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Zhou H, Zhang P, Yin Y, Liu L, Li J, Xu H, Fan Y, Su X, Lyu Z, Gu W, Mu Y. Long-term cardiometabolic outcomes of primary bilateral macronodular adrenal hyperplasia. J Endocrinol Invest 2025:10.1007/s40618-025-02561-0. [PMID: 40252189 DOI: 10.1007/s40618-025-02561-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 02/28/2025] [Indexed: 04/21/2025]
Abstract
PURPOSE This study investigated long-term alterations in cardiometabolic comorbidities among patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) who received surgical or conservative treatments. METHODS A single-center, retrospective study analyzed 132 patients with PBMAH, divided into a surgery group (n = 68) and a control group (n = 64) based on treatment modalities. The main outcomes included changes in blood pressure (BP), blood glucose, lipids, and body weight. RESULTS Among the 132 patients, hypertension, abnormal glucose metabolism, dyslipidemia, and overweight/obesity were prevalent in over 50% of cases. The surgery group demonstrated significantly greater improvements in BP, blood glucose, and weight control compared with the control group. Adrenalectomy was associated with enhanced BP control, blood glucose control, and at least one cardiometabolic risk factor control. In a group of 95 patients with mild autonomous cortisol secretion, the surgery group also exhibited higher rates of improvement in BP and blood glucose than the control group. Adrenalectomy was associated with improved BP, blood glucose, and at least one cardiometabolic risk factor. CONCLUSION Our study observed that most patients with PBMAH exhibited at least one cardiometabolic risk factor. Adrenalectomy was associated with improved BP and blood glucose for patients with PBMAH, including those with mild autonomous cortisol secretion.
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Affiliation(s)
- Huixin Zhou
- School of Medicine, Nankai University, 94 Weijin Road, 300071, Tianjin, China
- Department of Endocrinology, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, 100853, Beijing, China
| | - Peng Zhang
- Department of Urology, Third Medical Center, Chinese PLA General Hospital, 69 Yongding Road, 100039, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, 100853, Beijing, China
| | - Lupeng Liu
- Department of Urology, Third Medical Center, Chinese PLA General Hospital, 69 Yongding Road, 100039, Beijing, China
| | - Jie Li
- Department of Pathology, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, 100853, Beijing, China
| | - Huaijin Xu
- School of Medicine, Nankai University, 94 Weijin Road, 300071, Tianjin, China
- Department of Endocrinology, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, 100853, Beijing, China
| | - Yu Fan
- Department of Urology, Third Medical Center, Chinese PLA General Hospital, 69 Yongding Road, 100039, Beijing, China
| | - Xiaonan Su
- Department of Urology, Zoucheng People's Hospital, 5677 Chongyi Road, 273500, Jining, China
| | - Zhaohui Lyu
- Department of Endocrinology, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, 100853, Beijing, China.
| | - Weijun Gu
- Department of Endocrinology, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, 100853, Beijing, China.
| | - Yiming Mu
- School of Medicine, Nankai University, 94 Weijin Road, 300071, Tianjin, China.
- Department of Endocrinology, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, 100853, Beijing, China.
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Ritzel K, Fazel J, August L, Fedtke V, Nowak E, Vogel F, Braun L, Zopp S, Then C, Künzel H, Reisch N, Zimmermann P, Thorsteinsdottir J, Schopohl J, Bidlingmaier M, Beuschlein F, Reincke M, Rubinstein G. Biochemical Control in Cushing's Syndrome: Outcomes of the Treatment in a Large Single Center Cohort. J Clin Endocrinol Metab 2025; 110:e1038-e1045. [PMID: 38767080 DOI: 10.1210/clinem/dgae337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/22/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Normalization of hypercortisolism is essential to reduce morbidity and mortality in patients with Cushing's syndrome (CS). The aim of this analysis was to assess biochemical control rates in patients with Cushing's disease (CD), ectopic Cushing's syndrome (ECS), and adrenal Cushing's syndrome (ACS). METHODS Patients with confirmed CS (n = 296) treated in a single tertiary care center were retrospectively analyzed (185 CD, 27 ECS, 84 uni- and bilateral ACS). RESULTS First-line treatment led to biochemical control in 82% of the patients. Time to biochemical control (median, interquartile range) was longer in CD (11.0 weeks, 5.6-29.8; P < .05) than in ACS (7.7 weeks, 4.1-17.1) and ECS (5.6 weeks, 4.1-23.3). Disease persistence or recurrence after first-line therapy was observed more often in CD (24% and 18%; P < .05) than in ECS (15% and 15%) and ACS (6% and 4%). Total time in hypercortisolism since diagnosis was significantly shorter in patients with CD diagnosed since 2013, after specialized patient care was implemented, compared to patients diagnosed before 2013 (13.5 weeks vs 26.1 weeks; P < .0070). Control of hypercortisolism at last follow-up (76 months, 38-163) was achieved in 94% of patients with ACS, 100% of patients with ECS, and 92% of patients with CD. CONCLUSION Biochemical control can be achieved in most patients with different subtypes of CS within a reasonable time frame. Control of hypercortisolism has improved over time.
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Affiliation(s)
- Katrin Ritzel
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Julia Fazel
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Leah August
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Vanessa Fedtke
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Elisabeth Nowak
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Frederick Vogel
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Leah Braun
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Stephanie Zopp
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Cornelia Then
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Heike Künzel
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Nicole Reisch
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Petra Zimmermann
- Department of General, Visceral and Transplantation Surgery, LMU University Hospital, LMU Munich, 81377 Munich, Germany
| | - Jun Thorsteinsdottir
- Department of Neurosurgery, LMU University Hospital, LMU Munich, 81377 Munich, Germany
| | - Jochen Schopohl
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Martin Bidlingmaier
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Felix Beuschlein
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich and University of Zurich, 8091 Zurich, Switzerland
- The LOOP Zurich-Medical Research Center, 8044 Zurich, Switzerland
| | - Martin Reincke
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - German Rubinstein
- Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany
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Zhou H, Yin Y, Zhang P, Li B, Wang Y, Lyu Z, Gu W, Mu Y. Long-term outcome of unilateral adrenalectomy for primary bilateral macronodular adrenal hyperplasia. Endocrine 2025; 87:810-821. [PMID: 39382825 DOI: 10.1007/s12020-024-04030-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 09/03/2024] [Indexed: 10/10/2024]
Abstract
PURPOSE Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a form of Cushing's syndrome (CS) characterized by heterogeneous cortisol secretion and clinical comorbidities. Previously, bilateral adrenalectomy was the standard treatment for PBMAH, but this approach carried a high risk of primary adrenocortical insufficiency. In recent decades, unilateral adrenalectomy (U-Adx) has emerged as an effective alternative. However, limited research exists on its postoperative efficacy and prognostic predictors. Therefore, the present study aimed to investigate the long-term effectiveness and prognostic predictors of U-Adx in treating PBMAH. METHODS A total of 61 patients with PBMAH diagnosis who underwent U-Adx at a single center between 2004 and 2022 were retrospectively evaluated. Patients were categorized into persistent hypercortisolism and remission groups based on postoperative biochemical outcomes at the last follow-up (>12 months after U-Adx). Clinical characteristics, comorbidities, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-h urinary-free cortisol (24-h UFC) levels were analyzed pre- and postoperatively. We further examined whether baseline plasma ACTH, serum cortisol, 24-h UFC levels, and the inhibition of cortisol and 24-h UFC after a low-dose dexamethasone suppression test (LDDST) could predict non-remission following U-Adx. Additionally, we explored the improvements in hypertension, abnormal glucose metabolism, osteoporosis, and other complications in patients with PBMAH post-U-Adx. RESULTS After U-Adx, 22 of the 45 patients (48.89%) achieved initial remission within 6 months. At the last follow-up, 25 of the 45 patients underwent all required biochemical tests and cortisol assessment tests, among which eight of 25 (32.00%) were in remission and 17 of 25 (68.00%) were experiencing persistent hypercortisolism. Moreover, five of those 25 patients exhibited recurrence after initial remission. Baseline 24-h UFC level > 2 times the upper limit of normal (2ULN) and unsuppressed 24-h UFC after LDDST may predict persistent hypercortisolism postoperatively. Lastly, long-term postoperative follow-up revealed that hypertension decreased with hypercortisolism remission, whereas osteoporosis worsened with persistent hypercortisolism. CONCLUSION The short-term remission rate of hypercortisolism was 48.89% in patients with PBMAH treated with U-Adx, while a long-term remission rate of 32.00% was achieved after a median follow-up of 38.58 months. Furthermore, this finding suggests that baseline 24-h UFC level > 2ULN and unsuppressed 24-h UFC after LDDST predict persistent hypercortisolism in the long-term post-U-Adx. Finally, U-Adx improved cortisol circadian rhythm alterations and ACTH suppression in the patients in the remission group, thereby substantially alleviating hypertension and delaying the development of osteoporosis linked to PBMAH.
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Affiliation(s)
- Huixin Zhou
- School of Medicine, Nankai University, Tianjin, China
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Peng Zhang
- Department of Urology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Binqi Li
- School of Medicine, Nankai University, Tianjin, China
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yuepeng Wang
- School of Medicine, Nankai University, Tianjin, China
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhaohui Lyu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weijun Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
| | - Yiming Mu
- School of Medicine, Nankai University, Tianjin, China.
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
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Prete A, Bancos I. Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches. Nat Rev Endocrinol 2024; 20:460-473. [PMID: 38649778 DOI: 10.1038/s41574-024-00984-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/25/2024] [Indexed: 04/25/2024]
Abstract
The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.
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Affiliation(s)
- Alessandro Prete
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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Vassiliadi DA, Delivanis DA, Papalou O, Tsagarakis S. Approach to the Patient With Bilateral Adrenal Masses. J Clin Endocrinol Metab 2024; 109:2136-2148. [PMID: 38478374 DOI: 10.1210/clinem/dgae164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Indexed: 07/13/2024]
Abstract
Bilateral adrenal masses, increasingly encountered in clinical practice, manifest across diverse contexts, including incidental discovery, malignancy staging, and targeted imaging after hormonal diagnosis of adrenal disorders. The spectrum encompasses various pathologies, such as cortical adenomas, macronodular adrenal disease, pheochromocytomas, myelolipomas, infiltrative disorders, and primary and secondary malignancies. Notably, not all masses in both adrenal glands necessarily share the same etiology, often exhibiting diverse causes. Recently, the European Society of Endocrinology and the European Network for the Study of Adrenal Tumors updated guidelines, introduced a 4-option schema based on imaging, aiding in targeted hormonal testing and management. This "Approach to the Patient" review delves into the latest advancements in imaging, biochemical, and genetic approaches for the diagnostic and management nuances of bilateral adrenal masses. It provides insights and a contemporary framework for navigating the complexities associated with this clinical entity.
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Affiliation(s)
- Dimitra Argyro Vassiliadi
- Department of Endocrinology, Diabetes and Metabolism, European Reference Network on Rare Endocrine Conditions (ENDO-ERN), Evangelismos Hospital, 10676, Athens, Greece
| | - Danae Anastasia Delivanis
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
| | - Olga Papalou
- Department of Endocrinology, Diabetes and Metabolism, European Reference Network on Rare Endocrine Conditions (ENDO-ERN), Evangelismos Hospital, 10676, Athens, Greece
| | - Stylianos Tsagarakis
- Department of Endocrinology, Diabetes and Metabolism, European Reference Network on Rare Endocrine Conditions (ENDO-ERN), Evangelismos Hospital, 10676, Athens, Greece
- Private Practice, 10675, Athens, Greece
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6
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Tizianel I, Detomas M, Deutschbein T, Fassnacht M, Albiger N, Iacobone M, Scaroni C, Ceccato F. Corticotropin-releasing hormone test predicts the outcome of unilateral adrenalectomy in primary bilateral macronodular adrenal hyperplasia. J Endocrinol Invest 2024; 47:749-756. [PMID: 37796369 PMCID: PMC10904413 DOI: 10.1007/s40618-023-02204-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/17/2023] [Indexed: 10/06/2023]
Abstract
PURPOSE Primary bilateral adrenal hyperplasia (PBMAH) is associated with hypercortisolism and a heterogeneous clinical expression in terms of cortisol secretion and related comorbidities. Historically, treatment of choice was bilateral adrenalectomy (B-Adx); however, recent data suggest that unilateral adrenalectomy (U-Adx) may be an effective alternative. For the latter, factors predicting the postsurgical outcome (e.g., biochemical control) have not been identified yet. METHODS PBMAH patients undergoing U-Adx for overt Cushing's syndrome (CS) in two tertiary care centers were retrospectively analysed. Remission was defined as a normalization of urinary free cortisol (UFC) without the need for medical treatment. The potential of hCRH test as a predictor of U-Adx outcome was evaluated in a subgroup. RESULTS 23 patients were evaluated (69% females, mean age 55 years). Remission rate after U-Adx was 74% at last follow up (median 115 months from UAdx). Before U-Adx, a positive ACTH response to hCRH (Δ%ACTH increase > 50% from baseline) was associated with higher remission rates. CONCLUSIONS Three of four patients with PBMAH are surgically cured with U-Adx. Pre-operative hCRH testing can be useful to predict long-term remission rates.
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Affiliation(s)
- I Tizianel
- Endocrine Unit, Department of Medicine DIMED, Padua, Italy
- Endocrine Unit, University-Hospital of Padova, Padua, Italy
| | - M Detomas
- University Hospital, University of Würzburg, Würzburg, Germany, Department of Internal Medicine I, Division of Endocrinology and Diabetes, Würzburg, Germany
| | - T Deutschbein
- University Hospital, University of Würzburg, Würzburg, Germany, Department of Internal Medicine I, Division of Endocrinology and Diabetes, Würzburg, Germany
- Medicover Oldenburg MVZ, Oldenburg, Germany
| | - M Fassnacht
- University Hospital, University of Würzburg, Würzburg, Germany, Department of Internal Medicine I, Division of Endocrinology and Diabetes, Würzburg, Germany
| | - N Albiger
- Radiotherapy Unit, Istituto Oncologico Veneto, Endocrinology, ULSS6, Padua, Euganea, Italy
| | - M Iacobone
- Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - C Scaroni
- Endocrine Unit, Department of Medicine DIMED, Padua, Italy
- Endocrine Unit, University-Hospital of Padova, Padua, Italy
| | - F Ceccato
- Endocrine Unit, Department of Medicine DIMED, Padua, Italy.
- Endocrine Unit, University-Hospital of Padova, Padua, Italy.
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7
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Wang XR, Xu DD, Guo MJ, Wang YX, Zhang M, Zhu DX. Effect of ultrasound-guided lumbar square muscle block on stress response in patients undergoing radical gastric cancer surgery. World J Gastrointest Oncol 2023; 15:2093-2100. [PMID: 38173435 PMCID: PMC10758646 DOI: 10.4251/wjgo.v15.i12.2093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/07/2023] [Accepted: 11/25/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND Radical surgery is a common treatment for patients with gastric cancer; however, it can lead to postoperative complications and intestinal barrier dysfunction. Ultrasound-guided quadratus lumborum block is often used for postoperative analgesia, but its effects on stress response and intestinal barrier function are not well understood. AIM To investigate the effects of an ultrasound-guided quadratus lumborum block on stress response and intestinal barrier function in patients undergoing radical surgery for gastric cancer. METHODS A total of 100 patients undergoing radical surgery for gastric cancer were randomly categorized into observation and control groups. Plasma adrenaline and cortisol levels, intestinal mucosal barrier indexes, and complication rates were compared between the two groups before, during, and 1 day after surgery. RESULTS The observation group had significantly lower plasma adrenaline and cortisol levels during surgery and at 1 day postoperatively than that of the control group (P < 0.05). Additionally, intestinal barrier indexes (endotoxin and D-dimer) at 1 day postoperatively were significantly lower in the observation group than in the control group (P < 0.05). CONCLUSION Ultrasound-guided quadratus lumborum block could reduce stress response, protect intestinal barrier function, and decrease the incidence of complications in patients undergoing radical surgery for gastric cancer. This technique has the potential for clinical applications.
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Affiliation(s)
- Xin-Ran Wang
- Department of Ultrasound, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Dan-Dan Xu
- Department of Ultrasound, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Meng-Jiao Guo
- Department of Ultrasound, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Yi-Xin Wang
- Department of Ultrasound, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Meng Zhang
- Department of Ultrasound, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Dong-Xiao Zhu
- Department of Ultrasound, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
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Gosmanov AR, Green M, Gerges AK, Ziganshina AP, Roy MP. Unilateral adrenalectomy as a treatment option in a patient with recurrent Cushing's disease. Oxf Med Case Reports 2023; 2023:omad084. [PMID: 37637361 PMCID: PMC10451106 DOI: 10.1093/omcr/omad084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/07/2023] [Accepted: 07/10/2023] [Indexed: 08/29/2023] Open
Abstract
In recurrent Cushing's disease (CD), therapeutic management options may pose challenges related to risk-benefit profile of available pharmacological agents or bilateral adrenalectomy. Here, we describe a patient with recurrent CD who in context of progressive worsening of diabetes control and new diagnosis of coronary artery disease was offered a unilateral adrenalectomy (UA) to help alleviate the metabolic burden of hypercortisolemia. Within 6 months following UA she was able to stop her blood pressure medications; her anti-diabetes medications were significantly titrated down and she experienced significant weight loss. Currently, 18 months after the UA, the patient has not experienced new clinical events, her weight is stable and diabetes control is consistently optimal, and she remains off anti-hypertensive medications. This report adds to currently scarce body of literature that patients with difficult to manage CD can be considered as candidates for UA to potentially alleviate the metabolic burden of hypercortisolemia.
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Affiliation(s)
- Aidar R Gosmanov
- Section of Endocrinology, Stratton VAMC, Albany, NY, USA
- Division of Endocrinology, Department of Medicine, Albany Medical College, Albany, 12208 NY, USA
| | - Maria Green
- Division of Endocrinology, Department of Medicine, Albany Medical College, Albany, 12208 NY, USA
| | - Antoni Kafrouni Gerges
- Division of Endocrinology, Department of Medicine, Albany Medical College, Albany, 12208 NY, USA
| | - Anna P Ziganshina
- Division of Endocrinology, Department of Medicine, Albany Medical College, Albany, 12208 NY, USA
| | - Mary P Roy
- Section of Endocrinology, Stratton VAMC, Albany, NY, USA
- Division of Endocrinology, Department of Medicine, Albany Medical College, Albany, 12208 NY, USA
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9
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Nowak E, Vogel F, Albani A, Braun L, Rubinstein G, Zopp S, Ritzel K, Beuschlein F, Theodoropoulou M, Reincke M. Diagnostic challenges in cyclic Cushing's syndrome: a systematic review. Lancet Diabetes Endocrinol 2023:S2213-8587(23)00150-X. [PMID: 37429301 DOI: 10.1016/s2213-8587(23)00150-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/12/2023] [Accepted: 05/12/2023] [Indexed: 07/12/2023]
Abstract
Cyclic Cushing's syndrome is a subentity of Cushing's syndrome in which phases of biochemical hypercortisolism (peaks) are followed by spontaneous periods of physiological or even hypocortisolaemic cortisol secretion (troughs). To identify common features of cyclic Cushing's syndrome, we systematically reviewed single case reports and case series in MEDLINE from database inception to Oct 10, 2022, and identified 707 articles, of which 149 articles were assessed for eligibility and 118 articles (covering 212 cases) were included in the analysis. Pituitary tumours accounted for 67% of cases of cyclic Cushing's syndrome (n=143), ectopic tumours for 17% (n=36), and adrenal tumours for 11% (n=23). Occult tumours accounted for 2% of cases (n=4), and 3% of cases were unclassified (n=6). We compared the clinical symptoms and comorbidities of patients with cyclic Cushing's syndrome with those of patients with non-cyclic Cushing's syndrome and observed no major difference. In adrenocorticotropic hormone (ACTH)-dependent cyclic Cushing's syndrome, bilateral inferior petrosal sinus sampling had a positive (ie, true pituitary) and negative (ie, true ectopic) predictive value of 100% when performed during periods of hypercortisolism, versus a positive predictive value of 73% and a negative predictive value of 86% when performed, irrespective of cortisolaemic status. Overall, 6% of patients (n=12) with cyclic Cushing's syndrome had unnecessary surgery due to misclassification. Remission rates were significantly lower and the time to remission significantly longer in patients with cyclic Cushing's syndrome compared with patients with non-cyclic Cushing's syndrome (p<0·001). Variations in biochemical test results due to unpredictable cycle duration and frequency might cause diagnostic challenges resulting in misdiagnoses and missed diagnoses.
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Affiliation(s)
- Elisabeth Nowak
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany.
| | - Frederick Vogel
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Adriana Albani
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Leah Braun
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - German Rubinstein
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Stephanie Zopp
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Katrin Ritzel
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Felix Beuschlein
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany; Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zürich, Zürich, Switzerland
| | | | - Martin Reincke
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany.
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10
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Sol B, Carprieaux M, De Leu N. ARMC5-negative primary bilateral macronodular adrenal hyperplasia. BMJ Case Rep 2023; 16:e254099. [PMID: 37419498 PMCID: PMC10347486 DOI: 10.1136/bcr-2022-254099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/09/2023] Open
Abstract
A woman in her 60s with chronic fatigue, depressed mood and proximal muscle weakness was referred to our endocrinology department. Physical examination revealed facial plethora, atrophic skin and ankle oedema. Adjuvant blood and urine analyses indicated endogenous ACTH-independent Cushing syndrome. Abdominal imaging showed bilateral macronodular adrenals, measuring 58.9 × 29.7 mm on the right and 55.6 × 42.6 mm on the left. Primary bilateral macronodular adrenal hyperplasia was confirmed by pathology after bilateral adrenalectomy. Gradual mental and physical recovery was observed in the months following surgery. Genetic sequencing failed to reveal mutations in the ARMC5 gene.Cushing syndrome is a rare entity that should be suspected when typical clinical signs, including skin atrophy with ecchymosis, muscle weakness or coloured stretch marks, are present. Primary bilateral macronodular adrenal hyperplasia is an uncommon cause of endogenous Cushing syndrome. It is a benign condition characterised by adrenal macronodules exceeding 1 cm and hypercorticism.
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Affiliation(s)
- Bastiaan Sol
- Endocrinology, AZ Alma Campus Eeklo, Eeklo, Belgium
| | | | - Nico De Leu
- Beta Cell Neogenesis Unit, Vrije Universiteit Brussel, Jette, Belgium
- Endocrinology, ASZ Campus Aalst, Aalst, Belgium
- Endocrinology-Diabetology, UZ Brussel, Jette, Belgium
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11
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Шевэ А, Елфимова АР, Бельцевич ДГ. [Primary bilateral macronodular adrenal hyperplasia: clinical and laboratory features]. PROBLEMY ENDOKRINOLOGII 2023; 69:58-67. [PMID: 37448248 PMCID: PMC10350612 DOI: 10.14341/probl13301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 04/30/2023] [Indexed: 07/15/2023]
Abstract
BACKGROUND Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by bilateral benign adrenocortical lesions, which in some cases lead to Cushing syndrome (CS). Due to the low detection, non-specific, erased clinical picture and slow, long-term progression, it is difficult to assess the true prevalence of PBMAH. This also leads to fairly limited literature data. A detailed analysis of biochemical, imaging parameters, the clinical presentations, in particular, an assessment of the course of comorbidities (arterial hypertension (AH), diabetes (DM), osteoporosis), is necessary to develop an algorithm for managing patients with PBMAH. AIM Analysis of clinical and laboratory characteristics of patients with various forms of PBMAH. MATERIALS AND METHODS A single-center, retrospective, observational, cross-sectional study was carried out. This study included 110 patients with PBMAH who got referred to the National Research Center for Endocrinology in the period from 2013-2023. We carried out comparative and correlation analysis of hormonal (plasma cortisol concentrations after 1 mg dexamethasone (1-mg DST), urinary free cortisol (СКМ), ACTH), biochemical (glycated hemoglobin), radiological data (nodular tissue volume), course of comorbidities (metabolic syndrome, DM, AH, osteoporosis) in three groups of patients: with overt CS, mild autonomous cortisol excess (MACE) and comorbid diseases, and patients with PBMAH without hormonal activity. RESULTS Among 110 patients 79.1% were women, median age - 60 [51; 68]. The proportion of hormonally inactive forms of PBMAH was 37.3%, the overt CS and MACE was detected in 25.4 and 37.3% consequently. According to the hormonal -examination data: the cortisol level during 1-mg DST was 173.8 nmol/l [86.0; 441.0], ACTH - 3.35 pg/ml [1.00; 8.00], СКМ - 445.5 [249.0; 900.0]. Statistically significant positive moderate correlations were found between the volume of nodular tissue and the level of cortisol after PDT1 (r=0.40, p<0.001), СКМ (r=0.29, p<0.004), as well as a negative moderate correlation between the volume and the level of ACTH (r=-0.40, p<0.001). When analyzing the prevalence and clinical severity of comorbid conditions, DM was diagnosed in 22 (53.7%), AH in 36 (87.8%), obesity and osteoporosis - 23 (56%) and 3 (7.3%) patients. There was no statistically significant difference in the prevalence of CS-associated diseases among the above groups (p=0.56). CONCLUSION PBMAH is a heterogeneous pathology with different clinical, hormonal, and imaging characteristics. A correlation was found between the volume of nodular tissue and the degree of hormonal activity of PBMAH. The obtained results emphasize the difficulty in determining clear indications for surgical treatment in the group of patients with MACE. The radicality of proposed surgical procedure should be weighed against its potential complications.
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Affiliation(s)
- А. Шевэ
- Национальный медицинский исследовательский центр эндокринологии
| | - А. Р. Елфимова
- Национальный медицинский исследовательский центр эндокринологии
| | - Д. Г. Бельцевич
- Национальный медицинский исследовательский центр эндокринологии
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12
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Tang P, Zhang J, Peng S, Yan X, Wang Y, Wang S, Zhang Y, Liu G, Xu J, Huang Y, Zhang D, Liu Q, Jiang J, Lan W. Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) patient with ARMC5 mutations. BMC Endocr Disord 2023; 23:77. [PMID: 37029354 PMCID: PMC10080789 DOI: 10.1186/s12902-023-01324-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 03/14/2023] [Indexed: 04/09/2023] Open
Abstract
BACKGROUND Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a highly heterogeneous disease with divergent manifestations ranging from asymptomatic subclinical Cushing syndrome (CS) to overt Cushing syndrome with severe complications. ARMC5 mutations occur in 20 to 55% PBMAH patients usually with more severe phenotypes. Different ARMC5 mutations might be associated with diverse phenotypes of PBMAH. CASE PRESENTATION A 39-year-old man was admitted to our hospital with progressive weight gain and severe hypertension. He presented typical CS and its classical metabolic and bone complications like hypertension and osteoporosis. The laboratory results showed high levels of cortisol and low levels of ACTH. Low- and high-dosed dexamethasone suppression tests were negative. Contrast-enhanced computed tomography (CT) revealed multiple bilateral irregular macronodular adrenal masses. Adrenal venous sampling (AVS) confirmed that the right adrenal gland with larger nodules secreted more hormone that the left side did. Right adrenalectomy and subsequent contralateral subtotal resection were conducted. His blood pressure and CS symptoms as well as comorbidities including backache and muscle weakness improved. Whole exome sequencing identified one ARMC5 germline mutation (c.1855C > T, p. R619*), five ARMC5 somatic mutations (four novel mutations) in his right and left adrenal nodules. CONCLUSIONS This PBMAH patient was identified with one ARMC5 germline mutation and five different somatic ARMC5 mutations (four novel mutations) in the different nodules of the bilateral adrenal masses. AVS combined with CT imagine could be helpful to determine the dominant side for adrenalectomy. Genetic testing is important for the diagnosis and management of the patient with PBMAH.
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Affiliation(s)
- Peng Tang
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Jun Zhang
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Song Peng
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Xuzhi Yan
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Yapeng Wang
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Shuo Wang
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Yao Zhang
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Gaolei Liu
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Jing Xu
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Yiqiang Huang
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Dianzheng Zhang
- Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA, 19131, USA
| | - Qiuli Liu
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China
| | - Jun Jiang
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China.
| | - Weihua Lan
- Department of Urology, Daping Hospital, Army Medical University, 10#, ChangjiangZhilu, Yuzhong District, Chongqing, 400042, People's Republic of China.
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13
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Araujo-Castro M, Reincke M. Primary bilateral macronodular adrenal hyperplasia: A series of 32 cases and literature review. ENDOCRINOL DIAB NUTR 2023; 70:229-239. [PMID: 37116968 DOI: 10.1016/j.endien.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/17/2022] [Indexed: 04/30/2023]
Abstract
Primary bilateral macronodular adrenal hyperplasia (PBMAH) accounts for <2% of cases of Cushing's syndrome. The majority of patients present with no obvious steroid excess it means with autonomous cortisol secretion (ACS). The classic treatment for patients with overt Cushing's syndrome is bilateral adrenalectomy, but unilateral resection of the larger adrenal gland can result in clinical and/or biochemical remission in >90% of cases, especially in cases of ACS. In this article, a series of 32 cases with PBMAH is described. Most of the cases of PBMAH had ACS, except for one case with overt Cushing's syndrome. A study of aberrant receptors was performed in six patients, being negative in three cases, positive in the metoclopramide test in two cases and positive in the metoclopramide test and in the mixed meal test in another patient. The patient with overt Cushing's syndrome was treated with adrenostatic therapy achieving biochemical control, while two patients with ACS underwent unilateral adrenalectomy with resection of the largest adrenal gland, demonstrating hypercortisolism remission and improvement of cardiovascular risk factors after surgery. This article describes a series of 32 cases of PBMAH and offers a comprehensive review of PBMAH.
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Affiliation(s)
- Marta Araujo-Castro
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal [Ramon y Cajal University Hospital], Instituto de Investigación Ramón y Cajal (IRYCIS) [Ramon y Cajal Research Institute], Spain; Universidad de Alcalá [University of Alcalá], Madrid, Spain.
| | - Martín Reincke
- Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
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14
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Yu Z, Gao J, Sun F. The effect of unilateral adrenalectomy on patients with primary bilateral macronodular adrenal hyperplasia. Hormones (Athens) 2023; 22:235-242. [PMID: 36800160 DOI: 10.1007/s42000-023-00428-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 01/09/2023] [Indexed: 02/18/2023]
Abstract
PURPOSE To evaluate the long-term effect of unilateral adrenalectomy (uADX) on patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). METHODS We retrospectively reviewed 29 patients (including 11 men and 18 women) with PBMAH and Cushing's syndrome (CS) between 2005 and 2019 who underwent uADX in our center. Clinical symptoms, serum cortisol (8:00 a.m., 4:00 p.m., and 0:00 a.m.), 24 h urinary free cortisol (UFC), computed tomography (CT) scan of the adrenal gland, and pituitary nuclear magnetic resonance (MR) scan performed before and after operation were analyzed. RESULTS The median follow-up time was 39 (13-134) months. uADX decreased significantly at 24 h UFC (median: 357.14 vs. 89.50 ug/24 h, P < 0.001) and serum cortisol (8:00 a.m.) (median: 22.88 vs. 12.50 ug/uL, P < 0.001) 1 year after surgery. In total, 17 of 29 patients had normal UFC again 1 year after surgery, while one of them suffered a relapse after 61 months. However, uADX failed to decrease UFC to the normal range in the other patients. Ten of the remaining 12 uncured patients and the relapsed patient finally underwent contralateral adrenalectomy (cADX). The 24 h UFC of the patients who were cured (n = 17) after uADX was significantly lower than that of the uncured patients (n = 12) (222.30 vs. 579.10 ug/24 h, P = 0.011). CONCLUSION uADX may be an appropriate treatment for patients with mildly elevated cortisol, while contralateral adrenalectomy (cADX) may be required for patients with highly elevated cortisol. The level of 24 h UFC is helpful to predict patients' prognosis.
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Affiliation(s)
- Zhongwei Yu
- Department of Urology, RuiJin Hospital Lu Wan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, 200020, China
| | - Jie Gao
- Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Fukang Sun
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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15
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Johnson PC, Thompson SM, Adamo D, Fleming CJ, Bancos I, McKenzie TJ, Cheville J, Young WF, Andrews JC. Adrenal venous sampling for lateralization of cortisol hypersecretion in patients with bilateral adrenal masses. Clin Endocrinol (Oxf) 2023; 98:177-189. [PMID: 36263687 DOI: 10.1111/cen.14833] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The objective of this study was to evaluate the role of adrenal venous sampling (AVS) in guiding the management of patients with corticotropin (ACTH)-independent glucocorticoid secretory autonomy and bilateral adrenal masses. DESIGN AND PATIENTS A cohort with 25 patients underwent AVS and surgical management. MEASUREMENTS Cortisol was measured from the adrenal veins (AVs) and inferior vena cava (IVC). AV/IVC cortisol ratio and cortisol lateralization ratio (CLR) (dominant AV cortisol concentration divided by the nondominant AV cortisol concentration) were calculated. Posthoc receiver-operating characteristic curves were generated to determine the specificity of revised AV/IVC cortisol ratio and CLR in differentiating unilateral from bilateral disease. RESULTS Patients underwent unilateral (n = 21) or bilateral (n = 4) adrenalectomy. The mean AV/IVC cortisol ratio for unilateral adrenalectomy was 12.1 ± 9.6 (dominant) and 4.7 ± 3.8 (contralateral) with a mean CLR of 3.6 ± 3.5. The mean AV/IVC cortisol ratio for bilateral adrenalectomy was 7.5 ± 2.1, with a mean CLR of 1.1 ± 0.6. At a mean follow-up of 22 months, one patient who underwent unilateral adrenalectomy for the predicted bilateral disease developed recurrent mild autonomous cortisol secretion. Posthoc analyses demonstrated a specificity of 95%-100% for unilateral disease with AV/IVC cortisol ratio >9 for one side, <2.0 for the opposite side and a CLR > 2.3. The specificity was 80%-90% for bilateral disease with AV/IVC cortisol ratio >5.1 bilaterally and a CLR < 1.1. CONCLUSIONS Among patients with bilateral adrenal masses and ACTH-independent autonomous cortisol secretion, AVS can distinguish between unilateral and bilateral disease with high specificity and may guide surgical management.
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Affiliation(s)
- Paige C Johnson
- Department of Radiology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Scott M Thompson
- Department of Radiology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel Adamo
- Department of Radiology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Chad J Fleming
- Department of Radiology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Travis J McKenzie
- Division of Endocrine and Metabolic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - John Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - William F Young
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - James C Andrews
- Department of Radiology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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16
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Unilateral Adrenalectomy for Primary Aldosteronism Due to Bilateral Adrenal Disease Can Result in Resolution of Hypokalemia and Amelioration of Hypertension. World J Surg 2023; 47:314-318. [PMID: 36207420 DOI: 10.1007/s00268-022-06780-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Bilateral idiopathic hyperaldosteronism (IHA) is responsible for 60% of primary aldosteronism (PA) cases. Medical management is standard of care for IHA. Unilateral adrenalectomy (UA) with the intent of debulking total aldosterone production as a palliative measure remains controversial. METHODS Single-center retrospective review (2010-2020) of patients undergoing UA with a diagnosis of PA due to IHA (lateralization index [LI] on adrenal venous sampling [AVS] < 4). Demographic, pre-operative, intra-operative, and post-operative variables were assessed. Hypertensive regimens were converted to the WHO Defined Daily Dose (DDD). RESULTS Twenty-four patients were identified, 14, 58% male and mean age 52 ± 10 years. Preoperative hypokalemia was present in 22, 92% of patients. Median number of antihypertensives taken was 3 (interquartile range [IQR], 2-4) and median DDD was 4 (IQR, 3-5.3). Median lateralization index on AVS was 3.52 (range, 1.19-3.88). All operations were performed in minimally invasive fashion. There were no conversions to open procedure, ICU admissions, or post-operative complications. Median follow-up was 10.5 months (range, 1-145 months). Hypokalemia resolved in 17, 76% of patients at last follow-up. Post-operative median number of antihypertensives taken was 1 (IQR, 1-3) and median DDD was 2 (IQR, 0.5-2.75) from 4, P = 0.003. Three (%) patients required continuation of mineralocorticoid receptor antagonists post-operatively. Blood pressure control improved in 65% of patients. CONCLUSION Unilateral adrenalectomy in the setting of bilateral hyperaldosteronism can improve blood pressure control and stabilize potassium levels in selected patients. Further prospective studies in larger cohorts will be necessary to further define the role of unilateral adrenalectomy in the setting of PA due to bilateral adrenal disease.
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17
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Advances in Endocrine Surgery. Surg Oncol Clin N Am 2023; 32:199-220. [PMID: 36410918 DOI: 10.1016/j.soc.2022.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Recent changes in the landscape of endocrine surgery include a shift from total thyroidectomy for almost all patients with papillary thyroid cancer to the incorporation of thyroid lobectomy for well-selected patients with low-risk disease; minimally invasive parathyroidectomy with, and potentially without, intraoperative parathyroid hormone monitoring for patients with well-localized primary hyperparathyroidism; improvement in the management of parathyroid cancer with the incorporation of immune checkpoint blockade and/or targeted therapies; and the incorporation of minimally invasive techniques in the management of patients with benign tumors and selected secondary malignancies of the adrenal gland.
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Bertherat J, Bourdeau I, Bouys L, Chasseloup F, Kamenicky P, Lacroix A. Clinical, pathophysiologic, genetic and therapeutic progress in Primary Bilateral Macronodular Adrenal Hyperplasia. Endocr Rev 2022:6957368. [PMID: 36548967 DOI: 10.1210/endrev/bnac034] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 10/07/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome, but may represent up to one third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G-protein coupled receptors aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation, led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20-25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by GIP-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over or down-regulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and co-morbidities assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses taking in account co-morbidities. It previously relied on bilateral adrenalectomy; however recent studies tend to favor unilateral adrenalectomy, or less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR.
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Affiliation(s)
- Jerôme Bertherat
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Cochin Hospital, Assistance Publique Hôpitaux de Paris, 24 rue du Fg St Jacques, Paris 75014, France
| | - Isabelle Bourdeau
- Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
| | - Lucas Bouys
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Cochin Hospital, Assistance Publique Hôpitaux de Paris, 24 rue du Fg St Jacques, Paris 75014, France
| | - Fanny Chasseloup
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Service d'Endocrinologie et des Maladies de la Reproduction, 94276 Le Kremlin-Bicêtre, France
| | - Peter Kamenicky
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Service d'Endocrinologie et des Maladies de la Reproduction, 94276 Le Kremlin-Bicêtre, France
| | - André Lacroix
- Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
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Yip L, Duh QY, Wachtel H, Jimenez C, Sturgeon C, Lee C, Velázquez-Fernández D, Berber E, Hammer GD, Bancos I, Lee JA, Marko J, Morris-Wiseman LF, Hughes MS, Livhits MJ, Han MA, Smith PW, Wilhelm S, Asa SL, Fahey TJ, McKenzie TJ, Strong VE, Perrier ND. American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary. JAMA Surg 2022; 157:870-877. [PMID: 35976622 PMCID: PMC9386598 DOI: 10.1001/jamasurg.2022.3544] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/30/2022] [Indexed: 12/14/2022]
Abstract
Importance Adrenalectomy is the definitive treatment for multiple adrenal abnormalities. Advances in technology and genomics and an improved understanding of adrenal pathophysiology have altered operative techniques and indications. Objective To develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy. Evidence Review A multidisciplinary panel identified and investigated 7 categories of relevant clinical concern to practicing surgeons. Questions were structured in the framework Population, Intervention/Exposure, Comparison, and Outcome, and a guided review of medical literature from PubMed and/or Embase from 1980 to 2021 was performed. Recommendations were developed using Grading of Recommendations, Assessment, Development and Evaluation methodology and were discussed until consensus, and patient advocacy representation was included. Findings Patients with an adrenal incidentaloma 1 cm or larger should undergo biochemical testing and further imaging characterization. Adrenal protocol computed tomography (CT) should be used to stratify malignancy risk and concern for pheochromocytoma. Routine scheduled follow-up of a nonfunctional adrenal nodule with benign imaging characteristics and unenhanced CT with Hounsfield units less than 10 is not suggested. When unilateral disease is present, laparoscopic adrenalectomy is recommended for patients with primary aldosteronism or autonomous cortisol secretion. Patients with clinical and radiographic findings consistent with adrenocortical carcinoma should be treated at high-volume multidisciplinary centers to optimize outcomes, including, when possible, a complete R0 resection without tumor disruption, which may require en bloc radical resection. Selective or nonselective α blockade can be used to safely prepare patients for surgical resection of paraganglioma/pheochromocytoma. Empirical perioperative glucocorticoid replacement therapy is indicated for patients with overt Cushing syndrome, but for patients with mild autonomous cortisol secretion, postoperative day 1 morning cortisol or cosyntropin stimulation testing can be used to determine the need for glucocorticoid replacement therapy. When patient and tumor variables are appropriate, we recommend minimally invasive adrenalectomy over open adrenalectomy because of improved perioperative morbidity. Minimally invasive adrenalectomy can be achieved either via a retroperitoneal or transperitoneal approach depending on surgeon expertise, as well as tumor and patient characteristics. Conclusions and Relevance Twenty-six clinically relevant and evidence-based recommendations are provided to assist surgeons with perioperative adrenal care.
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Affiliation(s)
- Linwah Yip
- Division of Endocrine Surgery, University of Pittsburgh, Pennsylvania
| | - Quan-Yang Duh
- Department of Surgery, University of California, San Francisco
| | - Heather Wachtel
- Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia
| | - Camilo Jimenez
- Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston
| | - Cord Sturgeon
- Department of Surgery, Section of Endocrine Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Cortney Lee
- Department of Surgery, University of Kentucky College of Medicine, Lexington
| | | | - Eren Berber
- Center for Endocrine Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Gary D Hammer
- Department of Internal Medicine, University of Michigan, Ann Arbor
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor
| | - Irina Bancos
- Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - James A Lee
- Department of Surgery, Department of Internal Medicine, Columbia University College of Physicians and Surgeons, New York, New York
| | - Jamie Marko
- Department of Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Maryland
| | | | - Marybeth S Hughes
- Division of Surgical Oncology, Department of Surgery, Eastern Virginia Medical School, Norfolk
| | - Masha J Livhits
- Department of General Surgery, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Mi-Ah Han
- Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, Korea
| | - Philip W Smith
- Department of Surgery, University of Virginia, Charlottesville
| | - Scott Wilhelm
- Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio
| | - Thomas J Fahey
- Division of Endocrine & Minimally Invasive Surgery, Department of Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York
| | - Travis J McKenzie
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Vivian E Strong
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy D Perrier
- Section of Surgical Endocrinology, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston
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Gao J, Yu Z, Sun F, Xu B, Zhang C, Wang H, Lu J, Lei T. The Relationship Between Baseline Cortisol Levels and Surgery Method of Primary Bilateral Macronodular Adrenal Hyperplasia. Horm Metab Res 2022; 54:354-360. [PMID: 35697044 DOI: 10.1055/a-1850-2169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Aim was to explore the associations between baseline cortisol levels and surgery method of primary bilateral macronodular adrenal hyperplasia (PBMAH). We retrospectively reviewed the clinical features and management of 30 patients (18 females and 12 males) who were diagnosed with PBMAH in our center between 2005 and 2019. Based on surgery method, we divided the patients into two groups: unilateral adrenalectomy (UA) group; and bilateral adrenalectomy (BA) group. Serum cortisol rhythm and 24-hour urinary free cortisol (UFC/24 h) levels were assayed using chemiluminescence method. Associations between baseline cortisol levels and BA were assessed using logistic regression. The predictive value of baseline cortisol levels for BA was calculated using receiver operating characteristic (ROC) curves. Twenty patients (66.7%) underwent UAs and ten patients (33.3%) underwent BAs. After adjusting for age, sex, BMI, SBP, and adrenal volume, the concentrations of baseline serum cortisol (8 AM, 4 PM, and 0 AM) and UFC/24 h were associated with bilateral adrenalectomy (all p<0.05). The area under the ROC curve based on 8 AM serum cortisol level model was larger than that in models based on 4 PM, 0 AM serum cortisol levels and UFC/24 h, but the differences were non-significant (all p>0.05). According to maximum Youden index criteria, the optimal cutoffs of 8 AM serum cortisol level and UFC were 26.89 μg/dl and 406.65 μg/24 h, respectively, for BA. The baseline cortisol levels are positively associated with BA. Increased levels of baseline cortisol levels may predict higher possibility of BA, which should be confirmed by prospective studies.
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Affiliation(s)
- Jie Gao
- Department of Endocrinology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhongwei Yu
- Department of Urology, Ruijin Hospital Lu Wan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fukang Sun
- Department of Urology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
| | - Bilin Xu
- Department of Endocrinology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cuiping Zhang
- Department of Endocrinology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongping Wang
- Department of Endocrinology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jun Lu
- Department of Endocrinology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Lei
- Department of Endocrinology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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21
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Bouys L, Vaczlavik A, Jouinot A, Vaduva P, Espiard S, Assié G, Libé R, Perlemoine K, Ragazzon B, Guignat L, Groussin L, Bricaire L, Cavalcante IP, Bonnet-Serrano F, Lefebvre H, Raffin-Sanson ML, Chevalier N, Touraine P, Jublanc C, Vatier C, Raverot G, Haissaguerre M, Maione L, Kroiss M, Fassnacht M, Christin-Maitre S, Pasmant E, Borson-Chazot F, Tabarin A, Vantyghem MC, Reincke M, Kamenicky P, North MO, Bertherat J. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients. Eur J Endocrinol 2022; 187:123-134. [PMID: 35521700 DOI: 10.1530/eje-21-1032] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 04/14/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants. METHODS We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively. RESULTS 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant. CONCLUSION We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.
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Affiliation(s)
- Lucas Bouys
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
| | - Anna Vaczlavik
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Anne Jouinot
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
- Institut Curie, INSERM U900, MINES ParisTech, PSL-Research University, CBIO-Centre for Computational Biology, Paris, France
| | - Patricia Vaduva
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France
| | - Stéphanie Espiard
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, Lille, France
| | - Guillaume Assié
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Rossella Libé
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Karine Perlemoine
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
| | - Bruno Ragazzon
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
| | - Laurence Guignat
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Lionel Groussin
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Léopoldine Bricaire
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | | | - Fidéline Bonnet-Serrano
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Unit of Hormonology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Hervé Lefebvre
- Department of Endocrinology, Diabetes and Metabolic Diseases, CHU Rouen, Rouen, France
| | - Marie-Laure Raffin-Sanson
- Department of Endocrinology, Diabetology and Nutrition, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne-Billancourt, France
| | - Nicolas Chevalier
- Department of Endocrinology, Diabetology and Reproduction, CHU Nice, Nice, France
| | - Philippe Touraine
- Department of Endocrinology and Reproduction, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Christel Jublanc
- Department of Endocrinology and Metabolism, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Camille Vatier
- Department of Endocrinology, Diabetology and Reproduction, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Gérald Raverot
- Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Magalie Haissaguerre
- Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France
| | - Luigi Maione
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Department of Endocrinology and Reproduction, Reference Center for Rare Pituitary Diseases, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Matthias Kroiss
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, University of Würzburg, Würzburg, Germany
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Martin Fassnacht
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, University of Würzburg, Würzburg, Germany
| | - Sophie Christin-Maitre
- Department of Endocrinology, Diabetology and Reproduction, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Eric Pasmant
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Françoise Borson-Chazot
- Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Antoine Tabarin
- Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France
| | - Marie-Christine Vantyghem
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, Lille, France
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Peter Kamenicky
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Department of Endocrinology and Reproduction, Reference Center for Rare Pituitary Diseases, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Marie-Odile North
- Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Jérôme Bertherat
- Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
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22
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Fernandez C, Bhatia S, Rucker A, Celio L. Intermittent Blurry Vision: An Unexpected Presentation of Cushing’s Syndrome Due to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH). Cureus 2022; 14:e25017. [PMID: 35712330 PMCID: PMC9197089 DOI: 10.7759/cureus.25017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 11/28/2022] Open
Abstract
Cushing’s syndrome (CS) is an uncommon endocrine disorder resulting from prolonged exposure to elevated glucocorticoids, with 10-15 million annual cases per the American Association of Neurological Surgeons. Exogenous and endogenous causes can further be divided into adrenocorticotropic hormone (ACTH) dependent (i.e Cushing’s Disease) or ACTH independent. ACTH-independent CS can be caused by primary bilateral macronodular adrenal hyperplasia (PBMAH) representing less than 1% cases of CS. We report a case of a woman presenting with chronic resistant hypertension, episodic blurry vision, weight gain and wasting of extremities. She was diagnosed with Cushing’s syndrome due to PBMAH. Our patient’s presentation was unusual as she presented at 40 years old, 10 years earlier than expected for PBMAH; and primarily with complaints of episodic blurry vision. Her symptoms also progressed rapidly as signs and symptoms largely presented over the course of 12 months, however responded well to surgical resection.
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23
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Rubinstein G, Osswald A, Braun LT, Vogel F, Kroiss M, Pilz S, Deniz S, Aigner L, Knösel T, Bertherat J, Bouys L, Ladurner R, Riester A, Bidlingmaier M, Beuschlein F, Reincke M. The role of adrenal venous sampling (AVS) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH): a study of 16 patients. Endocrine 2022; 76:434-445. [PMID: 35274284 PMCID: PMC9068666 DOI: 10.1007/s12020-022-03020-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 02/16/2022] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing's syndrome. Current guidelines recommend bilateral adrenalectomy for PBMAH, but several studies showed clinical effectiveness of unilateral adrenalectomy despite bilateral disease in selected patients. Our aim was to evaluate the gain of information which can be obtained through adrenal venous sampling (AVS) based cortisol lateralization ratios for guidance of unilateral adrenalectomy. DESIGN We performed a retrospective analysis of 16 patients with PBMAH and clinical overt cortisol secretion in three centers METHODS: Selectivity of adrenal vein sampling during AVS was defined as a gradient of cortisol or a reference adrenal hormone ≥2.0 between adrenal and peripheral vein. Lateralization was assumed if the dominant to non-dominant ratio of cortisol to reference hormone was ≥4.0. RESULTS AVS was technically successful in all patients based on absolute cortisol levels and in 13 of 16 patients (81%) based on reference hormone levels. Lateralization was documented in 8 of 16 patients. In patients with lateralization, in 5 of 8 cases this occurred toward morphologically larger adrenals, while in 3 patients lateralization was present in bilaterally identical adrenals. The combined volume of adrenals correlated positively with urinary free cortisol, suggesting that adrenal size is the dominant determinant of cortisol secretion. CONCLUSIONS In this study the gain of information through AVS for unilateral adrenalectomy was limited in patients with PBMAH and marked adrenal asymmetry.
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Affiliation(s)
- German Rubinstein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | - Andrea Osswald
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | - Leah Theresa Braun
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | - Frederick Vogel
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | - Matthias Kroiss
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University of Würzburg, University Hospital Würzburg, Würzburg, Germany
| | - Stefan Pilz
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Sinan Deniz
- Klinik und Poliklinik für Radiologie, Klinikum der Universität München, München, Germany
| | - Laura Aigner
- Klinik und Poliklinik für Radiologie, Klinikum der Universität München, München, Germany
- Department for Diagnostic and Interventional Radiology and Neuroradiology, Klinikverbund Allgäu, Kempten, Germany
| | - Thomas Knösel
- Pathologisches Institut, Klinikum der Universität München, München, Deutschland
| | - Jérôme Bertherat
- Université de Paris, 75006, Paris, France
- Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014, Paris, France
| | - Lucas Bouys
- Université de Paris, 75006, Paris, France
- Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014, Paris, France
| | - Roland Ladurner
- Klinik für Allgemeine, Unfall- und Wiederherstellungschirurgie, Campus Innenstadt, Klinikum der Universität München, München, Germany
| | - Anna Riester
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
| | - Felix Beuschlein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich (USZ) and Universität Zürich (UZH), Zürich, Switzerland
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.
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24
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Wang W, Lian P, Deng J, Li H, Zhang X. A 30-year single-center experience of unilateral adrenalectomy for primary bilateral macronodular adrenal hyperplasia. Endocr Pract 2022; 28:690-695. [PMID: 35487460 DOI: 10.1016/j.eprac.2022.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/18/2022] [Accepted: 04/20/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The aim of this study is to assess the short- and long-term outcomes of unilateral adrenalectomy (UA) in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). METHODS We conducted a retrospective study of 124 patients with PBMAH who underwent UA. RESULTS 124 adrenalectomies were performed without intraoperative mortality. After a median duration of 28.5months (1∼165months, mean 51.92 ± 47.21 months), 116 patients were available for follow-up. Cushingoid features remitted in 70.8% (43/65) of patients with overt Cushing's Syndrome (CS). Hypertension and diabetes mellitus improved in 82.3% (79/96) and 69.0% (29/42) of patients respectively. 6.0% (7/116) of patients developed glucocorticoid insufficiency postoperatively, and all resolved during the follow-up. The mean 24h-UFC (reference range 12.3∼103.5μg/24h) decreased gradually from 456.02±422.33μg/24hr at baseline to 84.47±70.06μg/24hr within 3 months and then climbed progressively in some patients. 55.2% (64/116) had biochemical recurrence with/without symptom recurrence and 67.2% (43/64) of them received contralateral adrenalectomy. The median interval time of the second operation from the first UA was 24 months (1∼165months, mean 43.58 ± 44.54 months), and it took less time in patients with overt CS (median 22 months, 1∼165 months, mean 37.24 ± 41.85 months) than those without overt CS (median 72 months, 1∼144 months, mean 61.45 ± 46.73 months). Patients with overt CS had larger surgical-side or contralateral adrenal volume than that of patients without overt CS. Patients with contralateral adrenal volume larger than 33.54ml or with pre-operative UFC more than 216.08μg/24hr were more likely to have recurrence. CONCLUSION The efficiency of UA is transient for majority of patients, and the indications should be strictly limited to those with subclinical or milder CS. The successful UA patients still require close lifetime follow-up for recurrence of hypercortisolism.
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Affiliation(s)
- Wenda Wang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Penghu Lian
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianhua Deng
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hanzhong Li
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuebin Zhang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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25
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Reincke M, Williams TA. True unilateral primary aldosteronism exists, and unilateral adrenalectomy saves lives. Eur J Endocrinol 2022; 186:C5-C7. [PMID: 35380984 DOI: 10.1530/eje-22-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/30/2022] [Indexed: 11/08/2022]
Affiliation(s)
- Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, München, Germany
| | - Tracy Ann Williams
- Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, München, Germany
- Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Torino, Italy
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26
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Araujo-Castro M, Marazuela M. Cushing´s syndrome due to bilateral adrenal cortical disease: Bilateral macronodular adrenal cortical disease and bilateral micronodular adrenal cortical disease. Front Endocrinol (Lausanne) 2022; 13:913253. [PMID: 35992106 PMCID: PMC9389040 DOI: 10.3389/fendo.2022.913253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
Cushing´s syndrome (CS) secondary to bilateral adrenal cortical disease may be caused by bilateral macronodular adrenal cortical disease (BMACD) or by bilateral micronodular adrenal cortical disease (miBACD). The size of adrenal nodules is a key factor for the differentiation between these two entities (>1cm, BMACD and <1cm; miBACD). BMACD can be associated with overt CS, but more commonly it presents with autonomous cortisol secretion (ACS). Surgical treatment of BMACD presenting with CS or with ACS and associated cardiometabolic comorbidities should be the resection of the largest adrenal gland, since it leads to hypercortisolism remission in up to 95% of the cases. Medical treatment focused on the blockade of aberrant receptors may lead to hypercortisolism control, although cortisol response is frequently transient. miBACD is mainly divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). miBACD can present at an early age, representing one of the main causes of CS at a young age. The high-dose dexamethasone suppression test can be useful in identifying a paradoxical increase in 24h-urinary free cortisol, that is a quite specific in PPNAD. Bilateral adrenalectomy is generally the treatment of choice in patients with overt CS in miBACD, but unilateral adrenalectomy could be considered in cases with asymmetric disease and mild hypercortisolism. This article will discuss the clinical presentation, genetic background, hormonal and imaging features and treatment of the main causes of primary bilateral adrenal hyperplasia associated with hypercortisolism.
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Affiliation(s)
- Marta Araujo-Castro
- Endocrinology & Nutrition Department, Ramón y Cajal University Hospital, Madrid, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, Madrid, Spain
- Departament of Medicine, Alcalá University, Madrid, Spain
- *Correspondence: Marta Araujo-Castro,
| | - Mónica Marazuela
- Endocrinology & Nutrition Department, La Princesa University Hospital, Madrid, Spain
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27
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Beltsevich DG, Troshina EA, Melnichenko GA, Platonova NM, Ladygina DO, Chevais A. Draft of the clinical practice guidelines “Adrenal incidentaloma”. ENDOCRINE SURGERY 2021. [DOI: 10.14341/serg12712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The wider application and technical improvement of abdominal imaging procedures in recent years has led to an increasingly frequent detection of adrenal gland masses — adrenal incidentaloma, which have become a common clinical problem and need to be investigated for evidence of hormonal hypersecretion and/or malignancy. Clinical guidelines are the main working tool of a practicing physician. Laconic, structured information about a specific nosology, methods of its diagnosis and treatment, based on the principles of evidence-based medicine, make it possible to give answers to questions in a short time, to achieve maximum efficiency and personalization of treatment. These clinical guidelines include data on the prevalence, etiology, radiological features and assessment of hormonal status of adrenal incidentalomas. In addition, this clinical practice guideline provides information on indications for surgery, postoperative rehabilitation and follow-up.
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28
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Chevalier B, Vantyghem MC, Espiard S. Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment. Biomedicines 2021; 9:biomedicines9101397. [PMID: 34680514 PMCID: PMC8533142 DOI: 10.3390/biomedicines9101397] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/28/2021] [Accepted: 10/03/2021] [Indexed: 01/06/2023] Open
Abstract
Bilateral adrenal hyperplasia is a rare cause of Cushing’s syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades’ findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.
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Affiliation(s)
- Benjamin Chevalier
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, F-59000 Lille, France; (B.C.); (M.-C.V.)
| | - Marie-Christine Vantyghem
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, F-59000 Lille, France; (B.C.); (M.-C.V.)
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1190, European Genomic Institute for Diabetes (EGID), CHU Lille, F-59000 Lille, France
| | - Stéphanie Espiard
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, F-59000 Lille, France; (B.C.); (M.-C.V.)
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1190, European Genomic Institute for Diabetes (EGID), CHU Lille, F-59000 Lille, France
- Correspondence:
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Nishiyama M, Karashima T, Iwasaki Y, Terada Y, Fujimoto S. Unilateral adrenalectomy partially improved hyperglycemia in a patient with primary bilateral macronodular adrenal hyperplasia. Diabetol Int 2021; 12:480-484. [PMID: 34567928 DOI: 10.1007/s13340-021-00503-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/28/2021] [Indexed: 11/27/2022]
Abstract
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by bilateral multiple adrenal macro-nodules that often cause mild over-secretion of cortisol in the form of subclinical Cushing's syndrome. We herein describe a case, wherein unilateral adrenalectomy partially improved hyperglycemia in a patient with PBMAH and suggest the usefulness and limitations of this surgical strategy. A 64-year-old woman with type 2 diabetes had an incidental diagnosis of bilateral adrenal lesions. She had a family history of type 2 diabetes, and her HbA1c level was 8.9% under insulin therapy. She did not present with any symptoms associated with Cushing's syndrome. The basal cortisol level was in the normal range (12.0 μg/dL); however, the adrenocorticotropic hormone (ACTH) level was suppressed (2.1 pg/mL) and the serum cortisol level was not suppressed in the dexamethasone test. Computed tomography and magnetic resonance imaging showed bilateral adrenal macro-nodules and 131I-adosterol accumulated in the bilateral adrenal lesions. Collectively, she was diagnosed with subclinical Cushing's syndrome due to PBMAH complicated with diabetes mellitus, hypertension, and dyslipidemia. Laparoscopic left adrenalectomy was performed, and the pathologic findings were consistent with PBMAH. After unilateral adrenalectomy, serum cortisol levels decreased, and hypertension improved. Both HbA1c levels and insulin requirement also decreased, but insulin therapy was continuously needed. It should be noted that hyperglycemia may not be cured after successful surgery in a patient with PBMAH. Additional operation or medical therapy should be considered if unilateral adrenalectomy is unable to correct hypercortisolism in PBMAH patients.
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Affiliation(s)
- Mitsuru Nishiyama
- Health Care Center, Kochi University, 1-5-2, Akebono-cho, Kochi-City, Kochi 780-8520 Japan.,Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, 1-185, Kohasu, Okoh-cho, Nankoku-City, Kochi 783-8505 Japan
| | - Takashi Karashima
- Department of Urology, Kochi Medical School, Kochi University, 1-185, Kohasu, Okoh-cho, Nankoku-City, Kochi 783-8505 Japan
| | - Yasumasa Iwasaki
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, 1-185, Kohasu, Okoh-cho, Nankoku-City, Kochi 783-8505 Japan
| | - Yoshio Terada
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, 1-185, Kohasu, Okoh-cho, Nankoku-City, Kochi 783-8505 Japan
| | - Shimpei Fujimoto
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, 1-185, Kohasu, Okoh-cho, Nankoku-City, Kochi 783-8505 Japan
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He WT, Wang X, Song W, Song XD, Lu YJ, Lv YK, He T, Yu XF, Hu SH. A novel nonsense mutation in ARMC5 causes primary bilateral macronodular adrenocortical hyperplasia. BMC Med Genomics 2021; 14:126. [PMID: 33971873 PMCID: PMC8108324 DOI: 10.1186/s12920-021-00896-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/07/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare form of adrenal Cushing's syndrome. The slowly progressing expansion of bilateral adrenal tissues usually persists for dozens of years, leading to delayed onset with severe conditions due to chronic mild hypercortisolism. About 20-50% cases were found to be caused by inactivating mutation of armadillo repeat-containing protein 5 (ARMC5) gene. CASE PRESENTATION A 51-year-old man was admitted for severe diabetes mellitus, resistant hypertension, centripedal obesity and edema. PBMAH was diagnosed after determination of adrenocorticotropic hormone and cortisol levels, dexamethasone suppression tests and abdominal contrast-enhanced CT scanning. The metabolic disorders of the patient remarkably improved after sequentially bilateral laparoscopic adrenalectomy combined with hormone replacement. Sanger sequencing showed germline nonsense mutation of ARMC5 c.967C>T (p.Gln323Ter). The second somatic missense mutation of ARMC5 was detected in one out of two resected nodules, reflecting the second-hit model of tumorigenesis. Routine genetic testing in his apparently healthy offspring showed one of two daughters and one son harbored the germline mutation. CONCLUSIONS In conclusion, our case report highlight the importance of genetic testing in the molecular diagnosis of PBMAH. Genetic screening in related family members will find out asymptomatic variant carriers to guide life-long follow-up.
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Affiliation(s)
- Wen-Tao He
- Branch of National Clinical Research Center for Metabolic Disease, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiong Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wen Song
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiao-Dong Song
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan-Jun Lu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan-Kai Lv
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ting He
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xue-Feng Yu
- Branch of National Clinical Research Center for Metabolic Disease, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shu-Hong Hu
- Branch of National Clinical Research Center for Metabolic Disease, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Ivović M, Marina LV, Šojat AS, Tančić-Gajić M, Arizanović Z, Kendereški A, Vujović S. Approach to the Patient with Subclinical Cushing's Syndrome. Curr Pharm Des 2021; 26:5584-5590. [PMID: 32787757 DOI: 10.2174/1381612826666200813134328] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 07/08/2020] [Indexed: 01/07/2023]
Abstract
A growing number of patients with adrenal incidentalomas and subclinical Cushing's syndrome (SCS) led to an increasing number of different guidelines, and diagnostic and treatment recommendations. Excess cortisol secretion in patients with SCS is associated with several comorbidities, such as hypertension, dyslipidemia, type 2 diabetes mellitus, and obesity, which in the long-term increase mortality of these patients. Subtle cortisol secretion affects bone health, quality of life and causes depression, but due to the unapparent clinical features, patients with SCS are often at risk between over and under treatment. This narrative review aimed to summarize the latest recommendations on the approach to the patient with subclinical Cushing's syndrome.
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Affiliation(s)
- Miomira Ivović
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Ljiljana V Marina
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Antoan S Šojat
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Milina Tančić-Gajić
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Zorana Arizanović
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Aleksandra Kendereški
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Svetlana Vujović
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
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Bouys L, Chiodini I, Arlt W, Reincke M, Bertherat J. Update on primary bilateral macronodular adrenal hyperplasia (PBMAH). Endocrine 2021; 71:595-603. [PMID: 33587256 DOI: 10.1007/s12020-021-02645-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 01/21/2021] [Indexed: 01/05/2023]
Abstract
Primary bilateral macronodular adrenal hyperplasia (PBMAH), characterized by bilateral benign adrenal macronodules (>1 cm) potentially responsible for variable levels of cortisol excess, is a rare and heterogeneous disease. However, its frequency increases due to incidentally diagnosed cases on abdominal imaging carried out for reasons other than suspected adrenal disease. Mostly isolated, it can also be associated with dominantly inherited genetic conditions in rare cases. Considering the bilateral nature of adrenal involvement and the description of familial cases, the search of a genetic predisposition has led to the identification of germline heterozygous inactivating mutations of the putative tumor suppressor gene ARMC5, causing around 25% of the apparent sporadic cases. Rigorous biochemical and imaging assessment are key elements in the management of this challenging disease in terms of diagnosis. Treatment is reserved for symptomatic patients with overt or subclinical Cushing syndrome, and was historically based on bilateral adrenalectomy, which nowadays tends to be replaced by unilateral adrenalectomy or lifelong treatment with cortisol synthesis inhibitors.
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Affiliation(s)
- Lucas Bouys
- Institut Cochin, Université de Paris, Inserm U1016, CNRS UMR8104, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Iacopo Chiodini
- Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, ENDO-ERN HCP, University of Milan, Milan, Italy
| | - Wiebke Arlt
- Institute of Metabolism and Systems Research, ENDO-ERN HCP, University of Birmingham, Birmingham, B15 2TT, UK
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, ENDO-ERN HCP, Klinikum der Universität, Ludwig-Maximilians-Universität München, Ziemssenstraße 1, 80336, Munich, Germany
| | - Jérôme Bertherat
- Institut Cochin, Université de Paris, Inserm U1016, CNRS UMR8104, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France.
- Centre de Référence Maladies Rares de la Surrénale, Service d'Endocrinologie, ENDO-ERN HCP, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.
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Meloche-Dumas L, Mercier F, Lacroix A. Role of unilateral adrenalectomy in bilateral adrenal hyperplasias with Cushing's syndrome. Best Pract Res Clin Endocrinol Metab 2021; 35:101486. [PMID: 33637447 DOI: 10.1016/j.beem.2021.101486] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Primary bilateral adrenocortical hyperplasias are rare forms of pituitary ACTH-independent Cushing's syndrome (CS). They are divided between primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia (MiBAH), which is subdivided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). One of the most debated aspects surrounding these entities is their most appropriate therapy. Although bilateral adrenalectomy (BA) has previously been the most utilized therapy for patients with overt CS, recent studies have indicated that unilateral adrenalectomy (UA) can be effective in patients with PBMAH and some with MiBAH with fewer long-term side effects. Medical therapies can also be used for bridging to surgery or rarely in the long-term for these patients. We review the various degrees of CS resulting from PBMAH and MiBAH, with a special focus on their respective therapies including UA, taking into account the recent pathophysiological and genetics findings.
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Affiliation(s)
- Léamarie Meloche-Dumas
- Surgical Oncology Service, Department of Surgery, Centre Hospitalier de L'Université de Montréal (CHUM), Université de Montréal, Montréal, Canada.
| | - Frédéric Mercier
- Surgical Oncology Service, Department of Surgery, Centre Hospitalier de L'Université de Montréal (CHUM), Université de Montréal, Montréal, Canada.
| | - André Lacroix
- Division of Endocrinology, Department of Medicine, Centre Hospitalier de L'Université de Montréal (CHUM), Université de Montréal, Montréal, Canada.
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Vogel F, Braun L, Rubinstein G, Zopp S, Oßwald A, Schilbach K, Schmidmaier R, Bidlingmaier M, Reincke M. Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study. Front Endocrinol (Lausanne) 2021; 12:765067. [PMID: 34777259 PMCID: PMC8578886 DOI: 10.3389/fendo.2021.765067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/11/2021] [Indexed: 11/24/2022] Open
Abstract
CONTEXT Glucocorticoid excess exhibits multiple detrimental effects by its catabolic properties. Metformin was recently suggested to protect from adverse metabolic side-effects of glucocorticoid treatment. Whether metformin is beneficial in patients with endogenous glucocorticoid excess has not been clarified. OBJECTIVE To evaluate the phenotype in patients with endogenous Cushing's syndrome (CS) treated with metformin at the time of diagnosis. PATIENTS AND METHODS As part of the German Cushing's Registry we selected from our prospective cohort of 96 patients all 10 patients who had been on pre-existing metformin treatment at time of diagnosis (CS-MET). These 10 patients were matched for age, sex and BMI with 16 patients without metformin treatment (CS-NOMET). All patients had florid CS at time of diagnosis. We analyzed body composition, metabolic parameters, bone mineral density and bone remodeling markers, muscle function and quality of life. RESULTS As expected, diabetes was more prevalent in the CS-MET group, and HbA1c was higher. In terms of comorbidities and the degree of hypercortisolism, the two groups were comparable. We did not observe differences in terms of muscle function or body composition. In contrast, bone mineral density in metformin-treated patients was superior to the CS-NOMET group at time of diagnosis (median T-Score -0.8 versus -1.4, p = 0.030). CS-MET patients showed decreased β-CTX levels at baseline (p = 0.041), suggesting reduced bone resorption under metformin treatment during glucocorticoid excess. CONCLUSION This retrospective cohort study supports potential protective effects of metformin in patients with endogenous glucocorticoid excess, in particular on bone metabolism.
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35
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Wurth R, Tirosh A, Kamilaris CDC, Camacho J, Faucz FR, Maria AG, Berthon A, Papadakis GZ, Nilubol N, Hamimi A, Gharib AM, Demidowich A, Zilbermint M, Eisenhofer G, Braun L, Reincke M, Stratakis CA, Hannah-Shmouni F. Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia. J Endocr Soc 2021; 5:bvaa162. [PMID: 33305158 PMCID: PMC7716656 DOI: 10.1210/jendso/bvaa162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Indexed: 11/19/2022] Open
Abstract
CONTEXT Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated. OBJECTIVE We hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed. DESIGN A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019. SETTING Tertiary care clinical research center. PATIENTS Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics. INTERVENTION Clinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota). MAIN OUTCOME AND MEASURES 17-hydroxycorticosteroids (17-OHS), ARMC5 genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume. RESULTS A cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ± 11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76, P = 0.028), urinary free cortisol (R = 0.70, P = 0.035), and 17-OHS (R = 0.87, P = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in ARMC5 (R = 0.72, P = 0.018; R = 0.65, P = 0.042; and R = 0.73, P = 0.016, respectively). CONCLUSIONS Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients.
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Affiliation(s)
- Rachel Wurth
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Amit Tirosh
- Neuroendocrine Tumors Service, Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Crystal D C Kamilaris
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Jancarlos Camacho
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Fabio R Faucz
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Andrea Gutierrez Maria
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Annabel Berthon
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Georgios Z Papadakis
- Foundation for Research and Technology (FORTH), Institute of Computer Science (ICS), Computational Biomedicine Laboratory, Heraklion, Greece
- Department of Radiology, Medical School, University of Crete, Heraklion, Greece
| | - Naris Nilubol
- Surgical Oncology Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Ahmed Hamimi
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Ahmed M Gharib
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Andrew Demidowich
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Mihail Zilbermint
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
- Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baltimore, MD, USA
- Johns Hopkins Community Physicians at Suburban Hospital, Bethesda, MD, USA
| | - Graeme Eisenhofer
- Institute of Clinical Chemistry and Laboratory Medicine, and Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Leah Braun
- Medizinische Klinik und Poliklinik IV, Division of Endocrinology, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Division of Endocrinology, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Constantine A Stratakis
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Fady Hannah-Shmouni
- Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
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Chevais A, Selivanova LS, Kuznetzov NS, Derkatch DА, Yukina MY, Beltsevich DG. [Immunohistochemical study on the expression/hyperexpression of aberrant/eutopic receptors in patients with bilateral macronodular adrenal hyperplasia]. ACTA ACUST UNITED AC 2020; 66:4-12. [PMID: 33481362 DOI: 10.14341/probl12516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 10/06/2020] [Accepted: 11/27/2020] [Indexed: 01/05/2023]
Abstract
Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome. In this case cortisol production can be regulated by both genetic factors and various molecular mechanisms. The presence of aberrant or overexpression of eutopic receptors on the membrane of adrenal cortex may lead to activation of cAMP/PKA signaling pathways and consequently, pathological stimulation of steroidogenesis. Since proving the effectiveness of unilateral adrenalectomy in BMAH by achievement of stable remission, preoperative clinical and laboratory tests (ligand-induced tests) are no longer of relevant. Nevertheless, in the absence of normalization of the level of cortisol in the postoperative period or its recurrence, subsequent specific targeted medical options can be offered only if expression/hyperexpression predominance of one or another receptor. Their detection becomes possible using more reliable diagnostic methods such as polymerase chain reaction (PCR) and immunohistochemical studies (IHC) than clinical laboratory tests. At the moment, PCR has gained a wider application. This article summarizes data on the use of immunohistochemical study in BMAH.
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Sherlock M, Scarsbrook A, Abbas A, Fraser S, Limumpornpetch P, Dineen R, Stewart PM. Adrenal Incidentaloma. Endocr Rev 2020; 41:bnaa008. [PMID: 32266384 PMCID: PMC7431180 DOI: 10.1210/endrev/bnaa008] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 04/06/2020] [Indexed: 12/14/2022]
Abstract
An adrenal incidentaloma is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management. The majority of patients can be reassured and discharged, but a personalized approach based upon image analysis, endocrine workup, and clinical symptoms and signs are required in every case. Adrenocortical carcinoma remains a real concern but is restricted to <2% of all cases. Functional adrenal incidentaloma lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of autonomous cortisol secretion. Modern-day surgery has improved outcomes and novel radiological and urinary biomarkers will improve early detection and patient stratification in future years to come.
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Affiliation(s)
- Mark Sherlock
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
- Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Andrew Scarsbrook
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, St James University Hospital, Leeds, UK
| | - Afroze Abbas
- Department of Endocrinology, Leeds Teaching Hospitals NHS Trust, St James University Hospital, Leeds, UK
| | - Sheila Fraser
- Department of Endocrine Surgery, Leeds Teaching Hospitals NHS Trust, St James University Hospital, Leeds, UK
| | - Padiporn Limumpornpetch
- Faculty of Medicine & Health, University of Leeds, Worsley Building, Clarendon Way, Leeds, UK
| | - Rosemary Dineen
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
- Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Paul M Stewart
- Faculty of Medicine & Health, University of Leeds, Worsley Building, Clarendon Way, Leeds, UK
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Braun LT, Fazel J, Zopp S, Benedix S, Osswald-Kopp A, Riester A, Rubinstein G, Seidensticker M, Beuschlein F, Drey M, Bidlingmaier M, Schmidmaier R, Reincke M. The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2-Year Follow-Up Study. J Bone Miner Res 2020; 35:1711-1717. [PMID: 32315096 DOI: 10.1002/jbmr.4033] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/01/2020] [Accepted: 04/13/2020] [Indexed: 12/16/2022]
Abstract
Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long-term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen-IN-propeptide (PINP), alkaline bone phosphatase, CTX-I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex-, age-, and body mass index (BMI)-matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T-score = -1.4 ± 1.1). Two years after successful surgery, the T-score had improved in 78% of patients (mean T-score 2 years postoperatively -1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX-I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three- to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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Affiliation(s)
- Leah T Braun
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Julia Fazel
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Stephanie Zopp
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Sarina Benedix
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Andrea Osswald-Kopp
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Anna Riester
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - German Rubinstein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Max Seidensticker
- Klinik und Poliklinik für Radiologie, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Felix Beuschlein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany.,Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland
| | - Michael Drey
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Ralf Schmidmaier
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
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39
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Yoshiaki Tanno F, Srougi V, Almeida MQ, Ide Yamauchi F, Morbeck Almeida Coelho F, Nishi MY, Claudia Nogueira Zerbini M, Silvia Correa Soares I, Adelaide Albergaria Pereira M, Laiz Silva Charchar H, Meneses Ferreira Lacombe A, Balderrama Brondani V, Srougi M, Carlos Nahas W, Mendonca BB, Luis Chambô J, Candida Barisson Villares Fragoso M. A New Insight into the Surgical Treatment of Primary Macronodular Adrenal Hyperplasia. J Endocr Soc 2020; 4:bvaa083. [PMID: 32724871 PMCID: PMC7375340 DOI: 10.1210/jendso/bvaa083] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose This prospective study presents the results of a new approach in the treatment of primary macronodular adrenal hyperplasia (PMAH), with simultaneous total adrenalectomy of the larger adrenal gland and partial adrenalectomy of the contralateral adrenal gland (adrenal-sparing surgery). Materials and Methods We performed a prospective study including 17 patients with PMAH treated surgically with adrenal-sparing surgery in a tertiary referral hospital, with a median follow-up of 41 months. Clinical, hormonal, and genetic parameters were evaluated before surgery and during follow-up. All patients had at least 1 radiological examination before and after the procedure. Results Among the 17 patients, all but 1 patient had complete hypercortisolism control, and 12 recovered normal adrenal function after surgery. Significant improvement in clinical parameters was observed: weight loss (P = .004); reduction of both systolic (P = .001) and diastolic (P = .001) blood pressure; and reduction in the number of antihypertensive drugs (P < .001). Intra-, peri-, and postoperative complications were not observed. Conclusion Adrenal-sparing surgery is a safe and feasible procedure to treat patients with PMAH, providing a substantial chance of hypercortisolism control without the disadvantages of lifetime corticosteroid replacement.
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Affiliation(s)
- Fabio Yoshiaki Tanno
- Divisão de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Victor Srougi
- Divisão de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Madson Q Almeida
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Fernando Ide Yamauchi
- Instituto de Radiologia- INRAD, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Fernando Morbeck Almeida Coelho
- Instituto de Radiologia- INRAD, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Mirian Yumie Nishi
- Divisão de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | | | - Iracy Silvia Correa Soares
- Serviço de Anestesiologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Maria Adelaide Albergaria Pereira
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Helaine Laiz Silva Charchar
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Amanda Meneses Ferreira Lacombe
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Vania Balderrama Brondani
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Miguel Srougi
- Divisão de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Willian Carlos Nahas
- Divisão de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Berenice B Mendonca
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - José Luis Chambô
- Divisão de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Maria Candida Barisson Villares Fragoso
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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40
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Vassiliadi DA, Partsalaki E, Tsagarakis S. Approach to patients with bilateral adrenal incidentalomas. Curr Opin Endocrinol Diabetes Obes 2020; 27:125-131. [PMID: 32209820 DOI: 10.1097/med.0000000000000536] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
PURPOSE OF REVIEW The current review provides a summary on the most recent developments regarding the cause, work-up and management of bilateral adrenal incidentalomas (BAI). RECENT FINDINGS The recent ENS@T/ESE guidelines provide comprehensive directions on the evaluation and management of patients with adrenal incidentalomas with special focus on those with bilateral tumours. Intraadrenal ACTH synthesis that may locally stimulate cortisol secretion challenging the traditionally used term 'ACTH-independent'. Inactivating mutations of a new tumour suppressor gene, armadillo repeat containing 5 (ARMC5), are implicated in a number of patients, especially those with multiple macronodules (bilateral macronodular hyperplasia) and evidence of hypercortisolism. Loss-of-function mutations of the glucocorticoid receptor gene (NR3C1) consist a new possible genetic cause of BAIs. Regarding management an increasing number of studies provide data on the benefits and safety of unilateral rather than bilateral adrenalectomy. There is also emerging data on the beneficial use of steroidogenesis inhibitors in a dosing schedule that aims to mimic the normal cortisol rhythm with promising short-term results, but the long-term clinical benefits of this approach remain to be demonstrated. SUMMARY The diagnostic approach consists of imaging and hormonal evaluation. Imaging characterization should be done separately for each lesion. Hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1-mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary-free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism ACTH levels should be measured to establish ACTH-independency. The appropriate management of BAI associated with cortisol excess remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with overt and severe hypercortisolism. Unilateral adrenalectomy might be considered in selected patients. Medical therapy is not an established approach yet but it may be considered when control of hypercortisolism is desired, but surgery is not an option.
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Affiliation(s)
- Dimitra A Vassiliadi
- Department of Endocrinology, Diabetes, and Metabolism, National Expertise Center for Rare Endocrine Disorders, Evangelismos Hospital, Athens, Greece
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Abstract
Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be secondary to primary bilateral macronodular adrenocortical hyperplasia (PBMAH) or micronodular bilateral adrenal hyperplasia (MiBAH) which may be divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). Both lead to oversecretion of cortisol and potentially to Cushing's syndrome. Moreover, adrenocortical hyperplasia may be secondary to longstanding ACTH stimulation in ACTH oversecretion as in Cushing's disease, ectopic ACTH secretion or glucocorticoid resistance syndrome and congenital adrenal hyperplasia secondary to various enzymatic defects within the cortex. Finally, idiopathic bilateral adrenal hyperplasia is the most common cause of primary aldosteronism. We will discuss recent findings on the multifaceted forms of adrenocortical hyperplasia.
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Affiliation(s)
- Isabelle Bourdeau
- Division of Endocrinology, Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, Canada.
| | - Stéfanie Parisien-La Salle
- Division of Endocrinology, Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, Canada.
| | - André Lacroix
- Division of Endocrinology, Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, Canada.
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42
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Abstract
Overt Cushing's syndrome is a severe condition responsible for multiple comorbidities and increased mortality. Effective treatment is essential to reduce mortality, improve comorbidities and long-term quality of life. Surgical resection of the causal lesion(s) is generally the first-line and most effective treatment to normalize cortisol secretion. Adjunctive symptomatic treatments of co-morbidities are often necessary both during the active phase of the disease and for persisting co-morbidities after cessation of hypercortisolism. Second-line treatments include various pharmacological treatments, bilateral adrenalectomy, and radiotherapy of corticotroph tumors. The choice of these treatments is complex, must be performed in a multidisciplinary expert team to be individualized for each patient, and use a shared decision-making approach.
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Affiliation(s)
- Amandine Ferriere
- Service d'endocrinologie, Diabétologie et maladies métaboliques, CHU de bordeaux, Avenue Magellan 33600, Pessac, France.
| | - Antoine Tabarin
- Service d'endocrinologie, Diabétologie et maladies métaboliques, CHU de bordeaux, Avenue Magellan 33600, Pessac, France; INSERM and University of Bordeaux, Neurocentre Magendie, U1215, France.
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43
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Regazzo D, Barbot M, Scaroni C, Albiger N, Occhi G. The pathogenic role of the GIP/GIPR axis in human endocrine tumors: emerging clinical mechanisms beyond diabetes. Rev Endocr Metab Disord 2020; 21:165-183. [PMID: 31933128 DOI: 10.1007/s11154-019-09536-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the gastrointestinal tract in response to nutrients. GIP has a variety of effects on different systems, including the potentiation of insulin secretion from pancreatic β-cells after food intake (i.e. incretin effect), which is probably the most important. GIP effects are mediated by the GIP receptor (GIPR), a G protein-coupled receptor expressed in several tissues, including islet β-cells, adipocytes, bone cells, and brain. As well as its involvement in metabolic disorders (e.g. it contributes to the impaired postprandial insulin secretion in type 2 diabetes (T2DM), and to the pathogenesis of obesity and associated insulin resistance), an inappropriate GIP/GIPR axis activation of potential diagnostic and prognostic value has been reported in several endocrine tumors in recent years. The ectopic GIPR expression seen in patients with overt Cushing syndrome and primary bilateral macronodular adrenal hyperplasia or unilateral cortisol-producing adenoma has been associated with an inverse rhythm of cortisol secretion, with low fasting morning plasma levels that increase after eating. On the other hand, most acromegalic patients with an unusual GH response to oral glucose suppression have GIPR-positive somatotropinomas, and a milder phenotype, and are more responsive to medical treatment. Neuroendocrine tumors are characterized by a strong GIPR expression that may correlate positively or inversely with the proliferative index MIB-1, and that seems an attractive target for developing novel radioligands. The main purpose of this review is to summarize the role of the GIP/GIPR axis in endocrine neoplasia, in the experimental and the clinical settings.
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Affiliation(s)
- Daniela Regazzo
- Department of Medicine Endocrinology Unit, Padova University Hospital, Padova, Italy
| | - Mattia Barbot
- Department of Medicine Endocrinology Unit, Padova University Hospital, Padova, Italy
| | - Carla Scaroni
- Department of Medicine Endocrinology Unit, Padova University Hospital, Padova, Italy
| | - Nora Albiger
- Endocrinology Service, ULSS 6 Euganea, Padova, Italy
| | - Gianluca Occhi
- Department of Biology, University of Padova, Padova, Italy.
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Ragnarsson O. Cushing's syndrome - Disease monitoring: Recurrence, surveillance with biomarkers or imaging studies. Best Pract Res Clin Endocrinol Metab 2020; 34:101382. [PMID: 32139169 DOI: 10.1016/j.beem.2020.101382] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pituitary surgery is the first-line treatment for patients with Cushing's disease. For patients who are not considered candidates for pituitary surgery, pituitary radiation and bilateral adrenalectomy are further treatment alternatives. Not all patients are cured with pituitary surgery, and a substantial number of patients develop recurrence, sometimes many years after an apparently successful treatment. The same applies to patients treated with radiotherapy. Far from all patients are cured, and in many cases the disease recurs. Bilateral adrenalectomy, although always curative, causes chronic adrenal insufficiency and the remaining pituitary tumour can continue to grow and cause symptoms due to pressure on adjacent tissues, a phenomenon called Nelson's syndrome. In this paper the rate of recurrence of hypercortisolism, as well as the rate of development of Nelson's syndrome, following treatment of patients with Cushing's syndrome, will be reviewed. The aim of the paper is also to summarize clinical and biochemical factors that are associated with recurrence of hypercortisolism and how the patients should be monitored following treatment.
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Affiliation(s)
- Oskar Ragnarsson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and The Department of Endocrinology, Sahlgrenska University Hospital, Göteborg, SE-41302, Sweden.
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45
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Oßwald A, Reincke M. Response to the Letter to the Editor: "Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy". J Clin Endocrinol Metab 2020; 105:5607877. [PMID: 31665333 DOI: 10.1210/clinem/dgz106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 10/06/2019] [Indexed: 11/19/2022]
Affiliation(s)
- Andrea Oßwald
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Germany
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46
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Chabre O, Young J, Caron P, Tabarin A. Letter to the Editor: "Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy". J Clin Endocrinol Metab 2020; 105:5607876. [PMID: 31665316 DOI: 10.1210/clinem/dgz105] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/03/2019] [Indexed: 11/19/2022]
Affiliation(s)
- Olivier Chabre
- Endocrinologie, Centre Hospitalier Universitaire Grenoble-Alpes, Grenoble, France
| | - Jacques Young
- University of Paris-Sud and University Paris-Saclay, Le Kremlin-Bicêtre, FranceAssistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Department of Endocrinology, Le Kremlin-Bicêtre, France
| | - Philippe Caron
- Department of Endocrinology and Metabolic Diseases, Pôle Cardio-Vasculaire et Métabolique, CHU Larrey, Toulouse, France
| | - Antoine Tabarin
- Department of Endocrinology, Diabetes and Nutrition. University of Bordeaux, Bordeaux, France
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Sarda Y, Shenoy D, Shetty S, Ullal S, Katyal S. Lean Cushing's. J Family Med Prim Care 2020; 9:3759-3761. [PMID: 33102366 PMCID: PMC7567194 DOI: 10.4103/jfmpc.jfmpc_230_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/13/2020] [Accepted: 04/07/2020] [Indexed: 11/17/2022] Open
Abstract
This is a case report of 59 years old male with adrenocorticotropic hormone ACTH-independent macronodular adrenal hyperplasia (AIMAH), which is a rare cause of Cushing's syndrome. He was detected to have adrenal lesions incidentally on imaging. The biochemical evaluation was suggestive of endogenous ACTH-independent Cushing's syndrome. Contrast Enhanced CT of the abdomen done to characterize the lesion was suggestive of bilateral macro-nodular adrenal hyperplasia. There was no evidence of cushingoid features except for type 2 diabetes mellitus suggestive of subclinical Cushing's. He was not planned for any immediate medical/surgical management since metabolic control was achieved with oral anti-diabetics (OADs) and anti-hypertensive medications. He is on regular follow up with well-controlled sugars and blood pressure.
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48
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Cristante J, Chabre O. Unilateral adrenalectomy in primary bilateral macronodular hyperplasia. ACTA ACUST UNITED AC 2019. [DOI: 10.1016/j.coemr.2019.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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49
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Chabre O, Cristante J. TREATMENT OF CUSHING'S SYNDROME : WHAT PLACE FOR MEDICAL TREATMENT? ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2019; 15:237-243. [PMID: 31508183 PMCID: PMC6711638 DOI: 10.4183/aeb.2019.237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Surgery plays a major role as a first-line treatment of the different etiologies of Cushing's syndrome (CS) and bilateral adrenalectomy (BA) is extremely effective as a second line, so that there seems to be little room for medical treatment (MT). However, during the past years several drugs acting either on ACTH secretion or cortisol synthesis have been developed, so that MT of CS might be reassessed. After briefly analyzing the efficiency and tolerance of surgical and medical treatments of CS we try to distinguish consensual and controversial indications for MT. We believe the former include "pre-operative treatment" in rare patients in whom the severity of CS is likely to increase the risks of surgery; "inoperability" for rare patients who cannot be operated even when CS is controlled and "surgical failure or recurrence", mainly in patients Cushing's disease (CD) not in remission after TSS. Controversial indications include "unavailability of an expert surgeon", which we believe does not make sense when the cost of MT is taken into consideration. Finally in patients with the "surgical failure or recurrence" indication the balance between efficacy and side effects of MT should be balanced with the efficacy and side effects of BA.
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Affiliation(s)
- O. Chabre
- Grenoble Alpes University Hospital (CHUGA) - Endocrinology, Grenoble, France
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