William F. Young, Jr., MD, MSc Professor of Medicine, Mayo Clinic, Rochester, MN USA
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1 The Year in Adrenal William F. Young, Jr., MD, MSc Professor of Medicine, Mayo Clinic, Rochester, MN USA Division of ENDOCRINOLOGY, DIABETES, METABOLISM & NUTRITION 2018 Mayo Foundation for Medical Education and Research. All rights reserved.
2 DISCLOSURE* Relevant Financial Relationship(s): None Off Label Usage: None *A provider must disclose the above information to learners prior to beginning of the educational activity (ACCME)
3 Disclosure of ABIM Service I chair the Endocrine Specialty Board (July 2014 present) I am a member of the Endocrine Exam Committee (July 2013 present) I am a member of the ABIM Council (July 2014 present) As is true for any ABIM candidate who has taken the certification exam, I have signed a Pledge of Honesty in which I have agreed to keep the ABIM exam confidential No exam questions will be disclosed in my presentation
4 It has been an interesting year in adrenal... I will highlight 6 topics and associated articles that I view as important All have been published within that last 18 months There are many other adrenal topics and outstanding articles that I will not highlight today, and... Apologies, if I don t cover your favorites.
5 May 2016 Primary Aldosteronism What is New?
6 17-Year-Old Woman Hypertension x 3 mo Reg menses, no hirsutism or acne, wt stable Does this patient need confirmatory testing? What else could this be with: Senior in high school, very athletic Meds: Amlodipine 5 mg/d, KCL 20 meq tabs 4 tabs 3x/d (240 meq/d) BP = 146/82 mm Hg, 72 bpm, BMI = 24.4 kg/m 2 Appears well; not cushingoid Labs: Na + = 143 meq/l; K + = 3.2 meq/l; Creatinine = 1.0 mg/dl (N, ) Plasma aldosterone concentration = 51 ng/dl (510 pg/ml; 1415 pmol/l) Plasma renin activity (PRA) = < 0.6 ng/ml/hr
7 * 2016 Updated Endocrine Society Guideline*
8 K + APA Clinical Phenotype PAC> 30 ng/dl (831 pmol/l) In addition, the development of adrenal nodularity is a function of age; nonfunctional adrenal nodules are rare in young people APA clinical phenotype in a young patient (<35 yr) with unilateral adrenal macroadenoma (>1-cm)? Is AVS needed
9 * 2016 Updated Endocrine Society Guideline*
10 * 2016 Updated Endocrine Society Guideline* What is New? 3 things 1. Confirmatory testing not needed if PAC >20 ng/dl & spontaneous hypokalemia 2. AVS not needed in patients <35 yrs & marked PA (eg, spontaneous K +, PAC >30 ng/dl) & unilateral macroadenoma on CT 3. Encourage more broad use of MR antagonists (eg, spironolactone)
11 What s New in Imaging Pheochromocytoma? The historical molecular imaging reference standard: 123 I-metaiodobenzylguanidine (MIBG) combined with anatomic imaging with CT or MRI. 123 I-MIBG Coronal planar image CT axial image
12 What s New in Imaging Pheochromocytoma? Positron emitter imaging with PET/CTs: F-18 FDG PET CT is more sensitive than 123- I-MIBG for detecting metastatic pheochromocytoma/ paraganglioma (PPGL)
13 A-P planar P-A planar 123 I-MIBG SPECT Images Coronal Chest Sagittal Axial Abdomen Axial 123 I-MIBG 123 I-MIBG
14 A-P planar A-P For the past 10 yrs FDG-PET has been the standard for metastatic PPGL 123 I-MIBG 18 FDG-PET
15 What s New in Imaging Pheochromocytoma? Somatostatin receptor based imaging has also been performed with In-111 DTPA pentetreotide ( octretotide scan ) scintigraphy and SPECT/CT. Gallium 68 (68-Ga) 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA)-octreotate is a PET imaging molecule Three DOTA-coupled peptides are in clinical use (DOTATATE, DOTANOC and DOTATOC), all showing high affinity for somatostatin surface receptor type-2 A kit for preparation of 68-Ga DOTATATE injection as a radioactive diagnostic agent for PET imaging (Netspot) was approved by the US FDA in June Ga DOTATATE PET/CT is clearly superior to conventional 111-In pentetreotide scanning.
16 Imaging Pheochromocytoma Recent publications are demonstrating the superiority of 68- Ga DOTATATE PET/CT in imaging metastatic PPGL when compared to 123-I-MIBG, computed cross sectional imaging, and even FDG- PET!
17 September 2016 Pheochromocytoma 22 pts (15 men, 7 women) with metastatic PPGL who underwent 68Ga-DOTATATE, 18F-FDG-PET/CT, and CT/MRI; 12 patients underwent (18F-FDOPA) PET/CT scan and 11 patients underwent an additional (18F-FDA) PET/CT scan.
18 68Ga-DOTATATE PET/CT wins! 68Ga-DOTATATE PET/CT showed a lesion-based detection rate of 97.6% (450 of 461 lesions) 18F-FDG PET/CT 49.2% 18F-FDOPA PET/CT 74.8% 18F-FDA PET/CT- 77.7% CT/MRI 81.6%
19 68-Ga-DOTATATE- PET FDG-PET F-DOPA-PET F-DA-PET 39-yr-old man with sporadic and metastatic PGL
20 68-Ga-DOTATATE- PET FDG-PET F-DOPA-PET F-DA-PET 64-yr-old man with sporadic and metastatic PHEO
21 Imaging Pheochromocytoma-My Conclusions Initial imaging remains CT/MRI of abdomen & pelvis: 85% of catecholamine-secreting tumors are in the adrenal glands and 95% in the abdomen & pelvis If a typical (eg, round 5 cm mass) unilateral adrenal pheo is found on CT/MRI, no additional imaging is needed If large (>10 cm) adrenal pheo OR neg CT/MRI OR PGL, then 68-Ga DOTATATE PET/CT to detect either mets or extra-abdominal PGLs If known metastatic disease, use either FDG-PET or 68- Ga DOTATATE PET/CT to determine extent, locations, and monitor No role for 123-I-MIBG scan unless to determine potential for high dose 131-I-MIBG therapy or unique need for specificity
22 Dennedy MC, et al. Low DHEAS: A Sensitive and Specific Test for the Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas. J Clin Endocrinol Metab Mar 1;102(3):
23 Background Adrenal DHEA production and secretion is regulated by ACTH Sustained suppression of ACTH suppresses DHEA DHEA has a 25 min half-life; but, DHEA-S has a hr half-life and is stable thru-out the day and can be used to reflect long term ACTH suppression Dennedy MC, et al. Low DHEAS: A Sensitive and Specific Test for the Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas. J Clin Endocrinol Metab Mar 1;102(3):
24 185 patients with adrenal incidentaloma: 1-mg overnight DST, 24h UFC, midnight serum cortisol, ACTH serum DHEA-S 48-hr low dose DST plasma renin and aldosterone plasma metanephrines Dennedy MC, et al. Low DHEAS: A Sensitive and Specific Test for the Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas. J Clin Endocrinol Metab Mar 1;102(3):
25 J Clin Endocrinol Metab Mar 1;102(3): pts (16%) were dx with subclinical CS (SCS): ACTH was <10 pg/ml (<2.2 pmol/l) in all pts with SCS They used DHEA-S ratios (derived by dividing the DHEA-S by the lower limit of the respective reference range). A DHEA-S ratio of 1.12 was sensitive (>99%) and specific (91.9%) for the diagnosis of SCS 1-mg DST cortisol of 1.9 mcg/dl (53 nmol/l) was a sensitive (>99%) case detection test for SCS, but had lower specificity (82.9%) 24-hr UFC lacked sensitivity (69%) & specificity (72%).
26 J Clin Endocrinol Metab Mar 1;102(3): For example, 40-yr-old woman with DHEA-S of <15 mcg/dl: DHEA-S ratio = 15/26 = is <1.12 and has a 92% specificity for diagnosing SCS
27 J Clin Endocrinol Metab Mar 1;102(3): How should these data be used? This report is confirmatory Unless another dx is evident (eg, pheo), all patients with adrenal incidentalomas should have: morning blood test for: cortisol, ACTH, DHEA-S & on separate day, 1-mg overnight DST If data are consistent with SCS, confirm with 8-mg overnight DST
28 How should these data be used? J Clin Endocrinol Metab Mar 1;102(3): Remember: DHEA-S is like glycosylated hemoglobin it is a memory test reflecting long-term serum ACTH levels Low DHEA-S = chronic ACTH suppression SCS = If DHEA-S is low or near lower limit of normal
29 Two articles in Jan 2018 on medical therapy for primary aldosteronism First large longitudinal study assessing efficacy of medical management of PA 602 pts with PA Rx with MRAs matched with 41,853 pts with essential hypertension both with comparable CV risk profiles and BP control CV events 2-X in PA group PA also associated with risk of mortality (1.34), diabetes (1.26), and atrial fib (1.93) These risks were limited to the PA subgroup where PRA remained <1 ng/ml/hr
30 83% SPL (45 mg/d); 17% EPL (54 mg/d) PRA not suppressed in 134 while on MRA: 2.8 risk of CV events 1.8 risk of death Surgically Tx patients with PA had 0.58 risk of CV events compared with essential hypertension Hundemer GL, et al. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol Jan;6(1):51-59.
31 Prior QoL studies compared PA to general population. This is 1 st study to compare surgery to medical Rx 184 pts with PA 92 Rx with adrenalectomy (ADX) 92 Rx with MRAs Followed x 1 yr QoL assessed at baseline, 6 mo, 1 yr: RAND SF-36 & EQ-5D
32 At baseline, 7 of 8 RAND SF-36 subscales and both summary scores, as well as 3 of 5 EQ-5D dimensions and the visual analog scale, were lower in patients with PA compared with the general population, especially in women The beneficial effects of ADX were larger than for MRAs for 7 RAND SF-36 subscales, both summary scores, and health change. For the EQ-5D, a difference in favor of ADX in 2 dimensions and the visual analog scale After 1 yr, almost all QoL measures had normalized for ADX pts. For MRA pts, most QoL measures had improved but not all to the level of the general population. Velema M, et al.. JCEM 2018 Jan 1;103(1):16-24.
33 Medical Rx vs Surgery for PA My Conclusions: Most medically treated patients are on suboptimal dosages of MRAs If you don t use adequate doses of MRAs, your patients are at increased CV risk Surgery is superior to medical therapy in reversing low QoL scores in patients with PA This is why we look for aldosterone producing adenomas and why centers of excellence need good AVS programs and expert adrenal surgeons!
34 Hamidi O, Young WF Jr, Iñiguez-Ariza NM, Kittah NE, Gruber L, Bancos C, Tamhane S, Bancos I. Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years. J Clin Endocrinol Metab Sep 1;102(9):
35 Metastatic PPGL 272 Patients: Of 3280 patients with PPGL over 56 yrs ( ), 272, 8.3% had malignant disease. Dx at the median age of 39 yrs (range, 7-83), with synchronous metastases in 96 (35%) patients In 176 (65%) pts, metastases developed at a median of 5.5 (range, ) yrs from the initial dx Median overall and disease-specific survivals were 24.6 and 33.7 yrs, respectively 13% died within 5 yrs of dx. Shorter survival correlated with: male sex (P=.014), older age (P=.0011), synchronous metastases (P<0.0001), larger primary tumor size (P = ), elevated dopamine (P= ), and not undergoing primary tumor resection (P<0.0001).
36 Metastatic PPGL Conclusions: Patients with malignant PPGL have a markedly variable course of the disease & longer overall and disease specific survival than previously reported Although death can occur within 1 year of dx, metastatic disease can be stable for more than 40 yrs Metastatic spread can be discovered more than 50 yrs after the primary diagnosis lifelong follow-up of patients with PPGL is indicated A multidisciplinary and individualized approach is needed determine the pace of disease and match the penalty (your treatment) to the crime (the tumor). There is no curative treatment... Hamidi O, Young WF Jr, et ali. Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years. J Clin Endocrinol Metab Sep 1;102(9):
37 Metastatic PPGL Conclusions: Hamidi O, Young WF Jr, et ali. Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years. J Clin Endocrinol Metab Sep 1;102(9): I tell patients: Yes, this is cancer, but it is different from most cancers you hear about. Although there is no cure, this is more like chronic disease management with targeted treatments (ablation Tx, surgery, RoTx) when tumor sites pop up. We delay systemic therapies until marked tumor burden develops.
38 3 rd Edition was in 2004
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