Freel EM and Connell JM
- Subjects
- Humans, Hypertension, Renal genetics, Hypertension, Renal metabolism, Aldosterone physiology, Hypertension, Renal physiopathology
- Abstract
Hypertension is a common disorder that affects a large heterogeneous patient population. Subgroups can be identified on the basis of their responses to hormonal and biologic stimuli. These subgroups include low-renin hypertensives and nonmodulators. Aldosterone, the principal human mineralocorticoid, is increasingly recognized as playing a significant role in cardiovascular morbidity, and its role in hypertension has recently been reevaluated with studies that suggest that increased aldosterone biosynthesis (as defined by an elevated aldosterone to renin ratio) is a key phenotype in up to 15% of individuals with hypertension. It was reported previously that a polymorphism of the gene (C to T conversion at position -344) encoding aldosterone synthase is associated with hypertension, particularly in individuals with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11beta-hydroxylation. This review explores the evidence for this and provides a hypothesis linking impaired 11beta-hydroxylation and hypertension with a raised aldosterone to renin ratio. It is also speculated that there is substantial overlap between this group of patients and previously identified low-renin hypertensives and nonmodulators. Thus, these groups may form a neurohormonal spectrum reflecting different stages of hypertension or indeed form sequential steps in the natural history of hypertension in genetically susceptible individuals.
- Published
- 2004
- Full Text
- View/download PDF
46. Modulation of iron-regulatory protein (IRP) activity in monocytes by nitric oxide, phorbol ester and gamma-interferon.
- Author
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Brock JH, Bhandari S, and Freel EM
- Subjects
- Animals, Cell Line, Deferoxamine pharmacology, Ferritins biosynthesis, Homeostasis, Humans, Iron-Regulatory Proteins, Kinetics, Lipopolysaccharides pharmacology, Macrophages drug effects, Mice, Monocytes drug effects, Nitric Oxide physiology, Receptors, Transferrin biosynthesis, Interferon-gamma pharmacology, Iron-Sulfur Proteins metabolism, Macrophages physiology, Monocytes physiology, RNA-Binding Proteins metabolism, Tetradecanoylphorbol Acetate pharmacology, omega-N-Methylarginine pharmacology
- Published
- 1997
- Full Text
- View/download PDF
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