Normotensive Primary Aldosteronism Research Articles

FRI124 Insights From The Incidence Of Primary Aldosteronism In Patients With Hypokalemia (IPAHK+) - Study

Abstract Disclosure: S. Gruber: None. E. Stasi: None. A. Boan Pion: None. R. Steiner: None. I. Sudano: None. F. Beuschlein: None. Background: Hypokalemia plays an important role in the diagnosis and management of primary aldosteronism (PA). The hypokalemic variant of the disease accounts for about one third of all cases. However, little is known about the incidence of PA in a hypokalemic population. Design: The IPAHK+ study is an epidemiological, monocentric, cross-sectional trial to provide evidence on the incidence of PA in a hypokalemic outpatient population. Methods: Recruitment of outpatients with hypokalemia ≤3 mmol/l is carried out on a continuous referral-basis through an automated data delivery system at the University Hospital Zurich (USZ). Todate, 69 patients underwent the study protocol, which includes guideline-compliant workup for PA. Results: The mean age of the participants was 52.5±1.5 years with a sex ratio of 35:34 women to men, a mean potassium value of 2.77±0.03 mmol/l [1.8; 3.0] and a prevalence of arterial hypertension of71%. PA was diagnosed in 45.9% of all participants, all of whom had a history of hypertension. The incidence of PA increased continuously with decreasing potassium level with proportions of 26.7%,45.8% and 59.1% in the subgroups of 3.0 mmol/l (n=15), 2.8-2.9 (n=24) and ≤2.7 mmol/l (n=22),respectively. In the subgroup of hypertensives the incidence of PA was as high as 65.1%. Prior testing,60.9% of all patients presented at least with one plausible other cause for their hypokalemia with potential drug triggers accounting for the largest portion (33.3%). Among participants on diuretics the incidence of PA was 57.9%. Conclusions: The incidence of PA in the investigated outpatient population was more than 4 out of 10and inversely correlated with baseline potassium levels. Moderate or severe hypokalemia, regardless of its cause, should therefore prompt evaluation for PA in hypertensive individuals. Normotensive PA was not observed in our cohort. The significance of the study is limited by the still low number of enrolled patients with a potential selection bias. Presentation: Friday, June 16, 2023

PSUN61 Primary Aldosteronism Presenting as Chronic Hypokalemia in a Normotensive Patient

Abstract Introduction Conn first described the hallmark features of primary aldosteronism (PA) as a state of aldosterone excess in the setting of hypertension and hypokalemia. Recent work has shed light on a wide spectrum of disease that likely includes normotensive patients with elevated aldosterone and suppressed renin. Mineralocorticoid excess appears to be the main driver of disease progression; however, it is not known whether individual differences in intra-arterial plasticity and effective sodium potassium exchange alter the overt clinical presentation. Here, we describe a patient with chronic hypokalemia and normal blood pressure with the diagnosis of a unilateral aldosterone-producing adenoma. Clinical Case A 47-year-old woman with no significant medical history was referred to endocrinology for evaluation of isolated hypokalemia since 2012. Her potassium was 2.8mEq/L at its lowest a month prior to her visit and had numerous other values less than 3.5mEq/L over the past 10 years. She did not carry a diagnosis of hypertension nor was she hypertensive at the time of her initial and subsequent evaluations. Results on initial endocrinology evaluation demonstrated a potassium of 3.2mEq/L (3.5-5.0mEq/L), Plasma Aldosterone Concentration (PAC) of 29ng/dL (≤21ng/dL), Plasma Renin Activity (PRA) of 0.42ng/mL/h (0.25-5.82ng/mL/h), and Aldosterone Renin Ratio (ARR) of 69. PA was suspected based on hypokalemia with an ARR >30 and PAC >20ng/dL. Further work-up was pursued to confirm the diagnosis as the patient did not have hypertension. She underwent 3-day oral sodium loading. 24-hour urine collection at the conclusion revealed adequate sodium loading with a urine sodium content of 208mEq/24hr (>200mEq/24hr) and aldosterone secretion of 41.3mcg/24hr (<12mcg/24hr). She subsequently underwent a CT abdomen demonstrating a 1.3×0.8 cm right adrenal nodule. Adrenal venous sampling was performed (continuous cosyntropin infusion with simultaneous adrenal venous sampling) which revealed a cortisol-corrected aldosterone lateralization ratio (right to left) of 406 at -5 minutes, 368 at 0 minutes, 33 at 10 minutes and 85 at 15 minutes. Results were consistent with strong lateralization to the right with contralateral suppression. Diagnosis of a right-sided aldosterone-producing adenoma was confirmed and she was referred to surgery for right adrenalectomy. Conclusion This case highlights one of the many presentations of PA. The persistent hypokalemia for a decade suggests a history of longstanding untreated PA prior to eventual diagnosis, yet the patient has remained normotensive. Though normotensive PA is a recognized entity, most patients develop hypertension within 5 years. The ability to remain normotensive despite intravascular volume expansion may highlight the patient's highly compliant vasculature and kidneys that have likely adapted to excrete high sodium loads in the setting of sodium excess. This case emphasizes that isolated hypokalemia in patients without hypertension should prompt consideration of PA and that patients with PA may maintain normotension for multiple years. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

OR20-3 Characterization of the Pathophysiologic Spectrum of Subclinical Primary Aldosteronism in Normotension

Abstract Context Accumulating evidence suggests that primary aldosteronism can manifest across a broad phenotypic spectrum and that its origins can at times be detected among normotensive individuals. Herein, we conducted deep-phenotyping studies to interrogate the pathophysiologic continuum of the primary aldosteronism phenotype among normotensive participants. Methods Normotensive participants with obesity, metabolic syndrome, and/or high-normal untreated blood pressure underwent dietary sodium loading and restriction protocols (to maximally suppress and stimulate angiotensin II-mediated aldosterone production), dexamethasone suppression and cosyntropin stimulation protocols (to maximally suppress and stimulate ACTH-mediated aldosterone production), and 24h ambulatory blood pressure monitoring. Measurement of aldosterone and 18-hybrid steroids via LC-MS/MS was conducted to quantify the degree of dysregulated CYP11B2 expression. Urinary extracellular vesicles (uEV) were isolated to measure renal tubular protein content associated with mineralocorticoid receptor activation. In order to characterize parameters across the severity spectrum of non-suppressible and renin-independent aldosterone production, participants with suppressed renin activity were categorized by tertile of 24h urinary aldosterone production following oral sodium suppression testing. Repeated measures linear mixed models were used to analyze trends for each parameter across tertiles of autonomous aldosterone production; for ease of presentation, the mean [SD] of the first vs. third tertile are presented for selected parameters. Results Following oral sodium loading, greater non-suppressible renin-independent aldosterone production was associated with greater kaliuresis, higher daytime ambulatory systolic blood pressure within the normal range, and a progressive impairment in the ability to suppress production of serum aldosterone (P-trend=0.009), 18-hydroxycorticosterone (9.3 [5.0] vs. 19.6 [6.5] ng/dL, P-trend=0.004), 18-hydroxycortisol (45.0 [25.4] vs. 70.9 [29.9] ng/dL, P-trend=0.03), and 18-oxocortisol (1.2 [0.03] vs. 3.4 [7.2], P-trend=0.01). Similarly, following dexamethasone suppression testing, there was a progressive inability to suppress 18-hydroxycorticosterone (8.3 [5.0] vs. 15.4 [8.2] ng/dL, P-trend=0.004), 18-hydroxycortisol (6.6 [3.8] vs. 10.2 [3.6] ng/dL, P-trend=0.03), and 18-oxocortisol (1.2 [0.01] vs. 1.4 [0.6] ng/dL, P-trend=0.01) in parallel with greater renin-independent aldosterone production. In contrast, following stimulation with cosyntropin, greater non-suppressible and renin-independent aldosterone production was associated with progressively enhanced production of 18-hydroxycorticosterone (77.6 [25.4] vs. 121.1 [31.1] ng/dL, P-trend=0.004), 18-hydroxycortisol (68.5 [28.4] vs. 86.2 [26.3] ng/dL, P-trend=0.03), and 18-oxocortisol (3.2 [2.8] vs. 7.3 [3.5] ng/dL, P-trend=0.01). Excretion of uEV's of pendrin (P=0.002) and aquaporin 2 (P=0.002) all increased with greater non-suppressible aldosterone production. Conclusions Dynamic phenotyping studies in normotensive individuals demonstrate a continuum of non-suppressible and renin-independent aldosterone production that parallels higher blood pressure, greater kaliuresis, increased 18-hybrid steroid production indicative of dysregulated CYP11B2 expression, and increased uEV excretion indicative of renal mineralocorticoid receptor activation. This pathophysiologic continuum of normotensive primary aldosteronism provides phenotypic support for histopathology studies showing ectopic CYP11B2 expression within adrenal glands of normotensive humans, and for epidemiologic studies demonstrating renin-independent aldosterone production in normotensive populations increases risk for developing hypertension. Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.

The Genotype-Based Morphology of Aldosterone-Producing Adrenocortical Disorders and Their Association with Aging.

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosterone-producing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.

Normotensive presentation in primary aldosteronism: A report of two cases

Normotensive patients with primary aldosteronism (PA) are relatively rare. Herein, we report two patients with normotensive PA and present a literature review to improve an understanding of the disease. Patient 1, a 56-year-old man, presented with recurrent hypokalemia that lasted for more than 2 years. Patient 2 was a 33-year-old man who presented with sexual dysfunction and was diagnosed with a prolactinoma combined with adrenal insufficiency and hypogonadism. Neither of these patients had hypertension that was detectable on repeated manual measurements. In both patients, a typical biological profile of PA was demonstrated that included hypokalemia with kaliuresis, elevated plasma aldosterone concentration (PAC), suppressed plasma renin concentration, and a high aldosterone-to-renin ratio. Both patients did not have sufficiently suppressed PAC on the saline infusion test, confirming the diagnosis of PA. Computed tomography of the adrenal gland and adrenal venous sampling suggested an aldosteronoma, which was confirmed by lateralized hypersecretion of aldosterone. After removal of the benign adenoma, the biochemical abnormalities were corrected. As hypertension is not necessarily a sign of PA, we propose that all patients with hypokalemia should be screened for PA in order to prevent cardiovascular complications while balancing economics and effectiveness.

Normotensive primary aldosteronism in a young woman taking minipill – case report

Normotensive primary aldosteronism in a young woman taking minipill – case report

Normotensive hypokalemic primary hyperaldosteronism mimicking clinical features of anorexia nervosa in a young patient

Rationale:The typical clinical presentations of patients with primary aldosteronism (PA) include generalized weakness, fatigue, high blood pressure, and potassium deficiency. However, normotensive PA is rare. Therefore, an atypical presentation of normal blood pressure is a challenge for the diagnosis and treatment of PA.Patient concerns:A 43-year-old, thin, and tall woman (body mass index, 18.6 kg/m2) with generalized weakness for 1 day presented to our emergency department, where hypokalemia was a significant finding. The initial diagnosis was anorexia nervosa with the evidence of renal potassium wasting with low urinary sodium and chloride levels, metabolic alkalosis, normal blood pressure, and low body mass index. However, neither vomiting features nor other specific induced vomiting features were noted.Diagnoses:The laboratory examination revealed high plasma aldosterone level, low plasma renin activity, and extremely high aldosterone-to-renin ratio indicating the diagnosis of PA, confirmed via adrenal computed tomography.Interventions:Surgical adrenalectomy was performed. Pathological diagnosis was a benign cortical adenoma.Outcomes:Patient's serum potassium level and hormonal status became normalized after surgical removal of adrenal adenoma. She fully recovered without any further sequelae.Lessons:It is too early to rule out PA based on the presence of normal blood pressure in a patient with metabolic alkalosis and renal wasting hypokalemia. Moreover, PA should be considered in a normotensive patient with an unknown hypokalemic etiology to avoid delayed diagnosis and treatment.

Intraoperative Hypertensive Crisis in a Patient with Normotensive Primary Aldosteronism. Lessons from a Clinical Case

Primary hyperaldosteronism is the most frequent cause of secondary hypertension. However, it can also be found in apparently normotensive patients, often associated with recurrent hypokalemia and isolated hypertensive episodes.
 We hereby present the case of a normotensive 50-year-old female patient with a surgical left kidney mass; however, after anaesthetic induction, surgery was aborted due to a severe hypertensive crisis. She was referred to our Hypertension Outpatient Clinic to rule out pheochromocytoma/ paraganglioma. The anamnesis revealed unexplained episodes of hypokalemia. Ambulatory blood pressure monitoring showed normal mean values of blood pressure and heart rate, with an isolated hypertensive peak. Plasma glucose, ions, creatinine, lipids, metanephrines and chromogranin A were normal, but plasma aldosterone was clearly elevated with suppressed plasma renin activity and high aldosterone/renin activity ratio. Primary aldosteronism was confirmed by the captopril test. Abdominal CT was compatible with left adrenal hyperplasia. Treatment with low-dose spironolactone was well tolerated and resulted in normal blood pressure, normokalemia and unsuppressed plasma renin activity. The patient underwent successful laparoscopic removal of a renal oncocytoma. 
 We conclude that normotensive primary aldosteronism is not harmless; it can be associated with severe hypokalemia, anxiety, depression, hypertensive crisis and cardiovascular damage. Patients can also develop resistant hypertension. Adequate treatment can decisively improve the survival and quality of life of the patients with primary aldosteronism, but a correct diagnosis is needed first. Therefore, it must be considered as a diagnostic possibility in normotensive patients with unexplained hypokalemia or isolated hypertensive episodes.

Normotensive hypokalemic primary aldosteronism: How is this Possible?

Normotensive hypokalemic primary aldosteronism: How is this Possible?

Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na–Cl cotransporter mutations

Primary aldosteronism (PA) is the most common form of secondary hypertension, while Gitelman's syndrome (GS) is the most common inherited renal tubular disease. However, coexistence of these two diseases has never been previously reported. AIM AND SUBJECTS: The aim of our study was to describe the association of GS and PA in two unrelated patients and compare their clinical presentation with a group of patients with GS. Ten subjects suspected to have only GS were assigned to the control group. Saline infusion test was used to confirm the diagnosis of PA. GS was confirmed by sequencing of the causal genes (SLC12A3 and CLCNKB) and functional analyses in Xenopus laevis oocytes. Confirmatory tests, gene analysis, and functional studies demonstrated the coexistence of GS and PA in both patients. In total, nine novel SLC12A3 gene variants, including seven missense mutations, one splice mutation, and one frameshift deletion, were found in 12 subjects. Four mutations (p.T60M, p.T304M, p.T465P, and p.N611T) harbored by the two patients with both PA and GS were revealed to be loss-of-function variants. Although both patients were normotensive, neither of them had normal nocturnal dip. Two rare diseases GS and PA may occasionally coexist in one subject. In these patients, salt depletion and volume constriction might explain the absence of hypertension normally seen in PA patients. However, the protective mechanism against hypertension via down-regulation of renal sodium handling was probably not sufficient in those patients, since their normal circadian rhythm of blood pressure was disrupted.

Hyperaldostéronisme primaire avec hypokaliémie sans hypertension artérielle: à propos d'un cas

We report a hypokaliemic and normotensive primary aldosteronism in a 62 y.o. woman. BP was 130/80 mmHg. Blood level of aldosterone was increased with a constant hyporeninemia. Both levels were unresponsive. Abdominal CT scan found a left adrenal tumor. At surgery, the left adenal, bearing a benign adenoma, was removed. The precise etiology of this normotensive primary aldosteronism remains to be elucidated.

A case of normotensive primary aldosteronism-comparison with 13 previously experienced cases with hypertension.

A 47-year-old woman with normotensive primary aldosteronism is reported. In this case, hypopotassemia was found, but the patient's blood pressure was within the normal range. Her condition was diagnosed as primary aldosteronism without hypertension, which is very rare, based on an increased level of plasma aldosterone concentration, low plasma renin activity, and a typical finding of aldosterone-producing adenoma by adrenal scintigraphy. In the present case, similar values for urinary volume, renal function, plasma aldosterone concentration, plasma renin activity, plasma volume, total exchangeable sodium, urinary kallikrein excretion and a similar weight of the resected adenoma, but a shorter duration between the onset of symptom and hospital admission were observed as compared with those in 13 previously experienced cases of primary aldosteronism with hypertension. Thus, a shorter duration of primary aldosteronism appears to be an important factor in explaining the mechanism of normotension. However, we were unable to reach a definite conclusion and this is only a hypothesis. Further investigation will be required to clarify the mechanism of normotension in primary aldosteronism.

Normotensive primary aldosteronism

A very unusual case of normotensive primary aldosteronism is described. A 25 year old woman first noticed numbness of both hands followed by a typical tetany attack. The blood pressure was within normal ranges. The results of other physical examinations were negative except for the findings of Trousseau's sign. Hypokalemia, increased potassium clearance, disturbed urine concentration and increased circulating plasma volume were noticeable. Diagnosis was established by (1) increased levels of plasma aldosterone, (2) low plasma renin activity, (3) normal adrenocortical function and (4) typical aldosterone-producing adenoma. After removal of the adenoma, the abnormalities subsided. The lack of hypertension in primary aldosteronism is a rare condition. Several possible causes of normotension must be considered, such as the early phase of primary aldosteronism, essential hypotension associated with primary aldosteronism and lack of concomitant secretion of other mineralocorticoids from the adenoma, but these were all negligible. As blood pressure response to the administration of angiotensin II was lower than is typical for primary aldosteronism, and the patient transiently suffered from frequent attacks of blackouts soon after the operation, the cause of normotension was thought to be due to the existence of a hypotensive mechanism which counteracts the increase in blood pressure in primary aldosteronism.

Normotensive primary aldosteronism

Normotensive primary aldosteronism