Primary Aldosteronism; a growing challenge Mikael Boustedt Eleftheria Gkaniatsa Department of Internal Medicine and Clinical Nutrition Institute of Medicine Sahlgrenska Academy, University of Gothenburg Gothenburg 2024 i Cover illustration: by Verity Tolcher “We theorized that resistance to repletion of potassium was the result of an intracellular overabundance of sodium, being held by excessive activity of © Eleftheria Gkaniatsa 2024 aldosterone and concluded that total adrenalectomy followed by eleftheria.gkaniatsa@gu.se substitution therapy should abolish the entire metabolic abnormality. To our surprise and delight, a cortical adenoma, 4 cm. in diameter was ISBN 978-91-8069-855-9 (PRINT) observed to be arising from the right adrenal gland.” ISBN 978-91-8069-856-6 (PDF) by Jerome W. Conn http://hdl.handle.net/2077/82298 NENMÄENMÄRKVAN RKE VA E Printed in Borås, Sweden 2024 Printed by Stema Specialtryck AB Trycksak3T0r4y1c k0s2a3k43041 0234 ii iii SS TT Cover illustration: by Verity Tolcher “We theorized that resistance to repletion of potassium was the result of an intracellular overabundance of sodium, being held by excessive activity of © Eleftheria Gkaniatsa 2024 aldosterone and concluded that total adrenalectomy followed by eleftheria.gkaniatsa@gu.se substitution therapy should abolish the entire metabolic abnormality. To our surprise and delight, a cortical adenoma, 4 cm. in diameter was ISBN 978-91-8069-855-9 (PRINT) observed to be arising from the right adrenal gland.” ISBN 978-91-8069-856-6 (PDF) by Jerome W. Conn http://hdl.handle.net/2077/82298 Printed in Borås, Sweden 2024 Printed by Stema Specialtryck AB ii iii Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa Department of Internal Medicine and Clinical Nutrition, Institute of Medicine Sahlgrenska Academy, University of Gothenburg Gothenburg, Sweden ABSTRACT Primary aldosteronism (PA), caused by excessive aldosterone production, is a frequently overlooked cause of hypertension. Cardiovascular complications are more common in patients with PA than patients with essential hypertension. However, disease-specific treatment with either mineralocorticoid receptor antagonists (MRAs) or unilateral adrenalectomy, effectively reduces the risk for these complications. The aim with this thesis was to investigate several contentious issues related to epidemiology, subtype classification, and treatment of patients with PA. The key findings are summarized below. The incidence of PA in Region Västra Götaland has increased from 2 patients per million in 1987–1996 to 17 patients per million in 2007–2016. Despite this, PA is still significantly underdiagnosed. International guidelines postulate that adrenal venous sampling (AVS) is not necessary to confirm unilateral PA in young adults with visible adenoma on imaging. However, our review of 45 young patients (<40 years of age) who had undergone AVS at our institution showed that 20% of these patients would have received inappropriate treatment based solely on imaging studies. A nationwide cohort study of 2419 patients with PA showed that mortality was increased compared to age- and sex-matched controls from the general population (HR 1.23, 95% CI 1.10–1.38), especially in patients with established cardiovascular disease or age >56 years at the time of diagnosis and in patients treated with low doses of MRAs, but not in patients treated with adrenalectomy. Patients with PA also had an increased risk of hip fracture (HR iv v Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa Department of Internal Medicine and Clinical Nutrition, Institute of Medicine Sahlgrenska Academy, University of Gothenburg Gothenburg, Sweden ABSTRACT Primary aldosteronism (PA), caused by excessive aldosterone production, is a frequently overlooked cause of hypertension. Cardiovascular complications are more common in patients with PA than patients with essential hypertension. However, disease-specific treatment with either mineralocorticoid receptor antagonists (MRAs) or unilateral adrenalectomy, effectively reduces the risk for these complications. The aim with this thesis was to investigate several contentious issues related to epidemiology, subtype classification, and treatment of patients with PA. The key findings are summarized below. The incidence of PA in Region Västra Götaland has increased from 2 patients per million in 1987–1996 to 17 patients per million in 2007–2016. Despite this, PA is still significantly underdiagnosed. International guidelines postulate that adrenal venous sampling (AVS) is not necessary to confirm unilateral PA in young adults with visible adenoma on imaging. However, our review of 45 young patients (<40 years of age) who had undergone AVS at our institution showed that 20% of these patients would have received inappropriate treatment based solely on imaging studies. A nationwide cohort study of 2419 patients with PA showed that mortality was increased compared to age- and sex-matched controls from the general population (HR 1.23, 95% CI 1.10–1.38), especially in patients with established cardiovascular disease or age >56 years at the time of diagnosis and in patients treated with low doses of MRAs, but not in patients treated with adrenalectomy. Patients with PA also had an increased risk of hip fracture (HR iv v 1.55, 95% CI 1.18–2.03), especially women and patients diagnosed at an older age as well as patients treated with an MRA. SAMMANFATTNING PÅ SVENSKA To conclude, PA is an underdiagnosed and undertreated condition that can lead Högt blodtryck utgör en av de viktigaste riskfaktorerna för hjärtkärlsjukdom. to cardiovascular complications, hip fractures, and increased mortality. Early Aldosteron har en central roll i reglering av blodtryck. Primär aldosteronism är and targeted treatment improves patient outcome. en sjukdom som orsakas av överproduktion av aldosteron och leder till högt blodtryck och ofta lågt kalium, samt inflammation i blodkärlen som ytterligare Keywords: hyperaldosteronism, incidence, mortality, hip fractures ökar risken för hjärtkärlsjukdom. Sjukdomen är vanlig bland personer med högt blodtryck och ännu vanligare bland dem som inte svarar på ISBN 978-91-8069-855-9 (PRINT) blodtryckssänkande behandling. Läkemedel som blockerar ISBN 978-91-8069-856-6 (PDF) aldosteronreceptorer (MRA) finns tillgängliga och har god effekt. Dessutom kan ungefär en tredjedel av alla patienter få kirurgisk behandling, vilket rekommenderas vid ensidig hormonproduktion. Denna avhandling baseras på fyra studier där förekomst av primär aldosteronism i Sverige, betydelse av binjurevenskateterisering bland unga patienter och prognos vad det gäller långtidsperspektivet undersöktes. Första studien visar att antalet individer som diagnostiseras med primär aldosteronism i Västra Götalands Regionen har ökat de senaste åren. Trots det är sjukdomen fortfarande kraftigt underdiagnostiserad. Internationella riktlinjer postulerar att binjurevenskateterisering (BVK) inte är nödvändig för att bekräfta ensidig PA hos unga vuxna med synligt adenom på datortomografi. I vår genomgång av 45 unga patienter (<40 år) som genomgått BVK på vår institution visades motsatsen. En femtedel av patienterna hade fått fel behandling om endast fynd på datortomografi av binjurarna hade använts. En nationell studie med över 2419 patienter med primär aldosteronism och 24189 kontrollpersoner med samma kön och ålder visade att primär aldosteronism tydligt ökar risken för död. Patienter som genomgick en adrenalektomi eller högre dos MRA än genomsnittet hade dock snarlik överlevnad med den i allmänna befolkningen. Patienter som löpte störst risk var framför allt personer med samexisterande hjärtsjukdom vid diagnos, lägre dos av MRA än genomsnitt eller ålder >56. Slutligen, löper patienter med primär aldosteronism ökad risk för höftfrakturer. Detta gäller särskilt kvinnor, patienter med hjärtsjukdom vid diagnos, patient som har fått diagnosen vid ålder >56 och patienter som fick MRA. Sammanfattningsvis visar denna avhandling att primär aldosteronism är underdiagnostiserat och förknippat med ökad risk för allvarliga konsekvenser, vi vii 1.55, 95% CI 1.18–2.03), especially women and patients diagnosed at an older age as well as patients treated with an MRA. SAMMANFATTNING PÅ SVENSKA To conclude, PA is an underdiagnosed and undertreated condition that can lead Högt blodtryck utgör en av de viktigaste riskfaktorerna för hjärtkärlsjukdom. to cardiovascular complications, hip fractures, and increased mortality. Early Aldosteron har en central roll i reglering av blodtryck. Primär aldosteronism är and targeted treatment improves patient outcome. en sjukdom som orsakas av överproduktion av aldosteron och leder till högt blodtryck och ofta lågt kalium, samt inflammation i blodkärlen som ytterligare Keywords: hyperaldosteronism, incidence, mortality, hip fractures ökar risken för hjärtkärlsjukdom. Sjukdomen är vanlig bland personer med högt blodtryck och ännu vanligare bland dem som inte svarar på ISBN 978-91-8069-855-9 (PRINT) blodtryckssänkande behandling. Läkemedel som blockerar ISBN 978-91-8069-856-6 (PDF) aldosteronreceptorer (MRA) finns tillgängliga och har god effekt. Dessutom kan ungefär en tredjedel av alla patienter få kirurgisk behandling, vilket rekommenderas vid ensidig hormonproduktion. Denna avhandling baseras på fyra studier där förekomst av primär aldosteronism i Sverige, betydelse av binjurevenskateterisering bland unga patienter och prognos vad det gäller långtidsperspektivet undersöktes. Första studien visar att antalet individer som diagnostiseras med primär aldosteronism i Västra Götalands Regionen har ökat de senaste åren. Trots det är sjukdomen fortfarande kraftigt underdiagnostiserad. Internationella riktlinjer postulerar att binjurevenskateterisering (BVK) inte är nödvändig för att bekräfta ensidig PA hos unga vuxna med synligt adenom på datortomografi. I vår genomgång av 45 unga patienter (<40 år) som genomgått BVK på vår institution visades motsatsen. En femtedel av patienterna hade fått fel behandling om endast fynd på datortomografi av binjurarna hade använts. En nationell studie med över 2419 patienter med primär aldosteronism och 24189 kontrollpersoner med samma kön och ålder visade att primär aldosteronism tydligt ökar risken för död. Patienter som genomgick en adrenalektomi eller högre dos MRA än genomsnittet hade dock snarlik överlevnad med den i allmänna befolkningen. Patienter som löpte störst risk var framför allt personer med samexisterande hjärtsjukdom vid diagnos, lägre dos av MRA än genomsnitt eller ålder >56. Slutligen, löper patienter med primär aldosteronism ökad risk för höftfrakturer. Detta gäller särskilt kvinnor, patienter med hjärtsjukdom vid diagnos, patient som har fått diagnosen vid ålder >56 och patienter som fick MRA. Sammanfattningsvis visar denna avhandling att primär aldosteronism är underdiagnostiserat och förknippat med ökad risk för allvarliga konsekvenser, vi vii hjärtkärlsjukdom, höftfrakturer och dödlighet. Sjukdomen bör uppmärksammas så att patienter identifieras för att de ska få möjlighet att LIST OF PAPERS behandlas. Patienter bör erbjudas binjurevenskateterisering, vilket kan bidra till att förbättra den enskilde patientens prognos och detta gäller särskilt unga This thesis is based on the following studies, referred to in the text by their patienter. Det krävs en mer inriktad och individanpassad behandling, då kön, Roman numerals. samsjuklighet, ålder och användning av MRA i rätt dos påverkar prognosen. I. Gkaniatsa E, Ekerstad E, Gavric M, Muth A, Trimpou P, Det är viktigt med framtida forskning med fokus på att fastställa Olsson DS, Johannsson G, Ragnarsson O. Increasing patientrapporterade utfallsmått och identifiera patientgrupper som bör erbjudas Incidence of primary aldosteronism in Western Sweden adrenalektomi. during 3 Decades – Yet An Underdiagnosed Disorder. J Clin Endocrinol Metab. 2021;106:e3603-e3610 Studier har finansierats med hjälp av anslag från Avtal om Läkarutbildning och Forskning (ALF 971027), och Göteborgs Läkaresällskap. II. Gkaniatsa E, Sakinis A, Palmér M, Muth A, Trimpou P, Ragnarsson O. Adrenal venous sampling in young patients with primary aldosteronism. Extravagance or irreplaceable? J Clin Endocrinol Metab. 2021;106:e2087- e2095 III. Gkaniatsa E, Zverkova Sandström T, Rosengren A, Trimpou P, Olsson DS, Lind M, Muth A, Johannsson G, Ragnarsson O. Mortality in patients with primary aldosteronism: a Swedish nationwide study. Hypertension. 2023;80:2601- 2610 IV. Gkaniatsa E, Sandström TZ, Rosengren A, Trimpou P, Muth A, Johannsson G, Ragnarsson O. Hip fractures in patients with primary aldosteronism – a Swedish nationwide study. Osteoporos Int. 2024;35:1585-1593 viii ix hjärtkärlsjukdom, höftfrakturer och dödlighet. Sjukdomen bör uppmärksammas så att patienter identifieras för att de ska få möjlighet att LIST OF PAPERS behandlas. Patienter bör erbjudas binjurevenskateterisering, vilket kan bidra till att förbättra den enskilde patientens prognos och detta gäller särskilt unga This thesis is based on the following studies, referred to in the text by their patienter. Det krävs en mer inriktad och individanpassad behandling, då kön, Roman numerals. samsjuklighet, ålder och användning av MRA i rätt dos påverkar prognosen. I. Gkaniatsa E, Ekerstad E, Gavric M, Muth A, Trimpou P, Det är viktigt med framtida forskning med fokus på att fastställa Olsson DS, Johannsson G, Ragnarsson O. Increasing patientrapporterade utfallsmått och identifiera patientgrupper som bör erbjudas Incidence of primary aldosteronism in Western Sweden adrenalektomi. during 3 Decades – Yet An Underdiagnosed Disorder. J Clin Endocrinol Metab. 2021;106:e3603-e3610 Studier har finansierats med hjälp av anslag från Avtal om Läkarutbildning och Forskning (ALF 971027), och Göteborgs Läkaresällskap. II. Gkaniatsa E, Sakinis A, Palmér M, Muth A, Trimpou P, Ragnarsson O. Adrenal venous sampling in young patients with primary aldosteronism. Extravagance or irreplaceable? J Clin Endocrinol Metab. 2021;106:e2087- e2095 III. Gkaniatsa E, Zverkova Sandström T, Rosengren A, Trimpou P, Olsson DS, Lind M, Muth A, Johannsson G, Ragnarsson O. Mortality in patients with primary aldosteronism: a Swedish nationwide study. Hypertension. 2023;80:2601- 2610 IV. Gkaniatsa E, Sandström TZ, Rosengren A, Trimpou P, Muth A, Johannsson G, Ragnarsson O. Hip fractures in patients with primary aldosteronism – a Swedish nationwide study. Osteoporos Int. 2024;35:1585-1593 viii ix CONTENTS 3.1 Patients and study design .................................................................... 21 3.1.1 Data sources and ethical considerations ...................................... 21 Preface .......................................................................................................... xiii 3.1.2 Paper I – Incidence of primary aldosteronism ............................. 23 Abbreviations ............................................................................................... xiv 3.1.3 Paper II − Adrenal vein sampling in young patients with primary Definitions in short ....................................................................................... xvi aldosteronism ............................................................................... 23 1 Introduction ................................................................................................ 1 3.1.4 Paper III − Mortality in primary aldosteronism .......................... 24 1.1 History of primary aldosteronism ......................................................... 1 3.1.5 Paper IV − Hip fractures in primary aldosteronism .................... 25 1.2 Primary aldosteronism – a growing challenge ...................................... 2 3.2 Statistical analysis ............................................................................... 25 1.3 Aldosterone ........................................................................................... 2 3.3 Methodological considerations ........................................................... 27 1.3.1 Regulation of aldosterone secretion .............................................. 4 4 Results ...................................................................................................... 30 1.3.2 Effects of mineralocorticoid receptor overactivation .................... 5 4.1 Paper I – Incidence of primary aldosteronism..................................... 30 1.4 Primary aldosteronism .......................................................................... 7 4.2 Paper II – Adrenal vein sampling in young patients with primary aldosteronism ...................................................................................... 32 1.4.1 Definition ...................................................................................... 7 4.3 Paper III – Mortality in primary aldosteronism .................................. 33 1.4.2 Clinical presentation ...................................................................... 7 4.4 Paper IV – Hip fractures in primary aldosteronism ............................ 35 1.4.3 Epidemiology of primary aldosteronism ....................................... 8 5 Discussion ................................................................................................ 37 1.4.4 Histopathologic classification of primary aldosteronism .............. 8 5.1 Key findings ........................................................................................ 37 1.4.5 Somatic and germline mutations associated with primary aldosteronism ................................................................................ 9 5.2 Trends in incidence of primary aldosteronism and priorities .............. 38 1.5 Assessment and diagnosis of primary aldosteronism .......................... 10 5.3 Why should young patients undergo adrenal vein sampling? ............. 39 1.5.1 Aldosterone and renin measurements .......................................... 11 5.4 Can specific treatment with a mineralocorticoid receptor antagonist or adrenalectomy prevent mortality in primary aldosteronism? .............. 40 1.5.2 Confirmatory tests ....................................................................... 12 5.4.1 Appropriate dose of mineralocorticoid receptor antagonist is 1.5.3 Assessing the etiology of primary aldosteronism ........................ 12 critical .......................................................................................... 41 1.6 Treatment and outcome of primary aldosteronism ............................. 14 5.4.2 Importance of timely management .............................................. 42 1.6.1 Surgery ........................................................................................ 14 5.4.3 Comorbid conditions and outcomes in patients with primary 1.6.2 Mineralocorticoid receptor antagonists ....................................... 15 aldosteronism ............................................................................... 43 1.6.3 Morbidity attributable to primary aldosteronism ........................ 16 5.5 Is adrenalectomy more effective than a mineralocorticoid receptor 1.7 Challenges in the diagnosis and individualized treatment of primary antagonist? .......................................................................................... 43 aldosteronism ...................................................................................... 17 5.5.1 Should adrenalectomy be preserved for patients with predictors of 1.8 Gaps of knowledge.............................................................................. 18 complete cure? ............................................................................. 44 2 Aim ........................................................................................................... 20 5.6 Risk of fracture in primary aldosteronism ........................................... 45 3 Patients and methods ................................................................................ 21 6 Conclusion ................................................................................................ 47 x xi CONTENTS 3.1 Patients and study design .................................................................... 21 3.1.1 Data sources and ethical considerations ...................................... 21 Preface .......................................................................................................... xiii 3.1.2 Paper I – Incidence of primary aldosteronism ............................. 23 Abbreviations ............................................................................................... xiv 3.1.3 Paper II − Adrenal vein sampling in young patients with primary Definitions in short ....................................................................................... xvi aldosteronism ............................................................................... 23 1 Introduction ................................................................................................ 1 3.1.4 Paper III − Mortality in primary aldosteronism .......................... 24 1.1 History of primary aldosteronism ......................................................... 1 3.1.5 Paper IV − Hip fractures in primary aldosteronism .................... 25 1.2 Primary aldosteronism – a growing challenge ...................................... 2 3.2 Statistical analysis ............................................................................... 25 1.3 Aldosterone ........................................................................................... 2 3.3 Methodological considerations ........................................................... 27 1.3.1 Regulation of aldosterone secretion .............................................. 4 4 Results ...................................................................................................... 30 1.3.2 Effects of mineralocorticoid receptor overactivation .................... 5 4.1 Paper I – Incidence of primary aldosteronism..................................... 30 1.4 Primary aldosteronism .......................................................................... 7 4.2 Paper II – Adrenal vein sampling in young patients with primary aldosteronism ...................................................................................... 32 1.4.1 Definition ...................................................................................... 7 4.3 Paper III – Mortality in primary aldosteronism .................................. 33 1.4.2 Clinical presentation ...................................................................... 7 4.4 Paper IV – Hip fractures in primary aldosteronism ............................ 35 1.4.3 Epidemiology of primary aldosteronism ....................................... 8 5 Discussion ................................................................................................ 37 1.4.4 Histopathologic classification of primary aldosteronism .............. 8 5.1 Key findings ........................................................................................ 37 1.4.5 Somatic and germline mutations associated with primary aldosteronism ................................................................................ 9 5.2 Trends in incidence of primary aldosteronism and priorities .............. 38 1.5 Assessment and diagnosis of primary aldosteronism .......................... 10 5.3 Why should young patients undergo adrenal vein sampling? ............. 39 1.5.1 Aldosterone and renin measurements .......................................... 11 5.4 Can specific treatment with a mineralocorticoid receptor antagonist or adrenalectomy prevent mortality in primary aldosteronism? .............. 40 1.5.2 Confirmatory tests ....................................................................... 12 5.4.1 Appropriate dose of mineralocorticoid receptor antagonist is 1.5.3 Assessing the etiology of primary aldosteronism ........................ 12 critical .......................................................................................... 41 1.6 Treatment and outcome of primary aldosteronism ............................. 14 5.4.2 Importance of timely management .............................................. 42 1.6.1 Surgery ........................................................................................ 14 5.4.3 Comorbid conditions and outcomes in patients with primary 1.6.2 Mineralocorticoid receptor antagonists ....................................... 15 aldosteronism ............................................................................... 43 1.6.3 Morbidity attributable to primary aldosteronism ........................ 16 5.5 Is adrenalectomy more effective than a mineralocorticoid receptor 1.7 Challenges in the diagnosis and individualized treatment of primary antagonist? .......................................................................................... 43 aldosteronism ...................................................................................... 17 5.5.1 Should adrenalectomy be preserved for patients with predictors of 1.8 Gaps of knowledge.............................................................................. 18 complete cure? ............................................................................. 44 2 Aim ........................................................................................................... 20 5.6 Risk of fracture in primary aldosteronism ........................................... 45 3 Patients and methods ................................................................................ 21 6 Conclusion ................................................................................................ 47 x xi 7 Future perspectives ................................................................................... 48 PREFACE Acknowledgement ......................................................................................... 50 References ..................................................................................................... 52 At least 1.8 million Swedish adults have hypertension, a major risk factor for stroke, heart attack, and heart failure. 1 Treatment of hypertension includes medication and lifestyle changes; however, many patients have poorly controlled blood pressure despite recent advances in molecular biology, genomics, and pharmacology. Primary aldosteronism is often the cause of poorly controlled hypertension and carries a risk of cardiovascular complications. When primary aldosteronism is diagnosed and treated correctly, blood pressure can be lowered and cardiovascular complications can be prevented. This thesis focuses on the epidemiology, subtype distinction, and outcomes of primary aldosteronism in Sweden and the influence of treatment and other risk factors on morbidity and mortality. Using registries, we can track patient characteristics, treatment, and outcomes longitudinally in a real-world healthcare setting. This data allows us to identify areas for improvement and may support changes in our practices to optimize treatment. I hope this thesis contributes to the improvement of healthcare in patients with primary aldosteronism. xii xiii 7 Future perspectives ................................................................................... 48 PREFACE Acknowledgement ......................................................................................... 50 References ..................................................................................................... 52 At least 1.8 million Swedish adults have hypertension, a major risk factor for stroke, heart attack, and heart failure. 1 Treatment of hypertension includes medication and lifestyle changes; however, many patients have poorly controlled blood pressure despite recent advances in molecular biology, genomics, and pharmacology. Primary aldosteronism is often the cause of poorly controlled hypertension and carries a risk of cardiovascular complications. When primary aldosteronism is diagnosed and treated correctly, blood pressure can be lowered and cardiovascular complications can be prevented. This thesis focuses on the epidemiology, subtype distinction, and outcomes of primary aldosteronism in Sweden and the influence of treatment and other risk factors on morbidity and mortality. Using registries, we can track patient characteristics, treatment, and outcomes longitudinally in a real-world healthcare setting. This data allows us to identify areas for improvement and may support changes in our practices to optimize treatment. I hope this thesis contributes to the improvement of healthcare in patients with primary aldosteronism. xii xiii ABBREVIATIONS MRA Mineralocorticoid receptor antagonist MRE Mineralocorticoid response element 11β-HSD2 11β-hydroxysteroid dehydrogenase MRI Magnetic resonance imaging ACTH Adrenocorticotropic hormone NFB Nuclear factor kappa B APA Aldosterone-producing adenoma NPR National Patient Register ARR Aldosterone-renin ratio OR Odds ratio ATC Anatomical Therapeutic Chemical Classification PA Primary aldosteronism AVS Adrenal vein sampling ROS Reactive oxygen species CI Confidence interval SD Standard deviation CT Computed tomography SIT Saline infusion test CVD Cardiovascular disease SSIT Seated saline infusion test CYP Cytochrome P450 DDD Defined daily dose DHEA Dehyrdroepiandrosterone ENaC Epithelial sodium channel GRA Glucocorticoid-remediable aldosteronism HR Hazard ratio ICD International Classification of Diseases IQR Interquartile range LISA Longitudinal Database of Health Insurance and Labour Market Studies MR Mineralocorticoid receptor xiv xv ABBREVIATIONS MRA Mineralocorticoid receptor antagonist MRE Mineralocorticoid response element 11β-HSD2 11β-hydroxysteroid dehydrogenase MRI Magnetic resonance imaging ACTH Adrenocorticotropic hormone NFB Nuclear factor kappa B APA Aldosterone-producing adenoma NPR National Patient Register ARR Aldosterone-renin ratio OR Odds ratio ATC Anatomical Therapeutic Chemical Classification PA Primary aldosteronism AVS Adrenal vein sampling ROS Reactive oxygen species CI Confidence interval SD Standard deviation CT Computed tomography SIT Saline infusion test CVD Cardiovascular disease SSIT Seated saline infusion test CYP Cytochrome P450 DDD Defined daily dose DHEA Dehyrdroepiandrosterone ENaC Epithelial sodium channel GRA Glucocorticoid-remediable aldosteronism HR Hazard ratio ICD International Classification of Diseases IQR Interquartile range LISA Longitudinal Database of Health Insurance and Labour Market Studies MR Mineralocorticoid receptor xiv xv Eleftheria Gkaniatsa DEFINITIONS IN SHORT 1 INTRODUCTION Prevalence The total number of cases of disease in a given timeframe 1.1 HISTORY OF PRIMARY Incidence The number of newly identified cases of ALDOSTERONISM disease during a specified timeframe The history of primary aldosteronism (PA) begins in 1952 when electrocortin, Mortality rate The number of deaths due to a disease later named aldosterone, was discovered and isolated by Simpson and Tait. 2 In 1955, Jerome Conn described the clinical features of severe PA and published divided by the total population the first report of a person with an aldosterone-producing adenoma to be treated Hazard ratio A measure of how often a particular event by adrenalectomy. 3 The patient was a 34-year-old woman who suffered from happens in one group compared to how generalized muscular weakness and periodic paralysis attributed to remarkable often it happens in another group over time. hypokalemia. Severe hypertension and salt loss were the only clues to pinpoint that the adrenal glands were diseased with the production of excessive A hazard ratio of 1 means that there is no aldosterone. Conn considered bilateral adrenalectomy as a treatment choice difference in the risk between the two due to the patient’s severe functional impairment. The finding of an adrenal groups. A hazard ratio of >1 or <1 means tumor exceeded all expectations and the patient made a full recovery after the that the risk of the event is higher or lower tumor was removed. She left the clinic 227 days later with a resolution of all in one of the groups, respectively. her symptoms. By the late 1960s, case reports proved the existence of another form of primary aldosteronism caused by bilateral hyperplasia of the adrenal glands. The efficacy of spironolactone, the first aldosterone antagonist launched in 1959, prompted physicians to reconsider potentially harmful bilateral adrenalectomy.4 Subtype prediction proved difficult as patients with bilateral disease shared clinical features with Conn’s original case.5 To address this issue, angiographic techniques to localize adrenal tumors have been used since the 1960s.6 Computed tomography (CT) scans were introduced in the 1970s. Decades later, it was acknowledged that nonfunctional adrenal tumors may coincide and undermine CT accuracy in diagnosing unilateral PA.7 Primary aldosteronism is not uncommon but until the early 1990s only clinically overt cases had come to light. Aldosterone-renin ratio (ARR), introduced in 1981, quickly became standard and greatly improved screening for PA.8 The 1990s witnessed significant developments in laparoscopic surgery.9,10 1987 marked the identification of the mineralocorticoid receptor (MR) and opened the door to understanding molecular signaling pathways.11 In the decades that followed, major aldosterone biosynthetic pathways were mapped12,13 and insights into PA genetics were gained.14-18 Through recent xvi 1 Eleftheria Gkaniatsa DEFINITIONS IN SHORT 1 INTRODUCTION Prevalence The total number of cases of disease in a given timeframe 1.1 HISTORY OF PRIMARY Incidence The number of newly identified cases of ALDOSTERONISM disease during a specified timeframe The history of primary aldosteronism (PA) begins in 1952 when electrocortin, Mortality rate The number of deaths due to a disease later named aldosterone, was discovered and isolated by Simpson and Tait. 2 In 1955, Jerome Conn described the clinical features of severe PA and published divided by the total population the first report of a person with an aldosterone-producing adenoma to be treated Hazard ratio A measure of how often a particular event by adrenalectomy. 3 The patient was a 34-year-old woman who suffered from happens in one group compared to how generalized muscular weakness and periodic paralysis attributed to remarkable often it happens in another group over time. hypokalemia. Severe hypertension and salt loss were the only clues to pinpoint that the adrenal glands were diseased with the production of excessive A hazard ratio of 1 means that there is no aldosterone. Conn considered bilateral adrenalectomy as a treatment choice difference in the risk between the two due to the patient’s severe functional impairment. The finding of an adrenal groups. A hazard ratio of >1 or <1 means tumor exceeded all expectations and the patient made a full recovery after the that the risk of the event is higher or lower tumor was removed. She left the clinic 227 days later with a resolution of all in one of the groups, respectively. her symptoms. By the late 1960s, case reports proved the existence of another form of primary aldosteronism caused by bilateral hyperplasia of the adrenal glands. The efficacy of spironolactone, the first aldosterone antagonist launched in 1959, prompted physicians to reconsider potentially harmful bilateral adrenalectomy.4 Subtype prediction proved difficult as patients with bilateral disease shared clinical features with Conn’s original case.5 To address this issue, angiographic techniques to localize adrenal tumors have been used since the 1960s.6 Computed tomography (CT) scans were introduced in the 1970s. Decades later, it was acknowledged that nonfunctional adrenal tumors may coincide and undermine CT accuracy in diagnosing unilateral PA.7 Primary aldosteronism is not uncommon but until the early 1990s only clinically overt cases had come to light. Aldosterone-renin ratio (ARR), introduced in 1981, quickly became standard and greatly improved screening for PA.8 The 1990s witnessed significant developments in laparoscopic surgery.9,10 1987 marked the identification of the mineralocorticoid receptor (MR) and opened the door to understanding molecular signaling pathways.11 In the decades that followed, major aldosterone biosynthetic pathways were mapped12,13 and insights into PA genetics were gained.14-18 Through recent xvi 1 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa advances in immunohistochemical methods19 and genomics, our inner medulla. Aldosterone is a steroid hormone produced by the adrenal understanding of PA has improved (figure 1). 18,20,21 cortex. Aldosterone is the most physiologically important mineralocorticoid, widely known for its role in the kidney, where it interacts with the MR to regulate blood pressure (BP) by increasing sodium reabsorption (figure 2).32,36 Aldosterone also has an important role in cell proliferation, cell differentiation, and macrophage infiltration.37,38 Figure 1. Timeline highlighting key milestones for primary aldosteronism. Abbreviations: 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; APA, aldosterone-producing adenoma; AVS, adrenal vein sampling; CT, computed tomography; CYP, cytochrome P450; GRA, glucocorticoid-remediable aldosteronism; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist. Figure 2. Aldosterone, the specific MR ligand, regulates target gene expression. The predominant biological effect of aldosterone on renal epithelium is the transcription 1.2 PRIMARY ALDOSTERONISM – A of ENaC. MRE is the specific aldosterone DNA response element. Abbreviations: ENaC, epithelial sodium channel; MR, mineralocorticoid receptor; MRE, GROWING CHALLENGE mineralocorticoid response element. [Reproduced from Byrd et al.32 with permission from ©Wolters Kluwer Health] Conn predicted the evolution of PA.22 Comprehensive research suggests that PA is more common than previously thought.23-27 Recent research has The first steps of steroidogenesis from cholesterol are common for all steroid identified the heterogeneous nature of PA, ranging from clinically overt to hormones. Steroidogenesis differs among the different adrenal cortex layers normokalemic and normotensive patients that often go undetected.28-30 Some (zona glomerulosa, zona fasciculata, and zona reticularis) because of the experts argue that we need to be more pragmatic and target subgroups where presence of specific enzymes.39 In the final steps of cortisol and aldosterone PA has the most detrimental effects.31-33 As the prevalence of PA is biosynthesis, the enzymes coded by CYP11B1 and CYP11B2 genes are increasing,27,34 more research is needed to guide clinicians on how to required, respectively (figure 3). The zona glomerulosa, the outer layer of the individualize PA treatment.35 adrenal cortex, is the only layer where CYP11B2 is expressed.39 The organization of adrenal cortex layers and cell population differentiation is dynamic.40 Dysregulation of cell differentiation can lead to adrenal gland 1.3 ALDOSTERONE pathologies such as adrenal tumors or overproduction of hormones.41,42 The human adrenal glands are localized in the retroperitoneal space, near the upper poles of the kidneys. Macroscopically, each has an outer cortex and an 2 3 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa advances in immunohistochemical methods19 and genomics, our inner medulla. Aldosterone is a steroid hormone produced by the adrenal understanding of PA has improved (figure 1). 18,20,21 cortex. Aldosterone is the most physiologically important mineralocorticoid, widely known for its role in the kidney, where it interacts with the MR to regulate blood pressure (BP) by increasing sodium reabsorption (figure 2).32,36 Aldosterone also has an important role in cell proliferation, cell differentiation, and macrophage infiltration.37,38 Figure 1. Timeline highlighting key milestones for primary aldosteronism. Abbreviations: 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; APA, aldosterone-producing adenoma; AVS, adrenal vein sampling; CT, computed tomography; CYP, cytochrome P450; GRA, glucocorticoid-remediable aldosteronism; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist. Figure 2. Aldosterone, the specific MR ligand, regulates target gene expression. The predominant biological effect of aldosterone on renal epithelium is the transcription 1.2 PRIMARY ALDOSTERONISM – A of ENaC. MRE is the specific aldosterone DNA response element. Abbreviations: ENaC, epithelial sodium channel; MR, mineralocorticoid receptor; MRE, GROWING CHALLENGE mineralocorticoid response element. [Reproduced from Byrd et al.32 with permission from ©Wolters Kluwer Health] Conn predicted the evolution of PA.22 Comprehensive research suggests that PA is more common than previously thought.23-27 Recent research has The first steps of steroidogenesis from cholesterol are common for all steroid identified the heterogeneous nature of PA, ranging from clinically overt to hormones. Steroidogenesis differs among the different adrenal cortex layers normokalemic and normotensive patients that often go undetected.28-30 Some (zona glomerulosa, zona fasciculata, and zona reticularis) because of the experts argue that we need to be more pragmatic and target subgroups where presence of specific enzymes.39 In the final steps of cortisol and aldosterone PA has the most detrimental effects.31-33 As the prevalence of PA is biosynthesis, the enzymes coded by CYP11B1 and CYP11B2 genes are increasing,27,34 more research is needed to guide clinicians on how to required, respectively (figure 3). The zona glomerulosa, the outer layer of the individualize PA treatment.35 adrenal cortex, is the only layer where CYP11B2 is expressed.39 The organization of adrenal cortex layers and cell population differentiation is dynamic.40 Dysregulation of cell differentiation can lead to adrenal gland 1.3 ALDOSTERONE pathologies such as adrenal tumors or overproduction of hormones.41,42 The human adrenal glands are localized in the retroperitoneal space, near the upper poles of the kidneys. Macroscopically, each has an outer cortex and an 2 3 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa causes transient increases in aldosterone synthesis by binding to the melanocortin 2 receptor.44 Plasma potassium concentration has a direct effect on the electronegative potential of the zona glomerulosa cell membrane.44 The cascade of aldosterone secretion responds to negative feedback loops to maintain fluid and electrolyte homeostasis. A rate-limiting step in the secretion of aldosterone from the zona glomerulosa cells of the adrenal cortex is the production of renin (figure 4A). The renin-angiotensin-aldosterone system adapts to sodium intake.45,46 Thus, people with hypertension benefit from salt restriction.46,47 Figure 3. Overview of steroidogenesis from the adrenal cortex. Abbreviations: 3βHSD2, 3β-hydroxysteroid dehydrogenase type 2; CYP, cytochrome P450; DHEA, dehyrdroepiandrosterone; SULT2A1, sulfotransferase 2A1. [Reproduced with permission from Pereira et al.39 with permission from ©Springer] 1.3.1 REGULATION OF ALDOSTERONE SECRETION The zona glomerulosa cells regulate their secretion in response to angiotensin 2, changes in extracellular potassium, and to a lesser extent by adrenocorticotropic hormone (ACTH). Angiotensin 2, the main regulator of Figure 4. A. Physiology of regulation of the renin-angiotensin-aldosterone system. B. Angiotensin-independent aldosterone secretion leads to volume overload, aldosterone synthesis, is part of the renin-angiotensin-aldosterone system. This hypertension, and hypokalemia. This suppresses renin through negative feedback. ARR complex hormone network is continually responding to changes in blood is often above the reference range. Abbreviations: ACE, angiotensin-converting volume, vascular tone, and electrolyte levels. A decrease in the flow rate of enzyme; ARR, aldosterone-renin ratio. [Reproduced from Reincke et al.48 with filtered fluid through the kidney (sensed by the macula densa) or a drop in permission from ©Elsevier] arterial BP (sensed by baroreceptors) triggers the release of renin. In 1.3.2 EFFECTS OF MINERALOCORTICOID circulation, released renin reacts with plasma angiotensinogen to form angiotensin 1, which is further converted by angiotensin-converting enzyme RECEPTOR OVERACTIVATION into angiotensin 2. Stimulation of aldosterone secretion by angiotensin 2 The MR mediates the cellular response to aldosterone.36 MRs regulate gene combined with vasoconstriction increases BP. transcription across different tissues.36 They are abundantly expressed in the renal nephron but are also present in the heart, vasculature, intestine, salivary Recent research has shed light on the complex intracellular signaling pathways glands, adipocytes, and bone.39,49 The MR has a similar structure to the that modulate aldosterone secretion and their dynamics.43 Angiotensin II glucocorticoid receptor.50 The concentration of circulating glucocorticoids is receptor type 1, a membrane-bound G-protein-coupled receptor, allows 1000-fold the concentration of aldosterone.36 In target tissues, the enzyme 11β- angiotensin 2 to exert physiological regulation of aldosterone secretion. ACTH hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to 4 5 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa causes transient increases in aldosterone synthesis by binding to the melanocortin 2 receptor.44 Plasma potassium concentration has a direct effect on the electronegative potential of the zona glomerulosa cell membrane.44 The cascade of aldosterone secretion responds to negative feedback loops to maintain fluid and electrolyte homeostasis. A rate-limiting step in the secretion of aldosterone from the zona glomerulosa cells of the adrenal cortex is the production of renin (figure 4A). The renin-angiotensin-aldosterone system adapts to sodium intake.45,46 Thus, people with hypertension benefit from salt restriction.46,47 Figure 3. Overview of steroidogenesis from the adrenal cortex. Abbreviations: 3βHSD2, 3β-hydroxysteroid dehydrogenase type 2; CYP, cytochrome P450; DHEA, dehyrdroepiandrosterone; SULT2A1, sulfotransferase 2A1. [Reproduced with permission from Pereira et al.39 with permission from ©Springer] 1.3.1 REGULATION OF ALDOSTERONE SECRETION The zona glomerulosa cells regulate their secretion in response to angiotensin 2, changes in extracellular potassium, and to a lesser extent by adrenocorticotropic hormone (ACTH). Angiotensin 2, the main regulator of Figure 4. A. Physiology of regulation of the renin-angiotensin-aldosterone system. B. Angiotensin-independent aldosterone secretion leads to volume overload, aldosterone synthesis, is part of the renin-angiotensin-aldosterone system. This hypertension, and hypokalemia. This suppresses renin through negative feedback. ARR complex hormone network is continually responding to changes in blood is often above the reference range. Abbreviations: ACE, angiotensin-converting volume, vascular tone, and electrolyte levels. A decrease in the flow rate of enzyme; ARR, aldosterone-renin ratio. [Reproduced from Reincke et al.48 with filtered fluid through the kidney (sensed by the macula densa) or a drop in permission from ©Elsevier] arterial BP (sensed by baroreceptors) triggers the release of renin. In 1.3.2 EFFECTS OF MINERALOCORTICOID circulation, released renin reacts with plasma angiotensinogen to form angiotensin 1, which is further converted by angiotensin-converting enzyme RECEPTOR OVERACTIVATION into angiotensin 2. Stimulation of aldosterone secretion by angiotensin 2 The MR mediates the cellular response to aldosterone.36 MRs regulate gene combined with vasoconstriction increases BP. transcription across different tissues.36 They are abundantly expressed in the renal nephron but are also present in the heart, vasculature, intestine, salivary Recent research has shed light on the complex intracellular signaling pathways glands, adipocytes, and bone.39,49 The MR has a similar structure to the that modulate aldosterone secretion and their dynamics.43 Angiotensin II glucocorticoid receptor.50 The concentration of circulating glucocorticoids is receptor type 1, a membrane-bound G-protein-coupled receptor, allows 1000-fold the concentration of aldosterone.36 In target tissues, the enzyme 11β- angiotensin 2 to exert physiological regulation of aldosterone secretion. ACTH hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to 4 5 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa cortisone, allowing aldosterone to bind to the MR.12 When 11β-HSD2 is absent or inhibited (i.e. syndrome of apparent mineralocorticoid excess or licorice), the MR can be equally activated by glucocorticoids.51 In renal epithelial cells, MR overactivation increases the transcription of epithelial Na+ channels and enhances the activity of the Na+/K+-ATPase pump in the basolateral membrane. This increases blood volume and BP since more sodium is transported from urine into peritubular capillaries, while water is retained with the osmotically active sodium.32 Aldosterone also enhances the function of the H+-ATPase pump in the intercalated cells of the distal kidney nephron, which recycles potassium into the urine in exchange for H+ ions. Thus, aldosterone overproduction leads to hypertension, low potassium levels, and alkalosis (figure 4B). Overactivation of the MR leads to endothelial dysfunction, cardiac remodeling, and kidney injury (figure 5).52 Two early experiments in rats demonstrated the Figure 5 Principal mechanisms by which MR overactivation may cause cardiac and importance of MR overactivation in cardiac and renal disease. Aldosterone renal injury. Abbreviations: MR, mineralocorticoid receptor; NFB, nuclear factor kappa B; ROS, reactive oxygen species. [Reproduced from Savarese et al.55 with infusion along with a high-salt diet caused oxidative stress, myocardial and permission from ©Springer Nature] perivascular inflammation, accumulation of fibrillar collagen, and subsequent interstitial and perivascular fibrosis.53 In another experiment, exogenous aldosterone infusion induced thrombotic microangiopathies causing 1.4 PRIMARY ALDOSTERONISM glomerulosclerosis and proteinuria.54 1.4.1 DEFINITION Chronic overexposure to aldosterone can be caused by secondary factors such The Endocrine Society defines PA as “a group of disorders in which as renal artery stenosis, heart failure, or liver cirrhosis; therefore, inhibition of aldosterone production is inappropriately high for sodium status, relatively MRs is effective in treating these conditions.55 autonomous of the major regulators of secretion (angiotensin II, plasma potassium concentration), and not suppressible by sodium loading.”56 The definition of PA covers a spectrum of normotensive and hypertensive people with autonomous aldosterone secretion.30 1.4.2 CLINICAL PRESENTATION For most patients, the diagnosis of PA is made in their 50s but PA can occur at any age. Clinical presentation varies. Combined hypertension and hypokalemia are highly suggestive of PA, although not all patients present with these features.57,58 Hypokalemia relates to disease duration and aldosterone levels, affecting up to 37% of all prevalent patients.23,34 Patients with hypokalemia may experience muscle weakness and cramping, palpitations or arrhythmia, lack of energy, frequent urination, and constipation depending on severity. 6 7 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa cortisone, allowing aldosterone to bind to the MR.12 When 11β-HSD2 is absent or inhibited (i.e. syndrome of apparent mineralocorticoid excess or licorice), the MR can be equally activated by glucocorticoids.51 In renal epithelial cells, MR overactivation increases the transcription of epithelial Na+ channels and enhances the activity of the Na+/K+-ATPase pump in the basolateral membrane. This increases blood volume and BP since more sodium is transported from urine into peritubular capillaries, while water is retained with the osmotically active sodium.32 Aldosterone also enhances the function of the H+-ATPase pump in the intercalated cells of the distal kidney nephron, which recycles potassium into the urine in exchange for H+ ions. Thus, aldosterone overproduction leads to hypertension, low potassium levels, and alkalosis (figure 4B). Overactivation of the MR leads to endothelial dysfunction, cardiac remodeling, and kidney injury (figure 5).52 Two early experiments in rats demonstrated the Figure 5 Principal mechanisms by which MR overactivation may cause cardiac and importance of MR overactivation in cardiac and renal disease. Aldosterone renal injury. Abbreviations: MR, mineralocorticoid receptor; NFB, nuclear factor kappa B; ROS, reactive oxygen species. [Reproduced from Savarese et al.55 with infusion along with a high-salt diet caused oxidative stress, myocardial and permission from ©Springer Nature] perivascular inflammation, accumulation of fibrillar collagen, and subsequent interstitial and perivascular fibrosis.53 In another experiment, exogenous aldosterone infusion induced thrombotic microangiopathies causing 1.4 PRIMARY ALDOSTERONISM glomerulosclerosis and proteinuria.54 1.4.1 DEFINITION Chronic overexposure to aldosterone can be caused by secondary factors such The Endocrine Society defines PA as “a group of disorders in which as renal artery stenosis, heart failure, or liver cirrhosis; therefore, inhibition of aldosterone production is inappropriately high for sodium status, relatively MRs is effective in treating these conditions.55 autonomous of the major regulators of secretion (angiotensin II, plasma potassium concentration), and not suppressible by sodium loading.”56 The definition of PA covers a spectrum of normotensive and hypertensive people with autonomous aldosterone secretion.30 1.4.2 CLINICAL PRESENTATION For most patients, the diagnosis of PA is made in their 50s but PA can occur at any age. Clinical presentation varies. Combined hypertension and hypokalemia are highly suggestive of PA, although not all patients present with these features.57,58 Hypokalemia relates to disease duration and aldosterone levels, affecting up to 37% of all prevalent patients.23,34 Patients with hypokalemia may experience muscle weakness and cramping, palpitations or arrhythmia, lack of energy, frequent urination, and constipation depending on severity. 6 7 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 1.4.3 EPIDEMIOLOGY OF PRIMARY gland. Nonfunctional adrenal tumors do not stain for aldosterone synthase ALDOSTERONISM (figure 6). The prevalence of PA varies from 4% in individuals with mild hypertension to 20% in individuals with treatment-resistant hypertension.59 Assessing the prevalence of PA in different patient populations has been challenging, at least in part due to variability in definitions and criteria used to define it.24 In a meta- analysis of 42 510 patients,24 the prevalence of primary aldosteronism was lower in primary care (range 3.2%–12.7%) than in referral centers (1%– 29.8%). A regional study in Sweden estimated that 6% of patients with newly diagnosed hypertension (n=353) in specialized units (n=123) and primary care centers (n=230) had confirmed PA.60 In primary care settings, the prevalence ranged from 1.6% to 5.5%.61,62 PA is underdiagnosed.48,63,64 Screening rates for PA are reported to be low in the USA and Europe.64-66 A contemporary study raises further concerns that current screening cut-offs fail to identify some patients with PA.67 Clinical diagnostic accuracy remains suboptimal, even when hypokalemia is clinically manifest.57 Figure 6. Illustration of different histopathological types of primary aldosteronism. Abbreviation: APA, aldosterone-producing adenoma. [Reproduced from Scholl18 1.4.4 HISTOPATHOLOGIC CLASSIFICATION OF with permission from ©Wolters Kluwer Health] PRIMARY ALDOSTERONISM Patients with bilateral disease rarely undergo surgery, so access to adrenal Historically, PA has been classified as unilateral or bilateral depending on tissue specimens is limited. A study found that aldosterone-producing cell whether adrenal adenomas were present on histopathology. In 2021, consensus clusters were common in patients with bilateral PA in whom subtype was 69 classification of histopathological features of PA was updated by an expanded proven through adrenal vein sampling. group of pathologists to achieve consistency in terminology.68 Immunostaining for monoclonal antibodies against aldosterone synthase (CYP11B2), the Histopathology provides insights that the source of autonomous aldosterone enzyme needed for aldosterone synthesis, has served to identify the site- secretion can be viewed as a continuum from unilateral to bilateral disease. specific source of aldosterone production and subdivide PA into several Throughout this thesis, the terms unilateral and bilateral PA are used according categories.19 to the framework provided in the current guidelines. 56 Aldosterone-producing diffuse hyperplasia is characterized by an 1.4.5 SOMATIC AND GERMLINE MUTATIONS uninterrupted strip of aldosterone synthase-positive cells.21 The only difference ASSOCIATED WITH PRIMARY between aldosterone-producing adenomas >10 mm and aldosterone-producing ALDOSTERONISM nodules <10 mm is their size. Aldosterone-producing micronodules, also known as microscopic aldosterone-producing cell clusters, are not visible by Genetics have provided important insights into the pathogenesis of PA. In most hematoxylin and eosin staining but stain positive for aldosterone synthase. people, PA is not inherited. Somatic mutations in KCNJ5, CACNA1D, Multiple aldosterone-producing micronodules may be present in single adrenal ATP1A1, ATP2B3, and CTNNB1 genes can lead to impaired aldosterone secretion and have been identified in more than 90% of aldosterone-producing adenomas.15-18,21,70,71 These mutations do not fully explain the development of 8 9 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 1.4.3 EPIDEMIOLOGY OF PRIMARY gland. Nonfunctional adrenal tumors do not stain for aldosterone synthase ALDOSTERONISM (figure 6). The prevalence of PA varies from 4% in individuals with mild hypertension to 20% in individuals with treatment-resistant hypertension.59 Assessing the prevalence of PA in different patient populations has been challenging, at least in part due to variability in definitions and criteria used to define it.24 In a meta- analysis of 42 510 patients,24 the prevalence of primary aldosteronism was lower in primary care (range 3.2%–12.7%) than in referral centers (1%– 29.8%). A regional study in Sweden estimated that 6% of patients with newly diagnosed hypertension (n=353) in specialized units (n=123) and primary care centers (n=230) had confirmed PA.60 In primary care settings, the prevalence ranged from 1.6% to 5.5%.61,62 PA is underdiagnosed.48,63,64 Screening rates for PA are reported to be low in the USA and Europe.64-66 A contemporary study raises further concerns that current screening cut-offs fail to identify some patients with PA.67 Clinical diagnostic accuracy remains suboptimal, even when hypokalemia is clinically manifest.57 Figure 6. Illustration of different histopathological types of primary aldosteronism. Abbreviation: APA, aldosterone-producing adenoma. [Reproduced from Scholl18 1.4.4 HISTOPATHOLOGIC CLASSIFICATION OF with permission from ©Wolters Kluwer Health] PRIMARY ALDOSTERONISM Patients with bilateral disease rarely undergo surgery, so access to adrenal Historically, PA has been classified as unilateral or bilateral depending on tissue specimens is limited. A study found that aldosterone-producing cell whether adrenal adenomas were present on histopathology. In 2021, consensus clusters were common in patients with bilateral PA in whom subtype was 69 classification of histopathological features of PA was updated by an expanded proven through adrenal vein sampling. group of pathologists to achieve consistency in terminology.68 Immunostaining for monoclonal antibodies against aldosterone synthase (CYP11B2), the Histopathology provides insights that the source of autonomous aldosterone enzyme needed for aldosterone synthesis, has served to identify the site- secretion can be viewed as a continuum from unilateral to bilateral disease. specific source of aldosterone production and subdivide PA into several Throughout this thesis, the terms unilateral and bilateral PA are used according categories.19 to the framework provided in the current guidelines. 56 Aldosterone-producing diffuse hyperplasia is characterized by an 1.4.5 SOMATIC AND GERMLINE MUTATIONS uninterrupted strip of aldosterone synthase-positive cells.21 The only difference ASSOCIATED WITH PRIMARY between aldosterone-producing adenomas >10 mm and aldosterone-producing ALDOSTERONISM nodules <10 mm is their size. Aldosterone-producing micronodules, also known as microscopic aldosterone-producing cell clusters, are not visible by Genetics have provided important insights into the pathogenesis of PA. In most hematoxylin and eosin staining but stain positive for aldosterone synthase. people, PA is not inherited. Somatic mutations in KCNJ5, CACNA1D, Multiple aldosterone-producing micronodules may be present in single adrenal ATP1A1, ATP2B3, and CTNNB1 genes can lead to impaired aldosterone secretion and have been identified in more than 90% of aldosterone-producing adenomas.15-18,21,70,71 These mutations do not fully explain the development of 8 9 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa an adrenal tumor.21,42 The mechanisms underlying aldosterone-producing Hypertension (issued 2020).56,76 The early diagnosis of PA is challenging due diffuse hyperplasia need to be better characterized.21,42,72 to nonspecific symptoms. Without testing, PA can go unnoticed. Screening for PA is currently recommended if a patient with hypertension has: a) sustained PA is rarely inherited (1%–5%). A full review of the genetics of familial forms grade 2 hypertension (>150/100 mmHg); b) resistant hypertension (3 (I–V) and management is beyond the scope of this thesis.15,73,74 It is relevant antihypertensive medications including diuretics and BP >140/90 mmHg or from a clinical perspective to understand the genetic basis of glucocorticoid- need of ≥4 antihypertensive medications); c) young age (<40 years); d) early- remediable aldosteronism (GRA), which makes treatment with dexamethasone onset stroke; e) hypokalemia; f) incidentalomas (coincidental tumors in the efficient. In GRA, combination of cortisol and aldosterone synthase genes in a adrenal glands); g) sleep apnea; and h) a first-degree relative with PA or stroke chimeric gene result in upregulated aldosterone secretion, which is at a young age. pathologically activated by ACTH. GRA has a prevalence of 0.7% among patients with PA. 1.5.1 ALDOSTERONE AND RENIN MEASUREMENTS Screening involves measuring aldosterone and renin plasma concentrations. The diagnosis of PA is confirmed if a patient has a severe phenotype, i.e. high aldosterone levels >550 pmol/L and inappropriately low or suppressed renin (according to the local laboratory reference values) along with hypokalemia.56,77 Patients with a high ARR and a less severe phenotype need a confirmatory test.56 Due to the potential for false negative screening, repeated testing may be required.67 In up to 31% of patients, aldosterone levels vary on consecutive aldosterone measurements.78 Several physiological factors and medications have the potential to interfere with aldosterone and renin concentrations.56,76,79 Discontinuation of interfering medications causes distress and side effects.80 Interpretation without discontinuing treatment seems to be the best approach.33 Recent guidelines outline how to optimize testing conditions and how to interpret ARR in patients 56,75 Figure 7. Diagnostic work-up of primary aldosteronism. Abbreviations: PA, primary with interfering drugs. To avoid false-negative ARR, hypokalemia should aldosteronism; PAC, plasma aldosterone concentration. Figure was created with be identified and corrected before screening. If a patient is on an MRA BioRender.com medication and renin is not suppressed, it will be necessary to discontinue treatment at least 4 weeks before screening.56 1.5 ASSESSMENT AND DIAGNOSIS OF It is important that clinicians know about the assays used at their institution PRIMARY ALDOSTERONISM and interpret results accordingly. Most centers have replaced plasma renin The diagnosis of PA relies on biochemical evidence of angiotensin- activity, which measures the amount of angiotensinogen I generated over time, 81 independent aldosterone production. A combination of methods must be with direct renin concentration, which is less sensitive to poor sample employed to accomplish a complete assessment (figure 7). In Sweden, national handling and can be measured with a fully automated mass spectrometry 81,82 guidelines have been issued to help diagnose the different forms of PA and analyzer. were updated in 2023.75 They are in line with the guidelines from the Endocrine Society (updated 2016) and the consensus statement by European Society of 10 11 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa an adrenal tumor.21,42 The mechanisms underlying aldosterone-producing Hypertension (issued 2020).56,76 The early diagnosis of PA is challenging due diffuse hyperplasia need to be better characterized.21,42,72 to nonspecific symptoms. Without testing, PA can go unnoticed. Screening for PA is currently recommended if a patient with hypertension has: a) sustained PA is rarely inherited (1%–5%). A full review of the genetics of familial forms grade 2 hypertension (>150/100 mmHg); b) resistant hypertension (3 (I–V) and management is beyond the scope of this thesis.15,73,74 It is relevant antihypertensive medications including diuretics and BP >140/90 mmHg or from a clinical perspective to understand the genetic basis of glucocorticoid- need of ≥4 antihypertensive medications); c) young age (<40 years); d) early- remediable aldosteronism (GRA), which makes treatment with dexamethasone onset stroke; e) hypokalemia; f) incidentalomas (coincidental tumors in the efficient. In GRA, combination of cortisol and aldosterone synthase genes in a adrenal glands); g) sleep apnea; and h) a first-degree relative with PA or stroke chimeric gene result in upregulated aldosterone secretion, which is at a young age. pathologically activated by ACTH. GRA has a prevalence of 0.7% among patients with PA. 1.5.1 ALDOSTERONE AND RENIN MEASUREMENTS Screening involves measuring aldosterone and renin plasma concentrations. The diagnosis of PA is confirmed if a patient has a severe phenotype, i.e. high aldosterone levels >550 pmol/L and inappropriately low or suppressed renin (according to the local laboratory reference values) along with hypokalemia.56,77 Patients with a high ARR and a less severe phenotype need a confirmatory test.56 Due to the potential for false negative screening, repeated testing may be required.67 In up to 31% of patients, aldosterone levels vary on consecutive aldosterone measurements.78 Several physiological factors and medications have the potential to interfere with aldosterone and renin concentrations.56,76,79 Discontinuation of interfering medications causes distress and side effects.80 Interpretation without discontinuing treatment seems to be the best approach.33 Recent guidelines outline how to optimize testing conditions and how to interpret ARR in patients 56,75 Figure 7. Diagnostic work-up of primary aldosteronism. Abbreviations: PA, primary with interfering drugs. To avoid false-negative ARR, hypokalemia should aldosteronism; PAC, plasma aldosterone concentration. Figure was created with be identified and corrected before screening. If a patient is on an MRA BioRender.com medication and renin is not suppressed, it will be necessary to discontinue treatment at least 4 weeks before screening.56 1.5 ASSESSMENT AND DIAGNOSIS OF It is important that clinicians know about the assays used at their institution PRIMARY ALDOSTERONISM and interpret results accordingly. Most centers have replaced plasma renin The diagnosis of PA relies on biochemical evidence of angiotensin- activity, which measures the amount of angiotensinogen I generated over time, 81 independent aldosterone production. A combination of methods must be with direct renin concentration, which is less sensitive to poor sample employed to accomplish a complete assessment (figure 7). In Sweden, national handling and can be measured with a fully automated mass spectrometry 81,82 guidelines have been issued to help diagnose the different forms of PA and analyzer. were updated in 2023.75 They are in line with the guidelines from the Endocrine Society (updated 2016) and the consensus statement by European Society of 10 11 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 1.5.2 CONFIRMATORY TESTS activity. Conversely, CT and likewise magnetic resonance imaging (MRI) Recommended second-line tests to confirm PA include oral or intravenous carry the risk of identifying coincidental nonfunctional adrenal lesions. In sodium loading, fludrocortisone inhibition test, or captopril challenge test.56 about 33% of patients with a unilateral adenoma visualized on CT scans, the 7 Intravenous sodium loading (or saline infusion test, SIT) is primarily used in diagnosis is bilateral disease when AVS is performed. In a Swedish cohort Västra Götaland County. Aldosterone, renin, and potassium levels are comprising 130 aldosterone-secreting adenomas, 87 the mean (standard measured before and after saline infusion. Adequate suppression is defined as deviation [SD]) diameter was 15.4 (7.3) mm. Small adenomas <1 cm may not 88 an aldosterone concentration ≤140 pmol/L when SIT is performed in a be differentiated from focal adrenal enlargement. Thus, normal CT scans do recumbent position (saline infusion test, SIT).56 An SIT in a seated position not exclude unilateral PA. (seated saline infusion test, SSIT) does not compromise accuracy when a cut- Studies on functional imaging such as 11C-metomidate positron emission off is set at 165 pmol/L and aldosterone is measured by tandem liquid 83 tomography show promise in localizing the source of aldosterone secretion. 89 chromatography-mass spectrometry. Since SSIT does not require admission, 83 However, the use of this technique is limited due to the need for an on-site this approach has gained popularity in more recent years. In a validation study 84 cyclotron facility because the radiotracer that binds to adrenal enzymes has of SSIT, aldosterone >171 pmol/L measured by immunoassay was 95.4% such a short half-life. Other radiotracers are under investigation.89,90 sensitive but incorrectly identified 20% of unaffected individuals as having PA. As demonstrated, cut-offs should be interpreted according to the assay 1.5.3.3 ADRENAL VEIN SAMPLING used. Patients with unilateral disease have higher aldosterone levels after an AVS is currently the gold standard for the diagnosis of lateralized PA in SSIT.85 Confirmatory testing is contraindicated in patients with severe patients ≥35 years of age who are candidates for adrenalectomy regardless of uncontrolled hypertension, kidney failure, arrhythmia, or pronounced radiological findings.56,91-94 Lateralized PA refers to the functional dominance hypokalemia. of one adrenal gland compared to the other. This term is gaining traction, reflecting a better understanding of disease pathology. In this context, patients 1.5.3 ASSESSING THE ETIOLOGY OF PRIMARY with marked asymmetric aldosterone hypersecretion benefit from surgery. ALDOSTERONISM AVS is more accurate than CT scans for diagnosing lateralized PA.56,93,95 In Several diagnostic tools, often combined, are used to assess the underlying centers that perform AVS, approximately 35% of all patients show 96 cause of PA including imaging studies, AVS, and genetic tests. When lateralization. assessing the etiology of PA, it may be relevant to consider the potential benefits of a unilateral adrenalectomy. Performing adrenal vein catheterization is a technically difficult procedure that requires an experienced and dedicated physician.97,98 To determine whether 1.5.3.1 GENETIC TESTS there is a gradient in aldosterone secretion, it is important to catheterize both Genetic testing should be performed when PA is diagnosed before the age of adrenal veins and take samples for measurement of aldosterone and cortisol 20 years as well as in patients with early-onset stroke and PA, as familial forms levels. Hence, the distinction between unilateral and bilateral disease only require specific therapies (e.g. cortisol) that are not used in patients with makes sense if a patient is willing to proceed to surgery. nonfamilial forms of PA.74 Currently, genomic sequencing to detect sporadic mutations is confined to research purposes. Successful adrenal vein catheterization is determined by comparing cortisol levels in the adrenal veins and the inferior vena cava. If the aldosterone-to- 1.5.3.2 ADRENAL IMAGING cortisol ratio is significantly higher on one side compared to the other (reported CT scanning is central in the evaluation of newly diagnosed patients with PA. as the lateralization index), it indicates unilateral aldosterone excess. Finally, Although the most common causes of PA are benign, adenocarcinoma is a rare to assess if the contralateral gland is suppressed due to autonomous aldosterone culpable cause of PA that should be ruled out.86 CT is the imaging of choice to secretion, the contralateral suppression index is calculated by dividing the detect and characterize large adrenal masses but cannot establish endocrine lower aldosterone-to-cortisol ratio by that of the inferior vena cava. 12 13 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 1.5.2 CONFIRMATORY TESTS activity. Conversely, CT and likewise magnetic resonance imaging (MRI) Recommended second-line tests to confirm PA include oral or intravenous carry the risk of identifying coincidental nonfunctional adrenal lesions. In sodium loading, fludrocortisone inhibition test, or captopril challenge test.56 about 33% of patients with a unilateral adenoma visualized on CT scans, the 7 Intravenous sodium loading (or saline infusion test, SIT) is primarily used in diagnosis is bilateral disease when AVS is performed. In a Swedish cohort Västra Götaland County. Aldosterone, renin, and potassium levels are comprising 130 aldosterone-secreting adenomas, 87 the mean (standard measured before and after saline infusion. Adequate suppression is defined as deviation [SD]) diameter was 15.4 (7.3) mm. Small adenomas <1 cm may not 88 an aldosterone concentration ≤140 pmol/L when SIT is performed in a be differentiated from focal adrenal enlargement. Thus, normal CT scans do recumbent position (saline infusion test, SIT).56 An SIT in a seated position not exclude unilateral PA. (seated saline infusion test, SSIT) does not compromise accuracy when a cut- Studies on functional imaging such as 11C-metomidate positron emission off is set at 165 pmol/L and aldosterone is measured by tandem liquid 83 tomography show promise in localizing the source of aldosterone secretion. 89 chromatography-mass spectrometry. Since SSIT does not require admission, 83 However, the use of this technique is limited due to the need for an on-site this approach has gained popularity in more recent years. In a validation study 84 cyclotron facility because the radiotracer that binds to adrenal enzymes has of SSIT, aldosterone >171 pmol/L measured by immunoassay was 95.4% such a short half-life. Other radiotracers are under investigation.89,90 sensitive but incorrectly identified 20% of unaffected individuals as having PA. As demonstrated, cut-offs should be interpreted according to the assay 1.5.3.3 ADRENAL VEIN SAMPLING used. Patients with unilateral disease have higher aldosterone levels after an AVS is currently the gold standard for the diagnosis of lateralized PA in SSIT.85 Confirmatory testing is contraindicated in patients with severe patients ≥35 years of age who are candidates for adrenalectomy regardless of uncontrolled hypertension, kidney failure, arrhythmia, or pronounced radiological findings.56,91-94 Lateralized PA refers to the functional dominance hypokalemia. of one adrenal gland compared to the other. This term is gaining traction, reflecting a better understanding of disease pathology. In this context, patients 1.5.3 ASSESSING THE ETIOLOGY OF PRIMARY with marked asymmetric aldosterone hypersecretion benefit from surgery. ALDOSTERONISM AVS is more accurate than CT scans for diagnosing lateralized PA.56,93,95 In Several diagnostic tools, often combined, are used to assess the underlying centers that perform AVS, approximately 35% of all patients show 96 cause of PA including imaging studies, AVS, and genetic tests. When lateralization. assessing the etiology of PA, it may be relevant to consider the potential benefits of a unilateral adrenalectomy. Performing adrenal vein catheterization is a technically difficult procedure that requires an experienced and dedicated physician.97,98 To determine whether 1.5.3.1 GENETIC TESTS there is a gradient in aldosterone secretion, it is important to catheterize both Genetic testing should be performed when PA is diagnosed before the age of adrenal veins and take samples for measurement of aldosterone and cortisol 20 years as well as in patients with early-onset stroke and PA, as familial forms levels. Hence, the distinction between unilateral and bilateral disease only require specific therapies (e.g. cortisol) that are not used in patients with makes sense if a patient is willing to proceed to surgery. nonfamilial forms of PA.74 Currently, genomic sequencing to detect sporadic mutations is confined to research purposes. Successful adrenal vein catheterization is determined by comparing cortisol levels in the adrenal veins and the inferior vena cava. If the aldosterone-to- 1.5.3.2 ADRENAL IMAGING cortisol ratio is significantly higher on one side compared to the other (reported CT scanning is central in the evaluation of newly diagnosed patients with PA. as the lateralization index), it indicates unilateral aldosterone excess. Finally, Although the most common causes of PA are benign, adenocarcinoma is a rare to assess if the contralateral gland is suppressed due to autonomous aldosterone culpable cause of PA that should be ruled out.86 CT is the imaging of choice to secretion, the contralateral suppression index is calculated by dividing the detect and characterize large adrenal masses but cannot establish endocrine lower aldosterone-to-cortisol ratio by that of the inferior vena cava. 12 13 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa Lateralizing criteria are not consensual among different centers.99 When hypertension duration, and phenotype.102 In a Swedish study of 190 patients stimulation with ACTH is used, a lateralization index >4 indicates unilateral with PA treated by adrenalectomy,87 92% of the patients were biochemically aldosterone excess. Lateralization index in the range of 3 to 4 is indeterminate cured after adrenalectomy and 7% had improved potassium levels at follow- and indicates unilateral aldosterone production if the contralateral suppression up. Of note, 34% of the patients became normotensive without the need for index is <0.5 (figure 8).97,99 medication, while 60% experienced improvement in hypertension. No fatal events were reported in this cohort with the majority of patients treated with a minimally invasive approach. Following adrenalectomy, transient adrenal hormone deficiencies may occur in up to 5% of patients.103 In some patients, this may be related to cortisol co-secretion.104 A biochemical re-assessment should be performed 6 months after surgery.101 Histological features of the resected gland determine how long a patient needs to be followed biochemically. Despite histopathology evaluations showing hyperplasia, some patients are cured.105,106 Immunohistochemical staining for CYP11B2 is recommended to determine the functionality of resected adrenals but is not yet widely used.19,107 Adrenalectomy is generally not considered an option in most patients with bilateral disease but some experts argue that it might be an option for selected patients under certain circumstances.108,109 Some patients may benefit from selective adenoma removal, although the level of evidence is weak.110,111 Figure 8. Adrenal vein sampling in primary aldosteronism. [Reproduced from Turcu 1.6.2 MINERALOCORTICOID RECEPTOR et al.35 with permission from ©Springer Nature] ANTAGONISTS An MRA is the established treatment for patients with primary aldosteronism AVS measures adrenal activity in real time; however, it is not indisputable. who have bilateral disease, limited access to an accurate lateralization Factors such as timing of testing (due to circadian rhythm), interfering procedure, or who cannot undergo surgery.56 MRAs are effective in treating a medications, and cortisol co-secretion may affect the results of AVS. ACTH 100 range of medical conditions linked to mineralocorticoid overactivation. The stimulation can overcome some of these problems and enhance accuracy. two most used MRAs are spironolactone and eplerenone. Spironolactone is the most widely used but has more side effects.112,113 1.6 TREATMENT AND OUTCOME OF PRIMARY ALDOSTERONISM In patients with heart failure, treatment with spironolactone or eplerenone prevents hospitalizations and reduces mortality.114,115 In patients with hypertension, studies show that MRA treatment improves BP and left 1.6.1 SURGERY ventricular hypertrophy.116-119 In patients with resistant hypertension (on 3 Unilateral adrenalectomy performed laparoscopically is a potentially curative medications including a diuretic), spironolactone is the most effective fourth 120 treatment for PA and is therefore preferred when feasible in patients with medication to consider. In patients with primary aldosteronism, the unilateral disease. Treatment success is determined by clinical and biochemical effectiveness of MRA treatment in patients with primary aldosteronism goes outcomes postoperatively.101 When guided by AVS, aldosterone and renin beyond reducing BP. MRA treatment has the potential to reduce left 117 121 return to normal in most patients (96%–100%) but sustained hypertension is ventricular mass, improve metabolic complications, reverse albuminuria 121-123 124,125 common and additional medications may be needed depending on age, and renal complications, prevent cardiovascular events, reduce 14 15 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa Lateralizing criteria are not consensual among different centers.99 When hypertension duration, and phenotype.102 In a Swedish study of 190 patients stimulation with ACTH is used, a lateralization index >4 indicates unilateral with PA treated by adrenalectomy,87 92% of the patients were biochemically aldosterone excess. Lateralization index in the range of 3 to 4 is indeterminate cured after adrenalectomy and 7% had improved potassium levels at follow- and indicates unilateral aldosterone production if the contralateral suppression up. Of note, 34% of the patients became normotensive without the need for index is <0.5 (figure 8).97,99 medication, while 60% experienced improvement in hypertension. No fatal events were reported in this cohort with the majority of patients treated with a minimally invasive approach. Following adrenalectomy, transient adrenal hormone deficiencies may occur in up to 5% of patients.103 In some patients, this may be related to cortisol co-secretion.104 A biochemical re-assessment should be performed 6 months after surgery.101 Histological features of the resected gland determine how long a patient needs to be followed biochemically. Despite histopathology evaluations showing hyperplasia, some patients are cured.105,106 Immunohistochemical staining for CYP11B2 is recommended to determine the functionality of resected adrenals but is not yet widely used.19,107 Adrenalectomy is generally not considered an option in most patients with bilateral disease but some experts argue that it might be an option for selected patients under certain circumstances.108,109 Some patients may benefit from selective adenoma removal, although the level of evidence is weak.110,111 Figure 8. Adrenal vein sampling in primary aldosteronism. [Reproduced from Turcu 1.6.2 MINERALOCORTICOID RECEPTOR et al.35 with permission from ©Springer Nature] ANTAGONISTS An MRA is the established treatment for patients with primary aldosteronism AVS measures adrenal activity in real time; however, it is not indisputable. who have bilateral disease, limited access to an accurate lateralization Factors such as timing of testing (due to circadian rhythm), interfering procedure, or who cannot undergo surgery.56 MRAs are effective in treating a medications, and cortisol co-secretion may affect the results of AVS. ACTH 100 range of medical conditions linked to mineralocorticoid overactivation. The stimulation can overcome some of these problems and enhance accuracy. two most used MRAs are spironolactone and eplerenone. Spironolactone is the most widely used but has more side effects.112,113 1.6 TREATMENT AND OUTCOME OF PRIMARY ALDOSTERONISM In patients with heart failure, treatment with spironolactone or eplerenone prevents hospitalizations and reduces mortality.114,115 In patients with hypertension, studies show that MRA treatment improves BP and left 1.6.1 SURGERY ventricular hypertrophy.116-119 In patients with resistant hypertension (on 3 Unilateral adrenalectomy performed laparoscopically is a potentially curative medications including a diuretic), spironolactone is the most effective fourth 120 treatment for PA and is therefore preferred when feasible in patients with medication to consider. In patients with primary aldosteronism, the unilateral disease. Treatment success is determined by clinical and biochemical effectiveness of MRA treatment in patients with primary aldosteronism goes outcomes postoperatively.101 When guided by AVS, aldosterone and renin beyond reducing BP. MRA treatment has the potential to reduce left 117 121 return to normal in most patients (96%–100%) but sustained hypertension is ventricular mass, improve metabolic complications, reverse albuminuria 121-123 124,125 common and additional medications may be needed depending on age, and renal complications, prevent cardiovascular events, reduce 14 15 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa mortality,121 and improve quality of life in patients with primary Aldosterone excess has been associated with increased diabetes prevalence, aldosteronism.126,127 occurring in up to 23% of patients, almost 2-fold than in hypertensive controls, as reported in a German study.134 Overall, aldosterone excess inhibits insulin Key considerations when choosing the type of MRA should be tolerability secretion and increases insulin resistance, leading to impaired glucose issues, which often lead to undertreatment.116,128 Spironolactone has an tolerance and diabetes.135,136 inhibitory effect on the testosterone receptor and an agonistic effect on the progesterone receptor, and is therefore associated with gynecomastia and Aldosterone has a negative influence on calcium metabolism (increasing menstrual irregularities. Eplerenone is a selective antagonist that does not share calcium) as shown by hypercalciuria and a secondary rise in parathyroid spironolactone’s adverse effects but is costly and therefore considered a hormone.137 This may result in secondary osteoporosis with vertebral fractures second-line treatment in primary aldosteronism. Since eplerenone has a being common in patients with PA compared to patients with hypertension, as relatively short half-life, it should be taken twice daily. Eplerenone may be seen in three studies.138-140 preferred in premenopausal women as many patients discontinue spironolactone due to safety concerns before attempting pregnancy.129,130 A It has been recognized that patients with PA at long-term follow-up still have typical starting dose consists of spironolactone 25 mg once daily or eplerenone a worse cardiovascular risk profile than that of hypertensive controls.125 25 mg twice daily. In order of importance, regular re-evaluation is essential to monitor clinical and biochemical responses and adjust the dose accordingly. 1.7 CHALLENGES IN THE DIAGNOSIS AND 1.6.3 MORBIDITY ATTRIBUTABLE TO PRIMARY INDIVIDUALIZED TREATMENT OF ALDOSTERONISM PRIMARY ALDOSTERONISM The association between untreated PA and cardiovascular morbidity is well Despite important advances, the diagnosis of PA remains a daunting task.48,63 established, emphasizing the need for early diagnosis and effective treatment Screening for PA is considered cost-effective only in high-risk populations.141 to improve the prognosis. Lack of symptoms leads to missed opportunities for early intervention.63,64,141 Diagnostic delay may lead to a broad spectrum of coexisting disorders. PA is Both screening and confirmatory tests have diagnostic caveats, as provided associated with increased odd ratios (ORs) for stroke (2.58, 95% CI earlier. The necessity for confirmatory testing and interpretation of tests by [confidence interval] 1.93–3.45), coronary artery disease (1.77, 1.10–2.83), unfamiliar physicians affect the number of patients identified and prevalence atrial fibrillation (3.52, 2.06–5.99), and heart failure 2.05 (1.11–3.78) estimates. Ultimately, improving screening efficiency is the greatest challenge 63 compared to patients with essential hypertension.131 of modern times. Patients with PA may also experience renal impairment,132 albuminuria,133 Setting reasonable treatment expectations and explaining what defines a metabolic complications,121 and impaired quality of life.126 Renal damage in successful outcome is essential when counseling individual patients. Optimal PA is more prominent than in patients with essential hypertension and it affects management requires an understanding of four aspects: kidney function independently of BP.122,132,133 In a German study of disease i. Accurate subtype differentiation is necessary for the avoidance of severity,132 plasma aldosterone and serum potassium were independent unnecessary surgical procedures. AVS is the key diagnostic tool for predictors of a lower glomerular filtration rate. Treatment with adequate doses selecting surgical candidates but it is not possible for all patients and of an MRA or adrenalectomy can potentially reverse renal impairment and may be subject to sampling error.142,143 The availability of AVS albuminuria.122,132 remains a clinical problem that affects treatment decisions and outcomes for patients with primary aldosteronism. 16 17 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa mortality,121 and improve quality of life in patients with primary Aldosterone excess has been associated with increased diabetes prevalence, aldosteronism.126,127 occurring in up to 23% of patients, almost 2-fold than in hypertensive controls, as reported in a German study.134 Overall, aldosterone excess inhibits insulin Key considerations when choosing the type of MRA should be tolerability secretion and increases insulin resistance, leading to impaired glucose issues, which often lead to undertreatment.116,128 Spironolactone has an tolerance and diabetes.135,136 inhibitory effect on the testosterone receptor and an agonistic effect on the progesterone receptor, and is therefore associated with gynecomastia and Aldosterone has a negative influence on calcium metabolism (increasing menstrual irregularities. Eplerenone is a selective antagonist that does not share calcium) as shown by hypercalciuria and a secondary rise in parathyroid spironolactone’s adverse effects but is costly and therefore considered a hormone.137 This may result in secondary osteoporosis with vertebral fractures second-line treatment in primary aldosteronism. Since eplerenone has a being common in patients with PA compared to patients with hypertension, as relatively short half-life, it should be taken twice daily. Eplerenone may be seen in three studies.138-140 preferred in premenopausal women as many patients discontinue spironolactone due to safety concerns before attempting pregnancy.129,130 A It has been recognized that patients with PA at long-term follow-up still have typical starting dose consists of spironolactone 25 mg once daily or eplerenone a worse cardiovascular risk profile than that of hypertensive controls.125 25 mg twice daily. In order of importance, regular re-evaluation is essential to monitor clinical and biochemical responses and adjust the dose accordingly. 1.7 CHALLENGES IN THE DIAGNOSIS AND 1.6.3 MORBIDITY ATTRIBUTABLE TO PRIMARY INDIVIDUALIZED TREATMENT OF ALDOSTERONISM PRIMARY ALDOSTERONISM The association between untreated PA and cardiovascular morbidity is well Despite important advances, the diagnosis of PA remains a daunting task.48,63 established, emphasizing the need for early diagnosis and effective treatment Screening for PA is considered cost-effective only in high-risk populations.141 to improve the prognosis. Lack of symptoms leads to missed opportunities for early intervention.63,64,141 Diagnostic delay may lead to a broad spectrum of coexisting disorders. PA is Both screening and confirmatory tests have diagnostic caveats, as provided associated with increased odd ratios (ORs) for stroke (2.58, 95% CI earlier. The necessity for confirmatory testing and interpretation of tests by [confidence interval] 1.93–3.45), coronary artery disease (1.77, 1.10–2.83), unfamiliar physicians affect the number of patients identified and prevalence atrial fibrillation (3.52, 2.06–5.99), and heart failure 2.05 (1.11–3.78) estimates. Ultimately, improving screening efficiency is the greatest challenge 63 compared to patients with essential hypertension.131 of modern times. Patients with PA may also experience renal impairment,132 albuminuria,133 Setting reasonable treatment expectations and explaining what defines a metabolic complications,121 and impaired quality of life.126 Renal damage in successful outcome is essential when counseling individual patients. Optimal PA is more prominent than in patients with essential hypertension and it affects management requires an understanding of four aspects: kidney function independently of BP.122,132,133 In a German study of disease i. Accurate subtype differentiation is necessary for the avoidance of severity,132 plasma aldosterone and serum potassium were independent unnecessary surgical procedures. AVS is the key diagnostic tool for predictors of a lower glomerular filtration rate. Treatment with adequate doses selecting surgical candidates but it is not possible for all patients and of an MRA or adrenalectomy can potentially reverse renal impairment and may be subject to sampling error.142,143 The availability of AVS albuminuria.122,132 remains a clinical problem that affects treatment decisions and outcomes for patients with primary aldosteronism. 16 17 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa ii. Not all patients with unilateral disease can be clinically cured of Another long-standing question relates to long-term consequences after hypertension after surgery.87 This is evidenced by the fact that up to treatment for PA and mortality.145,148 Previous studies have reported potential 60% of patients may require additional treatment after adrenalectomy, links between PA and mortality,121,148-150 but a meta-analysis of six studies as shown in a recent study from Sweden.87 (n=3039) of patients with PA suggested that mortality risk may decline over iii. Available data suggests that surgery has a more favorable effect on time.151 Several limitations were acknowledged, such as enrollment of limited cardiovascular complications than medical therapy in patients with patients from large referral centers, short follow-up, and inadequate adjustment PA.144,145 However, the evidence is not substantial. An ongoing for disparities. A nationwide study using data from register linkage can provide randomized trial is evaluating whether eplerenone is as efficient as valuable insights into treatment effects, enabling control for some important adrenalectomy in patients with unilateral disease. factors that may have influenced mortality outcomes in earlier studies. A iv. The appropriate dose of MRAs is a contentious issue between comprehensive understanding of the association between morbidity, mortality, clinicians. It was previously recommended that patients who are not and primary aldosteronism, and furthering the influence of treatment can help eligible for surgery should be given a low-dose MRA as a first-line guide individual approaches. antihypertensive in PA.146 It has since been shown that patients achieving normal renin levels after treatment initiation have better Aldosterone excess might have a larger clinical impact on bone health than is outcomes.121 Although consensus has not yet been reached, currently recognized. Previous studies have linked PA with a higher prevalence normalization of renin levels appears to be a reasonable goal.147 of radiographic vertebral fractures than in patients with hypertension.138-140 However, determining the age of a vertebral fracture is difficult and fractures 1.8 GAPS OF KNOWLEDGE found through densitometric morphometry or lateral radiographs do not always correlate with clinical symptoms.152 A study of 2533 patients with PA and 3684 Several questions about the epidemiology, diagnosis, and complications of PA hypertensive controls matched on propensity score found increased fracture remain unanswered. risk in PA but did not specify site-specific fractures. 153 As a result of uncertain causality, we tested the hypothesis that patients with PA have an increased risk First, the incidence of PA is unclear. PA is the cause of hypertension in 1%– of hip fractures in our nationwide cohort. We picked hip fracture because it is 6% of patients in Sweden depending on the population tested,60-62 although it a robust outcome, which is associated with impaired quality of life, reduced is unknown how screening strategies perform in real-world settings. The life expectancy, and high economic costs.154,155 number of people diagnosed with PA who are currently in care is undetermined. A population-based study of PA incident rates in Sweden will potentially be useful in capacity management and allocation of resources to ensure optimal performance for the healthcare system. AVS is best practice to determine disease laterality irrespective of radiological findings.56,91,92,97 However, according to Endocrine Society guidelines from 2016, AVS is not deemed necessary in young patients with confirmed primary aldosteronism and a solitary adrenal adenoma on imaging.56 Seeking to justify this exception, we found that the original argument was based on small sample size studies.94 Since young patients have a greater chance of being clinically cured,101 it is particularly important that they receive a correct diagnosis. Paper II explores whether conventional imaging is reliable to assess laterality in young patients with PA. We hypothesize that relying on imaging alone can lead to wrong treatment decisions, as it may misclassify subtypes. 18 19 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa ii. Not all patients with unilateral disease can be clinically cured of Another long-standing question relates to long-term consequences after hypertension after surgery.87 This is evidenced by the fact that up to treatment for PA and mortality.145,148 Previous studies have reported potential 60% of patients may require additional treatment after adrenalectomy, links between PA and mortality,121,148-150 but a meta-analysis of six studies as shown in a recent study from Sweden.87 (n=3039) of patients with PA suggested that mortality risk may decline over iii. Available data suggests that surgery has a more favorable effect on time.151 Several limitations were acknowledged, such as enrollment of limited cardiovascular complications than medical therapy in patients with patients from large referral centers, short follow-up, and inadequate adjustment PA.144,145 However, the evidence is not substantial. An ongoing for disparities. A nationwide study using data from register linkage can provide randomized trial is evaluating whether eplerenone is as efficient as valuable insights into treatment effects, enabling control for some important adrenalectomy in patients with unilateral disease. factors that may have influenced mortality outcomes in earlier studies. A iv. The appropriate dose of MRAs is a contentious issue between comprehensive understanding of the association between morbidity, mortality, clinicians. It was previously recommended that patients who are not and primary aldosteronism, and furthering the influence of treatment can help eligible for surgery should be given a low-dose MRA as a first-line guide individual approaches. antihypertensive in PA.146 It has since been shown that patients achieving normal renin levels after treatment initiation have better Aldosterone excess might have a larger clinical impact on bone health than is outcomes.121 Although consensus has not yet been reached, currently recognized. Previous studies have linked PA with a higher prevalence normalization of renin levels appears to be a reasonable goal.147 of radiographic vertebral fractures than in patients with hypertension.138-140 However, determining the age of a vertebral fracture is difficult and fractures 1.8 GAPS OF KNOWLEDGE found through densitometric morphometry or lateral radiographs do not always correlate with clinical symptoms.152 A study of 2533 patients with PA and 3684 Several questions about the epidemiology, diagnosis, and complications of PA hypertensive controls matched on propensity score found increased fracture remain unanswered. risk in PA but did not specify site-specific fractures. 153 As a result of uncertain causality, we tested the hypothesis that patients with PA have an increased risk First, the incidence of PA is unclear. PA is the cause of hypertension in 1%– of hip fractures in our nationwide cohort. We picked hip fracture because it is 6% of patients in Sweden depending on the population tested,60-62 although it a robust outcome, which is associated with impaired quality of life, reduced is unknown how screening strategies perform in real-world settings. The life expectancy, and high economic costs.154,155 number of people diagnosed with PA who are currently in care is undetermined. A population-based study of PA incident rates in Sweden will potentially be useful in capacity management and allocation of resources to ensure optimal performance for the healthcare system. AVS is best practice to determine disease laterality irrespective of radiological findings.56,91,92,97 However, according to Endocrine Society guidelines from 2016, AVS is not deemed necessary in young patients with confirmed primary aldosteronism and a solitary adrenal adenoma on imaging.56 Seeking to justify this exception, we found that the original argument was based on small sample size studies.94 Since young patients have a greater chance of being clinically cured,101 it is particularly important that they receive a correct diagnosis. Paper II explores whether conventional imaging is reliable to assess laterality in young patients with PA. We hypothesize that relying on imaging alone can lead to wrong treatment decisions, as it may misclassify subtypes. 18 19 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 2 AIM 3 PATIENTS AND METHODS The present thesis aims to address unanswered questions concerning Table 1. Overview of each paper. epidemiology, diagnostic methods, treatment, and long-term outcomes in patients with PA. The specific aims were: Aim Study design Population Results Paper Incidence of Retrospective Patients Incidence rates of PA I PA review of medical registered with a increased. However, I. To estimate the incidence of PA in Western Sweden (Västra Götaland records of patients diagnostic code PA is still County) over three decades (1987–2016). identified with for PA in the underdiagnosed II. To evaluate whether young patients (up to 40 years of age) with PA diagnostic codes NPR 1987–2016 need to undergo AVS to determine the subtype before treatment in the NPR (n=570) strategy is decided. Paper Role of AVS Cross-sectional Consecutive One-fifth of young II in guiding study patients aged ≤40 patients with PA III. To study all-cause and cause-specific mortality in patients with PA as therapy in years who would have received well as the impact of factors such as age, sex, treatment modality, and young underwent AVS inappropriate cardiovascular comorbidity in a large population-based study. patients with at Sahlgrenska treatment if based on IV. To investigate the risk of hip fracture in patients with PA compared to PA Hospital 2005– imaging studies alone 2019 (n=45) and not AVS the general population. Paper Investigate Linkage of Patients Patients with PA have III mortality in national registries registered with a increased mortality PA diagnostic code compared to general for PA in the population controls NPR 1997–2019 during the study (n=2419) period (1997–2020) Paper Investigate Linkage of Same as in paper The risk of hip IV the incidence national registries III fracture is increased in of hip PA during the study fractures in period (1997–2019) patients with compared to the PA general population Abbreviations: AVS, adrenal venous sampling; NPR, National Patient Register; PA, primary aldosteronism. 3.1 PATIENTS AND STUDY DESIGN 3.1.1 DATA SOURCES AND ETHICAL CONSIDERATIONS This work consists of four observational studies (table 1). Each study included in this thesis was reviewed and approved by the Swedish Ethics Review Board: Papers I, III, and IV (Dnr 029-17) and Paper II (Dnr 826/16). Study II was based on existing data from patients who performed AVS investigations at Sahlgrenska Hospital, which is the tertiary referral center in Västra Götaland County. The data used in Papers I, II, and III was collected from the following 20 21 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 2 AIM 3 PATIENTS AND METHODS The present thesis aims to address unanswered questions concerning Table 1. Overview of each paper. epidemiology, diagnostic methods, treatment, and long-term outcomes in patients with PA. The specific aims were: Aim Study design Population Results Paper Incidence of Retrospective Patients Incidence rates of PA I PA review of medical registered with a increased. However, I. To estimate the incidence of PA in Western Sweden (Västra Götaland records of patients diagnostic code PA is still County) over three decades (1987–2016). identified with for PA in the underdiagnosed II. To evaluate whether young patients (up to 40 years of age) with PA diagnostic codes NPR 1987–2016 need to undergo AVS to determine the subtype before treatment in the NPR (n=570) strategy is decided. Paper Role of AVS Cross-sectional Consecutive One-fifth of young II in guiding study patients aged ≤40 patients with PA III. To study all-cause and cause-specific mortality in patients with PA as therapy in years who would have received well as the impact of factors such as age, sex, treatment modality, and young underwent AVS inappropriate cardiovascular comorbidity in a large population-based study. patients with at Sahlgrenska treatment if based on IV. To investigate the risk of hip fracture in patients with PA compared to PA Hospital 2005– imaging studies alone 2019 (n=45) and not AVS the general population. Paper Investigate Linkage of Patients Patients with PA have III mortality in national registries registered with a increased mortality PA diagnostic code compared to general for PA in the population controls NPR 1997–2019 during the study (n=2419) period (1997–2020) Paper Investigate Linkage of Same as in paper The risk of hip IV the incidence national registries III fracture is increased in of hip PA during the study fractures in period (1997–2019) patients with compared to the PA general population Abbreviations: AVS, adrenal venous sampling; NPR, National Patient Register; PA, primary aldosteronism. 3.1 PATIENTS AND STUDY DESIGN 3.1.1 DATA SOURCES AND ETHICAL CONSIDERATIONS This work consists of four observational studies (table 1). Each study included in this thesis was reviewed and approved by the Swedish Ethics Review Board: Papers I, III, and IV (Dnr 029-17) and Paper II (Dnr 826/16). Study II was based on existing data from patients who performed AVS investigations at Sahlgrenska Hospital, which is the tertiary referral center in Västra Götaland County. The data used in Papers I, II, and III was collected from the following 20 21 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa national registries and databases held by the Swedish National Board of Health  The Longitudinal Database of Health Insurance and Labour Market and Welfare, and Statistics Sweden (figure 9). Data linking was possible Studies (LISA) held by Sweden Statistics integrates data from the labor because of the universal use of the nationwide personal identification number market, education, and social sector, and offers insight into supply and by health care, private, and official authorities.156 demand and the economy in general.160 All registries contain sensitive personal data protected by the General Data Protection Regulations. To validate the PA diagnosis (Study I), the Swedish National Board of Health and Welfare provided the personal identifier for patients diagnosed between 1987 and 2016 in Västra Götaland County. To reduce the identification risk in Studies III and IV, identification numbers were replaced with serial numbers by the Swedish National Board of Health and Welfare. We followed laws and regulations governing data storage, access, and sharing rules. Since none of these studies involved direct contact with study participants and did not alter their management, the Swedish Ethics Review Board waived the requirement for obtaining informed consent. 3.1.2 PAPER I – INCIDENCE OF PRIMARY ALDOSTERONISM This study aimed to assess the incidence of primary aldosteronism in the Västra Figure 9 Data sources for Papers II, III, and IV. Abbreviations: ATC, Anatomical Götaland County between 1987 and 2016. A data file of individuals assigned Therapeutic Chemical Classification; ICD, International Classification of Diseases with a diagnostic code for PA in the NPR (i.e. ICD-9 255.B or ICD-10 E260) was provided by the Swedish National Board of Health and Welfare. Available  The Swedish National Patient Register (NPR) is a nationwide registry medical reports were reviewed and clinical, biochemical, imaging, and that collects diagnostic codes from hospital discharges since 1987 and histopathological data was assessed to validate PA diagnosis. The incidence specialist outpatient care since 2001 following the International and prevalence of PA were calculated by using the number of residents in the Classification of Diseases (ICD). Procedures are coded according to the Västra Götaland County as reference. Register coverage was assessed using a Nordic Classification of Surgical Procedures. The registry does not dataset of patients who underwent AVS at Sahlgrenska University Hospital, contain data on primary care. The Health Data Register Act (1998:543) the tertiary center for subtype investigation in the County. and the associated regulation (2001:707) support the National Board of Health and Welfare and oblige healthcare providers to provide 3.1.3 PAPER II − ADRENAL VEIN SAMPLING IN information to the Patient Register.157 YOUNG PATIENTS WITH PRIMARY  The Swedish Causes of Death Register covers all deaths that occurred in Sweden, including deaths of non-Swedes. It also includes deaths of ALDOSTERONISM Swedes who have died abroad.158 This was a cross-sectional, single-center study of 45 consecutive young  The Swedish Prescribed Drug Register “contains all prescribed drugs as patients diagnosed with PA at Sahlgrenska University Hospital between 2005 dispensed in pharmacies” from July 2005 onwards according to and 2019. The study aimed to evaluate CT/MRI performance compared to Anatomical Therapeutic Chemical Classification (ATC) codes.159 AVS for classifying PA as unilateral or bilateral in young patients (≤40 years  The Swedish Population Register contains demographic data for all of age at the time of AVS) with PA. Based on the re-evaluation of imaging Swedish residents.160 data by two experienced radiologists, the study estimated how many patients 22 23 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa national registries and databases held by the Swedish National Board of Health  The Longitudinal Database of Health Insurance and Labour Market and Welfare, and Statistics Sweden (figure 9). Data linking was possible Studies (LISA) held by Sweden Statistics integrates data from the labor because of the universal use of the nationwide personal identification number market, education, and social sector, and offers insight into supply and by health care, private, and official authorities.156 demand and the economy in general.160 All registries contain sensitive personal data protected by the General Data Protection Regulations. To validate the PA diagnosis (Study I), the Swedish National Board of Health and Welfare provided the personal identifier for patients diagnosed between 1987 and 2016 in Västra Götaland County. To reduce the identification risk in Studies III and IV, identification numbers were replaced with serial numbers by the Swedish National Board of Health and Welfare. We followed laws and regulations governing data storage, access, and sharing rules. Since none of these studies involved direct contact with study participants and did not alter their management, the Swedish Ethics Review Board waived the requirement for obtaining informed consent. 3.1.2 PAPER I – INCIDENCE OF PRIMARY ALDOSTERONISM This study aimed to assess the incidence of primary aldosteronism in the Västra Figure 9 Data sources for Papers II, III, and IV. Abbreviations: ATC, Anatomical Götaland County between 1987 and 2016. A data file of individuals assigned Therapeutic Chemical Classification; ICD, International Classification of Diseases with a diagnostic code for PA in the NPR (i.e. ICD-9 255.B or ICD-10 E260) was provided by the Swedish National Board of Health and Welfare. Available  The Swedish National Patient Register (NPR) is a nationwide registry medical reports were reviewed and clinical, biochemical, imaging, and that collects diagnostic codes from hospital discharges since 1987 and histopathological data was assessed to validate PA diagnosis. The incidence specialist outpatient care since 2001 following the International and prevalence of PA were calculated by using the number of residents in the Classification of Diseases (ICD). Procedures are coded according to the Västra Götaland County as reference. Register coverage was assessed using a Nordic Classification of Surgical Procedures. The registry does not dataset of patients who underwent AVS at Sahlgrenska University Hospital, contain data on primary care. The Health Data Register Act (1998:543) the tertiary center for subtype investigation in the County. and the associated regulation (2001:707) support the National Board of Health and Welfare and oblige healthcare providers to provide 3.1.3 PAPER II − ADRENAL VEIN SAMPLING IN information to the Patient Register.157 YOUNG PATIENTS WITH PRIMARY  The Swedish Causes of Death Register covers all deaths that occurred in Sweden, including deaths of non-Swedes. It also includes deaths of ALDOSTERONISM Swedes who have died abroad.158 This was a cross-sectional, single-center study of 45 consecutive young  The Swedish Prescribed Drug Register “contains all prescribed drugs as patients diagnosed with PA at Sahlgrenska University Hospital between 2005 dispensed in pharmacies” from July 2005 onwards according to and 2019. The study aimed to evaluate CT/MRI performance compared to Anatomical Therapeutic Chemical Classification (ATC) codes.159 AVS for classifying PA as unilateral or bilateral in young patients (≤40 years  The Swedish Population Register contains demographic data for all of age at the time of AVS) with PA. Based on the re-evaluation of imaging Swedish residents.160 data by two experienced radiologists, the study estimated how many patients 22 23 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa would have been given inappropriate treatment if the decision had been based gender. Comorbidity was based on ICD codes I20–I25 (ischemic heart solely on imaging studies. disease), I21 (myocardial infarction), I48 (atrial fibrillation or flutter), (I50 (heart failure), and I61–I64 (stroke), and E10–E14 (diabetes mellitus). 3.1.4 PAPER III − MORTALITY IN PRIMARY ALDOSTERONISM 3.1.5 PAPER IV − HIP FRACTURES IN PRIMARY This was a nationwide, register-based, matched cohort study. Data covers all ALDOSTERONISM patients with PA >18 years of age who were newly diagnosed between 1997 This nationwide observational study used the same population as in Study III and 2019 in Sweden. Patients were identified by search of ICD-10 diagnoses to assess the association between primary aldosteronism and hip fracture risk. for PA in the NPR. To distinguish between prevalent and incident patients, we Hip fractures were identified in the NPR from 1997 to 2019 based on ICD identified and excluded patients diagnosed from 1987 to 1996. Statistics codes S72.0, S72.1, and S72.2 (femoral neck fracture, intertrochanteric Sweden randomly selected 10 controls from the general population for each fracture, and subtrochanteric fracture, respectively). Adjustments included all case matching them by age, sex, and country of residence. The study included covariates assessed in Study III and additional risk factors for hip fracture, 2419 patients with PA and 24 187 age- sex- and residential area-matched including CVD comorbidity at baseline (defined as in Study III), osteoporosis controls from the general population. The study aimed to study mortality in PA (M80–M82), hyperparathyroidism (E21), and prior fracture at any site (ICD- and determine how age and cardiovascular comorbidity at diagnosis, sex, and 10 S02, S12, S22, S32, S42, S52, S62, S72, S82, and S92) assigned before the treatment mode impact outcome. index date. Record linkage with the Cause of Death Register allowed identification of all deaths and causes of death. Causes of death were subdivided by ICD codes 3.2 STATISTICAL ANALYSIS into: deaths from any cause (all-cause mortality), cardiovascular diseases Baseline characteristics of subjects included in Studies I–IV were presented as (CVDs) (ICD-10 I10–I99), coronary heart disease (ICD-10 I20–I25), stroke mean (SD) when continuous variables were normally distributed or as median (ICD-10 I61–I64), and other causes of death (all codes not listed above). (interquartile range; IQR) when variables were not normally distributed. Patients treated with adrenalectomy were identified by searching for diagnostic Categorical variables are presented as numbers with percentages. codes for adrenal resection (BCA20) or unilateral adrenalectomy (BCA30, BCA31) according to the Nordic Classification of Surgical Procedures. Data In Study I, the incidence and prevalence of PA were calculated by using the on MRA use was collected from the Swedish Prescribed Drug Registry, for number of residents in the Västra Götaland County as reference. To compare which data was available since 2006. MRA users were those patients who had patients’ characteristics diagnosed in earlier and later periods a t-test or the received an MRA (spironolactone or eplerenone) from pharmacies at least Mann-Whitney U-test was used for continuous variables depending on data twice annually during follow-up and were not treated by adrenalectomy. The distribution. To compare frequencies, Fisher’s exact test or Pearson’s chi- average MRA dose was defined in defined daily dose (DDD) units according squared test was used. to the World Health Organization. One DDD for spironolactone (ATC code C03DA01) is 75 mg and one DDD for eplerenone (ATC code C03DA04) is 50 In Study II, the results of AVS and imaging were treated as ordinal data mg.161 Patients receiving an average daily dose of MRA that was lower or (unilateral and bilateral) for concordance analysis. Inconclusive data was higher than the median MRA dose among all users were further classified as presented separately. We reported the number of concordant and discordant low- or high-dose MRA users, respectively. Patients who could not be pairs (AVS vs CT/MRI). Cohen’s kappa was used to assess agreement between classified as surgically treated or MRA users were considered untreated. readers. Detailed information on patients’ comorbidity before diagnosis was obtained from the NPR and socioeconomic factors from LISA including level of In Study III, the general population cohort was considered the reference cohort education, marital status, income, and country of birth. Sex was inferred by to study mortality in PA. To present and compare survival graphically in 24 25 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa would have been given inappropriate treatment if the decision had been based gender. Comorbidity was based on ICD codes I20–I25 (ischemic heart solely on imaging studies. disease), I21 (myocardial infarction), I48 (atrial fibrillation or flutter), (I50 (heart failure), and I61–I64 (stroke), and E10–E14 (diabetes mellitus). 3.1.4 PAPER III − MORTALITY IN PRIMARY ALDOSTERONISM 3.1.5 PAPER IV − HIP FRACTURES IN PRIMARY This was a nationwide, register-based, matched cohort study. Data covers all ALDOSTERONISM patients with PA >18 years of age who were newly diagnosed between 1997 This nationwide observational study used the same population as in Study III and 2019 in Sweden. Patients were identified by search of ICD-10 diagnoses to assess the association between primary aldosteronism and hip fracture risk. for PA in the NPR. To distinguish between prevalent and incident patients, we Hip fractures were identified in the NPR from 1997 to 2019 based on ICD identified and excluded patients diagnosed from 1987 to 1996. Statistics codes S72.0, S72.1, and S72.2 (femoral neck fracture, intertrochanteric Sweden randomly selected 10 controls from the general population for each fracture, and subtrochanteric fracture, respectively). Adjustments included all case matching them by age, sex, and country of residence. The study included covariates assessed in Study III and additional risk factors for hip fracture, 2419 patients with PA and 24 187 age- sex- and residential area-matched including CVD comorbidity at baseline (defined as in Study III), osteoporosis controls from the general population. The study aimed to study mortality in PA (M80–M82), hyperparathyroidism (E21), and prior fracture at any site (ICD- and determine how age and cardiovascular comorbidity at diagnosis, sex, and 10 S02, S12, S22, S32, S42, S52, S62, S72, S82, and S92) assigned before the treatment mode impact outcome. index date. Record linkage with the Cause of Death Register allowed identification of all deaths and causes of death. Causes of death were subdivided by ICD codes 3.2 STATISTICAL ANALYSIS into: deaths from any cause (all-cause mortality), cardiovascular diseases Baseline characteristics of subjects included in Studies I–IV were presented as (CVDs) (ICD-10 I10–I99), coronary heart disease (ICD-10 I20–I25), stroke mean (SD) when continuous variables were normally distributed or as median (ICD-10 I61–I64), and other causes of death (all codes not listed above). (interquartile range; IQR) when variables were not normally distributed. Patients treated with adrenalectomy were identified by searching for diagnostic Categorical variables are presented as numbers with percentages. codes for adrenal resection (BCA20) or unilateral adrenalectomy (BCA30, BCA31) according to the Nordic Classification of Surgical Procedures. Data In Study I, the incidence and prevalence of PA were calculated by using the on MRA use was collected from the Swedish Prescribed Drug Registry, for number of residents in the Västra Götaland County as reference. To compare which data was available since 2006. MRA users were those patients who had patients’ characteristics diagnosed in earlier and later periods a t-test or the received an MRA (spironolactone or eplerenone) from pharmacies at least Mann-Whitney U-test was used for continuous variables depending on data twice annually during follow-up and were not treated by adrenalectomy. The distribution. To compare frequencies, Fisher’s exact test or Pearson’s chi- average MRA dose was defined in defined daily dose (DDD) units according squared test was used. to the World Health Organization. One DDD for spironolactone (ATC code C03DA01) is 75 mg and one DDD for eplerenone (ATC code C03DA04) is 50 In Study II, the results of AVS and imaging were treated as ordinal data mg.161 Patients receiving an average daily dose of MRA that was lower or (unilateral and bilateral) for concordance analysis. Inconclusive data was higher than the median MRA dose among all users were further classified as presented separately. We reported the number of concordant and discordant low- or high-dose MRA users, respectively. Patients who could not be pairs (AVS vs CT/MRI). Cohen’s kappa was used to assess agreement between classified as surgically treated or MRA users were considered untreated. readers. Detailed information on patients’ comorbidity before diagnosis was obtained from the NPR and socioeconomic factors from LISA including level of In Study III, the general population cohort was considered the reference cohort education, marital status, income, and country of birth. Sex was inferred by to study mortality in PA. To present and compare survival graphically in 24 25 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa different treatment groups, we used Kaplan-Meier survival plots. The plots atrial fibrillation or flutter, congestive heart failure, and stroke), diabetes describe the relationship between survival probability and follow-up time. mellitus, and socioeconomic factors. As in Study III, a sensitivity analysis was Notably, the Kaplan-Meier method does not allow adjustments for performed that was restricted to patients who received the diagnostic code for confounders and depicts crude all-cause mortality. We used Cox regression PA in the NPR on two or more occasions. analysis, which allows adjustment for confounding factors, to compare all- cause mortality and cause-specific mortality in patients with PA and matched controls. The results from regression analysis are presented as hazard ratio 3.3 METHODOLOGICAL CONSIDERATIONS (HR) with 95% CI. CI provides information about the precision of estimates. Accurate diagnostic methods and a representative reference population are For the patient group, survival time is calculated from the date of diagnosis. crucial to produce accurate incidence and prevalence estimates. In Study I, the For the reference group, survival time is calculated from the diagnosis date of use of ICD codes for case identification is a limitation. Miscoding would bias their matching. Individuals who survived to the end of follow-up were our estimates: therefore, case ascertainment by review of medical records was censored. To utilize Cox regression analysis, we ensured that the proportional a strength. Overall, healthcare services in Sweden perform similarly across hazards assumption applied to the data. counties and the study area is the second most populated county. Hence, we consider the study population representative. It is important to understand that The association of PA and mortality was assessed in the following models. The the true incidence of PA cannot be captured for three reasons: a) chronic first model adjusted for sex and age at diagnosis of PA. In the second model, diseases develop gradually and patients are likely screened at different stages, further adjustments were made for socioeconomic factors at study entry (level b) varying screening tests and cut-offs; and c) increased awareness of PA, of education, marital status, income, and country of birth) as well as diabetes which may lead to increased recognition of prevalent patients. The value of our mellitus. In stratified (subgroup) analysis, we compared survival in different approach is that it shows how screening strategies perform in a real-world patient groups and corresponding controls from the general population. These setting. groups were a priori categorized based on the median age of the cohort, sex, and treatment category (adrenalectomy, MRA, low-dose MRA, high-dose The main limitation of Study II, which evaluated the diagnostic reliability of MRA, or no specific treatment) and by CVD (yes/no) at study entry. adrenal imaging to assess disease laterality in young patients, is the small Definitions of these terms are explained in the Methods section. Two patient sample based on data availability rather than statistical power sensitivity analyses were performed to assess the robustness of the hazard calculations. A reliable conclusion can be reached by pooling data from estimates. The first sensitivity analysis aimed to increase the validity of the PA relevant reports.162 A further limitation is potential selection bias. During the diagnosis by including only patients with multiple diagnostic codes. The study period, four young patients proceeded to surgery based on imaging alone. second sensitivity analysis aimed to assess whether the results would change Available information on their treatment outcomes was provided. Limitations when different identification sources were used to adjust for diabetes mellitus. of AVS, which is used as the reference test, are discussed in the Introduction. (i.e. clinical codes or dispensed drugs used to treat diabetes, a variable that Strengths related to the methods are the use of a well-established AVS captures all patients with diabetes regardless of their health provider). Because protocol, along with the success rate, and the detailed description of the CVD comorbidity is a mediator of the association between PA and mortality, patients’ characteristics and outcomes. Another strength is that we considered we only adjusted for CVD comorbidities at baseline, along with diabetes in a the possibility of different readings and obtained independent assessments by within-PA cohort analysis, to assess the independent influence effect of age, two readers for each imaging study. sex, and treatment underlying increased mortality risk among patients with PA. Studies III and IV utilized data from national registries and databases. The In Study IV, we used Cox regression analysis to estimate the HR for hip studies take advantage of the large sample size, long and almost complete fracture in PA (overall, by sex, age, and CVD at baseline) and by treatment. follow-up, and the unselected and representative population of patients HRs were adjusted for history of any prior fracture, osteoporosis, primary provided. On the other hand, several barriers exist when obtaining data from hyperparathyroidism, presence of CVD comorbidities (ischemic heart disease, registries and databases for research purposes (see as follows). 26 27 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa different treatment groups, we used Kaplan-Meier survival plots. The plots atrial fibrillation or flutter, congestive heart failure, and stroke), diabetes describe the relationship between survival probability and follow-up time. mellitus, and socioeconomic factors. As in Study III, a sensitivity analysis was Notably, the Kaplan-Meier method does not allow adjustments for performed that was restricted to patients who received the diagnostic code for confounders and depicts crude all-cause mortality. We used Cox regression PA in the NPR on two or more occasions. analysis, which allows adjustment for confounding factors, to compare all- cause mortality and cause-specific mortality in patients with PA and matched controls. The results from regression analysis are presented as hazard ratio 3.3 METHODOLOGICAL CONSIDERATIONS (HR) with 95% CI. CI provides information about the precision of estimates. Accurate diagnostic methods and a representative reference population are For the patient group, survival time is calculated from the date of diagnosis. crucial to produce accurate incidence and prevalence estimates. In Study I, the For the reference group, survival time is calculated from the diagnosis date of use of ICD codes for case identification is a limitation. Miscoding would bias their matching. Individuals who survived to the end of follow-up were our estimates: therefore, case ascertainment by review of medical records was censored. To utilize Cox regression analysis, we ensured that the proportional a strength. Overall, healthcare services in Sweden perform similarly across hazards assumption applied to the data. counties and the study area is the second most populated county. Hence, we consider the study population representative. It is important to understand that The association of PA and mortality was assessed in the following models. The the true incidence of PA cannot be captured for three reasons: a) chronic first model adjusted for sex and age at diagnosis of PA. In the second model, diseases develop gradually and patients are likely screened at different stages, further adjustments were made for socioeconomic factors at study entry (level b) varying screening tests and cut-offs; and c) increased awareness of PA, of education, marital status, income, and country of birth) as well as diabetes which may lead to increased recognition of prevalent patients. The value of our mellitus. In stratified (subgroup) analysis, we compared survival in different approach is that it shows how screening strategies perform in a real-world patient groups and corresponding controls from the general population. These setting. groups were a priori categorized based on the median age of the cohort, sex, and treatment category (adrenalectomy, MRA, low-dose MRA, high-dose The main limitation of Study II, which evaluated the diagnostic reliability of MRA, or no specific treatment) and by CVD (yes/no) at study entry. adrenal imaging to assess disease laterality in young patients, is the small Definitions of these terms are explained in the Methods section. Two patient sample based on data availability rather than statistical power sensitivity analyses were performed to assess the robustness of the hazard calculations. A reliable conclusion can be reached by pooling data from estimates. The first sensitivity analysis aimed to increase the validity of the PA relevant reports.162 A further limitation is potential selection bias. During the diagnosis by including only patients with multiple diagnostic codes. The study period, four young patients proceeded to surgery based on imaging alone. second sensitivity analysis aimed to assess whether the results would change Available information on their treatment outcomes was provided. Limitations when different identification sources were used to adjust for diabetes mellitus. of AVS, which is used as the reference test, are discussed in the Introduction. (i.e. clinical codes or dispensed drugs used to treat diabetes, a variable that Strengths related to the methods are the use of a well-established AVS captures all patients with diabetes regardless of their health provider). Because protocol, along with the success rate, and the detailed description of the CVD comorbidity is a mediator of the association between PA and mortality, patients’ characteristics and outcomes. Another strength is that we considered we only adjusted for CVD comorbidities at baseline, along with diabetes in a the possibility of different readings and obtained independent assessments by within-PA cohort analysis, to assess the independent influence effect of age, two readers for each imaging study. sex, and treatment underlying increased mortality risk among patients with PA. Studies III and IV utilized data from national registries and databases. The In Study IV, we used Cox regression analysis to estimate the HR for hip studies take advantage of the large sample size, long and almost complete fracture in PA (overall, by sex, age, and CVD at baseline) and by treatment. follow-up, and the unselected and representative population of patients HRs were adjusted for history of any prior fracture, osteoporosis, primary provided. On the other hand, several barriers exist when obtaining data from hyperparathyroidism, presence of CVD comorbidities (ischemic heart disease, registries and databases for research purposes (see as follows). 26 27 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa First, validation of registry data is essential since the validity of our results is analysis. For this reason, the low number of hip fractures in men may lead to closely linked to the quality of the data provided. Validation of the PA type II errors when assessing their fracture risk. diagnosis in the NPR was necessary to address misclassification, i.e. the possibility that individuals without PA were miscoded as diseased. It has been Finally, when interpreting associations, it is important to be aware that the shown that 85%–95% of diagnoses in the NPR are correct but, when it comes design cannot establish cause-effect relationships. Importantly, the observed to endocrine diseases, miscoding is a concern.163,164 To assess completeness, variations in the subgroup analysis (e.g. by age, sex, or presence of we searched and identified a subset of patients who underwent AVS in our comorbidities) depend on different baseline hazards and do not imply a institution in the NPR. Notwithstanding that individuals with suspected PA are differential treatment effect. In this context, a comparison between MRA and referred to secondary healthcare services for confirmatory testing, most surgery would not be fair due to limited control over several risk factors and patients with confirmed PA were included. Second, it was important to choose selection bias. The ideal setting to assess treatment effects comparatively outcomes that could be reliably assessed through administrative health data. In would be a randomized trial. To help guide whether these results can be validation studies of the Cause of Death Register, a cause of death was extrapolated to other populations, it is important to consider differences in provided for 97% of all deaths and agreed with medical records in 77%–98% demographic characteristics, disease severity, genetic characteristics, or of patients, with higher levels of agreement seen for CVD deaths.165 In Study sodium intake. IV, we relied on the NPR to assess the risk of hip fractures. Since most patients with hip fractures require specialized care and hospitalization, the NPR covers 97% of patients with hip fractures.166 Third, the NPR does not capture data from primary care. Patients with diabetes may be inadequately represented in the NPR, as most of these patients are followed by general practitioners A sensitivity analysis was conducted to address imbalances in diabetes prevalence, utilizing information from the Drug Register as an alternative to ICD codes. An important limitation that applies to retrospective and register-based studies is that data was not collected specifically for our research purposes. This makes it difficult to fully address potentially confounding factors. In Study I, the validation process was confined to earlier definitions and practices and limited in many cases due to missing data. In Study II, cortisol co-secretion and surgical outcome could not be assessed in a few patients. In Studies III and IV, adjustment for several socioeconomic factors that influence long-term outcomes was possible and the cohort was large enough for multivariable adjustments and stratification. However, it was not possible to study the independent role of hypertension, which partly mediates the development of complications in PA.131 Another missing variable of interest was renin levels, which limited individual assessments of dose adequacy in MRA users. In Study IV, we could not adjust for risk factors such as bone mineral density, glucocorticoid therapy, smoking, body mass index, and heredity, all of which might add to the risk of hip fracture.167 While the nationwide cohort had a large number of patients with PA, the number of events can be small in the subgroup 28 29 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa First, validation of registry data is essential since the validity of our results is analysis. For this reason, the low number of hip fractures in men may lead to closely linked to the quality of the data provided. Validation of the PA type II errors when assessing their fracture risk. diagnosis in the NPR was necessary to address misclassification, i.e. the possibility that individuals without PA were miscoded as diseased. It has been Finally, when interpreting associations, it is important to be aware that the shown that 85%–95% of diagnoses in the NPR are correct but, when it comes design cannot establish cause-effect relationships. Importantly, the observed to endocrine diseases, miscoding is a concern.163,164 To assess completeness, variations in the subgroup analysis (e.g. by age, sex, or presence of we searched and identified a subset of patients who underwent AVS in our comorbidities) depend on different baseline hazards and do not imply a institution in the NPR. Notwithstanding that individuals with suspected PA are differential treatment effect. In this context, a comparison between MRA and referred to secondary healthcare services for confirmatory testing, most surgery would not be fair due to limited control over several risk factors and patients with confirmed PA were included. Second, it was important to choose selection bias. The ideal setting to assess treatment effects comparatively outcomes that could be reliably assessed through administrative health data. In would be a randomized trial. To help guide whether these results can be validation studies of the Cause of Death Register, a cause of death was extrapolated to other populations, it is important to consider differences in provided for 97% of all deaths and agreed with medical records in 77%–98% demographic characteristics, disease severity, genetic characteristics, or of patients, with higher levels of agreement seen for CVD deaths.165 In Study sodium intake. IV, we relied on the NPR to assess the risk of hip fractures. Since most patients with hip fractures require specialized care and hospitalization, the NPR covers 97% of patients with hip fractures.166 Third, the NPR does not capture data from primary care. Patients with diabetes may be inadequately represented in the NPR, as most of these patients are followed by general practitioners A sensitivity analysis was conducted to address imbalances in diabetes prevalence, utilizing information from the Drug Register as an alternative to ICD codes. An important limitation that applies to retrospective and register-based studies is that data was not collected specifically for our research purposes. This makes it difficult to fully address potentially confounding factors. In Study I, the validation process was confined to earlier definitions and practices and limited in many cases due to missing data. In Study II, cortisol co-secretion and surgical outcome could not be assessed in a few patients. In Studies III and IV, adjustment for several socioeconomic factors that influence long-term outcomes was possible and the cohort was large enough for multivariable adjustments and stratification. However, it was not possible to study the independent role of hypertension, which partly mediates the development of complications in PA.131 Another missing variable of interest was renin levels, which limited individual assessments of dose adequacy in MRA users. In Study IV, we could not adjust for risk factors such as bone mineral density, glucocorticoid therapy, smoking, body mass index, and heredity, all of which might add to the risk of hip fracture.167 While the nationwide cohort had a large number of patients with PA, the number of events can be small in the subgroup 28 29 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 4 RESULTS 4.1 PAPER I – INCIDENCE OF PRIMARY ALDOSTERONISM In Study I, we determined the incidence of PA from 1987 to 2016 in Västra Götaland County. Results are summarized in figure 10. The total number of individuals assigned an ICD-9 (255.B) or ICD-10 code for PA (E260) in the NPR was 570. Out of the 553 individuals identified with available records, 473 (83%) were classified as having PA and 17 (3%) as probable PA. A common reason for misdiagnosis was that patients were coded as diseased at referral, as 31 of 63 incorrectly diagnosed patients had undergone a confirmatory test that ruled out PA. Among individual patients registered with ICD-10 E260 (since 1997), 87% were confirmed PA patients and 94% were assigned ICD-10 for PA more than once for confirmed PA. Additionally, 97% of patients in whom Figure 10. Background characteristics, investigations, and treatment by time period. Significant difference was found between 1997–2006 and 2007–2016 for saline AVS investigation was performed at Sahlgrenska University Hospital were infusion tests and AVS along with success rates but not in indicators of disease severity registered in the NPR. Patients with confirmed PA (n=416) had a mean (SD) such as hypokalemia and number of antihypertensive drugs. Abbreviations: AVS, age of 56 (12) years at diagnosis and about 40% (n=168) were women. adrenal vein sampling; PA, primary aldosteronism. Potassium supplementation was required in 80% of the patients with confirmed For incidence analysis, 416 patients (60% men and 40% women) diagnosed PA. Results of an SIT were available in half of the patients diagnosed between with PA between 1987 and 2016 were eligible. The median (IQR) annual 1997 and 2006. The diagnosis of PA was corroborated with an SIT in 87% of incidence of PA was estimated to be 2 (1–2) patients per million between 1987 patients diagnosed between 2007 and 2016. This trend may relate to changes and 1996, 6 (4–9) patients per million between 1997 and 2006, and 17 (12–24) in recommendations for screening. There has been an increase in the number patients per million between 2007 and 2016 (figure 11). At the end of the study of patients who have undergone AVS since 1997 (46% in 1998–2006 vs 80% (December 31, 2016), 386 patients with confirmed PA were still alive and in 2007–2016), leading to an increasing number of patients receiving living in Västra Götaland County, resulting in a prevalence of 231 patients per adrenalectomy. Among all patients, 43% received adrenalectomy: seven million (0.022%). The expected number of patients should have been 3500–20 patients between 1987 and 1996, 48 between 1997 and 2006, and 121 between 000 based on previous prevalence studies.60-62 Thus, only a small proportion of 2007 and 2016. hypertensive patients are being diagnosed with PA. 30 31 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 4 RESULTS 4.1 PAPER I – INCIDENCE OF PRIMARY ALDOSTERONISM In Study I, we determined the incidence of PA from 1987 to 2016 in Västra Götaland County. Results are summarized in figure 10. The total number of individuals assigned an ICD-9 (255.B) or ICD-10 code for PA (E260) in the NPR was 570. Out of the 553 individuals identified with available records, 473 (83%) were classified as having PA and 17 (3%) as probable PA. A common reason for misdiagnosis was that patients were coded as diseased at referral, as 31 of 63 incorrectly diagnosed patients had undergone a confirmatory test that ruled out PA. Among individual patients registered with ICD-10 E260 (since 1997), 87% were confirmed PA patients and 94% were assigned ICD-10 for PA more than once for confirmed PA. Additionally, 97% of patients in whom Figure 10. Background characteristics, investigations, and treatment by time period. Significant difference was found between 1997–2006 and 2007–2016 for saline AVS investigation was performed at Sahlgrenska University Hospital were infusion tests and AVS along with success rates but not in indicators of disease severity registered in the NPR. Patients with confirmed PA (n=416) had a mean (SD) such as hypokalemia and number of antihypertensive drugs. Abbreviations: AVS, age of 56 (12) years at diagnosis and about 40% (n=168) were women. adrenal vein sampling; PA, primary aldosteronism. Potassium supplementation was required in 80% of the patients with confirmed For incidence analysis, 416 patients (60% men and 40% women) diagnosed PA. Results of an SIT were available in half of the patients diagnosed between with PA between 1987 and 2016 were eligible. The median (IQR) annual 1997 and 2006. The diagnosis of PA was corroborated with an SIT in 87% of incidence of PA was estimated to be 2 (1–2) patients per million between 1987 patients diagnosed between 2007 and 2016. This trend may relate to changes and 1996, 6 (4–9) patients per million between 1997 and 2006, and 17 (12–24) in recommendations for screening. There has been an increase in the number patients per million between 2007 and 2016 (figure 11). At the end of the study of patients who have undergone AVS since 1997 (46% in 1998–2006 vs 80% (December 31, 2016), 386 patients with confirmed PA were still alive and in 2007–2016), leading to an increasing number of patients receiving living in Västra Götaland County, resulting in a prevalence of 231 patients per adrenalectomy. Among all patients, 43% received adrenalectomy: seven million (0.022%). The expected number of patients should have been 3500–20 patients between 1987 and 1996, 48 between 1997 and 2006, and 121 between 000 based on previous prevalence studies.60-62 Thus, only a small proportion of 2007 and 2016. hypertensive patients are being diagnosed with PA. 30 31 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa patient and negative biochemical success was seen in the other. Only one of the patients who was lateralized on AVS showed features of nodularity on histology but showed complete clinical success. Figure 11. Incidence of primary aldosteronism in Western Sweden over 3 decades. [Reproduced from Gkaniatsa et al.168 with permission from ©Oxford University Press] 4.2 PAPER II – ADRENAL VEIN SAMPLING IN Figure 12. Simplified overview of results in Paper II.169 Abbreviations: AVS, adrenal YOUNG PATIENTS WITH PRIMARY vein sampling; CT, computerized tomography; MRI, magnetic resonance imaging; PA, primary aldosteronism. ALDOSTERONISM Re-evaluation of the same images by two experienced radiologists showed that Study II, designed to compare CT/MRI scanning and AVS, included 45 inter-rater agreement of imaging studies in patients with PA was excellent consecutive patients with PA 26–40 years of age who underwent AVS in (k=0.90) for detecting adrenal lesions >1 cm and substantial (k=0.71) for addition to imaging studies at Sahlgrenska University Hospital between 2005 detecting lesions 0.8–1 cm in diameter. The only exceptions where different and 2019. Sixteen patients were ≤35 years of age and 34 were women. At interpretations involved adrenal lesions >1 cm were a patient with a unilateral referral, 60% required potassium supplements and median post-infusion 11-mm lesion classified as focal hyperplasia by one reviewer and a patient with aldosterone level was 552 pmol/L. a unilateral adenoma and a benign extra-adrenal lesion that confused the two Results are summarized in figure 12. Comparison of the radiological diagnosis readers. In this case, MRI was more informative than CT scanning. with AVS results unexpectedly revealed that 20% (n=9) of young patient with PA had an inaccurate prediction of laterality based on imaging studies. In total, 4.3 PAPER III – MORTALITY IN PRIMARY 22 patients had unilateral PA considering AVS as the criterion standard. Of these, two patients had a lateralization index between 3 and 4 but suppressed ALDOSTERONISM contralateral CL. AVS demonstrated that four of 25 patients with either normal Our population-based register study followed 2419 people >18 years of age or bilateral abnormal adrenal glands on imaging had unilateral aldosterone who were diagnosed with PA between 1998 and 2019, and 24 187 unaffected production, while five of 20 with solitary adrenal nodules had bilateral disease. people matched (1:10) for sex, birth year, and county of residence. Mean age Two patients with bilateral disease according to AVS and discordant imaging was 56 years and 44.4% were women. Patients with PA had a higher proceeded to adrenalectomy. Partial biochemical success was observed in one prevalence of CVD comorbidities and diabetes compared to controls at 32 33 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa patient and negative biochemical success was seen in the other. Only one of the patients who was lateralized on AVS showed features of nodularity on histology but showed complete clinical success. Figure 11. Incidence of primary aldosteronism in Western Sweden over 3 decades. [Reproduced from Gkaniatsa et al.168 with permission from ©Oxford University Press] 4.2 PAPER II – ADRENAL VEIN SAMPLING IN Figure 12. Simplified overview of results in Paper II.169 Abbreviations: AVS, adrenal YOUNG PATIENTS WITH PRIMARY vein sampling; CT, computerized tomography; MRI, magnetic resonance imaging; PA, primary aldosteronism. ALDOSTERONISM Re-evaluation of the same images by two experienced radiologists showed that Study II, designed to compare CT/MRI scanning and AVS, included 45 inter-rater agreement of imaging studies in patients with PA was excellent consecutive patients with PA 26–40 years of age who underwent AVS in (k=0.90) for detecting adrenal lesions >1 cm and substantial (k=0.71) for addition to imaging studies at Sahlgrenska University Hospital between 2005 detecting lesions 0.8–1 cm in diameter. The only exceptions where different and 2019. Sixteen patients were ≤35 years of age and 34 were women. At interpretations involved adrenal lesions >1 cm were a patient with a unilateral referral, 60% required potassium supplements and median post-infusion 11-mm lesion classified as focal hyperplasia by one reviewer and a patient with aldosterone level was 552 pmol/L. a unilateral adenoma and a benign extra-adrenal lesion that confused the two Results are summarized in figure 12. Comparison of the radiological diagnosis readers. In this case, MRI was more informative than CT scanning. with AVS results unexpectedly revealed that 20% (n=9) of young patient with PA had an inaccurate prediction of laterality based on imaging studies. In total, 4.3 PAPER III – MORTALITY IN PRIMARY 22 patients had unilateral PA considering AVS as the criterion standard. Of these, two patients had a lateralization index between 3 and 4 but suppressed ALDOSTERONISM contralateral CL. AVS demonstrated that four of 25 patients with either normal Our population-based register study followed 2419 people >18 years of age or bilateral abnormal adrenal glands on imaging had unilateral aldosterone who were diagnosed with PA between 1998 and 2019, and 24 187 unaffected production, while five of 20 with solitary adrenal nodules had bilateral disease. people matched (1:10) for sex, birth year, and county of residence. Mean age Two patients with bilateral disease according to AVS and discordant imaging was 56 years and 44.4% were women. Patients with PA had a higher proceeded to adrenalectomy. Partial biochemical success was observed in one prevalence of CVD comorbidities and diabetes compared to controls at 32 33 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa baseline. Cohorts were followed for a median duration of 8.1 vs 8.2 years, users had an HR of 2.51 (1.72–3.67) compared to matched controls, accounting respectively, during the period from 1 January 1997 to 31 December 2020 for socioeconomic factors and diabetes. (figure 13). Figure 14. Kaplan-Meier plots of overall survival throughout the study period in Figure 13. Baseline characteristics of the study population in Paper III. Abbreviations: patients with primary aldosteronism (solid line) and corresponding controls (dotted MRA, mineralocorticoid receptor antagonist; PA, primary aldosteronism; SD, line) for A) the entire cohort, B) by age group, C) men with PA, and D) women with standard deviation; yr, year. PA. P-values are from log-rank tests. Abbreviation: PA, primary aldosteronism. Reproduced from Gkaniatsa et al.170 with permission from ©Wolters Kluwer Health] Mortality results are summarized in figure 14. In total, 345 patients and 2736 controls (14% vs 11%) died during the study period. On average, we found that 4.4 PAPER IV – HIP FRACTURES IN patients with PA had a 20% greater risk of all-cause mortality (HR 1.23, 95% CI 1.10–1.38) and mortality due to CVD (1.57, 1.30–1.89) after adjustment for PRIMARY ALDOSTERONISM age, sex, diabetes, and socioeconomic variables. Mortality was increased in In Study IV, we explored hip fracture risk in patients with PA. The cohort of both women (1.36, 1.14–1.63) and men (1.17, 1.01–1.35) but varied according patients was the same as in Study III (n=2419) as was the matched general to age at diagnosis. When considering only patients diagnosed before the age population control cohort (n=24 187). Hip fractures were assessed during the of 56 years, mortality was not increased compared to corresponding controls study period 1997–2019 (figure 15). During a mean (SD) follow-up of 8 (5) without PA (0.98, 0.73–1.31). In stratified Cox proportional hazards models years, 64 (2.6%) patients had a hip fracture after being diagnosed with PA adjusted for age, sex, diabetes, and socioeconomic variables, the highest HRs compared to 401 (1.7%) controls. Cox regression analysis showed that the risk were observed in the following subgroups: patients with PA and CVD at of hip fracture was increased in PA compared to controls (HR 1.55, 95% CI diagnosis (1.53, 1.26–1.85), age >56 years at diagnosis (1.28, 1.13–1.45), and 1.18–2.03) after adjustment for history of any prior fracture, osteoporosis, those treated with a low-dose MRA (1.30, 1.02–1.66), all compared to primary hyperparathyroidism, diabetes mellitus, and socioeconomic factors. corresponding controls. Conversely, in patients treated by adrenalectomy and Patients at highest risk were women (1.76, 1.24–2.52), patients >56 years of patients receiving a higher dose of MRA than average, no excess mortality was age at the time of diagnosis (1.62, 1.21–2.17), and patients with CVD at observed. Patients who were not treated by adrenalectomy and were not MRA diagnosis (2.15, 1.37–3.37). No increased risk of hip fractures overall was seen 34 35 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa baseline. Cohorts were followed for a median duration of 8.1 vs 8.2 years, users had an HR of 2.51 (1.72–3.67) compared to matched controls, accounting respectively, during the period from 1 January 1997 to 31 December 2020 for socioeconomic factors and diabetes. (figure 13). Figure 14. Kaplan-Meier plots of overall survival throughout the study period in Figure 13. Baseline characteristics of the study population in Paper III. Abbreviations: patients with primary aldosteronism (solid line) and corresponding controls (dotted MRA, mineralocorticoid receptor antagonist; PA, primary aldosteronism; SD, line) for A) the entire cohort, B) by age group, C) men with PA, and D) women with standard deviation; yr, year. PA. P-values are from log-rank tests. Abbreviation: PA, primary aldosteronism. Reproduced from Gkaniatsa et al.170 with permission from ©Wolters Kluwer Health] Mortality results are summarized in figure 14. In total, 345 patients and 2736 controls (14% vs 11%) died during the study period. On average, we found that 4.4 PAPER IV – HIP FRACTURES IN patients with PA had a 20% greater risk of all-cause mortality (HR 1.23, 95% CI 1.10–1.38) and mortality due to CVD (1.57, 1.30–1.89) after adjustment for PRIMARY ALDOSTERONISM age, sex, diabetes, and socioeconomic variables. Mortality was increased in In Study IV, we explored hip fracture risk in patients with PA. The cohort of both women (1.36, 1.14–1.63) and men (1.17, 1.01–1.35) but varied according patients was the same as in Study III (n=2419) as was the matched general to age at diagnosis. When considering only patients diagnosed before the age population control cohort (n=24 187). Hip fractures were assessed during the of 56 years, mortality was not increased compared to corresponding controls study period 1997–2019 (figure 15). During a mean (SD) follow-up of 8 (5) without PA (0.98, 0.73–1.31). In stratified Cox proportional hazards models years, 64 (2.6%) patients had a hip fracture after being diagnosed with PA adjusted for age, sex, diabetes, and socioeconomic variables, the highest HRs compared to 401 (1.7%) controls. Cox regression analysis showed that the risk were observed in the following subgroups: patients with PA and CVD at of hip fracture was increased in PA compared to controls (HR 1.55, 95% CI diagnosis (1.53, 1.26–1.85), age >56 years at diagnosis (1.28, 1.13–1.45), and 1.18–2.03) after adjustment for history of any prior fracture, osteoporosis, those treated with a low-dose MRA (1.30, 1.02–1.66), all compared to primary hyperparathyroidism, diabetes mellitus, and socioeconomic factors. corresponding controls. Conversely, in patients treated by adrenalectomy and Patients at highest risk were women (1.76, 1.24–2.52), patients >56 years of patients receiving a higher dose of MRA than average, no excess mortality was age at the time of diagnosis (1.62, 1.21–2.17), and patients with CVD at observed. Patients who were not treated by adrenalectomy and were not MRA diagnosis (2.15, 1.37–3.37). No increased risk of hip fractures overall was seen 34 35 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa in patients treated by adrenalectomy (0.84, 0.35–2.0), while patients treated with MRAs retained a greater risk (1.84, 1.20–2.83). 5 DISCUSSION 5.1 KEY FINDINGS The thesis has uncovered several key findings. i. PA remains under-diagnosed. The notified incidence of PA is increasing. Without capacity, these trends will probably strain the healthcare system. ii. Conventional imaging compromises diagnostic accuracy and leads to inappropriate treatment in a substantial number of young patients. Recommendations to omit AVS in patients with a solitary adenoma and age under 35 years are not supported by our data. iii. Long-term mortality is increased in PA. The major contributors appear to be older age and comorbidities at the time of diagnosis and undertreatment, stressing the importance of early disease identification Figure 15. Cumulative risk for hip fracture in patients with PA and controls matched by and adequate treatment. age at diagnosis, sex, and county of residence adjusted for socioeconomic factors, prior iv. Patients with PA are at an increased risk for hip fractures. For the fractures, diabetes mellitus, osteoporosis, hyperparathyroidism, and cardiovascular disease for A) the entire cohort and B) women with PA. Results from Cox regression. outcome of the risk of hip fracture, women and patients with Abbreviations: CI, confidence interval; PA, primary aldosteronism. [Reproduced from established comorbidity are most vulnerable as are patients treated Gkaniatsa et al.171 with permission from ©Springer] with an MRA. Overall, this thesis provides valuable insights into the long-term consequences of PA in various patient populations, highlighting a need for improvement in the overall management of patients with PA. The potential of disease-specific treatment has been highlighted with evidence suggesting that high doses of an MRA and adrenalectomy reverse mortality. Concerns have been raised that medically treated patients receive insufficient MRA doses. Factors such as age at diagnosis and established CVD comorbidity have been explored and were associated with a further increase in mortality risk, which was not seen in young patients and patients without comorbidities: this highlights the consequences of delayed diagnosis. Impaired bone health has emerged as a complication of PA, although the underlying mechanism is poorly understood. To place findings in context, the following topics summarize available evidence and provide insights that might serve as a basis for further research. 36 37 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa in patients treated by adrenalectomy (0.84, 0.35–2.0), while patients treated with MRAs retained a greater risk (1.84, 1.20–2.83). 5 DISCUSSION 5.1 KEY FINDINGS The thesis has uncovered several key findings. i. PA remains under-diagnosed. The notified incidence of PA is increasing. Without capacity, these trends will probably strain the healthcare system. ii. Conventional imaging compromises diagnostic accuracy and leads to inappropriate treatment in a substantial number of young patients. Recommendations to omit AVS in patients with a solitary adenoma and age under 35 years are not supported by our data. iii. Long-term mortality is increased in PA. The major contributors appear to be older age and comorbidities at the time of diagnosis and undertreatment, stressing the importance of early disease identification Figure 15. Cumulative risk for hip fracture in patients with PA and controls matched by and adequate treatment. age at diagnosis, sex, and county of residence adjusted for socioeconomic factors, prior iv. Patients with PA are at an increased risk for hip fractures. For the fractures, diabetes mellitus, osteoporosis, hyperparathyroidism, and cardiovascular disease for A) the entire cohort and B) women with PA. Results from Cox regression. outcome of the risk of hip fracture, women and patients with Abbreviations: CI, confidence interval; PA, primary aldosteronism. [Reproduced from established comorbidity are most vulnerable as are patients treated Gkaniatsa et al.171 with permission from ©Springer] with an MRA. Overall, this thesis provides valuable insights into the long-term consequences of PA in various patient populations, highlighting a need for improvement in the overall management of patients with PA. The potential of disease-specific treatment has been highlighted with evidence suggesting that high doses of an MRA and adrenalectomy reverse mortality. Concerns have been raised that medically treated patients receive insufficient MRA doses. Factors such as age at diagnosis and established CVD comorbidity have been explored and were associated with a further increase in mortality risk, which was not seen in young patients and patients without comorbidities: this highlights the consequences of delayed diagnosis. Impaired bone health has emerged as a complication of PA, although the underlying mechanism is poorly understood. To place findings in context, the following topics summarize available evidence and provide insights that might serve as a basis for further research. 36 37 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 5.2 TRENDS IN INCIDENCE OF PRIMARY diagnosing edge cases with marginal PA has to be carefully weighed. As the prevalence of PA continues to evolve,34 our primary focus should be to identify ALDOSTERONISM AND PRIORITIES individuals where evidence suggests that targeted treatment can prevent Study I, a population-based study from Sweden, found that the incidence of complications rather than diagnosing as many individuals as possible. PA has increased from a median (IQR) of 2 (1–2) patients per million people between 1987 and 1996 to 6 (4–9) patients between 1997 and 2006 and 17 (12– The accurate and timely diagnosis of PA is crucial as it lays the groundwork 24) patients between 2007 and 2016. At the end of the study (December 31, for effective treatment and positive patient outcomes. Optimizing the 2016) the prevalence of PA was 231 patients per million (0.022%). Greater management strategy for PA involves comprehensive screening of groups with access to AVS has significantly affected the proportion of patients being a high probability of PA. 63 Efforts to simplify screening and standardize assessed and diagnosed with unilateral disease, as seen by the number of protocols for evaluating treatment options will be crucial in improving patient adrenalectomies, which became more frequent. Hence, trends also suggest that outcomes. Simplified diagnostic algorithms should emphasize that patients the number of individuals with unilateral disease requiring surgical with a severe phenotype do not need confirmatory testing, which is often 63 intervention will increase. Prevalence estimates were substantially lower than disregarded. Our study prompted a critical reflection on current screening the range of rates reported from cross-sectional studies from Sweden.60-62 The guidelines for PA in Sweden and internationally, emphasizing the need for a magnitude of undiagnosed PA ranged from 3500 to 20 000 people. more efficient screening process. 174,175 The incidence of PA appears to be increasing in the general population. This 5.3 WHY SHOULD YOUNG PATIENTS is likely due to increased awareness about the risk of CVD complications and less due to the broadening of the definition of PA. We compared patient UNDERGO ADRENAL VEIN SAMPLING? characteristics diagnosed in different time periods to understand factors driving In Study II, laterality determined by AVS in young patients was compared with these trends and their implications. Guidelines focus on screening high-risk that determined by imaging studies, both used as standard care at Sahlgrenska individuals for PA but the definitions and criteria used to verify PA vary University Hospital. Discordant findings were reported in nine of 45 (20%) widely.58,67,141 Although diagnostic methods were not the same during the patients <40 years of age. Despite the small number in the study group, this studied period, the bulk of these patients were diagnosed using conservative work complements previous studies in this field and supports using AVS to cut-offs and most had hypokalemia at presentation (80%).56 This contrasts with diagnose unilateral disease in young patients with PA accurately. previous studies which suggest that 37% of patients with confirmed PA present with hypokalemia.23,34 A study from Korea, in which clinical criteria and Nonfunctional adenomas are uncommon in young patients.96,176 This has led to comprehensive screening were used to identify patients with PA, reinforced doubts on whether AVS is truly indicated in the age group <40 years with previous observations with only 40% of patients presenting with hypokalemia visual evidence of unilateral disease. When guidelines were released in 2016, among patients diagnosed most recently (2016–2021).28 A study from 2016 the Task Force deemed there was not enough evidence to recommend AVS for found that screening recommendations for PA were not uniformly adopted by younger patients with a solitary adenoma. However, the reliability of general practitioners in Germany and Italy.172 We conclude that more efforts conventional imaging in this context has not been evaluated using large patient are needed to improve the diagnosis of patients with less severe phenotypes. samples.91,177 One of the factors that makes this presumption questionable is the heterogeneity of histopathological features in unilateral PA. In patients Despite these incremental increases in case identification, effective health with unilateral disease, small regions with strong aldosterone synthase activity, planning is required to address the higher overall healthcare needs of a growing known as aldosterone-producing cell clusters, may be the source of aldosterone population. It is increasingly appreciated that PA represents a spectrum of secretion.105 Patients with apparent normal adrenal glands benefit from AVS clinical disease severity.27 As the question of cost-effectiveness arises, we investigations. As reported by Riester et al.,178 seven out of 28 young patients should keep in mind that the most significant cost to the healthcare system is with apparently normal adrenal glands lateralized on AVS. Guidelines were that of untreated PA.173 However, looking across the continuum of PA, 38 39 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 5.2 TRENDS IN INCIDENCE OF PRIMARY diagnosing edge cases with marginal PA has to be carefully weighed. As the prevalence of PA continues to evolve,34 our primary focus should be to identify ALDOSTERONISM AND PRIORITIES individuals where evidence suggests that targeted treatment can prevent Study I, a population-based study from Sweden, found that the incidence of complications rather than diagnosing as many individuals as possible. PA has increased from a median (IQR) of 2 (1–2) patients per million people between 1987 and 1996 to 6 (4–9) patients between 1997 and 2006 and 17 (12– The accurate and timely diagnosis of PA is crucial as it lays the groundwork 24) patients between 2007 and 2016. At the end of the study (December 31, for effective treatment and positive patient outcomes. Optimizing the 2016) the prevalence of PA was 231 patients per million (0.022%). Greater management strategy for PA involves comprehensive screening of groups with access to AVS has significantly affected the proportion of patients being a high probability of PA. 63 Efforts to simplify screening and standardize assessed and diagnosed with unilateral disease, as seen by the number of protocols for evaluating treatment options will be crucial in improving patient adrenalectomies, which became more frequent. Hence, trends also suggest that outcomes. Simplified diagnostic algorithms should emphasize that patients the number of individuals with unilateral disease requiring surgical with a severe phenotype do not need confirmatory testing, which is often 63 intervention will increase. Prevalence estimates were substantially lower than disregarded. Our study prompted a critical reflection on current screening the range of rates reported from cross-sectional studies from Sweden.60-62 The guidelines for PA in Sweden and internationally, emphasizing the need for a magnitude of undiagnosed PA ranged from 3500 to 20 000 people. more efficient screening process. 174,175 The incidence of PA appears to be increasing in the general population. This 5.3 WHY SHOULD YOUNG PATIENTS is likely due to increased awareness about the risk of CVD complications and less due to the broadening of the definition of PA. We compared patient UNDERGO ADRENAL VEIN SAMPLING? characteristics diagnosed in different time periods to understand factors driving In Study II, laterality determined by AVS in young patients was compared with these trends and their implications. Guidelines focus on screening high-risk that determined by imaging studies, both used as standard care at Sahlgrenska individuals for PA but the definitions and criteria used to verify PA vary University Hospital. Discordant findings were reported in nine of 45 (20%) widely.58,67,141 Although diagnostic methods were not the same during the patients <40 years of age. Despite the small number in the study group, this studied period, the bulk of these patients were diagnosed using conservative work complements previous studies in this field and supports using AVS to cut-offs and most had hypokalemia at presentation (80%).56 This contrasts with diagnose unilateral disease in young patients with PA accurately. previous studies which suggest that 37% of patients with confirmed PA present with hypokalemia.23,34 A study from Korea, in which clinical criteria and Nonfunctional adenomas are uncommon in young patients.96,176 This has led to comprehensive screening were used to identify patients with PA, reinforced doubts on whether AVS is truly indicated in the age group <40 years with previous observations with only 40% of patients presenting with hypokalemia visual evidence of unilateral disease. When guidelines were released in 2016, among patients diagnosed most recently (2016–2021).28 A study from 2016 the Task Force deemed there was not enough evidence to recommend AVS for found that screening recommendations for PA were not uniformly adopted by younger patients with a solitary adenoma. However, the reliability of general practitioners in Germany and Italy.172 We conclude that more efforts conventional imaging in this context has not been evaluated using large patient are needed to improve the diagnosis of patients with less severe phenotypes. samples.91,177 One of the factors that makes this presumption questionable is the heterogeneity of histopathological features in unilateral PA. In patients Despite these incremental increases in case identification, effective health with unilateral disease, small regions with strong aldosterone synthase activity, planning is required to address the higher overall healthcare needs of a growing known as aldosterone-producing cell clusters, may be the source of aldosterone population. It is increasingly appreciated that PA represents a spectrum of secretion.105 Patients with apparent normal adrenal glands benefit from AVS clinical disease severity.27 As the question of cost-effectiveness arises, we investigations. As reported by Riester et al.,178 seven out of 28 young patients should keep in mind that the most significant cost to the healthcare system is with apparently normal adrenal glands lateralized on AVS. Guidelines were that of untreated PA.173 However, looking across the continuum of PA, 38 39 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa published in 2016 and some new studies have been published since then. The sex-matched controls without PA from the general population. Subgroup surgical outcome of 69 patients <40 years of age with severe PA and unilateral analysis provided valuable insights into the impact of different treatments on adenoma on imaging were presented in the study of Umakoshi et al.179 patient outcomes. Patients treated by adrenalectomy and patients treated with Concordance between CT/MRI and AVS was found in 79% (31/39) of patients high-dose MRAs had similar mortality risk to age- and sex-matched controls. between 35 and 40 years of age and 90% (27/30) of patients <35 years of age. On the contrary, targeted treatment for PA did not reverse excess mortality in Thus, recommendations to omit AVS in patients with a solitary adenoma and patients >56 years of age at the time of diagnosis, those with CVD comorbidity, age <35 years are not well supported by more recent data. and those treated with low doses of MRAs. As detailed in the Results section, mortality was increased in patients diagnosed in earlier time periods and in Inaccurate assessments have important implications for patients with PA. most recent patients, and remained significantly increased up to 10 years after Different readings have important consequences for patient care and may diagnosis. negatively influence long-term outcome. The potential for a minor measurement error to result in a missed opportunity for curative surgery is an In a prospective cohort study of 300 patients with PA from Germany, there example of variability in reading, while a nonfunctional adenoma puts a patient was no significant difference in survival between patients with PA and at unnecessary risk for surgery. Despite improvements in imaging techniques, hypertensive controls or normotensive controls.148 A meta-analysis of six difficulties remain in differentiating small nodules from hyperplasia, as shown observational studies quells concerns about long-term mortality in PA.151 An by discrepancies in interpretation among radiologists. increased crude 3-year mortality in 3039 patients with PA was reported compared to patients with essential hypertension (HR 2.0, 95% CI 1.3–2.9); A diagnostic test to assess laterality in PA should be accurate to offer patients however, no differences were observed at 5, 7, 5, and 10 years.151 Interestingly, the option of cure and have high specificity to avoid unnecessary the largest cohort included in the meta-analysis encompassed 2448 patients and adrenalectomy. As discussed as follows, early diagnosis can be particularly had a mean follow-up duration of 4.3 years,150 whereas one of the studies advantageous for younger patients in terms of CVD outcome by addressing the recorded no events in either arm after 7.5 years of follow-up.182 Long-term reversible cause of hypertension. Indeed, patient age is one of the most mortality and CVD outcomes may be affected by factors unrelated to important prognostic factors in those treated by adrenalectomy.180 There is healthcare services, such as socioeconomic factors, treatment adherence, and considerable international interest in this study, which has been proposed as a retention in care, which were not addressed in previous studies. basis for further revisions of the current guidelines.181 The large sample size of our cohort and the accumulated evidence of earlier 5.4 CAN SPECIFIC TREATMENT WITH A studies enable us to conclude that long-term mortality is increased in PA. Moreover, our study provides valuable information to help identify high-risk MINERALOCORTICOID RECEPTOR patients for optimal clinical management. Understanding how mortality varies ANTAGONIST OR ADRENALECTOMY by MRA dose, age at presentation, and comorbid conditions may help to tailor treatment and prevent complications in patients with PA effectively. PREVENT MORTALITY IN PRIMARY ALDOSTERONISM? 5.4.1 APPROPRIATE DOSE OF MINERALOCORTICOID RECEPTOR Study III used large nationwide administrative health records and databases to identify all Swedes age >18 years with PA from 2019 to 2019 and study ANTAGONIST IS CRITICAL mortality outcomes. A total of 2419 patients diagnosed from 1997 to 2019 were Nationwide data opens awareness that patients treated with an MRA (2006– identified in the NPR, of whom 686 received adrenalectomy. The study 2019) may not have been treated to target. In Study III, we specifically looked showed people with PA have a higher risk of all-cause mortality (HR 1.23, at a subpopulation of patients with PA with available information on drug 95% CI 1.10–1.38) and CVD mortality (1.57, 1.30–1.89) compared to age- and prescription since 2006 and found that the average dispensed dose of MRA 40 41 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa published in 2016 and some new studies have been published since then. The sex-matched controls without PA from the general population. Subgroup surgical outcome of 69 patients <40 years of age with severe PA and unilateral analysis provided valuable insights into the impact of different treatments on adenoma on imaging were presented in the study of Umakoshi et al.179 patient outcomes. Patients treated by adrenalectomy and patients treated with Concordance between CT/MRI and AVS was found in 79% (31/39) of patients high-dose MRAs had similar mortality risk to age- and sex-matched controls. between 35 and 40 years of age and 90% (27/30) of patients <35 years of age. On the contrary, targeted treatment for PA did not reverse excess mortality in Thus, recommendations to omit AVS in patients with a solitary adenoma and patients >56 years of age at the time of diagnosis, those with CVD comorbidity, age <35 years are not well supported by more recent data. and those treated with low doses of MRAs. As detailed in the Results section, mortality was increased in patients diagnosed in earlier time periods and in Inaccurate assessments have important implications for patients with PA. most recent patients, and remained significantly increased up to 10 years after Different readings have important consequences for patient care and may diagnosis. negatively influence long-term outcome. The potential for a minor measurement error to result in a missed opportunity for curative surgery is an In a prospective cohort study of 300 patients with PA from Germany, there example of variability in reading, while a nonfunctional adenoma puts a patient was no significant difference in survival between patients with PA and at unnecessary risk for surgery. Despite improvements in imaging techniques, hypertensive controls or normotensive controls.148 A meta-analysis of six difficulties remain in differentiating small nodules from hyperplasia, as shown observational studies quells concerns about long-term mortality in PA.151 An by discrepancies in interpretation among radiologists. increased crude 3-year mortality in 3039 patients with PA was reported compared to patients with essential hypertension (HR 2.0, 95% CI 1.3–2.9); A diagnostic test to assess laterality in PA should be accurate to offer patients however, no differences were observed at 5, 7, 5, and 10 years.151 Interestingly, the option of cure and have high specificity to avoid unnecessary the largest cohort included in the meta-analysis encompassed 2448 patients and adrenalectomy. As discussed as follows, early diagnosis can be particularly had a mean follow-up duration of 4.3 years,150 whereas one of the studies advantageous for younger patients in terms of CVD outcome by addressing the recorded no events in either arm after 7.5 years of follow-up.182 Long-term reversible cause of hypertension. Indeed, patient age is one of the most mortality and CVD outcomes may be affected by factors unrelated to important prognostic factors in those treated by adrenalectomy.180 There is healthcare services, such as socioeconomic factors, treatment adherence, and considerable international interest in this study, which has been proposed as a retention in care, which were not addressed in previous studies. basis for further revisions of the current guidelines.181 The large sample size of our cohort and the accumulated evidence of earlier 5.4 CAN SPECIFIC TREATMENT WITH A studies enable us to conclude that long-term mortality is increased in PA. Moreover, our study provides valuable information to help identify high-risk MINERALOCORTICOID RECEPTOR patients for optimal clinical management. Understanding how mortality varies ANTAGONIST OR ADRENALECTOMY by MRA dose, age at presentation, and comorbid conditions may help to tailor treatment and prevent complications in patients with PA effectively. PREVENT MORTALITY IN PRIMARY ALDOSTERONISM? 5.4.1 APPROPRIATE DOSE OF MINERALOCORTICOID RECEPTOR Study III used large nationwide administrative health records and databases to identify all Swedes age >18 years with PA from 2019 to 2019 and study ANTAGONIST IS CRITICAL mortality outcomes. A total of 2419 patients diagnosed from 1997 to 2019 were Nationwide data opens awareness that patients treated with an MRA (2006– identified in the NPR, of whom 686 received adrenalectomy. The study 2019) may not have been treated to target. In Study III, we specifically looked showed people with PA have a higher risk of all-cause mortality (HR 1.23, at a subpopulation of patients with PA with available information on drug 95% CI 1.10–1.38) and CVD mortality (1.57, 1.30–1.89) compared to age- and prescription since 2006 and found that the average dispensed dose of MRA 40 41 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa was low, which may be an important reason for limited treatment success. recently published meta-analyses confirmed that younger patients have not Patients receiving a high-dose MRA had a similar mortality risk to a matched only better clinical outcomes but also better renal outcomes after targeted population without PA. Although these results may not fully account for treatment for PA.145,186 Another meta-analysis suggests that older age is factors such as perception of care, renal function, and drug metabolism, the associated with less intensive lowering of BP after surgery.180 Confounding results do suggest that undertreatment is an important contributing factor to the factors can make the association between age and treatment outcomes appear excess mortality. stronger than it is. In a study of 450 patients with PA from Spain, similar benefits were observed in older patients as in young patients at 3-year follow- Hundemer et al. were among the first to draw an explicit connection between up.187 The authors concluded that the duration of hypertension may affect more MRA dose, treatment effects, and mortality.121 In a cohort study of 602 outcomes than age itself. medically treated patients with PA, no significant increase in mortality risk was found for patients with unsuppressed renin who received higher MRA doses; 5.4.3 COMORBID CONDITIONS AND OUTCOMES IN however, mortality for those with low renin was higher compared to hypertensive controls (HR 1.34, 95% CI 1.06–1.71).121 There is also evidence PATIENTS WITH PRIMARY ALDOSTERONISM from two prospective studies that improvements in BP, albuminuria, and left Established CVD at the time of diagnosis is a major determinant of mortality ventricular systolic dysfunction are more pronounced in patients with outcomes in patients with primary aldosteronism. Prolonged aldosterone unsuppressed renin.183,184 Consequently, renin concentration may become a excess results in a wide array of CVD, metabolic, and renal comorbidities that valuable tool for monitoring the efficacy of MRA treatment.147 might not be reversible with treatment.180,185 Although no justification is possible when using registry data, Study III confirms that established CVD These observations are important for informing clinical practice. Clinicians comorbidities are associated with a further increase in all-cause mortality (HR should be aware of the increased mortality in PA, especially in MRA-treated 1.53, 95% CI 1.26–1.85) following PA diagnosis compared to the general patients who are the largest patient group. Patients with bilateral disease can population. Multimorbid patients can be challenging to manage and more derive ancillary benefits if MRA doses are optimized. Patients with PA require studies in the relevant population are needed to assess optimal management higher doses of MRA than those used in primary hypertension. Independent and whether CVD prevention strategies apply to them. In these patients, practice will continue to be a challenge for unfamiliar clinicians. We argue that whether adrenalectomy confers a mortality advantage remains uncertain. In a consistent long-term management is crucial to prevent complications and meta-analysis, Chen et al.145 found less favorable outcomes after resource allocation is justified to secure continuity, coordination, and quality adrenalectomy in older patients; however, a subsequent meta-analysis of 15 of care. 541 patients showed that the relative risk of major adverse cardiovascular events) was lower with increasing age in patients treated with adrenalectomy, 5.4.2 IMPORTANCE OF TIMELY MANAGEMENT as shown in the meta-regression analysis.144 Future guidelines should consider In Study III, the time of diagnosis is considered the starting point of disease the complexities of effectively treating patients with comorbidities. onset. Consequently, the impact of delayed diagnosis of PA on mortality cannot be assessed. Nevertheless, excess mortality in Study III was limited to 5.5 IS ADRENALECTOMY MORE EFFECTIVE patients diagnosed with PA after 56 years of age. These results indicate that age at diagnosis is an important determinant of treatment outcome. This THAN A MINERALOCORTICOID finding is likely because of the low prevalence of comorbidities in young RECEPTOR ANTAGONIST? patients with PA and the timely diagnosis and management. It has been stated that young individuals with normal renal and vascular systems can effectively The choice of treatment should be based on individual assessments and the manage increased plasma volume without a significant increase in BP.27 In a patient’s values and preferences. Optimal management needs to consider retrospective cohort from Japan185 and a multicenter study from Europe,101 predictors of response such as the patient age and health status at the time of younger patients were more likely to benefit from surgical treatment. Two diagnosis, and treatment side effects. A major theme of recent literature on PA 42 43 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa was low, which may be an important reason for limited treatment success. recently published meta-analyses confirmed that younger patients have not Patients receiving a high-dose MRA had a similar mortality risk to a matched only better clinical outcomes but also better renal outcomes after targeted population without PA. Although these results may not fully account for treatment for PA.145,186 Another meta-analysis suggests that older age is factors such as perception of care, renal function, and drug metabolism, the associated with less intensive lowering of BP after surgery.180 Confounding results do suggest that undertreatment is an important contributing factor to the factors can make the association between age and treatment outcomes appear excess mortality. stronger than it is. In a study of 450 patients with PA from Spain, similar benefits were observed in older patients as in young patients at 3-year follow- Hundemer et al. were among the first to draw an explicit connection between up.187 The authors concluded that the duration of hypertension may affect more MRA dose, treatment effects, and mortality.121 In a cohort study of 602 outcomes than age itself. medically treated patients with PA, no significant increase in mortality risk was found for patients with unsuppressed renin who received higher MRA doses; 5.4.3 COMORBID CONDITIONS AND OUTCOMES IN however, mortality for those with low renin was higher compared to hypertensive controls (HR 1.34, 95% CI 1.06–1.71).121 There is also evidence PATIENTS WITH PRIMARY ALDOSTERONISM from two prospective studies that improvements in BP, albuminuria, and left Established CVD at the time of diagnosis is a major determinant of mortality ventricular systolic dysfunction are more pronounced in patients with outcomes in patients with primary aldosteronism. Prolonged aldosterone unsuppressed renin.183,184 Consequently, renin concentration may become a excess results in a wide array of CVD, metabolic, and renal comorbidities that valuable tool for monitoring the efficacy of MRA treatment.147 might not be reversible with treatment.180,185 Although no justification is possible when using registry data, Study III confirms that established CVD These observations are important for informing clinical practice. Clinicians comorbidities are associated with a further increase in all-cause mortality (HR should be aware of the increased mortality in PA, especially in MRA-treated 1.53, 95% CI 1.26–1.85) following PA diagnosis compared to the general patients who are the largest patient group. Patients with bilateral disease can population. Multimorbid patients can be challenging to manage and more derive ancillary benefits if MRA doses are optimized. Patients with PA require studies in the relevant population are needed to assess optimal management higher doses of MRA than those used in primary hypertension. Independent and whether CVD prevention strategies apply to them. In these patients, practice will continue to be a challenge for unfamiliar clinicians. We argue that whether adrenalectomy confers a mortality advantage remains uncertain. In a consistent long-term management is crucial to prevent complications and meta-analysis, Chen et al.145 found less favorable outcomes after resource allocation is justified to secure continuity, coordination, and quality adrenalectomy in older patients; however, a subsequent meta-analysis of 15 of care. 541 patients showed that the relative risk of major adverse cardiovascular events) was lower with increasing age in patients treated with adrenalectomy, 5.4.2 IMPORTANCE OF TIMELY MANAGEMENT as shown in the meta-regression analysis.144 Future guidelines should consider In Study III, the time of diagnosis is considered the starting point of disease the complexities of effectively treating patients with comorbidities. onset. Consequently, the impact of delayed diagnosis of PA on mortality cannot be assessed. Nevertheless, excess mortality in Study III was limited to 5.5 IS ADRENALECTOMY MORE EFFECTIVE patients diagnosed with PA after 56 years of age. These results indicate that age at diagnosis is an important determinant of treatment outcome. This THAN A MINERALOCORTICOID finding is likely because of the low prevalence of comorbidities in young RECEPTOR ANTAGONIST? patients with PA and the timely diagnosis and management. It has been stated that young individuals with normal renal and vascular systems can effectively The choice of treatment should be based on individual assessments and the manage increased plasma volume without a significant increase in BP.27 In a patient’s values and preferences. Optimal management needs to consider retrospective cohort from Japan185 and a multicenter study from Europe,101 predictors of response such as the patient age and health status at the time of younger patients were more likely to benefit from surgical treatment. Two diagnosis, and treatment side effects. A major theme of recent literature on PA 42 43 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa is whether adrenalectomy should be preserved for patients with a high randomized study is needed to determine whether MRAs and adrenalectomy probability of complete clinical cure.21 Determining factors for biochemical are equally efficacious in patients with unilateral disease. cure are preoperative use of only two or fewer antihypertensive drugs,188short duration of hypertension,101 higher post-SIT aldosterone levels,189 young age,101 female sex,189 and no sign of left ventricular hypertrophy.190 It has also 5.6 RISK OF FRACTURE IN PRIMARY been shown that patients with KCNJ5 mutations, the most common mutations ALDOSTERONISM found in aldosterone-producing adenomas, are more likely to be cured after adrenalectomy.191 All these factors should be weighed when counseling In Study IV, we found that patients with PA >56 years of age had a higher risk patients, even though individual response to treatment cannot be predicted. of hip fractures compared to controls of the same age and sex regardless of Enabling patients to understand uncertainties about achieving a complete cure previous fractures, diabetes, pre-existing heart disease, and social factors. Hip is crucial before considering different treatment options. The main problem is fracture risk was increased in patients treated with an MRA but not in patients that patients with predictors of sustained hypertension after adrenalectomy are who had undergone adrenalectomy compared to age- and sex-matched controls also at high risk for complications and mortality. from the general population. The results are supported by a previous study that found a higher prevalence of osteoporotic fractures in patients with PA.153 5.5.1 SHOULD ADRENALECTOMY BE PRESERVED The reasons for increased fracture risk in patients with PA are not fully FOR PATIENTS WITH PREDICTORS OF understood. The risk may be attributable to a direct effect of aldosterone on COMPLETE CURE? bone metabolism. The MR is expressed in osteoblasts and osteocytes, but its 193 So far, data comparing patients treated with MRA to patients treated with functionality is unclear. Another potential mechanism may involve adrenalectomy has come primarily from observational studies. According to disruption of parathyroid hormone secretion, which is common in patients with 194 pooled data from four studies, adrenalectomy (n=178) and MRA use (n=177) primary aldosteronism. In line with these observations, patients in our cohort showed similar reductions in left ventricular mass after up to 4 years of follow- were often diagnosed with primary hyperparathyroidism. However, it is up.119 In a meta-analysis published in 2024 which included studies from 2008 unlikely that aldosterone excess has long-lasting effects on bone because of to 2022 with a total of 15 541 patients (16 studies),144 adrenalectomy was continuous bone formation. Indeed, earlier studies have shown that parathyroid associated with lower mortality (HR 0.34, 95% CI 0.22–0.54) and lower risk hormone levels and urinary calcium excretion return to normal after successful 138,153,195,196 for major adverse cardiovascular events (0.55, 0.36–0.84) compared to MRA treatment. Although it has been difficult to disentangle the reasons treatment. Furthermore, patients treated with surgery were less likely to be for the observed sex differences, our findings suggest that women with PA are admitted for heart failure (0.48, 0.34–0.70) or developing chronic kidney more vulnerable to fracture. The prevalence of hip fractures was higher in 197 disease (0.62, 0.39–0.98).144 Altogether, these results suggest that an MRA women than men, a pattern that is also observed in individuals without PA. might not be as efficacious as unilateral adrenalectomy. A weakness in this For this reason, the sex differences observed in our estimates could be due to evidence is that MRA dose-response effects and other confounders are not a lack of statistical power. Another reason could be that a substantial taken into account.116 In line with previous studies, we observed that patients proportion of women with PA (65%) may be considered insufficiently treated who have undergone adrenalectomy had a better prognosis.144,145,192 The due to their low prescribed MRA doses. significance of our study lies in its contribution to understanding that clinical heterogeneity among patients may explain a wide variation in treatment Compared to age- and sex-matched controls without PA, patients who have outcomes. Study III indicates that patient age and comorbidities impact undergone adrenalectomy were not at increased fracture risk, while patients treatment strategies. Patients treated by adrenalectomy are younger than treated with an MRA had a higher risk of hip fracture. These results are not patients treated with an MRA, whereas patients with multiple chronic diseases fully explained by suboptimal MRA treatment. HRs for patients treated with are over-represented in the MRA group. All these factors may have influenced low doses of MRA were comparable to HRs of patients treated with high doses, treatment outcomes. Most importantly, the study highlights that a prospective, even though statistical significance was only reached in the subgroup treated 44 45 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa is whether adrenalectomy should be preserved for patients with a high randomized study is needed to determine whether MRAs and adrenalectomy probability of complete clinical cure.21 Determining factors for biochemical are equally efficacious in patients with unilateral disease. cure are preoperative use of only two or fewer antihypertensive drugs,188short duration of hypertension,101 higher post-SIT aldosterone levels,189 young age,101 female sex,189 and no sign of left ventricular hypertrophy.190 It has also 5.6 RISK OF FRACTURE IN PRIMARY been shown that patients with KCNJ5 mutations, the most common mutations ALDOSTERONISM found in aldosterone-producing adenomas, are more likely to be cured after adrenalectomy.191 All these factors should be weighed when counseling In Study IV, we found that patients with PA >56 years of age had a higher risk patients, even though individual response to treatment cannot be predicted. of hip fractures compared to controls of the same age and sex regardless of Enabling patients to understand uncertainties about achieving a complete cure previous fractures, diabetes, pre-existing heart disease, and social factors. Hip is crucial before considering different treatment options. The main problem is fracture risk was increased in patients treated with an MRA but not in patients that patients with predictors of sustained hypertension after adrenalectomy are who had undergone adrenalectomy compared to age- and sex-matched controls also at high risk for complications and mortality. from the general population. The results are supported by a previous study that found a higher prevalence of osteoporotic fractures in patients with PA.153 5.5.1 SHOULD ADRENALECTOMY BE PRESERVED The reasons for increased fracture risk in patients with PA are not fully FOR PATIENTS WITH PREDICTORS OF understood. The risk may be attributable to a direct effect of aldosterone on COMPLETE CURE? bone metabolism. The MR is expressed in osteoblasts and osteocytes, but its 193 So far, data comparing patients treated with MRA to patients treated with functionality is unclear. Another potential mechanism may involve adrenalectomy has come primarily from observational studies. According to disruption of parathyroid hormone secretion, which is common in patients with 194 pooled data from four studies, adrenalectomy (n=178) and MRA use (n=177) primary aldosteronism. In line with these observations, patients in our cohort showed similar reductions in left ventricular mass after up to 4 years of follow- were often diagnosed with primary hyperparathyroidism. However, it is up.119 In a meta-analysis published in 2024 which included studies from 2008 unlikely that aldosterone excess has long-lasting effects on bone because of to 2022 with a total of 15 541 patients (16 studies),144 adrenalectomy was continuous bone formation. Indeed, earlier studies have shown that parathyroid associated with lower mortality (HR 0.34, 95% CI 0.22–0.54) and lower risk hormone levels and urinary calcium excretion return to normal after successful 138,153,195,196 for major adverse cardiovascular events (0.55, 0.36–0.84) compared to MRA treatment. Although it has been difficult to disentangle the reasons treatment. Furthermore, patients treated with surgery were less likely to be for the observed sex differences, our findings suggest that women with PA are admitted for heart failure (0.48, 0.34–0.70) or developing chronic kidney more vulnerable to fracture. The prevalence of hip fractures was higher in 197 disease (0.62, 0.39–0.98).144 Altogether, these results suggest that an MRA women than men, a pattern that is also observed in individuals without PA. might not be as efficacious as unilateral adrenalectomy. A weakness in this For this reason, the sex differences observed in our estimates could be due to evidence is that MRA dose-response effects and other confounders are not a lack of statistical power. Another reason could be that a substantial taken into account.116 In line with previous studies, we observed that patients proportion of women with PA (65%) may be considered insufficiently treated who have undergone adrenalectomy had a better prognosis.144,145,192 The due to their low prescribed MRA doses. significance of our study lies in its contribution to understanding that clinical heterogeneity among patients may explain a wide variation in treatment Compared to age- and sex-matched controls without PA, patients who have outcomes. Study III indicates that patient age and comorbidities impact undergone adrenalectomy were not at increased fracture risk, while patients treatment strategies. Patients treated by adrenalectomy are younger than treated with an MRA had a higher risk of hip fracture. These results are not patients treated with an MRA, whereas patients with multiple chronic diseases fully explained by suboptimal MRA treatment. HRs for patients treated with are over-represented in the MRA group. All these factors may have influenced low doses of MRA were comparable to HRs of patients treated with high doses, treatment outcomes. Most importantly, the study highlights that a prospective, even though statistical significance was only reached in the subgroup treated 44 45 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa with low doses. Treatment-specific differences may be associated with MRA mechanisms of action. MRAs works by inhibiting overactivated MRs and 6 CONCLUSION aldosterone levels remain elevated after treatment initiation. This is important to consider because aldosterone may act through other pathways that are not 1. The incidence of PA is increasing. Notable progress has been made in mediated through the MR.198 Further research is needed to determine whether diagnostic strategies but PA is still under-recognized. Efforts should be nongenomic aldosterone effects contribute to bone impairment. made to raise awareness of PA while simultaneously increasing resources to optimize treatment management. 2. CT/MRI scans are unable to accurately differentiate unilateral from bilateral forms of PA. Consequently, conventional imaging is insufficient to guide optimal treatment. The most reliable means to assess PA laterality is AVS regardless of age at presentation and imaging findings. 3. One of the key findings of this thesis is that patients with PA have increased mortality risk compared to controls from the general population, which is mainly due to CVD. Age >56 years, established comorbidities at the time of diagnosis, and MRA undertreatment are significant determinants of mortality, emphasizing the need for continued monitoring of this population. 4. Hip fracture risk was elevated in patients with PA but further research is needed on the impact of aldosterone excess on bone health. Optimized screening strategies, timely diagnosis, accurate subtype distinction, and consistent long-term management of patients with PA are the keys to improving healthcare delivery for people with PA. 46 47 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa with low doses. Treatment-specific differences may be associated with MRA mechanisms of action. MRAs works by inhibiting overactivated MRs and 6 CONCLUSION aldosterone levels remain elevated after treatment initiation. This is important to consider because aldosterone may act through other pathways that are not 1. The incidence of PA is increasing. Notable progress has been made in mediated through the MR.198 Further research is needed to determine whether diagnostic strategies but PA is still under-recognized. Efforts should be nongenomic aldosterone effects contribute to bone impairment. made to raise awareness of PA while simultaneously increasing resources to optimize treatment management. 2. CT/MRI scans are unable to accurately differentiate unilateral from bilateral forms of PA. Consequently, conventional imaging is insufficient to guide optimal treatment. The most reliable means to assess PA laterality is AVS regardless of age at presentation and imaging findings. 3. One of the key findings of this thesis is that patients with PA have increased mortality risk compared to controls from the general population, which is mainly due to CVD. Age >56 years, established comorbidities at the time of diagnosis, and MRA undertreatment are significant determinants of mortality, emphasizing the need for continued monitoring of this population. 4. Hip fracture risk was elevated in patients with PA but further research is needed on the impact of aldosterone excess on bone health. Optimized screening strategies, timely diagnosis, accurate subtype distinction, and consistent long-term management of patients with PA are the keys to improving healthcare delivery for people with PA. 46 47 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 7 FUTURE PERSPECTIVES diagnostic procedures is unclear.20,191 Further studies are needed to clarify how steroid metabolomic profiles in conjunction with radiological and clinical Further research is needed in clinical research areas within PA along with new information could be used to guide clinical decisions in PA. 199,201 medications, advancements in functional imaging, and translation of genetic New therapeutic choices may become available. Clinical trials of aldosterone research into clinical practice. synthase inhibitors have shown promising results.202,203 Other novel PA is a progressive disease that starts much earlier than current diagnostic approaches such as ablation of adrenal tumors are under investigation. 204 criteria can capture. New diagnostic tools are needed to detect individuals with Testing their efficacy in preventing PA complications would be an interesting PA as early as possible and provide adequate treatment to improve long-term research area. outcomes. The Swedish healthcare system is facing a growing population with PA, which immediately raises the issue of individualized management for PA.199 Since access to lateralizing procedures is limited and costly, a “trade-off” perspective is worth exploring.63 Besides efforts to develop scalable noninvasive lateralizing methods, there is an increased focus on predictors that may help clinically to recognize patients with bilateral disease, which in turn could avoid unnecessary invasive investigations.77,177,200 Prognostic models based on patient characteristics and disease severity that predict likely treatment responses would be a clinically important advance. Input from patients who are directly affected is also important. A randomized clinical trial (adrenalectomy vs eplerenone) is currently underway addressing patient-related outcomes such as quality of life and cost-effectiveness. It is of great importance to study complications in PA and how to prevent them. Merging data from the NPR with other official registries provided advanced opportunities to study long-term outcomes in PA but some clinically important variables could not be assessed. An initiative has recently been undertaken by our research group to create a disease-specific register where important clinical data may be entered. As a first step, it can be used to study factors that have not been sufficiently studied such as BP levels, hyperlipidemia, and metabolic profile. A further goal is to study the diagnostic process and optimal treatment choices for patients with advanced age and comorbidity. Lastly, there is a major need for objective markers to evaluate treatment efficacy in patients treated with an MRA and determining optimal MRA dose for each patient. Genetic profiles open perspectives for earlier identification, noninvasive subtype distinction, and personalized medicine in the future.17,18,20,21,191 Whether mutation carriers with certain characteristics require different 48 49 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 7 FUTURE PERSPECTIVES diagnostic procedures is unclear.20,191 Further studies are needed to clarify how steroid metabolomic profiles in conjunction with radiological and clinical Further research is needed in clinical research areas within PA along with new information could be used to guide clinical decisions in PA. 199,201 medications, advancements in functional imaging, and translation of genetic New therapeutic choices may become available. Clinical trials of aldosterone research into clinical practice. synthase inhibitors have shown promising results.202,203 Other novel PA is a progressive disease that starts much earlier than current diagnostic approaches such as ablation of adrenal tumors are under investigation. 204 criteria can capture. New diagnostic tools are needed to detect individuals with Testing their efficacy in preventing PA complications would be an interesting PA as early as possible and provide adequate treatment to improve long-term research area. outcomes. The Swedish healthcare system is facing a growing population with PA, which immediately raises the issue of individualized management for PA.199 Since access to lateralizing procedures is limited and costly, a “trade-off” perspective is worth exploring.63 Besides efforts to develop scalable noninvasive lateralizing methods, there is an increased focus on predictors that may help clinically to recognize patients with bilateral disease, which in turn could avoid unnecessary invasive investigations.77,177,200 Prognostic models based on patient characteristics and disease severity that predict likely treatment responses would be a clinically important advance. Input from patients who are directly affected is also important. A randomized clinical trial (adrenalectomy vs eplerenone) is currently underway addressing patient-related outcomes such as quality of life and cost-effectiveness. It is of great importance to study complications in PA and how to prevent them. Merging data from the NPR with other official registries provided advanced opportunities to study long-term outcomes in PA but some clinically important variables could not be assessed. An initiative has recently been undertaken by our research group to create a disease-specific register where important clinical data may be entered. As a first step, it can be used to study factors that have not been sufficiently studied such as BP levels, hyperlipidemia, and metabolic profile. A further goal is to study the diagnostic process and optimal treatment choices for patients with advanced age and comorbidity. Lastly, there is a major need for objective markers to evaluate treatment efficacy in patients treated with an MRA and determining optimal MRA dose for each patient. Genetic profiles open perspectives for earlier identification, noninvasive subtype distinction, and personalized medicine in the future.17,18,20,21,191 Whether mutation carriers with certain characteristics require different 48 49 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa ACKNOWLEDGEMENT Lena Bokemark, Head of the Department of Endocrinology, for providing support to engage in research and an environment where we can thrive. I would like to express my immense gratitude to all following people: I am indebted to friends and colleagues, Margret Einarsdottir, Eleni Papakokkinou, and Dimitrios Chantzichristos, for providing guidance and Associate Professor Óskar Ragnarsson, my principal supervisor, who encouragement. Ragnhildur Bergthorsdottir, colleague and mentor, for greatly inspired and motivated me. Thank you for excellent guidance and for always encouraging people to do their best. sharing your knowledge. Your continued dedication to help patients with Cushing syndrome, primary aldosteronism, and pituitary tumors through both Colleagues and college mates, Elin Allansson Kjölhede and Karin clinical practice and research is truly inspiring. Tammelin, for pleasant times during academical courses. Colleague Aikaterini Farmaki for always bringing a positive attitude to work. Associate Professor Penelope Trimpou, co-supervisor and co-author. Thank you for your unwavering support and close mentorship, your spontaneity, and Great researchers in our group, Daniela Esposito, Marta Piasecka, Victor infectious good humor. Hantelius, Marcel Koci, Johanna McQueen, Konstantina Kousoula, and Kostantinos Dalakas, for fruitful discussions. Associate Professor Andreas Muth, co-supervisor and co-author. Thank you for your valuable contributions through our interdisciplinary research projects Professor Kerstin Landin-Wilhelmsen. Your commitment to reinforce and and for your engagement to incorporate research evidence into clinical promote the Institution’s mission and values serves as an example for others. practice. Professors Helena Filipsson, Staffan Edén, Jörgen Isgaard, Åsa Tivesten, Professor Gudmundur Johannsson, co-author. Thank you for fostering a and Björn Eliasson. I appreciate your dedication and expertise, working collaborative research environment and for sharing project ideas. together has been a rewarding experience. Professor Annika Rosengren, co-author. Your expertise, support, and All past and present colleagues and nurses at the Departments of constructive feedback have been invaluable for this work. Endocrinology and Metabolism, and Diabetology, and at the Center of Endocrinology and Metabolism for their support. Secretaries Anna Reibring Professor Marcus Lind, co-author. Thank you for your valuable and Anna Cederberg-Olsson. contributions. Peter Todd for editorial support. Adjunct Professor Daniel S. Olsson, co-author, for inspiring scientific collaboration. I am fortunate to have many good friends. It is almost impossible to name everyone. Having you by my side has made a world of difference! Tatiana Zverkova Sandström, co-author, for very skillful technical help with analyses. I have received immense support from my family: my parents, my parents-in- law, my brother, my brother-in-law, and their families, and lastly my husband All contributing authors, Augustinas Sakinis, Magnus Palmér, Eva Savvas and our kids, Anastasia and Sofia. Thank you for your never-ending Ekerstad, and Manuela Gavric, for collaborating and for their valuable input. support and your patience towards me. I am grateful to have you in my life! My sincere thanks to University of Gothenburg and the Institute of I gratefully acknowledge the support from the Swedish state, for grants Medicine at Sahlgrenska Academy for their exceptional organization. facilitated by the ALF agreement (Grant Number: 971027), and grants from the Gothenburg Society of Medicine. 50 51 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa ACKNOWLEDGEMENT Lena Bokemark, Head of the Department of Endocrinology, for providing support to engage in research and an environment where we can thrive. I would like to express my immense gratitude to all following people: I am indebted to friends and colleagues, Margret Einarsdottir, Eleni Papakokkinou, and Dimitrios Chantzichristos, for providing guidance and Associate Professor Óskar Ragnarsson, my principal supervisor, who encouragement. Ragnhildur Bergthorsdottir, colleague and mentor, for greatly inspired and motivated me. Thank you for excellent guidance and for always encouraging people to do their best. sharing your knowledge. Your continued dedication to help patients with Cushing syndrome, primary aldosteronism, and pituitary tumors through both Colleagues and college mates, Elin Allansson Kjölhede and Karin clinical practice and research is truly inspiring. Tammelin, for pleasant times during academical courses. Colleague Aikaterini Farmaki for always bringing a positive attitude to work. Associate Professor Penelope Trimpou, co-supervisor and co-author. Thank you for your unwavering support and close mentorship, your spontaneity, and Great researchers in our group, Daniela Esposito, Marta Piasecka, Victor infectious good humor. Hantelius, Marcel Koci, Johanna McQueen, Konstantina Kousoula, and Kostantinos Dalakas, for fruitful discussions. Associate Professor Andreas Muth, co-supervisor and co-author. Thank you for your valuable contributions through our interdisciplinary research projects Professor Kerstin Landin-Wilhelmsen. Your commitment to reinforce and and for your engagement to incorporate research evidence into clinical promote the Institution’s mission and values serves as an example for others. practice. Professors Helena Filipsson, Staffan Edén, Jörgen Isgaard, Åsa Tivesten, Professor Gudmundur Johannsson, co-author. Thank you for fostering a and Björn Eliasson. I appreciate your dedication and expertise, working collaborative research environment and for sharing project ideas. together has been a rewarding experience. Professor Annika Rosengren, co-author. Your expertise, support, and All past and present colleagues and nurses at the Departments of constructive feedback have been invaluable for this work. Endocrinology and Metabolism, and Diabetology, and at the Center of Endocrinology and Metabolism for their support. Secretaries Anna Reibring Professor Marcus Lind, co-author. Thank you for your valuable and Anna Cederberg-Olsson. contributions. Peter Todd for editorial support. Adjunct Professor Daniel S. Olsson, co-author, for inspiring scientific collaboration. I am fortunate to have many good friends. It is almost impossible to name everyone. Having you by my side has made a world of difference! Tatiana Zverkova Sandström, co-author, for very skillful technical help with analyses. I have received immense support from my family: my parents, my parents-in- law, my brother, my brother-in-law, and their families, and lastly my husband All contributing authors, Augustinas Sakinis, Magnus Palmér, Eva Savvas and our kids, Anastasia and Sofia. Thank you for your never-ending Ekerstad, and Manuela Gavric, for collaborating and for their valuable input. support and your patience towards me. I am grateful to have you in my life! My sincere thanks to University of Gothenburg and the Institute of I gratefully acknowledge the support from the Swedish state, for grants Medicine at Sahlgrenska Academy for their exceptional organization. facilitated by the ALF agreement (Grant Number: 971027), and grants from the Gothenburg Society of Medicine. 50 51 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa REFERENCES the glucocorticoid receptor. Science. 1987;237:268-275. doi: 10.1126/science.3037703 12. Curnow KM, Tusie-Luna MT, Pascoe L, Natarajan R, Gu JL, Nadler 1. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson JL, White PC. The product of the CYP11B2 gene is required for J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol. prevention of cardiovascular disease and death: a systematic review 1991;5:1513-1522. doi: 10.1210/mend-5-10-1513 and meta-analysis. Lancet. 2016;387:957-967. doi: 10.1016/s0140- 13. Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: 6736(15)01225-8 target tissue specificity is enzyme, not receptor, mediated. Science. 2. Simpson SA, Tait JF, Wettstein A, Neher R, Von Euw J, Reichstein T. 1988;242:583-585. doi: 10.1126/science.2845584 [Isolation from the adrenals of a new crystalline hormone with 14. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel especially high effectiveness on mineral metabolism]. Experientia. JM. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene 1953;9:333-335. doi: 10.1007/bf02155834 causes glucocorticoid-remediable aldosteronism and human 3. Conn JW. Primary aldosteronism. J Lab Clin Med. 1955;45:661-664. hypertension. Nature. 1992;355:262-265. doi: 10.1038/355262a0 4. TWEIT JACaRC. Steroidal Aldosterone Blockers. . J Org Chem 1959, 15. Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, 24, 8, 1109–1110. 1959. doi: Ji W, Cho Y, Patel A, Men CJ, et al. K+ channel mutations in adrenal https://pubs.acs.org/doi/abs/10.1021/jo01090a019 aldosterone-producing adenomas and hereditary hypertension. 5. Davis WW, Newsome HH, Jr., Wright LD, Jr., Hammond WG, Easton Science. 2011;331:768-772. doi: 10.1126/science.1198785 J, Bartter FC. Bilateral adrenal hyperplasia as a cause of primary 16. Scholl UI, Goh G, Stölting G, de Oliveira RC, Choi M, Overton JD, aldosteronism with hypertension, hypokalemia and suppressed renin Fonseca AL, Korah R, Starker LF, Kunstman JW, et al. Somatic and activity. Am J Med. 1967;42:642-647. doi: 10.1016/0002- germline CACNA1D calcium channel mutations in aldosterone- 9343(67)90065-4 producing adenomas and primary aldosteronism. Nat Genet. 6. Lecky JW. Percutaneous transjugular approach to adrenal venography. 2013;45:1050-1054. doi: 10.1038/ng.2695 Am J Roentgenol Radium Ther Nucl Med. 1968;104:380-385. doi: 17. Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, 10.2214/ajr.104.2.380 Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, et al. 7. Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone- Schultze Kool LJ, Hermus AR, Deinum J. Systematic review: producing adenomas and secondary hypertension. Nat Genet. diagnostic procedures to differentiate unilateral from bilateral adrenal 2013;45:440-444, 444e441-442. doi: 10.1038/ng.2550 abnormality in primary aldosteronism. Ann Intern Med. 18. Scholl UI. Genetics of Primary Aldosteronism. Hypertension. 2009;151:329-337. doi: 10.7326/0003-4819-151-5-200909010-00007 2022;79:887-897. doi: 10.1161/hypertensionaha.121.16498 8. Hiramatsu K, Yamada T, Yukimura Y, Komiya I, Ichikawa K, Ishihara 19. Gomez-Sanchez CE, Qi X, Velarde-Miranda C, Plonczynski MW, M, Nagata H, Izumiyama T. A screening test to identify aldosterone- Parker CR, Rainey W, Satoh F, Maekawa T, Nakamura Y, Sasano H, producing adenoma by measuring plasma renin activity. Results in et al. Development of monoclonal antibodies against human CYP11B1 hypertensive patients. Arch Intern Med. 1981;141:1589-1593. and CYP11B2. Mol Cell Endocrinol. 2014;383:111-117. doi: 9. Rossi H, Kim A, Prinz RA. Primary hyperaldosteronism in the era of 10.1016/j.mce.2013.11.022 laparoscopic adrenalectomy. Am Surg. 2002;68:253-256; discussion 20. Wu VC, Peng KY, Kuo YP, Liu H, Tan BC, Lin YH, Lai TS, Chen 256-257. YM, Chueh JS. Subtypes of Histopathologically Classical 10. Iacobone M, Citton M, Viel G, Rossi GP, Nitti D. Approach to the Aldosterone-Producing Adenomas Yield Various Transcriptomic surgical management of primary aldosteronism. Gland Surg. Signaling and Outcomes. Hypertension. 2021;78:1791-1800. doi: 2015;4:69-81. doi: 10.3978/j.issn.2227-684X.2015.01.05 10.1161/hypertensionaha.121.18006 11. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, 21. Azizan EAB, Drake WM, Brown MJ. Primary aldosteronism: Housman DE, Evans RM. Cloning of human mineralocorticoid molecular medicine meets public health. Nat Rev Nephrol. receptor complementary DNA: structural and functional kinship with 2023;19:788-806. doi: 10.1038/s41581-023-00753-6 52 53 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa REFERENCES the glucocorticoid receptor. Science. 1987;237:268-275. doi: 10.1126/science.3037703 12. Curnow KM, Tusie-Luna MT, Pascoe L, Natarajan R, Gu JL, Nadler 1. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson JL, White PC. The product of the CYP11B2 gene is required for J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol. prevention of cardiovascular disease and death: a systematic review 1991;5:1513-1522. doi: 10.1210/mend-5-10-1513 and meta-analysis. Lancet. 2016;387:957-967. doi: 10.1016/s0140- 13. Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: 6736(15)01225-8 target tissue specificity is enzyme, not receptor, mediated. Science. 2. Simpson SA, Tait JF, Wettstein A, Neher R, Von Euw J, Reichstein T. 1988;242:583-585. doi: 10.1126/science.2845584 [Isolation from the adrenals of a new crystalline hormone with 14. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel especially high effectiveness on mineral metabolism]. Experientia. JM. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene 1953;9:333-335. doi: 10.1007/bf02155834 causes glucocorticoid-remediable aldosteronism and human 3. Conn JW. Primary aldosteronism. J Lab Clin Med. 1955;45:661-664. hypertension. Nature. 1992;355:262-265. doi: 10.1038/355262a0 4. TWEIT JACaRC. Steroidal Aldosterone Blockers. . J Org Chem 1959, 15. Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, 24, 8, 1109–1110. 1959. doi: Ji W, Cho Y, Patel A, Men CJ, et al. K+ channel mutations in adrenal https://pubs.acs.org/doi/abs/10.1021/jo01090a019 aldosterone-producing adenomas and hereditary hypertension. 5. Davis WW, Newsome HH, Jr., Wright LD, Jr., Hammond WG, Easton Science. 2011;331:768-772. doi: 10.1126/science.1198785 J, Bartter FC. Bilateral adrenal hyperplasia as a cause of primary 16. Scholl UI, Goh G, Stölting G, de Oliveira RC, Choi M, Overton JD, aldosteronism with hypertension, hypokalemia and suppressed renin Fonseca AL, Korah R, Starker LF, Kunstman JW, et al. Somatic and activity. Am J Med. 1967;42:642-647. doi: 10.1016/0002- germline CACNA1D calcium channel mutations in aldosterone- 9343(67)90065-4 producing adenomas and primary aldosteronism. Nat Genet. 6. Lecky JW. Percutaneous transjugular approach to adrenal venography. 2013;45:1050-1054. doi: 10.1038/ng.2695 Am J Roentgenol Radium Ther Nucl Med. 1968;104:380-385. doi: 17. Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, 10.2214/ajr.104.2.380 Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, et al. 7. Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone- Schultze Kool LJ, Hermus AR, Deinum J. Systematic review: producing adenomas and secondary hypertension. Nat Genet. diagnostic procedures to differentiate unilateral from bilateral adrenal 2013;45:440-444, 444e441-442. doi: 10.1038/ng.2550 abnormality in primary aldosteronism. Ann Intern Med. 18. Scholl UI. Genetics of Primary Aldosteronism. Hypertension. 2009;151:329-337. doi: 10.7326/0003-4819-151-5-200909010-00007 2022;79:887-897. doi: 10.1161/hypertensionaha.121.16498 8. Hiramatsu K, Yamada T, Yukimura Y, Komiya I, Ichikawa K, Ishihara 19. Gomez-Sanchez CE, Qi X, Velarde-Miranda C, Plonczynski MW, M, Nagata H, Izumiyama T. A screening test to identify aldosterone- Parker CR, Rainey W, Satoh F, Maekawa T, Nakamura Y, Sasano H, producing adenoma by measuring plasma renin activity. Results in et al. Development of monoclonal antibodies against human CYP11B1 hypertensive patients. Arch Intern Med. 1981;141:1589-1593. and CYP11B2. Mol Cell Endocrinol. 2014;383:111-117. doi: 9. Rossi H, Kim A, Prinz RA. Primary hyperaldosteronism in the era of 10.1016/j.mce.2013.11.022 laparoscopic adrenalectomy. Am Surg. 2002;68:253-256; discussion 20. Wu VC, Peng KY, Kuo YP, Liu H, Tan BC, Lin YH, Lai TS, Chen 256-257. YM, Chueh JS. Subtypes of Histopathologically Classical 10. Iacobone M, Citton M, Viel G, Rossi GP, Nitti D. Approach to the Aldosterone-Producing Adenomas Yield Various Transcriptomic surgical management of primary aldosteronism. Gland Surg. Signaling and Outcomes. Hypertension. 2021;78:1791-1800. doi: 2015;4:69-81. doi: 10.3978/j.issn.2227-684X.2015.01.05 10.1161/hypertensionaha.121.18006 11. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, 21. Azizan EAB, Drake WM, Brown MJ. Primary aldosteronism: Housman DE, Evans RM. Cloning of human mineralocorticoid molecular medicine meets public health. Nat Rev Nephrol. receptor complementary DNA: structural and functional kinship with 2023;19:788-806. doi: 10.1038/s41581-023-00753-6 52 53 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 22. Conn JW. The evolution of primary aldosteronism: 1954-1967. 33. Dogra P, Bancos I, Young WF, Jr. Primary Aldosteronism: A Harvey Lect. 1966;62:257-291. Pragmatic Approach to Diagnosis and Management. Mayo Clin Proc. 23. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, 2023;98:1207-1215. doi: 10.1016/j.mayocp.2023.04.023 Ganzaroli C, Giacchetti G, Letizia C, Maccario M, et al. A prospective 34. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso study of the prevalence of primary aldosteronism in 1,125 L, Gomez-Sanchez CE, Veglio F, Young WF, Jr. Increased diagnosis hypertensive patients. J Am Coll Cardiol. 2006;48:2293-2300. doi: of primary aldosteronism, including surgically correctable forms, in 10.1016/j.jacc.2006.07.059 centers from five continents. J Clin Endocrinol Metab. 2004;89:1045- 24. Käyser SC, Dekkers T, Groenewoud HJ, van der Wilt GJ, Carel Bakx 1050. doi: 10.1210/jc.2003-031337 J, van der Wel MC, Hermus AR, Lenders JW, Deinum J. Study 35. Turcu AF, Yang J, Vaidya A. Primary aldosteronism - a Heterogeneity and Estimation of Prevalence of Primary multidimensional syndrome. Nat Rev Endocrinol. 2022;18:665-682. Aldosteronism: A Systematic Review and Meta-Regression Analysis. doi: 10.1038/s41574-022-00730-2 J Clin Endocrinol Metab. 2016;101:2826-2835. doi: 10.1210/jc.2016- 36. Funder JW. Mineralocorticoids, glucocorticoids, receptors and 1472 response elements. Science. 1993;259:1132-1133. doi: 25. Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, 10.1126/science.8382375 Gabetti L, Mengozzi G, Williams TA, Rabbia F, et al. Prevalence and 37. Ferreira NS, Tostes RC, Paradis P, Schiffrin EL. Aldosterone, Clinical Manifestations of Primary Aldosteronism Encountered in Inflammation, Immune System, and Hypertension. Am J Hypertens. Primary Care Practice. J Am Coll Cardiol. 2017;69:1811-1820. doi: 2021;34:15-27. doi: 10.1093/ajh/hpaa137 10.1016/j.jacc.2017.01.052 38. Grossmann C, Gekle M. Interaction between mineralocorticoid 26. Funder JW, Carey RM. Primary Aldosteronism: Where Are We Now? receptor and epidermal growth factor receptor signaling. Mol Cell Where to From Here? Hypertension. 2022;79:726-735. doi: Endocrinol. 2012;350:235-241. doi: 10.1016/j.mce.2011.07.045 10.1161/hypertensionaha.121.18761 39. Pereira SS, Lobato CB, Monteiro MP. Cell Signaling Within 27. Vaidya A, Mulatero P, Baudrand R, Adler GK. The Expanding Endocrine Glands: Thyroid, Parathyroids and Adrenal Glands. In: Spectrum of Primary Aldosteronism: Implications for Diagnosis, Silva JV, Freitas MJ, Fardilha M, eds. Tissue-Specific Cell Signaling. Pathogenesis, and Treatment. Endocr Rev. 2018;39:1057-1088. doi: Cham: Springer International Publishing; 2020:63-91. 10.1210/er.2018-00139 40. Fu R, Walters K, Kaufman ML, Koc K, Baldwin A, Clay MR, Basham 28. Park SS, Ahn CH, Kim SW, Koh JM, Lee SH, Kim JH. Temporal KJ, Kiseljak-Vassiliades K, Fishbein L, Mukherjee N. In Situ Spatial trends in clinical features of patients with primary aldosteronism over Reconstruction of Distinct Normal and Pathological Cell Populations 20 years. Hypertens Res. 2024. doi: 10.1038/s41440-024-01703-w Within the Human Adrenal Gland. J Endocr Soc. 2023;7:bvad131. 29. Baudrand R, Guarda FJ, Fardella C, Hundemer G, Brown J, Williams doi: 10.1210/jendso/bvad131 G, Vaidya A. Continuum of Renin-Independent Aldosteronism in 41. Pihlajoki M, Dörner J, Cochran RS, Heikinheimo M, Wilson DB. Normotension. Hypertension. 2017;69:950-956. doi: Adrenocortical zonation, renewal, and remodeling. Front Endocrinol 10.1161/hypertensionaha.116.08952 (Lausanne). 2015;6:27. doi: 10.3389/fendo.2015.00027 30. Ito Y, Takeda R, Karashima S, Yamamoto Y, Yoneda T, Takeda Y. 42. Vaidya A, Hundemer GL, Nanba K, Parksook WW, Brown JM. Prevalence of primary aldosteronism among prehypertensive and Primary Aldosteronism: State-of-the-Art Review. Am J Hypertens. stage 1 hypertensive subjects. Hypertens Res. 2011;34:98-102. doi: 2022;35:967-988. doi: 10.1093/ajh/hpac079 10.1038/hr.2010.166 43. Beuschlein F. Regulation of aldosterone secretion: from physiology to 31. Funder JW. Primary aldosteronism as a public health issue. Lancet disease. Eur J Endocrinol. 2013;168:R85-93. doi: 10.1530/eje-13- Diabetes Endocrinol. 2016;4:972-973. doi: 10.1016/s2213- 0263 8587(16)30272-8 44. MacKenzie SM, van Kralingen JC, Davies E. Regulation of 32. Byrd JB, Turcu AF, Auchus RJ. Primary Aldosteronism: Practical Aldosterone Secretion. Vitam Horm. 2019;109:241-263. doi: Approach to Diagnosis and Management. Circulation. 2018;138:823- 10.1016/bs.vh.2018.07.001 835. doi: 10.1161/circulationaha.118.033597 45. Takeda Y, Demura M, Wang F, Karashima S, Yoneda T, Kometani M, Hashimoto A, Aono D, Horike SI, Meguro-Horike M, et al. 54 55 Primary Aldosteronism; a growing challenge Eleftheria Gkaniatsa 22. Conn JW. The evolution of primary aldosteronism: 1954-1967. 33. Dogra P, Bancos I, Young WF, Jr. Primary Aldosteronism: A Harvey Lect. 1966;62:257-291. Pragmatic Approach to Diagnosis and Management. Mayo Clin Proc. 23. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, 2023;98:1207-1215. doi: 10.1016/j.mayocp.2023.04.023 Ganzaroli C, Giacchetti G, Letizia C, Maccario M, et al. A prospective 34. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso study of the prevalence of primary aldosteronism in 1,125 L, Gomez-Sanchez CE, Veglio F, Young WF, Jr. Increased diagnosis hypertensive patients. J Am Coll Cardiol. 2006;48:2293-2300. doi: of primary aldosteronism, including surgically correctable forms, in 10.1016/j.jacc.2006.07.059 centers from five continents. J Clin Endocrinol Metab. 2004;89:1045- 24. Käyser SC, Dekkers T, Groenewoud HJ, van der Wilt GJ, Carel Bakx 1050. doi: 10.1210/jc.2003-031337 J, van der Wel MC, Hermus AR, Lenders JW, Deinum J. Study 35. Turcu AF, Yang J, Vaidya A. Primary aldosteronism - a Heterogeneity and Estimation of Prevalence of Primary multidimensional syndrome. Nat Rev Endocrinol. 2022;18:665-682. Aldosteronism: A Systematic Review and Meta-Regression Analysis. doi: 10.1038/s41574-022-00730-2 J Clin Endocrinol Metab. 2016;101:2826-2835. doi: 10.1210/jc.2016- 36. Funder JW. Mineralocorticoids, glucocorticoids, receptors and 1472 response elements. Science. 1993;259:1132-1133. doi: 25. Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, 10.1126/science.8382375 Gabetti L, Mengozzi G, Williams TA, Rabbia F, et al. Prevalence and 37. Ferreira NS, Tostes RC, Paradis P, Schiffrin EL. Aldosterone, Clinical Manifestations of Primary Aldosteronism Encountered in Inflammation, Immune System, and Hypertension. Am J Hypertens. Primary Care Practice. J Am Coll Cardiol. 2017;69:1811-1820. doi: 2021;34:15-27. doi: 10.1093/ajh/hpaa137 10.1016/j.jacc.2017.01.052 38. Grossmann C, Gekle M. Interaction between mineralocorticoid 26. Funder JW, Carey RM. Primary Aldosteronism: Where Are We Now? receptor and epidermal growth factor receptor signaling. Mol Cell Where to From Here? Hypertension. 2022;79:726-735. doi: Endocrinol. 2012;350:235-241. doi: 10.1016/j.mce.2011.07.045 10.1161/hypertensionaha.121.18761 39. Pereira SS, Lobato CB, Monteiro MP. Cell Signaling Within 27. Vaidya A, Mulatero P, Baudrand R, Adler GK. The Expanding Endocrine Glands: Thyroid, Parathyroids and Adrenal Glands. In: Spectrum of Primary Aldosteronism: Implications for Diagnosis, Silva JV, Freitas MJ, Fardilha M, eds. Tissue-Specific Cell Signaling. Pathogenesis, and Treatment. Endocr Rev. 2018;39:1057-1088. doi: Cham: Springer International Publishing; 2020:63-91. 10.1210/er.2018-00139 40. Fu R, Walters K, Kaufman ML, Koc K, Baldwin A, Clay MR, Basham 28. Park SS, Ahn CH, Kim SW, Koh JM, Lee SH, Kim JH. Temporal KJ, Kiseljak-Vassiliades K, Fishbein L, Mukherjee N. In Situ Spatial trends in clinical features of patients with primary aldosteronism over Reconstruction of Distinct Normal and Pathological Cell Populations 20 years. Hypertens Res. 2024. doi: 10.1038/s41440-024-01703-w Within the Human Adrenal Gland. J Endocr Soc. 2023;7:bvad131. 29. Baudrand R, Guarda FJ, Fardella C, Hundemer G, Brown J, Williams doi: 10.1210/jendso/bvad131 G, Vaidya A. 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