11C-metomidate PET CT versus Adrenal Vein Sampling for diagnosing surgically curable primary aldosteronism: prospective test validation, and impact of somatic genotype and ethnicity on outcomes

Abstract Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma (APA) is a common, curable cause of hypertension, but invasive methods of diagnosis and treatment contribute to <1% of patients being offered the chance of cure. The primary objective of our prospective within-patient study in 143 patients with PA was to compare accuracy of 11C-metomidate (MTO) PET-CT scanning with adrenal vein sampling (AVS) in predicting biochemical cure from PA and resolution of hypertension. Secondary outcomes addressed heterogeneity of underlying pathogenesis and prediction of patients most likely to achieve complete cure of hypertension. 128 patients reached 6-9 month follow-up. 77/78 surgical patients achieved one or more of the four hierarchically analysed Primary Aldosteronism Surgical Outcome (PASO) criteria for biochemical and clinical success. MTO was not superior to AVS but all four differences in accuracy favored MTO, with 95% CIs >-17%, the pre-specified margin of non-inferiority. The best univariate predictors of complete clinical cure were home systolic blood pressure (SBP) <135 mmHg after one month of spironolactone 100 mg daily (odds ratio 13.0 (3.72, 45.24) p<0.001) and KCNJ5 genotype of the APA (odds ratio 10.37 (2.50, 42.99) p=0.001). The latter remained significant in logistic regression on age, gender, ethnicity, and was itself predicted by elevated urine 18-hydroxycortisol:cortisol ratio. Our findings validate 11C-metomidate PET-CT for accurate, non-invasive detection of patients with unilateral PA, and identify patients most likely to benefit from adrenalectomy.

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OR34-01 11C Metomidate PET-CT Identifies More Unilateral Primary Aldosteronism Than Adrenal Vein Sampling

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.581 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Troy Puar ◽

Colin Tan ◽

Aaron Tong ◽

Meifen Zhang ◽

ChinMeng Khoo ◽

...

Keyword(s):

Primary Aldosteronism ◽

Prospective Trial ◽

Adrenal Vein ◽

Secondary Outcome ◽

Acth Stimulation ◽

Adrenal Vein Sampling ◽

Non Invasive ◽

Post Surgery ◽

Pet Ct ◽

Biochemical Cure

Abstract Introduction. Adrenal vein sampling (AVS) is the current reference test to identify unilateral, surgically-curable primary aldosteronism (PA). However, AVS is invasive and technically difficult. Even in AVS-proven unilateral PA, up to 6% of patients with fail to have biochemical cure after surgery using the PASO criteria. 11C-Metomidate PET-CT offers a non-invasive alternative. We compared the accuracy of both PET-CT and AVS using post-surgery cure (PASO criteria) as the reference. Methods. This multi-centre prospective trial recruited 25 patients with confirmed PA, and all underwent CT, AVS, and PET-CT tests. Sequential AVS under ACTH-stimulation was done by an experienced interventionalist, and cortisol gradient of >5 was taken to be successful cannulation. Lateralization ratio >4 was consistent with unilateral PA. All results were reviewed at a multidisciplinary meeting to decide on the diagnosis (unilateral or bilateral PA) and management (secondary outcome). Primary outcome was biochemical cure using PASO criteria at 6 months post-surgery (ClinicalTrials.gov: NCTxxxxxxxx). Results. Recruitment for the study has been complete with 25 patients, 49.2 ± 9.5 yr, 14 females (56.0%). All 25 patients had successful AVS. 22 of 25 patients (88.0%) had unilateral PA, and 3 patients (12.0%) had bilateral PA. PET-CT identified unilateral PA in 18 of 22 patients (sensitivity 81.8%), while AVS identified unilateral PA in 15 of 22 patients (sensitivity 68.2%). In one patient, repeat AVS done simultaneously without ACTH-stimulation aided to identify unilateral PA, when initial AVS failed to do so. Other cases where AVS failed to identify unilateral PA were due to venous anomalies, and limitation of the lateralization cut-off of 4. 18 of 22 patients have undergone surgery, with 3 patients awaiting surgery, and 1 opting for medical treatment. Post-surgery, all patients had complete normalization of aldosterone-renin ratio, and hypokalemia (if present). 2 patients had bilateral PA on both PET-CT and AVS. 1 patient had discordant AVS and PET-CT results, with AVS lateralizing to right, and PET-CT to left. This patient was classified as bilateral PA and treated medically. Conclusion. This is the first study to demonstrate that 11C-Metomidate PET-CT may identify cases of unilateral PA not detected with AVS, using the stringent PASO criteria for post-operative biochemical cure.

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11C-metomidate PET-CT in primary aldosteronism: five possible indications for a non-invasive alternative to adrenal vein sampling

Endocrine Abstracts ◽

10.1530/endoabs.37.oc1.4 ◽

2015 ◽

Author(s):

Andrew S Powlson ◽

Olympia Koulouri ◽

Elena Azizan ◽

Carmela Maniero ◽

Kevin Taylor ◽

...

Keyword(s):

Primary Aldosteronism ◽

Adrenal Vein ◽

Adrenal Vein Sampling ◽

Non Invasive ◽

Pet Ct

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Prospective clinical trial comparing 11c-metomidate pet-ct and adrenal vein sampling in identifying unilateral surgically-curable primary aldosteronism

Endocrine Abstracts ◽

10.1530/endoabs.73.aep787 ◽

2021 ◽

Author(s):

Puar Hai Kiat ◽

Colin Tan ◽

Aaron Tong ◽

Khoo Chin Meng ◽

Alvin Tan ◽

...

Keyword(s):

Clinical Trial ◽

Primary Aldosteronism ◽

Adrenal Vein ◽

Prospective Clinical Trial ◽

Adrenal Vein Sampling ◽

Pet Ct

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Primary Results From MATCH: A Randomised Controlled Trial in Primary Aldosteronism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1369 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A671-A671

Author(s):

Xilin Wu ◽

Russell Senanayake ◽

Emily Goodchild ◽

Waiel Bashari ◽

Jackie Salsbury ◽

...

Keyword(s):

Primary Aldosteronism ◽

Clinical Cure ◽

Controlled Trial ◽

African Ancestry ◽

Random Order ◽

Adrenal Vein ◽

Primary Analysis ◽

Adrenal Vein Sampling ◽

Pet Ct ◽

Secondary Outcomes

Abstract Primary aldosteronism (PA) is now considered the sole, often curable, cause of hypertension in 5-10% of patients. Yet there has been only one RCT, and practice has changed little since the advent of CT scanning. Adrenal vein sampling (AVS) and adrenalectomy remain the standard, invasive interventions, leading to a 50% reduction in pill count as the average clinical improvement. Study Design In MATCH (Is Metomidate PET-CT superior to Adrenal vein sampling in predicting ouTCome from adrenalectomy in patients with primary Hyperaldosteronism), 142 patients, mean age 52, 32% female, 32% of African ancestry, 46% hypokalemic, had both AVS and 11C-metomidate PET CT (MTO) in random order, and were referred for surgery if aldosterone/cortisol ratio differed >4-fold between adequately cannulated adrenal veins, and/or SUVmax on MTO was >1.25 higher, in a definite tumour, than the opposite adrenal. The primary outcome is the proportion of patients in whom adrenalectomy achieved complete or partial biochemical or clinical cure, analysed hierarchically using PASO criteria.1 Anticipating ~50% incidence of unilateral PA, MATCH is powered to detect 25% superiority of MTO vs AVS, or non-inferiority at a lower-bound CI of -17%. Secondary outcomes include non-randomised comparison of outcomes between unilateral and bilateral PA; prediction of clinical outcome from the home BP (12 readings over 3 days) before and after starting spironolactone 100 mg od for 4 weeks; quality-of-life assessments; and analyses, by RNAseq, of genotype and transcriptomes of 56 of the CYP11B2-positive tumors, correlated with ethnicity and outcomes. Results: The analysis set is 75 patients who, on 31 Dec 2020, had undergone adrenalectomy with > 6 months follow-up. 67 patients (89%) had complete biochemical cure following PASO criteria,1 and 63 (84%) had complete or partial clinical cure. In 39 of the surgical patients, only one of MTO or AVS was scored as high-probability using criteria above. This score was confirmed at the multi-centre, Multi-Disciplinary Team (MDT) meeting which reviewed all MTO scans without knowledge of AVS. In the primary analysis, comparing accuracy of MTO and AVS by McNemar test, the 39 discordant results were allocated as a win to the positive investigation, if the patient was cured, or to the negative investigation, if not cured. 50/56 CYP11B2-positive tumors had a known mutation; the frequency was CACNA1D>KCNJ5>ATP1A1>ATP2B3>CTNNB1>GNAQ>CLCN2, differing between patients whose hypertension was completely or partially cured. Two other tumors had novel gene mutations. Several RNAseq transcripts varied with genotype and outcome, including some encoding measurable, secreted proteins. Full primary and secondary outcomes will be presented. 1. Williams TA, et al. Lancet Diabetes Endocrinol. 2017;5:689-699

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Adrenal vein sampling versus CT scanning in primary aldosteronism

The Lancet Diabetes & Endocrinology ◽

10.1016/s2213-8587(16)30240-6 ◽

2016 ◽

Vol 4 (11) ◽

pp. 886 ◽

Cited By ~ 6

Author(s):

John W Funder ◽

Gian Paolo Rossi

Keyword(s):

Primary Aldosteronism ◽

Ct Scanning ◽

Adrenal Vein ◽

Adrenal Vein Sampling

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Adrenal vein sampling versus CT scanning in primary aldosteronism

The Lancet Diabetes & Endocrinology ◽

10.1016/s2213-8587(16)30235-2 ◽

2016 ◽

Vol 4 (11) ◽

pp. 885-886 ◽

Cited By ~ 1

Author(s):

Troy H Puar ◽

Joan J Khoo ◽

Keng S Ng ◽

Jia W Kam ◽

Kuo W Wang

Keyword(s):

Primary Aldosteronism ◽

Ct Scanning ◽

Adrenal Vein ◽

Adrenal Vein Sampling

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Adrenal vein sampling versus CT scanning in primary aldosteronism – Authors' reply

The Lancet Diabetes & Endocrinology ◽

10.1016/s2213-8587(16)30236-4 ◽

2016 ◽

Vol 4 (11) ◽

pp. 886-887

Author(s):

Gert-Jan van der Wilt ◽

Tanja Dekkers ◽

Jacques W W Lenders ◽

Jaap Deinum

Keyword(s):

Primary Aldosteronism ◽

Ct Scanning ◽

Adrenal Vein ◽

Adrenal Vein Sampling

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The Impact of ACTH on Peripheral Steroids Differs between Unilateral and Bilateral Primary Aldosteronism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.645 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A316-A316

Author(s):

Yuta Tezuka ◽

Kae Ishii ◽

Lili Zhao ◽

Yuto Yamazaki ◽

Ryo Morimoto ◽

...

Keyword(s):

Logistic Regression ◽

Primary Aldosteronism ◽

Repeated Measures ◽

Dynamic Testing ◽

Roc Curves ◽

Adrenal Vein ◽

Rank Test ◽

Adrenal Vein Sampling ◽

Non Invasive ◽

The Impact

Abstract Background: ACTH is thought to contribute to aldosterone excess in primary aldosteronism (PA), possibly via aberrant melanocortin type 2 receptor (MC2R) expression in aldosterone producing adenomas (APAs). Dynamic manipulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a non-invasive tool for distinguishing unilateral PA (UPA) from bilateral PA (BPA), but existing data are minimal. Objective: To characterize the steroid responses to intrinsic ACTH variations and extrinsic HPA manipulation in UPA and BPA. Methods: We conducted comprehensive dynamic testing in PA patients, who were subtyped based on adrenal vein sampling. Peripheral plasma samples were collected from each patient at 6 time-points: morning; midnight; after 1 mg dexamethasone suppression (DST); and after cosyntropin stimulation (at 15’, 30’, and 60’). We quantified 15 steroids by mass spectrometry in each sample. Next generation sequencing was used to detect aldosterone-driver somatic mutations in APAs from 39 cases with available tissue. The Mann-Whitney test, Wilcoxon signed rank test, and repeated measures two-way ANOVA were employed, as appropriate. Penalized logistic regression was used to select steroids that best distinguished UPA from BPA. Receiver operating characteristic (ROC) curves were then plotted using the predicted score from the logistic regression model with the selected steroids, and area under the curves (AUC) were computed. Results: We included 80 PA patients, median age 51 (range, 26–76), 50% men, 40 with each subtype, both groups with similar age and sex distribution. Morning and midnight concentrations of 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), aldosterone, and 18-hydroxycorticosterone (18OHB) were higher in patients with UPA vs. BPA (p<0.001 for all). In response to cosyntropin stimulation, the UPA group had larger increments of aldosterone, 18oxoF, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol than the BPA group (p<0.05 for all). Following DST, aldosterone,18OHF, and 18oxoF were higher in UPA than in BPA patients (p<0.01 for all). Overall, cortisol and cortisone serum concentrations were similar between the two subtypes. Of the UPA cases, 27 (69%) had KCNJ5 mutations. Relative to UPA patients with other mutations, the KCNJ5 group had higher 18oxoF and 18OHF at baseline; higher 18oxoF and corticosterone after both dynamic tests; and lower aldosterone after DST. The highest AUC for PA subtyping was achieved using cosyntropin stimulated steroids (0.957), while baseline data reached an AUC of 0.909. Conclusions: Steroid responses to dynamic HPA testing differs between UPA and BPA: 18oxoF and 18OHF are less suppressible, while several steroids are disproportionally amplified by ACTH in patients with UPA vs. BPA. Such non-invasive tests could circumvent the need for adrenal vein sampling in a subset of PA patients.

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