Michele Battistel

A stress reaction affects assessment of selectivity of adrenal venous sampling and of lateralization of aldosterone excess in primary aldosteronism

BACKGROUND A stress reaction involving increased cortisol release, which has not been documented thus far, might affect the assessment of selectivity of catheterization during adrenal venous sampling (AVS). OBJECTIVE To investigate whether an ACTH-driven cortisol release occurs during AVS and whether it influences the assessment of selectivity by the step-up of cortisol (plasma cortisol concentrations, PCC) between the adrenal vein blood (PCC(SIDE)) and the inferior vena cava (PCC(IVC)), e.g. the selectivity index (SI). DESIGN AND METHODS We determined the SI in samples obtained simultaneously at starting AVS (t-15) and again after 15  min (t0) in 34 consecutive patients with proven aldosterone-producing adenoma. We then calculated the SI with PCC(SIDE) obtained at t-15 and at t0, and the PCC(IVC) values obtained at the different time point, thus simulating sequential AVS. RESULTS The PCC(SIDE) and the SI fell significantly from t-15 to t0 on both the sides. When PCC(SIDE) obtained at t-15 was combined with PCC(IVC) at t0, the SI values were higher than those obtained with simultaneously drawn samples. This led to label as selective more AVS studies than with bilaterally simultaneous data, especially when using higher cutoffs for the SI. CONCLUSIONS A transient increase in cortisol release from both adrenal glands occurs in the majority of the patients who undergo AVS. This stress reaction can influence the assessment of both the selectivity of the catheterization during the sequential AVS technique and the lateralization of aldosterone excess.

Role of multidetector CT angiography and contrast-enhanced ultrasound in redefining follow-up protocols after endovascular abdominal aortic aneurysm repair

PurposeContrast-enhanced ultrasonography (CEUS) is an appealing alternative to computed tomography angiography (CTA) for the follow-up of patients who underwent endovascular abdominal aortic aneurysm repair (EVAR). We sought to evaluate the accuracy of CEUS compared with a particularly tailored protocol of CTA performed with a 64-row multidetector CT.Materials and methodsThe study prospectively enrolled 88 consecutive patients for CEUS and CTA imaging during follow-up after EVAR, yielding 142 paired examinations. The outcome is represented by three main goals: identification and characterisation of endoleaks, evaluation of graft patency and measurement of aneurysm diameter. Triple-phase CTA was the gold standard.ResultsSensitivity and specificity of CEUS compared with CTA in endoleak and graft patency evaluation were 91.89% and 100% and 72% and 100%, respectively. A very high correlation between CTA and CEUS diameter measurements was established. CEUS did not appear superior to CTA in endoleak detection, probably because a tailored CTA protocol with a delayed phase (180 s) allows detection of low-flow endoleaks.ConclusionsPatient management was not different stafollowing CEUS and CTA results. CTA cannot yet be completely replaced, but several limitations (radiation exposure, contrast agent) encourage redefining the routine follow-up imaging modality. We suggest an algorithm of surveillance alternating CTA and CEUS.RiassuntoObiettivoL’ecografia con mezzo di contrasto (CEUS) rappresenta una valida alternativa all’angio-tomografia computerizzata (CTA) nel follow-up dei pazienti sottoposti a trattamento endovascolare di aneurisma aortico addominale (EVAR). Abbiamo voluto valutare l’accuratezza di CEUS confrontata con CTA eseguita con apparecchio multidetettore a 64 strati e protocollo specifico.Materiali e metodiLo studio prospettico ha arruolato 88 pazienti consecutivi indagati con CEUS e CTA durante il follow-up post-EVAR, ottenendo 142 esami appaiati. Sono stati considerati tre parametri: identificazione e caratterizzazione degli endoleak, valutazione della pervietà della protesi, misura del diametro aneurismatico. La CTA trifasica costituiva il gold-standard.RisultatiSensibilità e specificità di CEUS versus CTA nella valutazione di endoleak e pervietà endoprotesica sono state 91,89% e 100%, 72% e 100%, rispettivamente. Si è ottenuta una correlazione molto elevata tra le due metodiche nella misurazione dei diametri. CEUS non è apparsa superiore a CTA nell’identificazione degli endoleak, probabilmente grazie al protocollo mirato comprendente la fase tardiva (180 s), che permette di riconoscere anche leak tardivi a basso flusso.ConclusioniLa gestione dei pazienti non sarebbe cambiata seguendo i risultati CEUS e CTA. Attualmente CTA non può essere completamente sostituita, ma importanti limiti impongono di ridefinire il follow-up strumentale post-EVAR: proponiamo un algoritmo che alterni CEUS e CTA.

Percutaneous thrombin embolization of a pancreatico-duodenal artery pseudoaneurysm after failing of the endovascular treatment.

Pancreatico-duodenal artery (PDA) pseudoaneurysms are rare vascular conditions with high mortality rates after rupture and they are frequently secondary to pancreatitis, surgery, trauma or infection. Due to the high risk of rupture and bleeding, it is mandatory to treat all pseudoaneurysms, regardless of their size or symptomatology. First option of treatment is open surgical repair, but it has high mortality rate, especially in hemodynamically unstable patients. In the recent years, percutaneous ultrasonography (US)- or computed tomography-guided thrombin injection was proposed as an alternative method for treating visceral aneurysms and pseudoaneurysms, but few reports described this therapy in case of peri-pancreatic pseudoaneurysms. We present a rare case of pseudoaneurysm of the PDA in a patient with no previous history of pancreatitis nor major surgery but with an occlusive lesion of the celiac axis. To the best of our knowledge this is the first reported case of PDA pseudoaneurysm successfully treated in emergency by single transabdominal US-guided injection of thrombin after failed attempts of percutaneous catheterization of the feeding vessel of the pseudoaneurysm.

Metoclopramide unmasks potentially misleading contralateral suppression in patients undergoing adrenal vein sampling for primary aldosteronism.

Objective: As metoclopramide stimulates aldosterone secretion, we tested its usefulness in the assessment of lateralization of primary aldosteronism by adrenal vein sampling (AVS). Design: Prospective within-patient study in consecutive patients undergoing AVS for primary aldosteronism subtyping. Methods: We compared the diagnostic accuracy of baseline and postmetoclopramide lateralization index and relative (to cortisol) aldosterone secretion indices (RASI) for each adrenal gland with aldosterone-producing adenoma (APA) determined by the four corners criteria as the reference diagnosis. Results: We recruited 93 consecutive patients (mean age: 52 years; women 31%). Metoclopramide increased plasma aldosterone in the inferior vena cava and in both adrenal veins. The postmetoclopramide lateralization index was accurate in identifying APA, but did not increase diagnostic accuracy over baseline lateralization index, because the RASI increased similarly in both sides. Conversely, metoclopramide raised RASI to values more than 0.90 bilaterally in non-APA patients allowing accurate identification of factitious aldosterone suppression. In contrast, RASI was 0.90 or less in 48% contralateral to the tumor in APA patients. Regression analysis showed the APA patients with persistent suppression of RASI contralaterally showed a more florid primary aldosteronism phenotype. Conclusion: Metoclopramide does not enhance lateralization of aldosterone excess in APA, but consistently increased the value of RASI in non-APA cases, thus unmasking potentially misleading suppression of aldosterone. Postmetoclopramide RASI may therefore allow a more precise diagnosis when AVS can be achieved only unilaterally.

Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism

Abstract Purpose: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. Methods and design: We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K+, systolic and diastolic blood pressure. Discussion: We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations.

The subtyping of primary aldosteronism by adrenal vein sampling: sequential blood sampling causes factitious lateralization

Background: The pulsatile secretion of adrenocortical hormones and a stress reaction occurring when starting adrenal vein sampling (AVS) can affect the selectivity and also the assessment of lateralization when sequential blood sampling is used. We therefore tested the hypothesis that a simulated sequential blood sampling could decrease the diagnostic accuracy of lateralization index for identification of aldosterone-producing adenoma (APA), as compared with bilaterally simultaneous AVS. Methods and results: In 138 consecutive patients who underwent subtyping of primary aldosteronism, we compared the results obtained simultaneously bilaterally when starting AVS (t-15) and 15 min after (t0), with those gained with a simulated sequential right-to-left AVS technique (R ⇒ L) created by combining hormonal values obtained at t-15 and at t0. The concordance between simultaneously obtained values at t-15 and t0, and between simultaneously obtained values and values gained with a sequential R ⇒ L technique, was also assessed. We found a marked interindividual variability of lateralization index values in the patients with bilaterally selective AVS at both time point. However, overall the lateralization index simultaneously determined at t0 provided a more accurate identification of APA than the simulated sequential lateralization indexR ⇒ L (P = 0.001). Moreover, regardless of which side was sampled first, the sequential AVS technique induced a sequence-dependent overestimation of lateralization index. While in APA patients the concordance between simultaneous AVS at t0 and t-15 and between simultaneous t0 and sequential technique was moderate-to-good (K = 0.55 and 0.66, respectively), in non-APA patients, it was poor (K = 0.12 and 0.13, respectively). Conclusion: Sequential AVS generates factitious between-sides gradients, which lower its diagnostic accuracy, likely because of the stress reaction arising upon starting AVS.

LB02.07: EFFECT OF ACUTE DA2 DOPAMINERGIC RECEPTOR BLOCKADE ON PERFORMANCE OF ADRENAL VEIN SAMPLING FOR SUBTYPING OF PRIMARY ALDOSTERONISM.

Objective: As dopamine tonically inhibits aldosterone release via DA2 receptors, we hypothesized that acute DA2 blockade during adrenal vein sampling (AVS) might improve the assessment of lateralization of aldosterone excess in the subtyping of primary aldosteronism. Design and method: we prospectively investigated the acute effect of metoclopramide on the lateralization index [LI, defined as the ratio of aldosterone over cortisol plasma concentration (PAC:PCC) in the dominant over the PAC:PCC in the contralateral side] and on the relative aldosterone secretion index in adrenal vein blood [RI, defined as the ratio of plasma aldosterone concentration (PAC) in the adrenal vein over PAC in inferior vena cava (IVC), normalized by the ipsilateral Selectivity Index]. To this end we compared baseline and post-metoclopramide LI and RI values in 92 consecutive patients undergoing AVS from 2008 to 2014. As gold standard we used the diagnosis of aldosterone-producing adenoma (APA), based on pathology and follow-up data according to the four corners criteria. Results: Metoclopramide increased aldosterone in the IVC and in adrenal vein blood of both sides (p < 0.0001 for all). Even though post-metoclopramide LI provided an accurate identification of APA (AUC = 0.880, p = 0.0001 vs identity line; Youden Index >2.7, sensitivity 81%, specificity 83%), it showed no incremental diagnostic gain over baseline LI (p = 0.75 for ROC curves comparison). Metoclopramide also increased the RI (p < 0.001) both from the dominant and the non-dominant side [3.13 (2.53–4.33) to 8.76 (5.31–12.21); 0.91 (0.68–1.36) to 2.19 (1.61–3.23), respectively]. However, metoclopramide raised the RI on the APA side to values > 1.00 in all the 39 unequivocally diagnosed APA patients. Therefore, a post metoclopramide cut-off for the RI < 1.00 offered 100% specificity in excluding an APA on that side. Conclusions: acute DA2 antagonism exerts a prominent secretagogue effect on aldosterone, but due to a proportionally similar effect on the RI of both sides it did not increase the LI. However, it can increase the specificity of the RI for excluding an APA. This finding might be of particular diagnostic value for AVS studies that are not bilaterally selective.

Cure With Cryoablation of Arterial Hypertension Due to a Renin-Producing Tumor

BACKGROUND We herein report on a 20 years old woman with stage I hypertension, who was found to carry a renin-producing tumor (RPT). METHODS Due to her young age, the patient underwent screening measurement of plasma renin and aldosterone, abdominal computed tomography (CT) angiography, and selective renal vein renin assessment to identify secondary hypertension. RESULTS The patient was screened for secondary causes of hypertension and was diagnosed with secondary aldosteronism. Therefore, she underwent an abdominal computed tomography (CT) angiography that was reported as unremarkable. Selective renal vein renin studies showed overproduction of renin in the right kidney and a re-evaluation of her CT allowed detection of an 8-mm mass in her right kidney, suggesting the presence of a RPT. Considering the technical difficulty of renal sparing surgery a CT-guided cryoablation was undertaken, which provided long-term cure of arterial hypertension and normalization of plasma active renin concentration. CONCLUSIONS RPTs usually present with a clinical phenotype featuring stage III and/or malignant hypertension and are held to be exceptionally rare. This case is unique in that it presented with stage I hypertension and a mild clinical phenotype. Moreover, to our knowledge this is the first case of RPTs shown to be safely treated with CT-guided cryoablation and found to be cured at long-term.

[OP.3A.03] IMPACT OF STRESS REACTION ON THE ASSESSMENT OF LATERALIZATION DURING SEQUENTIAL ADRENAL VEIN SAMPLING FOR PRIMARY ALDOSTERONISM.

Objective: Emotional and pain-related stress occurring upon starting Adrenal Vein Sampling (AVS) has been shown to wane swiftly and to influence the selectivity of the procedure. It can also conceivably affect lateralization assessment when the sequential catheterization technique is used, which occurs in about half of cases at major referral centers. We set up this study to investigate the impact of stress reaction on accuracy of sequential AVS for the subtyping of Primary aldosteronism (PA). Design and method: We prospectively collected adrenal veins and VCI blood samples simultaneously at starting AVS (t-15) and after 15 min (t0) in 140 consecutive PA patients. In patients with selective AVS, a sequential technique was simulated by calculating the LI with plasma aldosterone (PAC) and cortisol (PCC) obtained at t-15 from one side and values at t0 from the contralateral side. These LI values (LIseq) were compared to those obtained with simultaneous sampling at t0 (LI_t0) using paired T and McNemar tests, and ROC curves analysis, for diagnostic accuracy, using a conclusive diagnosis of aldosterone-producing adenoma (APA) diagnosis (by the four corners criteria), as gold standard. Results: LI_t0 provided a significantly more accurate identification of APA compared to LI_seq, regardless of the sequential protocol simulated (AUC t0 = 0.869; “first right” AUC = 0.794 and “first left” AUC = 0.721; p = 0.029 and p = 0.002 for AUC comparison with t0, respectively). Figure. No caption available. Conclusions: In the subtyping of PA by AVS, when the sequential technique is used and the time delay between the first and the second adrenal vein sampling is about 15 minutes, a stress reaction lowers the accuracy of AVS for ascertaining lateralization of aldosterone excess, likely due to generation of artificial gradients between the sides.