Publications

The Primary Aldosteronism Foundation maintains a list of salient publications. Topics range from pathogenesis to the implications of excess aldosterone. We regularly update the list with new topics, and new articles are added as they become public.

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Abstract/Summary:

Cytochrome P450 mediated metabolism is the rate-limiting step of elimination for many drugs. CYP3A4 is the most abundant hepatic isoform and CYP3A4/5 metabolize the largest fraction of drugs. Pharmacogenetic studies have not been able to characterize population variability in CYP3A4 activity because few variant alleles associated with aberrant enzyme activity have been found. Substrate probes such as midazolam and testosterone have been utilized in-vivo and in-vitro to determine catalytic activity of these enzymes, but they suffer from several limitations. Eplerenone, an aldosterone antagonist, is also metabolized by CYP3A enzymes, and it has the potential to be an excellent substrate probe for CYP3A4/5. Eplerenone’s primary metabolite, 6 beta-hydroxyeplerenone is formed preferentially via CYP3A4, however, the relative contribution of CYP3A5 to the 21-hydroxyeplerenone metabolite formation is unknown. Through in-vitro microsomal incubations with recombinant CYP3A4 and CYP3A5 enzymes, we identified their relative contributions to 21-hydroxyeplerenone metabolism. The 21-hydroxy metabolite is formed preferentially via CYP3A5 Vmax/KM (3.3) versus CYP3A4 Vmax/KM (1.9). Based on these findings, eplerenone has the potential to serve as an in-vivo substrate probe for CYP3A4 by monitoring 6-beta-hydroxy metabolite formation as well as CYP3A4/5 by monitoring 21-hydroxy metabolite formation.

Authors: Joseph McGraw, Mitchell Cherney, Katherine Bichler, Armin Gerhardt, Mirielle Naumanb
Keywords: eplerenone, cytochrome P450, CYP3A4, CYP3A5
DOI Number: 10.1016/j.toxlet.2019.08.003
Publication Year: 2019

Abstract/Summary:

Primary aldosteronism (PA) and diabetes mellitus (DM) are clinical conditions that increase cardiovascular risk. Approximately one in five patients with PA have DM. Nevertheless, the pathophysiology linking these two entities is not entirely understood. In addition, the majority of patients with PA have glucocorticoid co-secretion, which is associated with increased risk of impaired glucose homeostasis. In the present review, we aim to comprehensively discuss all the available research data concerning the interplay between mineralocorticoid excess and glucose metabolism, with separate analysis of the sequalae in muscle, adipose tissue, liver and pancreas. Aldosterone binds both mineralocorticoid and glucocorticoid receptors and amplifies tissue glucocorticoid activity, via 11-β-hydroxysteroid dehydrogenase type 1 stimulation. A clear classification of the molecular events as per specific receptor in insulin-sensitive tissues is impossible, while their synergistic interaction is plausible. Furthermore, aldosterone induces oxidative stress and inflammation, perturbs adipokine expression, thermogenesis and lipogenesis in adipose tissue, and increases hepatic steatosis. In pancreas, enhanced oxidative stress and inflammation of beta cells, predominantly upon glucocorticoid receptor activation, impair insulin secretion. No causality between hypokalemia and impaired insulin response is yet proven; in contrast, hypokalemia appears to be implicated with insulin resistance and hepatic steatosis. The superior efficacy of adrenalectomy in ameliorating glucose metabolism vs. mineralocorticoid receptor antagonists in clinical studies highlights the contribution of non-mineralocorticoid receptor-mediated mechanisms in the pathophysiologic process. The exact role of hypokalemia, the mechanisms linking mineralocorticoid excess with hepatic steatosis, and possible disease-modifying role of pioglitazone warrant further studies.

Authors: Melpomeni Moustaki, Stavroula A. Paschou, Eleni C. Vakali, Andromachi Vryonidou
Keywords: diabetes mellitus, glucose, adipose tissue, liver, pancreas, hepatic steatosis
DOI Number: 10.1007/s12020-022-03168-8
Publication Year: 2022

Abstract/Summary:

Primary aldosteronism (PA) is a highly prevalent yet underdiagnosed secondary cause of hypertension. PA is associated with increased cardiovascular and renal morbidity compared with patients with primary hypertension. Thus, prompt identification and targeted therapy of PA are essential to reduce cardiovascular and renal morbidity and mortality in a large population with hypertension. Unilateral adrenalectomy is preferred for lateralized PA as the only potentially curative therapy. Surgery also mitigates the risk of cardiovascular and renal complications associated with PA. Targeted medical therapy, commonly including a mineralocorticoid receptor antagonist, is offered to patients with bilateral PA and those who are not surgical candidates. Novel therapies, including nonsteroidal mineralocorticoid receptor antagonists and aldosterone synthase inhibitors, are being developed as alternative options for PA treatment. In this review article, we discuss how to best individualize therapy for patients with PA.

Authors: Hiba Obeid, Stanley M. Chen Cardenas, Shafaq Khairi, Adina F. Turcu
Keywords: personalized treatment, individualized therapy
DOI Number: 10.1016/j.eprac.2022.10.008
Publication Year: 2022

Abstract/Summary:

Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cut-off for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone to renin ratio with PAC as an index for screening, and saline infusion test (SIT) in a seated position for confirmatory testing. The cut-off values for screening and confirmatory testing showed significant variation among centers. Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises two issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.

Authors: Mitsuhide Naruse, Masanori Murakami, Takuyuki Katabami, Tomaz Kocjan, Mirko Parasiliti-Caprino, Marcus Quinkler, Matthieu St-Jean, Sam O’Toole, Filippo Ceccato, Ivana Kraljevic, Darko Kastelan, Mika Tsuiki, Jaap Deinum, Edelmiro Menéndez Torre, Troy Puar, Athina Markou, George Piaditis, Kate Laycock, Norio Wada, Marianne Aardal Grytaas, Hiroki Kobayashi, Akiyo Tanabe, Chin Voon Tong, Nuria Valdés Gallego, Sven Gruber, Felix Beuschlein, Lydia Kürzinger, Norlela Sukor, Elena Aisha Azizan, Oskar Ragnarsson, Michiel F Nijhoff, Giuseppe Maiolino, Guido Di Dalmazi, Valentina Kalugina, André Lacroix, Raluca Maria Furnica, Tomoko Suzuki
Keywords: standardization, diagnostic process
DOI Number: 10.1093/ejendo/lvac002
Publication Year: 2023

Abstract/Summary:

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA (NCT02945904) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = −6.5 to 24.1%) and 3.8% (95% confidence interval = −11.9 to 9.4) lay within the pre-specified −17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.

Authors: Xilin Wu, Russell Senanayake, Emily Goodchild, Waiel A. Bashari, Jackie Salsbury, Claudia P. Cabrera, Giulia Argentesi, Samuel M. O’Toole, Matthew Matson, Brendan Koo, Laila Parvanta, Nick Hilliard, Vasilis Kosmoliaptsis, Alison Marker, Daniel M. Berney, Wilson Tan, Roger Foo, Charles A. Mein, Eva Wozniak, Emmanuel Savage, Anju Sahdev, Nicholas Bird, Kate Laycock, Istvan Boros, Stefan Hader, Victoria Warnes, Daniel Gillett, Anne Dawnay, Elizabeth Adeyeye, Alessandro Prete, Angela E. Taylor, Wiebke Arlt, Anish N. Bhuva, Franklin Aigbirhio, Charlotte Manisty, Alasdair McIntosh, Alexander McConnachie, J. Kennedy Cruickshank, Heok Cheow, Mark Gurnell, William M. Drake, Morris J. Brown
Keywords: [11C]metomidate PET-CT, positron emission tomography computed tomography
DOI Number: 10.1038/s41591-022-02114-5
Publication Year: 2023

Abstract/Summary:

Primary aldosteronism (PA) and oral contraception (OC) can both cause hypertension in young women. However, the effect of OC on the screening test for PA, the aldosterone to renin ratio (ARR), is not clear. The objective of the study was to evaluate the impact of OC on the screening test for PA. We analysed data from the female offspring (Gen2) of women enrolled in the Raine Study, a population-based birth cohort, who had BP measurements, blood samples and information about OC use at age 17y (N = 484) and/or age 27y (N = 486). Aldosterone concentration was significantly higher in OC users than non-users at 17y (median 486 pmol/L vs 347 pmol/L, p < 0.001). Renin concentration was significantly lower in OC-users at both 17y (13.4 mU/L vs 20.6 mU/L) and 27y (9.2 mU/L vs 11.8 mU/L), hence the ARR was significantly higher in OC-users compared to non-users at both 17y (31.5 vs 18.3) and 27y (27.3 vs 21.1). The proportion of participants with ARR > 70 pmol/mU (current threshold for PA detection) was significantly higher in OC-users at both 17y (12.6% vs 2.1%) and 27y (6.4% vs 0.4%), however, they had comparable BP to those with ARR < 70. OC use at any age abolished the relationship between ARR and BP that is observed in non-OC users. OC can increase the ARR and cause a false positive PA screening result. Until more reliable criteria for PA screening in OC users are established, alternative contraception should be considered during screening.

Authors: Jun Yang, Stella May Gwini, Lawrence J Beilin, Markus Schlaich, Michael Stowasser, Morag J Young, Peter J Fuller, Trevor A Mori
Keywords: contraception, screening
DOI Number: 10.1210/clinem/dgad010
Publication Year: 2023