Aberrant hormone receptors in primary aldosteronism. André Lacroix, MD

Transcription

1 Aberrant hormone receptors in primary aldosteronism André Lacroix, MD Professor of Medicine Centre hospitalier de l Université de Montréal (CHUM) Controversias Clinicas en Enfermedades Suprarenales Buenos Aires, May 13, 2011

2 Aberrant hormone receptors Ectopic receptors GIPR β-adren receptors in adrenocortical cells ACTHR HTR4 LHCGR Eutopic Receptors AVPR1A G s AC G s AC camp G s AC ATP G q/i PLC ATP + camp ATP Cholesterol DAG, IP3 PKA P N M TF mrnas Protein Cortisol M Cortisol ACTHindependent Cushing s syndrome in AIMAH and adenomas Modified from Lacroix, Endocrine Reviews 22: 75, 2001

3 Aberrant receptors in all types of adrenal adenomas? Lacroix et al TEM 15: , 2004

4 Definition: primary aldosteronism Syndrome resulting from excess production of aldosterone Renin-independent production from unknown mechanism Causes cardiovascular damage, hypertension, sodium retention, renin suppression, potassium excretion that if prolonged and severe may lead to hypokalemia Funder et al J Clin Endocrinol Metab 93: 3266, 2008

5 Epidemiology of primary aldosteronism % incidence of HBP in USA population > 18 yo (NHANES) Low-renin essential hypertension: 25% Primary aldo: % of HBP ( ) Primary aldo: 7-10% of HBP ( ) Mulatero et al J Clin Endo Metab, 89:1045, 2004 Rossi et al J Am Coll Cardiol 48:2293, 2006 Mosso et al Hypertension 42: 161, 2003 Gordon et al Clin Exp Pharmacol Physiol 21:315:1994

6 Etiologies of Primary Aldosteronism Aldosterone-producing adenomas (APA): % ACTH-responsive (80-85%) Renin-responsive (15-20%) Idiopathic hyperaldosteronism (IHA; bilateral): % Primary adrenal hyperplasia (PAH; unilateral): < 2% Bilateral macronodular adrenal hyperplasia: < 2% Aldo/DOC-producing adrenal carcinoma: < 2% Aldosterone-producing ovarian tumor: < 1% Familial hyperaldosteronism (FH): < 2% Glucocorticoid-remediable aldosteronism (GRA;FH type I) Familial hyperaldosteronism type II (APA or IHA)

7 Primary aldosteronism Angiotensinogen Angiotensinogen Renin Renin A-II-independant aldosterone secretion Angiotensin-I Angiotensin-II ACE Constitutive secretion? Angiotensin-I Activating mutation of AT1R? Aldosterone Angiotensin-II Loss of inhibition (ANP, dopamine)? ACE Aldosterone Aberrant activating receptor? AT1R AT1R AT1R AT1R Bilateral Hyperplasia Unilateral adenoma

8 Science 331: 768, / 22 APA (2.8 cms) familial hyperplasia

9 Hypothesis of sequential genetic events leading to unilateral tumors or bilateral macronodular adrenal hyperplasia (AIMAH) expressing aberrant receptors Lacroix et al, Clin Endocrinol, 75:1-15, 2010

10 Aberant hormone receptors in aldosterone producing adenomas Increased expression of ACTH receptor (MC2R) in aldosterone-producing adenoma (APA) Arnaldi, G., Mancini, V., Costantini, C., Giovagnetti, M., Petrelli, M., Masini, A., Bertagna, X. & Mantero, F. ACTH receptor mrna in human adrenocortical tumors: overexpression in aldosteronomas. Endocr Res, 24, , 1998 Schubert, B., Fassnacht, M., Beuschlein, F., Zenkert, S., Allolio, B. & Reincke, M. Angiotensin II type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms. Clin Endocrinol (Oxf), 54, , 2001 Ye, P., Mariniello, B., Mantero, F., Shibata, H. & Rainey, W.E. G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism. J Endocrinol, 195, 39-48, 2007 Diurnal rythmn of aldosterone in APA suppressible by dexamethasone Increase after ACTH stimulation, stress

11 Regulation of aldosterone by cisapride and 5-HTR4 expression in aldosteronomas Cisapride Pre-op HTR4 by PCR Post-op Pre-op Post-op Cartier et al. European Journal of Endocrinology, 153, , 2005 Lefebvre et al. JCEM 87: , 2002

12 LH receptor overexpression in APA Saner-Amigh, K... Mantero, Rainey et al. J Clin Endocrinol Metab;91: , 2006

13 Aberrant hormone receptors in aldosterone producing adenomas Recent transcriptome studies showing > 15-fold increased expression of GPCR in aldosterone-producing adenomas (APA) Serotonin (HTR4) LHCGR GNRHR Glutamate receptor metabotropic 3 Endothelin receptor type B-like protein ACTH MC2R Ye P, Mariniello B, Mantero F, Shibata H, Rainey, W.E. G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism. Journal of Endocrinology 195, 39-48, 2007

14 Strategy of in vivo investigation for aberrant receptors in primary aldosteronism Transient modulation of the ligands of potential aberrant adrenocortical hormone receptors Aldosterone response

15 Initial screening for aberrant responses Blood samples for aldosterone, renin, cortisol, ACTH, steroids/peptides q 30 min Perform under pretreatment with dexamethasone 1 mg q 6 h x 48h to suppress endogenous ACTH Modified from Lacroix et al The Endocrinologist 9, 9-15, 1999

16 Further investigation Lacroix et al The Endocrinologist 9, 9-15, 1999

17 Upright posture tests in primary aldosteronism Aldosterone (pmol/l) Upright posture patient A patient B patient C patient D patient E Time (minutes) Renin activity (ng/ml/h) 2 1,6 1,2 0,8 0,4 0 Upright posture patient A patient B patient C patient D patient E Time (minutes)

18 In vivo tests in a patient with aldosteronoma Lampron et al JCEM. 94:750-6, 2009

19 Aberrant receptors in aldosteronoma -B: GIPR+ adenoma -C: GIPR- adenoma -D: Adjacent adrenal GIPR immunohistochemistry Lampron et al JCEM. 94:750-6, 2009

20 Gene expression profiling of adrenals with GIP-dependent steroid production

21 In vivo screening for aberrant receptors in primary aldosteronism 12 patients 5 APA, 7 IHA vs 8 normals Aberrant aldosterone responses in vivo: increased response to metoclopramide in 11/12 renin-independent upright posture : 5/12 vasopressin: 6/12 LHRH: 3/12 TRH: 1, glucagon: 1 Mixed meal: none Zwermann, O., Suttmann, Y., Bidlingmaier, M., Beuschlein, F. & Reincke, M. Screening for Membrane Hormone Receptor Expression in Primary Aldosteronism. Eur J Endocrinol, 160, , 2009

22 In vitro screening for aberrant receptors in primary aldosteronism 14 APA, 1 unilateral hyperplasia vs 6 normals high levels of AGTR1, MC2R, AVPR1A and HTR4 LHCGR in APA and normal tissues GNRH: 4/15 TSHR: 1/15 Good correlation between in vivo and in vitro results in 3 cases studied with both aproaches Zwermann, O., Suttmann, Y., Bidlingmaier, M., Beuschlein, F. & Reincke, M. Screening for Membrane Hormone Receptor Expression in Primary Aldosteronism. Eur J Endocrinol, 160, , 2009

23 32 yo, 28 wk pregnant BP: 180/120, low K + High PAC/RA ratio 2 cm left APA Days Renin-independent increase of aldosterone after GnRH (114%) and HCG (77%) Aldosterone levels increase after longacting GnRH analog despite suppression of LH

24 Albiger, Eur J Endo 164: 405, 2011

25 In vivo screening for aberrant receptors in primary aldosteronism 21 patients (8F, 13M). 11 APA, 10 IHA Protocol under dexamethasone: 18 suppression Aberrant aldosterone responses in 83%: renin-independent upright posture : 9 vasopressin: 10 increased 5HT4 agonist response: 14 GnRH: 7; LH: 1 GIP:1; TRH: 1; isoproterenol:1 Aberrant mild cortisol co-response in 10 Grunenwald, Mazzuco, Mermejo, Bourdeau, Lacroix Endo Society 2010

26 Frequency of aberrant aldosterone response % of patients total IH APA Aberrant responses Grunenwald, Mermejo, Mazzuco, Bourdeau, Lacroix Endo Society 2010

27 Aberrant responses to various tests aldosterone response > 50% no response of aldosterone Grunenwald, Mermejo, Mazzuco, Bourdeau, Lacroix Endo Society HT4 agonist upright posture vasopressin LHRH TRH mixt meal Grunenwald, Mermejo, Mazzuco, Bourdeau, Lacroix Endo Society 2010

28 Aberrant responses to various tests % of aldosterone increase ACTH 5-HT4 agonist upright posture vasopressin LHRH TRH mixed meal Grunenwald, Mermejo, Mazzuco, Bourdeau, Lacroix Endo Society 2010

29 Aberrant cortisol co-response to various tests no response of cortisol cortisol response >50% HT4 agonist upright posture vasopressin LHRH TRH mixt meal 8/10 patients with cosecretion of cortisol (ACTH suppressed) and aldosterone had at least one aberrant response of cortisol Grunenwald et al, Endo Society 2010

30 Expression levels of mrna for various GPCR by quantitative PCR in resected aldosteronomas AVPR1A, AVPR1B, AVPR Relative receptor expression Control AVPR1A Control AVPR1B Control AVPR2 HT4R, HT7R HT4R Control HT7R Control AGTR1, AGTR2 AGTR1 Control AGTR2 Control GNRHR, LHCGR, GIPR GNRHR Control LHCGR Control GIPR MC2R, FSHR, GCGR Control MC2R Control FSHR Control GCGR Relative receptor expression Relative receptor expression Relative receptor expression Control ADRB1, ADRB2, ADRB Control ADRB1 Control ADRB2 Control ADRB3 Relative receptor expression Relative receptor expression Good correlations between in vivo stimulation and receptor levels Elevated mrna levels do not always predict clinical response Mermejo LM, Grunenwald S, MazzucoTL, Bourdeau I, Lacroix A Endo Society 2011

31 Clinical Case: AIMAH secreting aldosterone and cortisol 65 y.o. woman from Haiti, retired nurse High blood pressure x 8 yrs: 152/89 to 173/105 Recurrent hypokalemia on ARB, CCB requiring potassium supplements of 40 meq daily Diabetes x 4 years well controlled on metformin BMI of 24.3 No Cushing s signs or hirsutism No pertinent family history

32 Initial investigation Normal fasting blood glucose, creatinine Na + : 139 mmol/l, K + : 3.1 mmol/l Standing plasma aldosterone concentration: 962 pmol/l (N: ) Standing plasma renin activity: 0.2 ng/ml/h (N: < 5.3) Plasma aldosterone/renin ratio: > 1000 (N: < 555) 24-h urinary aldosterone on high salt: 106 nmol/d (N: <36) Urinary free cortisol: nmol/d (N:55-330) Dexa 1 mg : morning cortisol : 128 nmol/l (N < 50) Plasma ACTH: <0.5 pmol/l (N: 2-11) Urinary catecholamines/metanephrins: normal range

33 Consultant: your suggestions? Differential diagnosis: Primary aldosteronism Bilateral macronodular adrenal hyperplasia Sub-clinical cortisol secretion Further investigations: 1: CRH test: ACTH < 0.5 pmol/l 2: ACTH test: cortisol: 246 to 1375 nmol/l 17-OH-P: 4.4 to 52.9 nmol/l 3: Aberrant receptor protocol

34 Aldosterone and cortisol-secreting AIMAH Plasma Aldosterone (% of basal) Vasopressin DDAVP Tegaserod Posture Plasma Aldosterone (% of basal) Meal ACTH LHRH TRH Time (minutes) Renin activity: 0.2 ng/ml/h during all tests Time (minutes)

35 Aldosterone and cortisol-secreting AIMAH Vasopressin Tegaserod Meal ACTH LHRH TRH 500 DDAVP Posture 1000 Plasma cortisol (% of basal) Plasma cortisol (% of basal) Time (minutes) ACTH:< 0.5 pmol/l during various tests Time (minutes)

36 Further evaluation and therapy Possible coronary disease prevented isoproterenol infusion Pre-treatment with propranolol or ARB x 3 days did not modify aldosterone or cortisol response to upright posture Moderate hypertension, diabetes, osteopenia and sub-clinical cortisol production in addition to primary aldosteronism Diagnosis of mixed aldosterone and cortisol secreting AIMAH with regulation at least by by vasopressin (renin-and ACTH-independent) Surgical therapy Right adrenalectomy Response of aldosterone and cortisol to upright posture reduced by 50% Spironolactone 100 mg daily, CCB, stop potassium; Bisphosphonates, calcium, vit D, aspirin: BP below 135/80

37 Clinical Case: Primary aldosteronism and AIMAH 51 yo woman HBP x 15 years Hypokalemia Primary aldo x 1989 Bilateral nodular UFC: nmol/d Dex 1 mg: p F: 91 nmol/l 1990: Right adrenalectomy Rx: Aldactone, Midamor, Cardizem, Captopril Left adrenal size increase Plasma Cortisol (nmol/l) DEXA 1mg/hr AVP 10 iu im 2 Years Post-op op D2 9D3 Time (hours)

38 Aberrant Adrenal Hormone Receptors Therapeutic Potential in IHA? Aberrant receptor GIP β-adrenergic LH/hCG V 1 -vasopressin Serotonin R4 Angiotensin II TSH Therapy Somatostatin/GIPR blocker β-blockers GnRH analogs AVPR1A antagonist HTR4 antagonist AGTR1 antagonist L-thyroxine

39 CONCLUSIONS 1) Primary aldosteronism is renin-independent but not autonomous in the majority of cases 2) Aberrant adrenal hormone receptors appear to be frequently implicated in the regulation of aldosterone secretion in unilateral aldosteronomas and bilateral idiopathic hyperaldosteronism 3) The aberrant regulation of aldosterone secretion can be modulated by ectopic receptors or by increased activity of eutopic receptors 4) Single or multiple adrenal receptors can be aberrantly functional

40 Remaining questions Consequences of aberrant receptors on Aldo/Renin Ratios (ARR) depending on: posture? fasting? menstrual cycle? Consequences of aberrant hormone receptors (AVPR1A) on saline infusion tests in diagnosis of primary aldosteronism Consequences of ACTH receptor level on response to ACTH and interpretation of lateralisation during adrenal vein sampling? Link between aberrant receptors and K + channel mutations?

41 Aknowledgments Co-investigators Isabelle Bourdeau Pavel Hamet Johanne Tremblay Lab Endocrine Pathophysiology Livia Mermejo Antoine Lampron M H Soares Costa Tania Mazzuco Solange Grunenwald Sylvie Oble CHUM Endocrinology Ariane Godbout J-M Boutin Pierre D Amour Hortensia Mircescu Shirley Ferguson Sylvie Blaquière Chantal Dejou Philippe Arjane Walter Schurch Other centers Pierre Larochelle Hervé Lefebvre Funding Grant MA Canadian Institutes of Health Research