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Poster presented at: BES2018 Cushing’s Syndrome due to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) Clinical and Hormonal Characterisation Andreea Vlădan 1 , Șerban Radian 1,2 , Iuliana Barangă 1 , Cătălina Moraru 1 , Diana Deciu 1 , Anda Dumitrașcu 1 , Dan Hortopan 1 , Radu Iorgulescu 3 , Cătălina Poiană 1,2 C.I. Parhon National Institute of Endocrinology 1 , C. Davila University of Medicine and Pharmacy 2 , Surgery Dept, Sf. Ioan Clinical Emergency Hospital, Bucharest 3 INTRODUCTION: PBMAH is a rare cause of Cushing's syndrome (CS), less than 2% of endogenous CS [1,2]. CS due to PBMAH is classified as ACTH-independent CS, but cortisol secretion in PBMAH may be mediated by locally produced ACTH, in a paracrine or autocrine fashion [3]. PBMAH can be due to the aberrant hormone receptors expression [4] or it can have a genetic origin. Mutations in PKA pathway, APC, menin or FH can favor the development of PBMAH. Inactivating mutations in ARMC5, a novel tumor suppressor gene, were recently described, in up to 50% of PBMAH cases [1]. OBJECTIVE and METHODS: To describe a series of patients with CS due to PBMAH. Case series using hormonal and imaging evaluation. Cortisol stimulation testing to detect the presence of aberrant adrenal receptors using a modified version of the Lacroix protocol. PATIENT 1, female, 66 years Sep. 2011: clinical suspicion of CS, morbid obesity Cushingoid features BMI (kg/m 2 ) HT Diabetes mellitus Osteoporosis Yes 45.54 Yes Yes Nk 8 AM Cortisol (mcg/dL) Overnight 1 mg DEX (N< 1.8) LDDST (2x2 mg) UFC (x ULN) ACTH (pg/mL) 12.78 5.96 4.88 0.7 2.56 6 8 10 12 14 16 18 20 08:00 09.00 10.00 11.00 Cortisolemia (mcg/dL) 8AM baseline 30’ after meal Meal 60’ after meal 120’ after meal Jul. 2015: Refused adrenalectomy. Lost to follow-up. Contacted by phone, re-assesed by cortisol measurement postprandially, for food induced CS Patient refused adrenalectomy and was again lost to follow-up PATIENT 2, male, 61 years Nov. 2015: diagnosed incidentally (CT scans) with PBMAH Cushingoid features BMI (kg/m 2 ) HT DM Osteoporosis No 24.8 No No No 8 AM Cortisol (mcg/dL) Overnight 1 mg DEX (N< 1.8) LDDST (2x2) UFC (x ULN) ACTH (pg/mL) 9.86 2.75 1.8 (at dg) 4.8 (Sep 17) 0.6 7.21 0 2 4 6 8 10 12 14 16 18 20 07:45 08:30 09:30 11:00 12:00 13:00 14:00 15:00 16:00 Cortisolemia (ug/dL) Postural test Mixed meal GnRH agonist Active follow-up: 30 months – no change PATIENT 3, female, 50 years PATIENT 4, male, 62 years PATIENT 5, male, 62 years CONCLUSIONS: Clinical presentation in PBMAH is variable, from asymptomatic incidentalomas to severe CS. Screening for CS in patients at higher risk is warranted. UFC was within reference range in subclinical/mild CS, while DXM suppression testing and ACTH were diagnostic. Biochemical dynamic testing for aberrant adrenal receptors has therapeutic implications and should be performed. Management should be individualized, with targeted medical therapy where appropriate and/or with steroidogenesis inhibitors. Unilateral adrenalectomy may be curative [5]. May 2017: high suspicion of CS Cushingoid features BMI (kg/m 2 ) HTN Diabetes mellitus Yes 30 Stage 3 Yes (HbA1c 11.6%) 140 UI insulin/day Retinopathy , neuropathy, CKD stage 4 8 AM Cortisol (ug/dL) LDDST (2x2 mg) (N< 1.8) UFC (x ULN) ACTH (pg /mL) 27.17 29.38 0.86 1.63 May 2017: Metyrapone 750 mg/day 8 AM cortisol 21.3 mcg/dL 2 days after Metyrapone cessation 8 AM cortisol 41.7 mcg/dL Insulin ↑ 410 U/day, glycemia ~ 250 mg/dL Jun. 2017: left laparoscopic adrenalectomy: 8 AM cortisol 17 mcg/dL, no improvement in glycemic control Post-adrenalectomy: Metyrapone 1000 mg/day: 8 AM cortisol 7.9 mcg/dL, insulin 96 U/day, glycemia 137-253 mg/dL, HbA1c 6.1% Jul 2017: right open adrenalectomy, glycemia 94 mg/dL, 4 days postop septic shock, resuscitated cardiac arrest, exitus Jan. 2018: metabolic syndrome Cushingoid features BMI (kg/m 2 ) HT DM Osteoporosis No 29 Yes Yes Yes 8 AM cortisol Overnight 1 mg DEX (N< 1.8) LDDST (2x2) UFC (x ULN) ACTH (pg /mL) - 3.37 2.75 0.23 7.94 0 2 4 6 8 10 12 14 16 09:00 11:00 13:00 15:00 20:00 Cortisolemia (mcg/dL) 2 adm of Triptorelin 3,75 mg 1 adm of Triptorelin 3,75 mg Meal 0 2 4 6 8 10 12 14 16 10:15 11:00 12:30 13:00 14:00 15:00 17:00 18:00 Cortisolemia (mcg/dL) Postural test Mixed meal GnRH agonist active follow-up by day cortisol curve Mar 2018: CS features: round red face, abdominal obesity Cushingoid features BMI (kg/m 2 ) HT DM Osteoporosis Yes 36.31 Yes Yes Nk 8 AM cortisol (mcg/dL) Overnight 1mg DEX (N < 1.8) LDDST (2x2) UFC (x ULN) ACTH (pg /mL) 12.1 11.26 8.91 3.01 5.11 0 5 10 15 20 25 30 35 40 10:15 11:00 12:00 13:30 14:30 15:30 16:30 17:30 18:30 Cortisolemia (mcg/dL) Postural test Mixed meal GnRH agonist 0 5 10 15 20 25 30 35 40 09:00 11:00 13:00 15:00 18:00 Cortisolemia (mcg/dL) Meal Adrenalectomy delayed (dual antiplatelet TX for coronary angioplasty; on metyrapone 1. Lodish M, Stratakis CA. A genetic and molecular update on adrenocortical causes of Cushing syndrome. Nat Rev Endocrinol 2016;12:255–62. 2. Albiger NM, Regazzo D, Rubin B et al. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype. Endocrine 2017;55:959–68. 3. Louiset E, Duparc C, Young J et al. Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia. N Engl J Med 2013;369:2115–25. 4. Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009;23:245–59. 5. Debillon E, Velayoudom-Cephise FL, Salenave S et al. Unilateral adrenalectomy as a first-line treatment of cushing’s syndrome in patients with primary bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2015;100:4417–24. Cortisol day curve on 1000 mg Metyrapone/day 14--EP Serban Radian Adrenal and steroids
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Poster presented
at:
BES2018
Cushing’s Syndrome due to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH)
Clinical and Hormonal Characterisation Andreea Vlădan1, Șerban Radian1,2, Iuliana Barangă1, Cătălina Moraru1, Diana Deciu1, Anda Dumitrașcu1, Dan Hortopan1,
Radu Iorgulescu3, Cătălina Poiană1,2 C.I. Parhon National Institute of Endocrinology1, C. Davila University of Medicine and Pharmacy2, Surgery Dept, Sf. Ioan Clinical
Emergency Hospital, Bucharest3 INTRODUCTION: PBMAH is a rare cause of Cushing's syndrome (CS), less than 2% of endogenous CS [1,2]. CS due to PBMAH is classified as ACTH-independent CS, but cortisol secretion in PBMAH may be mediated by locally produced ACTH, in a paracrine or autocrine fashion [3]. PBMAH can be due to the aberrant hormone receptors expression [4] or it can have a genetic origin. Mutations in PKA pathway, APC, menin or FH can favor the development of PBMAH. Inactivating mutations in ARMC5, a novel tumor suppressor gene, were recently described, in up to 50% of PBMAH cases [1].
OBJECTIVE and METHODS: To describe a series of patients with CS due to PBMAH. Case series using hormonal and imaging evaluation. Cortisol stimulation testing to detect the presence of aberrant adrenal receptors using a modified version of the Lacroix protocol.
PATIENT 1, female, 66 years
Sep. 2011: clinical suspicion of CS, morbid obesity
Cushingoid features BMI (kg/m2) HT Diabetes mellitus Osteoporosis
Yes 45.54 Yes Yes Nk
8 AM Cortisol (mcg/dL)
Overnight 1 mg DEX (N< 1.8)
LDDST (2x2 mg) UFC (x ULN) ACTH (pg/mL)
12.78 5.96 4.88 0.7 2.56
6
8
10
12
14
16
18
20
08:00 09.00 10.00 11.00
Cortisolemia (mcg/dL)
8AM baseline
30’ after meal Meal
60’ after meal
120’ after meal
Jul. 2015: Refused adrenalectomy. Lost to follow-up. Contacted by phone, re-assesed by cortisol measurement postprandially, for food induced CS
Patient refused adrenalectomy and was again lost to follow-up
PATIENT 2, male, 61 years
Nov. 2015: diagnosed incidentally (CT scans) with PBMAH
Cushingoid features
BMI (kg/m2)
HT DM Osteoporosis
No 24.8 No No No
8 AM Cortisol (mcg/dL)
Overnight 1 mg DEX (N< 1.8)
LDDST (2x2) UFC (x ULN)
ACTH (pg/mL)
9.86 2.75 1.8 (at dg) 4.8 (Sep 17)
0.6 7.21
0
2
4
6
8
10
12
14
16
18
20
07:45 08:30 09:30 11:00 12:00 13:00 14:00 15:00 16:00
Cortisolemia (ug/dL)
Postural test Mixed meal GnRH agonist
Active follow-up: 30 months – no change
PATIENT 3, female, 50 years
PATIENT 4, male, 62 years PATIENT 5, male, 62 years
CONCLUSIONS: Clinical presentation in PBMAH is variable, from asymptomatic incidentalomas to severe CS. Screening for CS in patients at higher risk is warranted. UFC was within reference range in subclinical/mild CS, while DXM suppression testing and ACTH were diagnostic. Biochemical dynamic testing for aberrant adrenal receptors has therapeutic implications and should be performed. Management should be individualized, with targeted medical therapy where appropriate and/or with steroidogenesis inhibitors. Unilateral adrenalectomy may be curative [5].
May 2017: high suspicion of CS
Cushingoid features
BMI (kg/m2)
HTN Diabetes mellitus
Yes 30 Stage 3 Yes (HbA1c 11.6%) 140 UI insulin/day Retinopathy, neuropathy, CKD stage 4
8 AM Cortisol (ug/dL) LDDST (2x2 mg) (N< 1.8) UFC (x ULN) ACTH (pg/mL)
27.17 29.38 0.86 1.63
May 2017: Metyrapone 750 mg/day 8 AM cortisol 21.3 mcg/dL 2 days after Metyrapone cessation 8 AM cortisol 41.7 mcg/dL
Insulin ↑ 410 U/day, glycemia ~ 250 mg/dL
Jun. 2017: left laparoscopic adrenalectomy: 8 AM cortisol 17 mcg/dL, no improvement in glycemic control
Post-adrenalectomy: Metyrapone 1000 mg/day: 8 AM cortisol 7.9 mcg/dL,
insulin 96 U/day, glycemia 137-253 mg/dL, HbA1c 6.1% Jul 2017: right open adrenalectomy, glycemia 94 mg/dL, 4 days postop septic shock, resuscitated cardiac arrest, exitus
Jan. 2018: metabolic syndrome
Cushingoid features BMI (kg/m2) HT DM Osteoporosis
No 29 Yes Yes Yes
8 AM cortisol
Overnight 1 mg DEX (N< 1.8)
LDDST (2x2)
UFC (x ULN)
ACTH (pg/mL)
- 3.37 2.75 0.23 7.94
0
2
4
6
8
10
12
14
16
09:00 11:00 13:00 15:00 20:00
Cortisolemia (mcg/dL)
2 adm of Triptorelin 3,75 mg 1 adm of Triptorelin 3,75 mg
Meal
0
2
4
6
8
10
12
14
16
10:15 11:00 12:30 13:00 14:00 15:00 17:00 18:00
Cortisolemia (mcg/dL)
Postural test
Mixed meal GnRH agonist
active follow-up by day cortisol curve
Mar 2018: CS features: round red face, abdominal obesity
Cushingoid features BMI (kg/m2) HT DM Osteoporosis
Yes 36.31 Yes Yes Nk
8 AM cortisol (mcg/dL)
Overnight 1mg DEX (N < 1.8)
LDDST (2x2) UFC (x ULN) ACTH (pg/mL)
12.1 11.26 8.91 3.01 5.11
0
5
10
15
20
25
30
35
40
10:15 11:00 12:00 13:30 14:30 15:30 16:30 17:30 18:30
Cortisolemia (mcg/dL)
Postural test
Mixed meal
GnRH agonist
0
5
10
15
20
25
30
35
40
09:00 11:00 13:00 15:00 18:00
Cortisolemia (mcg/dL)
Meal
Adrenalectomy delayed (dual antiplatelet TX for coronary angioplasty; on metyrapone
1. Lodish M, Stratakis CA. A genetic and molecular update on adrenocortical causes of Cushing syndrome. Nat Rev Endocrinol 2016;12:255–62. 2. Albiger NM, Regazzo D, Rubin B et al. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype. Endocrine 2017;55:959–68.
3. Louiset E, Duparc C, Young J et al. Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia. N Engl J Med 2013;369:2115–25. 4. Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009;23:245–59. 5. Debillon E, Velayoudom-Cephise FL, Salenave S et al. Unilateral adrenalectomy as a first-line treatment of cushing’s syndrome in patients with primary bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2015;100:4417–24.
Cortisol day curve on 1000 mg Metyrapone/day
14--EPSerban Radian
Adrenal and steroids
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