Adrenal Symposium

S3-1 Prof. André Lacroix, M.D.

Personal Information

Nationality: Canadian

Professor, Department of Medicine, Division of Endocrinology CHUM

Director, Laboratory of endocrine pathophysiology, CRCHUM

Tour Viger, 900, rue Saint-Denis, Rm R08-474, Montréal (Québec) H2X 0A9

E-mail: andre.lacroix@umontreal.ca

Pr. Lacroix completed M.D. degree in 1972 and specialization in endocrinology in 1977 at Université de Montréal. This was followed by Endocrine fellowship at Vanderbilt University in Nashville, TN from 1976-78 with Grant W Liddle, David N Orth, TJ McKenna, and at the National Institutes of Health in Bethesda, MD from 1978-80 with Marc E Lippman and during a sabbatical year of biotechnology in 1986 with MB Sporn and Anita Roberts. Since 1980, he has been Director of Endocrine Pathophysiology laboratory at Institut de Recherches Cliniques de Montréal (IRCM) until 1992 and now at the CHUM Research center (CRCHUM). He served as chief of Endocrine Division at Hôtel-Dieu hospital and as Director of the Endocrinology Training Program of Université de Montréal. He was Chairman of the Department of Medicine from 2002-2008 and Associate Director General for Medical and Academic Affairs at CHUM (2008-2012). He served as president of the Canadian Society of Endocrinology and Metabolism (2005-2007) and on the executive board of the International Society of Endocrinology (2010-16). He is currently co-editor of the Adrenal Section of UpToDate (Boston, MA), Senior Editor of the European Journal of Endocrinology, editorial board member of Journal of Clinical Endocrinology and Metabolism. He received the Medical Leadership award from CHUM Foundation in 1999 and the Robert Volpé 2010 award from CSEM in recognition for his contributions to Endocrinology in Canada. He was elected Fellow of the Canadian Academy of Health Sciences in 2008 (FCAHS).

Major Areas of Research:

Genetics and pathophysiology of adrenal tumors and hyperplasias leading to Cushing’s syndrome, primary aldosteronism and adrenal tumorigenesis. Role of aberrant adrenal hormone receptors in adrenal overfunction. New drugs in the therapy of Cushing’s disease and primary aldosteronism, of adrenocortical cancer and pheochromocytomas.

He has published more than 180 articles or book chapters, 250 scientific meeting abstracts and was invited to give 250 conferences at national and international institutions or scientific meetings.

Selected publications

1.Lacroix, A., Bolté, E., Tremblay, J., Dupré, J., Poitras, P., Fournier, H., Garon, J., Garrel, D.,

Bayard, F., Taillefer, R., Flanagan, R., and Hamet, P. Gastric inhibitory polypeptide-dependent cortisol hypersecretion - a new cause of Cushing’s syndrome. N. Engl. J. Med.; 327:974-980. 1992 (274citations) IF 47.05 2.Gagner, M., Lacroix, A., and Bolté, E. Laparoscopic approach to adrenalectomy in Cushing’s syndrome and pheochromocytoma. Letter to the Editor. N. Engl. J. Med.; 327:1033. 1992 (1361 citations) IF 47.05

3.Lacroix, A., N’Diaye, N., Tremblay, J., and Hamet, P. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocrine Reviews, 22 :75-110, 2001 (278 citations). IF 19.76 4.Lacroix, A., Tremblay, J., Rousseau, G., Bouvier, M., and Hamet, P. Propranolol therapy for ectopic b-adrenergic receptors in adrenal Cushing’s syndrome. New Engl. J. Med.; 337:1429-1434. 1997 (178 citations) IF 47.05 5.Lacroix, A., Hamet, P., Boutin, JM. Leuprolide acetate therapy in Luteinizing Hormone-dependent

Cushing’s syndrome. New England Journal of Medicine. 341:1577-81. 1999 (169 citations). IF 47.05 6.Arnaldi, G., Angeli, A., Atkinson, A.B., Bertagna, X., Cavagnini, F., Chrousos, G., Fava, G.A.,

Findling, J., Gaillard, R.C., Grossman, A.B., Kola, B., Lacroix, A., Mancini, T., Mantero F.,

Newell-Price, J., Nieman, L.K., Sonino, N., Vance M.L., Giustina A., Boscaro M. Diagnosis and complications of Cushing’s syndrome : A consensus statement. J. Clin. Endocrinol. Metab., 88(12):5593-602, 2003. (927 citations) IF 6.20 7.Biller B.M.K., Grossman A.B., Stewart P.M., Melmed S., Bertagna X., Bertherat J., Buchfelder

M., Colao A., Hermus A.R., Hofland L.J., Klibanski A., Lacroix A., Lindsay J.R., Newell-Price J.,

Nieman L.K., Petersenn S., Sonino N., Stalla G.K., Swearingen B., Vance M.L., Wass J.A.H. and

Boscaro M. Treatment of ACTH-dependent Cushing’s Syndrome: A Consensus Statement. J. Clin.

Endocrinol. Metab. 93: 2454-62, 2008 (452 citations) 8.Lampron A, Bourdeau I, Oble S, Godbout A, Schurch W, Arjane P, Hamet P, and Lacroix A.

Regulation of aldosterone secretion by several aberrant receptors including for GIP in a patient with an aldosteronoma. J Clin Endocrinol Metab. 94:750-6, 2009. (27 citations) IF 6.20 9.Hsiao H-P, Verma S, Nandagopal R, Boikos SA, Bourdeau I, Keil MF, Robinson-White AJ,

Kirschner LS, Lacroix A, and Stratakis CA. A Molecular and Clinical Genetic Investigation of ACTH-Independent Macronodular Adrenal Hyperplasia Compared to Other, Common

Adrenocortical Tumors: Evidence for Heterogeneity, Overlap with Other Tumor Syndromes and

Frequent But Atypical Hormonal Secretion. J Clin Endo Metab 94: 2930-37, 2009. (53 citations) IF 6.20 10.Lacroix A. Approach to the patient with adrenal carcinoma. J Clin Endocrinol Metab. 95:4812-22, 2010. (52 citations) IF 6.20 11.Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J, Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf).73:1-15, 2010 (47 citations) IF 3.32 12.Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol. 163: 1-9, 2010 (83 citations) IF 3.48 13.Colao AM, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills

D, Salgado LR, and Biller BMK, on behalf of the Pasireotide B2305 Study Group (Lacroix A). A 12-Month Phase 3 Study of Pasireotide in Cushing’s Disease. N Engl J Med 366 : 914-24, 2012. IF 47.05 14.Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C,

Lacroix A Jarzab B, Sorbye H, Torpy D, Stepan V, Arlt W, Schteingart D, Kroiss M, Leboulleux

S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la

Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink

H, Sender M, Edgerly M, Kenn W, Fojo T, Mueller HH, Skogseid B, for the FIRM-ACT study group. Combination Chemotherapy in Advanced Adrenocortical Carcinoma. N Engl J Med

366(23):2189-97, 2012 May 2. (155 citations) IF 47.05 15.Lacroix A. Heredity and cortisol regulation in bilateral macronodular adrenal hyperplaisia. Editorial

N Engl J Med. 369 Nov 28:2147-2149, 2013(8 citations) IF 47.05 16.Alencar, G.A., Lerario, A.M., Nishi, M.Y., Mariani, B.M.M., Almeida, M.Q., Tremblay, J., Hamet,

P., Bourdeau, I., Zerbini, M.C.N., Pereira, M.A.A., Gomes, G.C., Rocha, M.D.S., Chambo, J.L.,

Lacroix, A., Mendonca, B.B., Fragoso, M.C.B.V. ARMC5 Mutations are a frequent cause of primary macronodular adrenal hyperplasia. J. Clin. Endocrinol. Metab. 99: E1501-1509, 2014. (12 citations) IF : 6.20 17.De Venanzi, A., Alencar, G.A., Bourdeau, I., Fragoso, M.C.B.V., and Lacroix, A. Primary bilateral macronodular adrenal hyperplasia. Curr. Opin. Endocrinol. Diabetes Obes. 21: 177-184, 2014 (doi: 10.1097/MED). 18.Bourdeau, I., Oble, S., Magne, S., Lévesque, I. Caceres, K., Nolet, S., Awadalla, P., Tremblay,

J., Hamet, P., Fragoso, M.C.B.V., Lacroix, A. ARMC5 mutations in a large French-Canadian family with cortisol-secreting B-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia. Eur. J. Endocrinol. 174: 85–96, 2016 19.El Ghorayeb, N., Bourdeau, I., Lacroix, A. Multiple aberrant hormone receptors in Cushing’s syndrome. Eur J Endocrinol. Eur J Endocrinol. 2015 Oct;173(4):M45-60. doi: 10.1530/EJE-150200. Epub 2015 May 13. Review 20.Lacroix A, Felders RA, Stratakis CA, Nieman L. Cushing’s syndrome. Invited Seminars. Lancet. 2015 Aug 29; 386(9996):913-27. doi: 10.1016/S0140-6736(14)61375-1. Epub 2015 May 21.

Review

S3-1 Primary Aldosteronism: Unilateral or Bilateral Disease?

ANDRÉ LACROIX

Professor of Medicine, Division of Endocrinology, Centre hospitalier de l’Université de Montréal (CHUM).

Primary aldosteronism (PA) is responsible for 6-13% of human hypertension and increases cardiovascular and other morbidities rates compared to essential hypertension. The most frequent causes of PA include bilateral idiopathic hyperplasia (IHA, 60-70%), and unilateral aldosteronoma (APA, 30-40%). This distinction was recently challenged by the findings of zona glomerulosa nodular hyperplasia adjacent to APA.

Currently, adrenal vein sampling (AVS) is recommended to differentiate lateralized from bilateral sources of PA. However, many of its technical aspects and interpretation remain controversial between the various AVS expert centers.

We present the results of our experience using bilateral simultaneous AVS with samples taken before and after ACTH bolus. ACTH administration is useful to increase selectivity ratios. A discordance of lateralization between basal (LR≥2) and post-ACTH (LR≥4) values was observed in 28% of cases, mostly lateralized cases basally that became bilateral post ACTH. Examining both basal and post-ACTH values are important for the interpretation of AVS. The basal CL ratio using absolute aldosterone level of non-dominant adrenal vein/periphery was superior to the commonly used aldosterone/cortisol (A/C) ratios to identify the frequent occurrence of contralateral hyperplasia even in lateralized cases and to predict outcome after unilateral adrenalectomy.

S3-2 Prof. Sihoon Lee, M.D., Ph.D.

Personal Information

Nationality: Korea

Position: Associate Professor of Medicine

Department: Internal Medicine/Endocrinology and Metabolism

Organization: Gachon University School of Medicine 嘉泉大學校 醫科大學

Email: shleemd@gachon.ac.kr

Educational background & professional experience (in sequence of the latest year)

2006-2008 Diabetes Unit/NCCAM/NIH Postdoc Fellow 2005-2006 Internal Medicine/Yonsei University College of Medicine Clinical Fellow 2004-2005 Tissue Engineering/University of Tokyo Visiting Fellow 1998-2003 Internal Medicine/Severance Hospital Intern and Resident 2000-2005 Yonsei University Graduate School Ph.D 1992-1998 Yonsei University College of Medicine M.D

Research Interests

1. Genomics and Translational Research of Adult and Pediatric Endocine diseases 2. Gene editing using CRISPR-CAS and its therapeutic application 3. Animal model development of human diseases

Publications (5 important publications – latest sequence)

1. Lee S et al. Homozygous [Cys25]PTH(1_84) Mutation that Impairs PTH/PTHrP Receptor Activation

Defines a Novel form of Hypoparathyroidism. J Bone Miner Res 30:1803-1813, 2015 2. Lee S et al. Identification and characterization of C106R, a novel mutation in the DNA-binding domain of GCMB, in a family with autosomal dominant hypoparathyroidism. Clin Endocrinol (Oxf) 76:625-633, 2012 3. Lee S et al. Current Approaches for Assessing Insulin Sensitivity and Resistance In Vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 294:E15-E26, 2008 4. Lee S et al. Protein Kinase C-ζ phosphorylates Insulin Receptor Substrate-1, -3, and -4, but not -2: isoform specific determinants of specificity in insulin signaling. Endocrinology 149:2451-2458, 2008 5. Lee S et al. Expression of Vasopressin V1b, V2 Receptors in the Adrenal Gland in the Familial

Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia. Clin Endocrinol (Oxf) 63:625-630, 2005

S3-2 Patients Who have Taught Me a Lot: Personal Experiences of Rare Adrenal Diseases

SIHOON LEE 李是勳

Department of Internal Medicine/Endo and Laboratory of Genomic and Translational Medicine, Gachon University School of Medicine, Incheon, Korea Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

Adrenal glands play pivotal role in maintaining our daily life and it is only after we lose their functional regulation either hyper- or hypo-that we acknowledge their considerable significance in essential contribution to our vitality. As many other physiology has been unveiled through investigating pathologic conditions, abundant knowledge and understanding of adrenal physiology was accumulated by seeing the patients. I am not exceptional with this regard.

The first patients who came to my scope were sisters, both suffering from overt Cushing syndrome aroused by bilateral macronodularadrenal hyperplasia (BMAH). Provocation tests in vivo suggested that AVP promoted cortisol secretion through vasopressin V1a as well as V1b and V2 receptors. RT-PCR analysis revealed an abnormal cDNA expression of vasopressin V1b and V2 receptors, none of which is known to be normally expressed in the adrenal glands. These results suggest that the expression of ectopic vasopressin V1b and V2 receptors may be involved in the etiology of AIMAH, at least in the case of the sibling patients. Furthermore, meningiomas were incidentally found in these two patients, and we postulated the possibility that they may be involved in the pathogenesis of BMAH which has been supported by accumulating both clinical and molecular genomic evidences.

With regard to the second BMAH patient who required the successive completion adrenalectomy due to hypersecretion of cortisol in the remaining adrenal gland detected during follow up, I will focus on the importance of understanding molecular pathophysiology of BMAH in terms of medical treatment with specific antagonizing agents or agonists as a possible alternative to bilateral adrenalectomy. This may help to avoid life-long steroid replacement therapy and poor quality of life.

Moreover, I would like to share several other experiences on adrenal patients in this lecture.

S3-3 Prof. Shih-Hua Lin, M.D.

Personal Information

Nationality: Taiwan, Republic of China

Position: Superintendent

Department: Tri-Service General Hospital

Organization: National Defense Medical Center

Email: l521116@gmail.com

Educational background & professional experience (in sequence of the latest year)

1981 - 1988 National Defense Medical Center, Taipei, Taiwan Bachelor 2011/12/1–2012/11/30 Department of Medicine, Tri-Service General Hospital Director 2012/12/1–2015/1/15 Tri-Service General Hospital Deputy Superintendent

2013/6/1-2015/1/15 National Defense Medical Center Associate Dean 2015/1/16-2015/12/31 Army Medical Affair Director 2016/1/16-present Tri-Service General Hospital Superintendent

Research Interests

1. Clinical acid-base and electrolyte disorders and metabolism 2. Genetic diagnosis in inherited renal tubular disorder 3. Disease-causing transgenic mice model

Publications (5 important publications – latest sequence)

1.Mechanism of thyrotoxic periodic paralysis. J Am Soc Nephrol 2012; 23: 985-988. 2.Genotype, phenotype and follow-up in Taiwanese patients with Gitelman’s syndrome. J Clin

Endocrinol Metab 2012; 97: E1478-1482. 3.Defective NCC phosphoryation impairs its stability and prevents pseudohypoaldosteronism type II.

J Am Soc Nephrol 2013; 24: 1587-1597. 4.Novel KCNJ 5 mutations in sporadic aldosterone-producing adenoma reduce Kir3.4 membrane abundance. J Clin Endocrinol Metab 2015; 100: E155-163. 5.Novel susceptibility gene for non-famililal periodic paralysis. Neurology 2016 (in press)

S3-3 Clinical and Genetic Heterogeneity of Aldosterone-Producing Adenoma in Taiwan

台灣醛固酮分泌腺瘤的臨床與基因多型性

SHIH-HUA LIN 林石化

Department of Medicine, Division of Nephrology, Tri-Service General Hospital, Taipei, Taiwan, R.O.C. 三軍總醫院 內科部腎臟科

Aldosterone secretion is physiologically stimulated by angiotensin II and high plasma potassium (K+) concentration, which transiently depolarize the membrane potential of adrenal zona glomerulosa cells, increase intracellular calcium (Ca2+) concentration and then aldosterone synthesis. Acquired primary aldosteronism is mainly caused by bilateral adrenal hyperplasia and aldosterone-producing adenoma (APA, some referred to Conn’s syndrome) with unclear pathogenesis. Recently, a series of genetic studies have identified somatic mutations in several genes, including KCNJ5 (G-protein sensitive Kir3.4 channel), CACNA1D (Cav1.3 Ca2+ channel), ATP1A1 (Na+, K+ ATPase subunit α-1), and ATP2B3 (Ca2+ ATPase) genes, indicating the genetic heterogeneity in APA. Most of these mutations caused small cation (e.g. Na+) leak and persistently depolarized membrane potential of adrenal cells, leading to unstoppable aldosterone synthesis in APA.

In our Taiwanese APA cohort, heterozygous KCNJ5 somatic mutations were identified in 37.8% patients, CACNA1D 4% and ATP1A1 1%. In those with KCNJ5 mutations, female predominance and higher disease severity, reflecting by younger onset age, larger tumor size and lower nadir serum potassium level, were noted. Two novel mutations (R115W, E246G), resulted in a hypofunctional Kir3.4 channel due to impaired membrane trafficking in vitro and reduced its overall expression in vivo. Patients with CACNA1D or ATP1A1 mutations had a milder disease with smaller tumor size and older onset age. Futhermore, adrenalectomy cured hypertension in 64% of APA patients and significantly improved hypertension in the remainders in our cohorts. Of note, 29% of APA patients developed hyperkalemia after adrenalectomy and associated with impaired renal function and longer duration of hypertension.

In conclusion, APA has been linked to the heterogeneous genes controling membrane potential, intracellular calcium, aldosterone synthesis and adrenocortical growth and differentiation. These diverse gene associations may thus contribute to the various disease severity and final outcome of APA.