The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease.

Excess aldosterone is associated with the increased risk of cardio-/cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects. The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation. Ninety-seven PA patients (43 unilateral, 54 with bilateral PA) from the database of the German Conn's Registry were included. Anti-TPO and anti-TG levels were measured pre and 6-12 months post therapeutic intervention. Patients were assessed for ACS according to their 24- hour urinary cortisol excretion, late night salivary cortisol and low-dose dexamethasone suppression test. Abnormal test results in line with ACS were identified in 74.2% of patients with PA. Following adrenalectomy, significant increases in anti-TPO levels were observed in patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy (MRA). Our data are in line with an immunosuppressive effect of mild glucocorticoid excess in PA on thyroid autoantibody titers. This effect is uncovered by adrenalectomy, but not by MRA treatment.

Patients With Primary Aldosteronism Respond to Unilateral Adrenalectomy With Long-Term Reduction in Salt Intake.

CONTEXT: High dietary salt intake is known to aggravate arterial hypertension. This effect could be of particular relevance in the setting of primary aldosteronism (PA), which is associated with cardiovascular damage independent of blood pressure levels. The aim of this study was to determine the impact of therapy on salt intake in PA patients. PATIENTS AND METHODS: A total of 148 consecutive PA patients (66 with unilateral and 82 with bilateral PA) from the database of the German Conn's Registry were included. Salt intake was quantified by 24-hour urinary sodium excretion before and after initiation of PA treatment. STUDY DESIGN: Observational longitudinal cohort study. SETTING: Tertiary care hospital. RESULTS: At baseline, unilateral PA patients had a significantly higher urinary sodium excretion than patients with bilateral disease (205 vs 178 mmol/d, P = 0.047). Higher urinary sodium excretion correlated with an increased cardiovascular risk profile including proteinuria, impaired lipid, and glucose metabolism and was associated with higher daily doses of antihypertensive drugs to achieve blood pressure control. In unilateral disease, urinary sodium excretion dropped spontaneously to 176 mmol/d (P = 0.012) 1 year after unilateral adrenalectomy and remained low at 3 years of follow-up (174 mmol/d). In contrast, treatment with mineralocorticoid receptor antagonists (MRA) in bilateral PA patients was not associated with a significant change in urinary sodium excretion at follow-up (179 mmol/d vs 183 mmol/d). CONCLUSION: PA patients consuming a high-salt diet, estimated based on urinary sodium excretion, respond to adrenalectomy with a significant reduction of salt intake, in contrast to MRA treatment.

Circulating miRNA Expression Profiling in Primary Aldosteronism.

Objective: Primary aldosteronism is a major cause of secondary hypertension. Its two principal forms are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal. There is a major clinical need for a reliable and easily accessible diagnostic biomarker for case identification and subtyping. Circulating microRNAs were shown to be useful as minimally invasive diagnostic markers. Our aim was to determine and compare the circulating microRNA expression profiles of adenoma and hyperplasia plasma samples, and to evaluate their applicability as minimally invasive markers. Methods: One hundred and twenty-three samples from primary aldosteronism patients were included. Next-generation sequencing was performed on 30 EDTA-anticoagulated plasma samples (discovery cohort). Significantly differently expressed miRNAs were validated by real-time reverse transcription-qPCR in an independent validation cohort (93 samples). Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p, and miR-7-5p in hyperplasia compared to adenoma by next-generation sequencing. Validation by qRT-PCR confirmed significant overexpression of hsa-miR-30e-5p, hsa-miR-30d-5p, and hsa-miR-7-5p in hyperplasia samples. Regarding the microRNA expressional variations, adenoma is more heterogeneous at the miRNA level compared to hyperplasia. Conclusion: Three microRNAs were significantly overexpressed in hyperplasia samples compared to adenoma samples, but their sensitivity and specificity values are not good enough for introduction to clinical practice.

Diverse Responses of Autoantibodies to the Angiotensin II Type 1 Receptor in Primary Aldosteronism.

Primary aldosteronism is a common form of endocrine hypertension mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). AT1R-Abs (autoantibodies to the angiotensin II type 1 receptor) have been reported in patients with disorders associated with hypertension. Our objective was to assess AT1R-Ab levels in patients with primary aldosteronism (APA, n=40 and BAH, n=40) relative to patients with primary hypertension (n=40), preeclampsia (n=23), and normotensive individuals (n=25). AT1R-Abs in whole sera were measured using 2 different ELISAs which gave contrasting results. A functional cell-based assay was used to quantify activation of the AT1R (angiotensin II type 1 receptor) using whole sera or affinity-purified antibodies in the absence or presence of losartan (a specific AT1R antagonist). Serum samples from all groups displayed different levels of AT1R activation with different responses to losartan. Patients with BAH displayed higher losartan-independent affinity-isolated agonistic AT1R-Ab levels compared with patients with APA (P<0.01) and with normotensive individuals (P<0.0001). In patients with APA, BAH, and primary hypertension combined, higher aldosterone-to-renin ratios and lower plasma renin concentrations were associated with higher compared with lower agonistic AT1R-Ab levels. In patients with primary aldosteronism, higher AT1R-Ab activity was associated with an increased likelihood of a diagnosis of BAH compared with APA and with the presence of adrenal hyperplasia detected by computed tomography. Taken together, these data suggest that agonistic AT1R-Abs may have a functional role in a subgroup of patients with primary aldosteronism.

Safety of medical adjustment and confirmatory testing in the diagnostic work-up of primary aldosteronism.

OBJECTIVE: Saline infusion test (SIT) and captopril challenge test (CCT) are standard confirmatory procedures routinely used in the diagnostic work-up of primary aldosteronism (PA). However, side effects and complications during testing have not been systematically studied. DESIGN: We performed a cohort study with patients undergoing SIT and/or CCT in two centers from 2016 until 2018. METHODS: We studied 272 study participants with suspected PA enrolled at two outpatient centers in Germany. We assessed the frequency and severity of side effects during adjustment of blood pressure medication and during SIT and CCT. RESULTS: During the adjustment phase prior confirmatory testing, side effects including palpitations, headaches, edema and hypertensive episodes occurred in 18.4% of study participants. Side effects were associated with higher defined daily doses (DDD) (r = 0.25, P < 0.005), number of antihypertensive drugs (r = 0.285, P < 0.005) and higher blood pressure (r = 0.145, P = 0.019). During SIT, 17.5% of study participants had side effects, associated with higher blood pressure (systolic: r = 0.541, P < 0.0005; diastolic: r = 0.426, P < 0.0005) and DDDs (r = 0.727, P < 0.0005). During CCT, only 1.5% of study participants developed side effects. CONCLUSIONS: In contrast to the high rate of side effects during SIT, CCT appears to be the safer test with a very low event rate. This makes CCT especially suitable for severely hypertensive patients.

Adrenal Insufficiency After Unilateral Adrenalectomy in Primary Aldosteronism: Long-Term Outcome and Clinical Impact.

CONTEXT: Primary aldosteronism (PA) represents a secondary form of arterial hypertension that can be cured by surgery. Evidence of adrenal insufficiency (AI) was recently found in patients with PA who had undergone unilateral adrenalectomy (uADX). OBJECTIVE: To study the incidence and long-term outcome of postoperative AI after uADX for PA. DESIGN: Prospective registry study (August 2014 until the end of 2018). SETTING: Tertiary referral center. PATIENTS: One hundred consecutive patients undergoing uADX for PA were included. All patients underwent postoperative ACTH stimulation testing. INTERVENTION: Postoperative ACTH stimulation testing to identify patients with AI. MAIN OUTCOME MEASURES: Incidence of patients with postoperative AI and definition of long-term outcome. RESULTS: Twenty-seven percent of patients developed postoperative AI. Of these, 48% had postoperative ACTH stimulation serum cortisol levels ≤13.5 µg/dL (severe AI); 52% were classified into the group with moderate AI (stimulated serum cortisol levels: 13.5 to 17 µg/dL). Patients with severe AI required significantly longer hydrocortisone replacement therapy than the moderate group (median [25th, 75th percentiles]: 353 [294, 476] days; 95% CI: 284 to 322 days; vs 74 [32, 293] days; 95% CI: 11 to 137 days; P = 0.016). One patient with severe AI was hospitalized for an acute adrenal crisis. With a cumulative follow-up of 14.5 years, this produced an incidence rate of 6.9 adrenal crises per 100 patient-years. CONCLUSION: We suggest performing postoperative ACTH stimulation tests in all patients who undergo uADX for PA.

Impaired Glucose Metabolism in Primary Aldosteronism Is Associated With Cortisol Cosecretion.

CONTEXT: Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and metabolic risks. Recent studies report glucocorticoid cosecretion as a relevant phenotype of PA, which could contribute to associated risks, including type 2 diabetes mellitus (T2DM). The relationship between autonomous cortisol secretion (ACS) and glucose metabolism in PA has not been investigated. OBJECTIVE: To evaluate the prevalence of impaired glucose homeostasis in patients with PA according to cortisol cosecretion. DESIGN: We performed oral glucose tolerance tests (OGTTs) and complete testing for hypercortisolism [1-mg dexamethasone suppression test (DST), late-night salivary cortisol, 24-hour urinary free cortisol] in 161 newly diagnosed patients with PA of the German Conn Registry. Seventy-six of 161 patients were reevaluated at follow-up. We compared our results to a population-based sample from the Cooperative Health Research in the Region of Augsburg (KORA)-F4 study matched to the participants with PA (3:1) by sex, age, and body mass index. RESULTS: At the time of diagnosis, 125 patients (77.6%) had a pathological response in at least one of the Cushing screening tests; T2DM was diagnosed in 6.4% of these 125 cases. Patients with a pathological DST exhibited significantly higher 2-hour plasma glucose in OGTTs and were significantly more often diagnosed with T2DM than were patients with a normal DST (20% vs 0.8%, P < 0.0001) and matched controls from the KORA study (20.6% vs 5.9%, P = 0.022). Patients with PA without ACS tended to have higher homeostatic model assessment of insulin resistance levels than did KORA control subjects (P = 0.05). CONCLUSION: ACS appears frequently in patients with PA and is associated with impaired glucose metabolism, which could increase the risk of T2DM. PA itself seems to enhance insulin resistance.

Primary aldosteronism: key characteristics at diagnosis: a trend toward milder forms.

OBJECTIVE: Primary aldosteronism (PA) is the most common endocrine form of arterial hypertension. The German Conn's Registry's purpose is to improve treatment outcomes of PA. We assessed whether key clinical, biochemical and epidemiological characteristics of newly diagnosed PA cases have changed over time, potentially indicating a different screening and referral practice in Germany evolving from 2008 to 2016. DESIGN: The German Conn's Registry is a multicenter database prospectively analyzing morbidity and long-term outcome of patients with PA. METHODS: Phenotypic changes between three year periods were calculated using Mann-Whitney U tests and Kruskal-Wallis tests for independent variables. RESULTS: Over three time periods from 2008 to 2016, we noted a relative decrease of unilateral PA cases (67 vs 43%). Significantly more females were diagnosed with PA (33 vs 43%). Median daily defined drug doses decreased (3.1 vs 2.0) in the presence of unchanged SBP (150 vs 150 mmHg), plasma aldosterone (199 vs 173 ng/L) and PRC (3.2 vs 3.2 U/L). Median ARR values decreased (70 vs 47 ng/U) and median potassium levels at diagnosis (3.5 vs 3.7 mmol/L) increased as the percentage of normokalemic patients (25 vs 41%), indicating milder forms of PA. CONCLUSIONS: Our results are in accordance with an increased screening intensity for PA. We identified a trend toward diagnosing milder forms, increasingly more females and less unilateral cases of PA.