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Background Adrenalectomy cures unilateral primary aldosteronism, and it improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success postsurgery, suggesting that surgery was ineffective. Methods We assessed all patients 6 to 12 months post-surgery for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2, and CONNsortium criteria. We estimated blood pressure changes after adjustment for changes in defined daily dosages of antihypertensive medications. We also reassessed all patients using PASO at their recent clinical visit. Results A total of 104 patients with unilateral primary aldosteronism underwent adrenalectomy at 2 tertiary centers from 2000 to 2019; 24 (23%), 31 (30%), and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2, and CONNsortium criteria, respectively. Among 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariable analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus, and lower defined daily dosages at baseline. After adjustment for changes in defined daily dosages, 7 of 24 patients showed blood pressure improvement ≥20/10 mm Hg post-surgery. After a follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show clinical improvement post-surgery using any of the 3 mentioned criteria or using PASO criteria at their recent clinical visit. Conclusion Although some patients may be classified with absent clinical success post-surgery, the assessment of clinical outcomes remains subject to many variables. In patients with unilateral primary aldosteronism, evidenced by lateralization on AVS, unilateral adrenalectomy should remain the recommended treatment.

Adrenal vein sampling (AVS) is recommended to subtype primary aldosteronism, but it is technically challenging. We compared 11C-Metomidate-PET-computed tomography (PET-CT) and AVS for subtyping of primary aldosteronism.Patients with confirmed primary aldosteronism underwent both AVS and 11C-Metomidate PET-CT (post-dexamethasone). All results were reviewed at a multidisciplinary meeting to decide on final subtype diagnosis. Primary outcome was accuracy of PET versus AVS to diagnosis of unilateral primary aldosteronism based on post-surgical biochemical cure. Secondary outcome was accuracy of both tests to final subtype diagnosis.All 25 patients recruited underwent PET and successful AVS (100%). Final diagnosis was unilateral in 22 patients, bilateral in two and indeterminate in one due to discordant lateralization. Twenty patients with unilateral primary aldosteronism underwent surgery, with 100% complete biochemical success, and 75% complete/partial clinical success. For the primary outcome, sensitivity of PET was 80% [95% confidence interval (95% CI): 56.3-94.3] and AVS was 75% (95% CI: 50.9-91.3). For the secondary outcome, sensitivity and specificity of PET was 81.9% (95% CI: 59.7-94.8) and 100% (95% CI: 15.8-100), and AVS was 68.2% (95% CI: 45.1-86.1) and 100% (95% CI: 15.8-100), respectively. Twelve out of 20 (60%) patients had both PET and AVS lateralization, four (20%) PET-only, three (15%) AVS-only, while one patient did not lateralize on PET or AVS. Post-surgery outcomes did not differ between patients identified by either test.In our pilot study, 11C-Metomidate PET-CT performed comparably to AVS, and this should be validated in larger studies. PET identified patients with unilateral primary aldosteronism missed on AVS, and these tests could be used together to identify more patients with unilateral primary aldosteronism.http://links.lww.com/HJH/B918.

CONTEXT Studies find surgery superior to medications in the treatment of primary aldosteronism (PA). It would be ideal to compare surgical and medical therapy in patients with unilateral PA only, who have the option between these treatment modalities. However, this is challenging as most patients with unilateral PA on adrenal vein sampling (AVS) undergo surgery. OBJECTIVE To compare outcomes of surgery and medications in patients with confirmed or likely unilateral PA. DESIGN Retrospective cohort study of 274 patients with PA managed at two referral centres from 2000 to 2019. PATIENTS 154 patients identified with unilateral PA using AVS and a validated clinical prediction model were treated with surgical (n = 86) or medical (n = 68) therapy. MEASUREMENTS Primary outcome was a composite incident cardiovascular event comprising acute myocardial infarction, coronary revascularization, stroke, atrial fibrillation or congestive cardiac failure. Secondary outcomes were clinical and biochemical control. RESULTS Cardiovascular outcomes were comparable, with the surgery group having an adjusted hazard ratio of 0.93 (95% CI: 0.32-2.67), p = .89. Both treatments improved clinical and biochemical control, but surgery resulted in better systolic blood pressure, 133.0 ± 11.7 mmHg versus 137.9 ± 14.6 mmHg, p = .02, and lower defined daily dosages of antihypertensive medications, 1.0 (IQR 0.0-2.0) versus 2.6 (IQR 0.8-4.3), p

Introduction Patients with primary aldosteronism (PA) have increased cardiovascular risk, and there are concerns about the efficacy of medical therapy. Objective We aimed to assess long-term tolerability and efficacy of medical therapy in PA patients. Methods We conducted a retrospective study on 201 PA patients treated with medical therapy (spironolactone, eplerenone, or amiloride) from 2000 to 2020 at 2 tertiary centers. Clinical and biochemical control and side effects were assessed. Results Among 155 patients on long-term medications, 57.4% achieved blood pressure (BP) 1 ng/mL/h. Concordance of biochemical control using potassium and renin levels was 49.1%. Side effects were experienced by 52.3% of patients, with 10.3% switching, 22.6% decreasing dose, and 11.0% stopping medications. Risk factors for side effects were spironolactone use, dose ≥ 50 mg, treatment duration ≥1 year, male gender, and unilateral PA. Patients with unilateral PA used higher spironolactone doses vs bilateral (57 vs 50 mg, P < 0.001) and had more side effects (63.2% vs 41.8%, P = 0.008). Forty-six unilateral PA patients who underwent surgery after initial medical therapy experienced improved BP (systolic from 141 to 135 mmHg, P = 0.045; diastolic from 85 to 79 mmHg, P = 0.002). Conclusion Dose-dependent side effects limit efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. For unilateral PA, surgery remains preferable, yielding better control with less long-term side effects.

Background In addition to increased cardiovascular risk, patients with primary aldosteronism (PA) also suffer from impaired health-related quality of life (HRQoL) and psychological symptoms. We assessed for changes in HRQoL and depressive symptoms in a cohort of Asian patients with PA, after surgical and medical therapy. Methods Thirty-four patients with PA were prospectively recruited and completed questionnaires from 2017 to 2020. HRQoL was assessed using RAND-36 and EQ-5D-3L, and depressive symptoms were assessed using Beck Depression Inventory (BDI-II) at baseline, 6 months, and 1 year post-treatment. Results At 1 year post-treatment, significant improvement was observed in both physical and mental summative scores of RAND-36, +3.65, P = 0.023, and +3.41, P = 0.033, respectively, as well as four subscale domains (physical functioning, bodily pain, role emotional, and mental health). Significant improvement was also seen in EQ-5D dimension of anxiety/depression at 1 year post-treatment. Patients treated with surgery (n = 21) had significant improvement in EQ-5D index score post-treatment and better EQ-5D outcomes compared to the medical group (n = 13) at 1 year post-treatment. 37.9, 41.6 and 58.6% of patients had symptoms in the cognitive, affective and somatic domains of BDI-II, respectively. There was a significant improvement in the affective domain of BDI-II at 1 year post-treatment. Conclusion Both surgical and medical therapy improve HRQoL and psychological symptoms in patients with PA, with surgery providing better outcomes. This highlights the importance of early diagnosis, accurate subtyping and appropriate treatment of PA.

Objective: Migrant workers, a marginalized and under-resourced population, are vulnerable to coronavirus disease 2019 (COVID-19) due to limited healthcare access. Moreover, metabolic diseases-such as diabetes mellitus (DM), hypertension, and hyperlipidemia-predispose to severe complications and mortality from COVID-19. We investigate the prevalence and consequences of undiagnosed metabolic illnesses, particularly DM and pre-diabetes, in international migrant workers with COVID-19. Methods: In this retrospective analysis, we analyzed the medical records of international migrant workers with laboratory-confirmed COVID-19 hospitalized at a tertiary hospital in Singapore from April 21 to June 1, 2020. We determined the prevalence of DM and pre-diabetes, and analyzed the risk of developing complications, such as pneumonia and electrolyte abnormalities, based on age and diagnosis of DM, and pre-diabetes. Results: Two hundred and fouty male migrant workers, with mean age of 44.2 years [standard deviation (SD), 8.5years], were included. Twenty one patients (8.8%) were diagnosed with pre-diabetes, and 19 (7.9%) with DM. DM was poorly controlled with a mean HbA1c of 9.9% (SD, 2.4%). 73.7% of the patients with DM and all the patients with pre-diabetes were previously undiagnosed. Pre-diabetes was associated with higher risk of pneumonia [odds ratio (OR), 10.8, 95% confidence interval (CI), 3.65-32.1; P < 0.0001], hyponatremia (OR, 8.83; 95% CI, 1.17-66.6; P = 0.0342), and hypokalemia (OR, 4.58; 95% CI, 1.52-13.82; P = 0.0069). Moreover, patients with DM or pre-diabetes developed COVID-19 infection with lower viral RNA levels. Conclusions: The high prevalence of undiagnosed pre-diabetes among international migrant workers increases their risk of pneumonia and electrolyte abnormalities from COVID-19.

Background The management of diabetes is complex. There is growing recognition of the use of patient-reported outcome measures (PROMs) as a standardized method of obtaining an outlook on patients’ functional status and well-being. However, no systematic reviews have summarized the studies that investigate the measurement properties of diabetes PROMs. Objective Our aims were to conduct a systematic review of studies investigating the measurement properties of diabetes PROMs by evaluating the methodological quality and overall level of evidence of these PROMs and to categorize them based on the outcome measures assessed. Methods This study was guided by the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. Relevant articles were retrieved from the Embase, PubMed, and PsychINFO databases. The PROMs were evaluated with the COSMIN (COnsensus-based Standards for the selection of health Measurement Instruments) guidelines. Results A total of 363 articles evaluating the measurement properties of PROMs for diabetes in the adult population were identified, of which 238 unique PROMs from 248 studies reported in 209 articles were validated in the type 2 diabetes population. PROMs with at least a moderate level of evidence for ≥5 of 9 measurement properties include the Chinese version of the Personal Diabetes Questionnaire (C-PDQ), Diabetes Self-Management Instrument Short Form (DSMI-20), and Insulin Treatment Appraisal Scale in Hong Kong primary care patients (C-ITAS-HK), of which the C-PDQ has a “sufficient (+)” rating for >4 measurement properties. A total of 43 PROMs meet the COSMIN guidelines for recommendation for use. Conclusions This study identified and synthesized evidence for the measurement properties of 238 unique PROMs for patients with type 2 diabetes and categorized the PROMs according to their outcome measures. These findings may assist clinicians and researchers in selecting appropriate high-quality PROMs for clinical practice and research. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42020180978; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020180978.

BACKGROUND The management of diabetes is complex. There is growing recognition of the use of patient-reported outcome measures (PROMs) as a standardized method of obtaining an outlook on patients’ functional status and well-being. However, no systematic reviews have summarized the studies that investigate the measurement properties of diabetes PROMs. OBJECTIVE Our aims were to conduct a systematic review of studies investigating the measurement properties of diabetes PROMs by evaluating the methodological quality and overall level of evidence of these PROMs and to categorize them based on the outcome measures assessed. METHODS This study was guided by the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. Relevant articles were retrieved from the Embase, PubMed, and PsychINFO databases. The PROMs were evaluated with the COSMIN (COnsensus-based Standards for the selection of health Measurement Instruments) guidelines. RESULTS A total of 363 articles evaluating the measurement properties of PROMs for diabetes in the adult population were identified, of which 238 unique PROMs from 248 studies reported in 209 articles were validated in the type 2 diabetes population. PROMs with at least a moderate level of evidence for ≥5 of 9 measurement properties include the Chinese version of the Personal Diabetes Questionnaire (C-PDQ), Diabetes Self-Management Instrument Short Form (DSMI-20), and Insulin Treatment Appraisal Scale in Hong Kong primary care patients (C-ITAS-HK), of which the C-PDQ has a “sufficient (+)” rating for >4 measurement properties. A total of 43 PROMs meet the COSMIN guidelines for recommendation for use. CONCLUSIONS This study identified and synthesized evidence for the measurement properties of 238 unique PROMs for patients with type 2 diabetes and categorized the PROMs according to their outcome measures. These findings may assist clinicians and researchers in selecting appropriate high-quality PROMs for clinical practice and research. CLINICALTRIAL PROSPERO International Prospective Register of Systematic Reviews CRD42020180978; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020180978.

Introduction Adrenal venous sampling (AVS) is the reference test for identifying unilateral primary aldosteronism (PA). However, in patients with corticol co-secreting adrenal nodules, elevated cortisol levels may affect the interpretation of aldosterone-cortisol (AC) ratios. ACTH-stimulation may further confound results. In such patients, the use of plasma metanephrines instead of cortisol as a correcting factor may be helpful. Case Summary A 54 year old lady presented with 8 years of hypertension and hypokalaemia (nadir 2.2mmol/L) while on amlodipine 10mg and valsartan 80mg daily. PA was confirmed by a post-saline infusion aldosterone 1075pmol/L. CT identified a 2.4cm right lipid rich adrenal adenoma. Serum cortisol post 1mg overnight dexa-suppression test was unsuppressed at 63mmol/L. First AVS was done sequentially under ACTH stimulation and suggested lateralization to the right, with lateralization ratio (LR) 3.4. However, this was She underwent right adrenalectomy and was cured of hypertension and hypokalaemia at 6 months post surgery. Aldosterone renin ratio has normalized: aldosterone Clinical Lessons While ACTH stimulation helps to improve success rates of cannulation by increasing cortisol gradients, most studies show that it lowers LR. Furthermore, this would be concerning in patients with cortisol co-secreting adenomas. In this case, repeat AVS without ACTH demonstrated improved lateralization to the right. The use of metanephrine as a correcting factor appears to be a better indicator of right sided disease. However, while plasma metanephrines have been shown to be useful to indicate correct catheter placement, it has not been adopted as a correction factor for dilution yet. Finally, in addition to affecting AVS results, cortisol-cosecreting tumors may also affect 11C-Metomidate PET-CT imaging. Conclusion In patients with suspected cortisol co-secreting adenomas, unstimulated AVS and use of plasma metanephrines may help to identify unilateral PA even when conventional AVS and metomidate scans fail to. Further studies on using metanephrines as a correcting factor for lateralisation would be helpful.

Introduction. Adrenal vein sampling (AVS) is the current reference test to identify unilateral, surgically-curable primary aldosteronism (PA). However, AVS is invasive and technically difficult. Even in AVS-proven unilateral PA, up to 6% of patients with fail to have biochemical cure after surgery using the PASO criteria. 11C-Metomidate PET-CT offers a non-invasive alternative. We compared the accuracy of both PET-CT and AVS using post-surgery cure (PASO criteria) as the reference. Methods. This multi-centre prospective trial recruited 25 patients with confirmed PA, and all underwent CT, AVS, and PET-CT tests. Sequential AVS under ACTH-stimulation was done by an experienced interventionalist, and cortisol gradient of >5 was taken to be successful cannulation. Lateralization ratio >4 was consistent with unilateral PA. All results were reviewed at a multidisciplinary meeting to decide on the diagnosis (unilateral or bilateral PA) and management (secondary outcome). Primary outcome was biochemical cure using PASO criteria at 6 months post-surgery (ClinicalTrials.gov: NCTxxxxxxxx). Results. Recruitment for the study has been complete with 25 patients, 49.2 ± 9.5 yr, 14 females (56.0%). All 25 patients had successful AVS. 22 of 25 patients (88.0%) had unilateral PA, and 3 patients (12.0%) had bilateral PA. PET-CT identified unilateral PA in 18 of 22 patients (sensitivity 81.8%), while AVS identified unilateral PA in 15 of 22 patients (sensitivity 68.2%). In one patient, repeat AVS done simultaneously without ACTH-stimulation aided to identify unilateral PA, when initial AVS failed to do so. Other cases where AVS failed to identify unilateral PA were due to venous anomalies, and limitation of the lateralization cut-off of 4. 18 of 22 patients have undergone surgery, with 3 patients awaiting surgery, and 1 opting for medical treatment. Post-surgery, all patients had complete normalization of aldosterone-renin ratio, and hypokalemia (if present). 2 patients had bilateral PA on both PET-CT and AVS. 1 patient had discordant AVS and PET-CT results, with AVS lateralizing to right, and PET-CT to left. This patient was classified as bilateral PA and treated medically. Conclusion. This is the first study to demonstrate that 11C-Metomidate PET-CT may identify cases of unilateral PA not detected with AVS, using the stringent PASO criteria for post-operative biochemical cure.

Background Identifying causative adrenal lesions presents a significant diagnostic burden for physicians and radiologists. We describe the use of radiolabelled metomidate to lateralise primary hyperaldosteronism. Case presentation A 52-year old Chinese man with a 5-year history of hypertension was referred for hypokalemia [K 2.7 mmol/L (3.6 - 5.0)]. He had been on Telmisartan 80 mg and Amlodipine 10 mg daily and blood pressure at home ranged 110-120 / 70-80 mmHg. There was no history of poor oral intake, persistent diarrhea or vomiting, and he was not on any other prescription or alternative medications. There was no significant family history of hypertension or sudden cardiac death. Clinic blood pressure was 140/84 mmHg. There were no features suggestive of Cushing’s syndrome. Repeat biochemical tests confirmed hypokalemia (K 3.1 mmol/L), and associated raised bicarbonate 37.3 mmol/L [19 - 29]. Magnesium and creatinine were normal. Aldosterone-renin Ratio was elevated at 8.1 (serum Aldosterone 611 pmol/L [97.3 - 834.0], active renin 2.7 pg/ml [1.8 – 59.4]). Post-saline infusion, non-suppressible serum aldosterone levels of 1137 pmol/L was demonstrated, consistent with autonomous aldosterone production. A computed tomography of the adrenal revealed a 2.3 cm x 1.9 cm nodule on the left adrenal gland consistent with lipid rich adenoma. Adrenal vein sampling (AVS) under continuous synacthen infusion was performed. Adrenal to peripheral cortisol ratio was ≥10 for either adrenal veins, confirming cannulation of the adrenal veins. Aldosterone-cortisol ratios showed lateralization to the left adrenal gland (lateralization ratio of 10.35). There was contralateral suppression of the right adrenal gland with ratio of 0.41. 11C-Metomidate PET-CT scan demonstrated a maximum standardised uptake value (SUVmax) of 26.8 over the left adrenal nodule, while the SUVmax of the right adrenal gland was 16.2. Ratio of the left to right adrenal gland SUVmax was 1.65 (above the threshold of 1.25); and was concordant with AVS. This confirmed that the patient had a left functional adrenal adenoma responsible for hyperaldosteronism. Our patient underwent a left adrenalectomy, and histology was consistent with adrenal cortical adenoma. Prior to surgery he required 72 mmol/l of potassium supplementation daily to maintain K levels of 3.3 – 4.0 mmol/L. Two weeks post-operatively, he was normokalemic (K 4.9 mmol/L) without potassium supplementation. Serum aldosterone normalized to 159.3 pmol/L (active renin 9.3 pg/ml). Blood pressure is well controlled on amlodipine 5mg daily. Conclusion Targeted molecular imaging such as 11C-Metomidate PET-CT could aid localisation of functional adrenal disease to guide definitive surgical management. In the future, this could obviate the need for invasive and technically complex procedures like AVS.

Objective Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict both subtypes and validate this externally. Methods Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and post-operative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in a clinical trial. Previously published prediction models were also tested in our cohorts. Results Backward stepwise logistic regression analysis yielded a final tool using baseline-aldosterone-to-lowest-potassium ratio (APR, ng/dL/mmol/L), with an area under receiver operating characteristic curve of 0.80 (95% CI: 0.70 - 0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR 15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR 15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA. Conclusion The novel aldosterone-potassium ratio (APR) is a convenient score to guide clinicians and patients of various ethnicities on the probability of PA subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.

Contains fulltext : 220540.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict both subtypes and validate this externally. METHODS: Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and postoperative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in the SPARTACUS trial who underwent AVS. Previously published prediction models were also tested in our cohorts. RESULTS: Backward stepwise logistic regression analysis yielded a final tool using baseline aldosterone-to-lowest-potassium ratio (APR, ng/dl/mmol/l), with an area under receiver-operating characteristic curve of 0.80 (95% CI 0.70-0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR 15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR 15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA. CONCLUSION: The novel aldosterone-to-lowest-potassium ratio is a convenient score to guide clinicians and patients of various ethnicities on the probability of primary aldosteronism subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.

Background It is estimated that one-third of patients with pheochromocytomas and paragangliomas (PPGL) have germline mutations. This patient with bilateral pheochromocytomas was initially diagnosed with MEN2A syndrome, underwent prophylactic total thyroidectomy, only to be diagnosed with a different germline mutation subsequently. Clinical case This patient first presented at 12 years of age, with hypertensive emergency and a right 8cm adrenal tumour with spontaneous haemorrhage. He underwent emergency right adrenalectomy, with histology confirming a pheochromocytoma. Post-operatively, urinary metanephrines were normal and symptoms resolved. 7 years later, he re-presented with headache, postural hypotension, cutaneous lichen amyloidosis and elevated urinary normetanephrine (NMT). CT abdomen showed 2 left adrenal masses with no residual right adrenal lesion. Open left adrenalectomy was performed and 3 pheochromocytoma nodules of 8 to 10mm in size were found. Urinary NMT was normal post-surgery. He was commenced on hydrocortisone and fludrocortisone replacement. In view of his young age and bilateral pheochromocytomas, genetic testing was done. RET proto-oncogene testing showed a silent mutation in Exon 13 Codon 769 CTT->CTG coding for Leucine, suggestive of MEN2A syndrome. His calcium and parathyroid hormone were normal. Although asymptomatic, he underwent prophylactic total thyroidectomy. However, histology revealed no endocrine cell hyperplasia. At age of 33 years, his symptoms recurred. Plasma free NMT was raised, 3.29nmol/L (reference C (Initiator codon) was identified, while his previous MEN2A mutation of indeterminate significance was deemed not pathogenic. His father subsequently tested positive for SDHD mutation and is undergoing further investigations. Conclusion Major advances in the understanding of hereditary PPGL have been made over the last decade. Identification of the correct germline mutation is important to predict risks of malignancy, recurrence and guide early treatment. This case highlights the importance of comprehensive, targeted genetic testing with trained geneticist over traditional single gene tests and the need to interpret results with caution. Reference Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. Jacques W.M. Lenders et al. J Clin Endocrinol Metab.2014; 99 (6): 1915-1942.

Background Diabetes mellitus is associated with inadequate delivery of oxygen to tissues. Cellular hypoxia is associated with mitochondrial dysfunction which increases oxidative stress and hyperglycaemia. Hyperbaric oxygenation therapy, which was shown to improve insulin sensitivity, is impractical for regular use. We evaluated the effects of water which is stably-enriched with oxygen (ELO water) to increase arterial blood oxygen levels, on mitochondrial function in the presence of normal- or high-glucose environments, and as glucose-lowering therapy in humans. Methods We compared arterial blood oxygen levels in Sprague-Dawley rats after 7 days of ad libitum ELO or tap water consumption. Mitochondrial stress testing, and flow cytometry analysis of mitochondrial mass and membrane potential, were performed on human HepG2 cells cultured in four Dulbecco’s Modified Eagle Medium media, made with ELO water or regular (control) water, at normal (5.5 mM) or high (25 mM) glucose concentrations. We also randomized 150 adults with type 2 diabetes (mean age 53 years, glycated haemoglobin HbA1c 8.9% [74 mmol/mol], average duration of diabetes 12 years) to drink 1.5 litres daily of bottled ELO water or drinking water. Results ELO water raised arterial oxygen tension pO2 significantly (335 ± 26 vs. 188 ± 18 mmHg, p = 0.006) compared with tap water. In cells cultured in control water, mitochondrial mass and membrane potential were both significantly lower at 25 mM glucose compared with 5.5 mM glucose; in contrast, mitochondrial mass and membrane potential did not differ significantly at normal or high glucose concentrations in cells cultured in ELO water. The high-glucose environment induced a greater mitochondrial proton leak in cells cultured in ELO water compared to cells cultured in control medium at similar glucose concentration. In type 2 diabetic adults, HbA1c decreased significantly (p = 0.002) by 0.3 ± 0.7% (4 ± 8 mmol/mol), with ELO water after 12 weeks of treatment but was unchanged with placebo. Conclusions ELO water raises arterial blood oxygen levels, appears to have a protective effect on hyperglycaemia-induced reduction in mitochondrial mass and mitochondrial dysfunction, and may be effective adjuvant therapy for type 2 diabetes.

Background: Primary aldosteronism (PA) is the most common treatable cause of secondary hypertension. In addition to increased cardiovascular risk, patients also suffer from impaired quality of life (QoL) and psychological symptoms. We assessed for changes in QoL and depressive symptoms in a cohort of Asian patients with PA, after surgical and medical therapy. Methods: We administered questionnaires to 34 patients with PA, mean age, 51.3 years, 29.4% females, in a prospective observational study from 2017 to 2020. QoL was assessed using RAND-36 and EQ-5D-3L, and depressive symptoms was assessed using Beck Depression Inventory (BDI-II) at baseline, 6 months, and 1 year post-treatment. Results: Significant improvement was observed 1 year after treatment in both physical and mental summative scores of RAND-36 from baseline, +3.65 (p = 0.023) and +3.41 (p = 0.033) respectively, as well as four subscale domains (physical functioning, bodily pain, role emotional and mental health). Significant improvement was also seen in EQ-5D dimension of anxiety/depression at 1 year post-treatment. Patients treated with surgery (N=21) had significant improvement in EQ-5D index score post-treatment, and better EQ-5D outcomes compared to medical group (N=13) at 1 year post-treatment. 37.9%, 41.6% and 60.7% of patients had symptoms in the cognitive, affective and somatic domains of the BDI-II respectively. There was significant improvement in the affective domain of BDI after 1 year of treatment. Conclusion: Appropriate treatment with surgical and medical therapy improves QoL and psychological symptoms in patients with PA, highlighting the importance of early diagnosis and treatment of this common condition.

Introduction: Adrenalectomy cures unilateral primary aldosteronism (PA), and improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success post-surgery, suggesting that surgery was ineffective. Methods: We assessed all patients 6–12 months after unilateral adrenalectomy for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2 and CONNsortium criteria. We estimated blood pressure (BP) changes after adjustment for changes in defined daily dosages (DDD) of antihypertensive medications. Finally, patients were reassessed using PASO at their most recent clinical visit. Results: 104 patients with unilateral PA underwent adrenalectomy at two tertiary centres from 2000–2019. 24 (23%), 31(30%) and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2 and CONNsortium criteria respectively. Amongst 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariate analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus and lower DDD at baseline. After adjustment for changes in DDD, 7 of 24 patients showed BP improvement ≥20/10mmHg. After follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show any clinical improvement after surgery. Conclusions: Although some patients may be classified with absent clinical success post-surgery, majority demonstrate evidence of clinical benefit. Unilateral adrenalectomy remains the recommended treatment option for patients with unilateral PA.

Obesity is less prevalent in Asian subjects with type 2 diabetes mellitus (T2DM) in contrast to Caucasians. Whether higher axial bone mineral density (BMD) often reported in T2DM is independent of body mass index (BMI) has not been clearly shown. BMD characterization in T2DM patients with hip fractures has also not been performed. We compared the BMD of Asian diabetic and nondiabetic patients with new hip fractures and explored how BMD was influenced by BMI.We included 255 diabetic and 148 nondiabetic patients. BMD adjusted for age; BMI; race; sex; renal function; and use of statins, proton pump inhibitors, steroids, anticonvulsants, and calcium and/or vitamin D supplements were compared between the groups. We were particularly interested in the BMD comparison between underweight diabetics and nondiabetics with hip fractures.The presence of T2DM was associated with higher BMD (g/cm(2)) at the femoral neck (0.527 ± 0.103 vs. 0.491 ± 0.102, P.01) and lumbar spine [LS] (0.798 ± 0.147 vs. 0.723 ± 0.156, P.01). This association persisted after adjustment for multiple confounding variables including BMI. The age-, BMI-, and sex-adjusted LS BMD was higher in underweight (BMI18.5 kg/m(2)) diabetics compared to similar weight nondiabetics (0.733 ± 0.126 vs. 0.649 ± 0.131 g/cm(2), P = .014).T2DM is independently associated with higher axial BMD in patients with new hip fractures. The finding of higher BMD even in underweight diabetics with hip fractures compared to their nondiabetic counterparts suggests that higher BMD in subjects with T2DM is not due to higher BMI.BMD = bone mineral density BMI = body mass index CV = coefficient of variation DXA = dual-energy X-ray absorptiometry HbA1c = glycated hemoglobin IGF-1 = insulin growth factor-1 LS = lumbar spine 25(OH)D = 25-hydroxyvitamin D T2DM = type 2 diabetes mellitus.

Adrenal insufficiency is an uncommon, but potentially fatal, condition in which the adrenal glands do not produce enough glucocorticoids and, in some cases, mineralocorticoids and androgens. It can result from primary adrenal failure or secondary to impairment of the hypothalamic-pituitary axis from chronic steroid use or pituitary tumours. Presenting symptoms are usually vague such as fatigue, weight loss, abdominal pain and vomiting, which can lead to a delay in diagnosis unless there is a high index of suspicion. Prompt diagnosis and management are essential to avoid acute adrenal insufficiency (adrenal or Addisonian crisis), a medical emergency. We summarize current knowledge on the background and etiology, clinical presentation, investigations and management of this disorder.

Objective Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing’s disease (CD). Corticotroph tumor progression, the so-called Nelson’s syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson’s tumors has not been studied in detail so far. Design and Methods Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. Results Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization ( Conclusion Somatic mutations in USP8 are common in Nelson’s tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson’s tumor.

Somatic mutations in the ubiquitin-specific protease 8 (Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of theFifteen out of 33 tumors (45%) presented with a mutation in the exon 14 ofSomatic mutations in

Context: Recurrence of hypercortisolism in patients after bilateral adrenalectomy for Cushing disease is extremely rare. Patient: We present a 27-year-old man who previously underwent bilateral adrenalectomy for Cushing disease with complete clinical resolution. Cushingoid features recurred 12 years later, with bilateral testicular enlargement. Hormonal tests confirmed adrenocorticotropic hormone (ACTH)-dependent Cushing disease. Surgical resection of the testicular tumors led to clinical and biochemical remission. Design and Results: Gene expression analysis of the tumor tissue by quantitative polymerase chain reaction showed high expression of all key steroidogenic enzymes. Adrenocortical-specific genes were 5.1 × 105 (CYP11B1), 1.8 × 102 (CYP11B2), and 6.3 × 104 (MC2R) times higher than nonsteroidogenic fibroblast control. This correlated with urine steroid metabolome profiling showing 2 fivefold increases in the excretion of the metabolites of 11-deoxycortisol, 21-deoxycortisol, and total glucocorticoids. Leydig-specific genes were 4.3 × 101 (LHCGR) and 9.3 × 100 (HSD17B3) times higher than control, and urinary steroid profiling showed twofold increased excretion of the major androgen metabolites androsterone and etiocholanolone. These distinctly increased steroid metabolites were suppressed by dexamethasone but unresponsive to human chorionic gonadotropin stimulation, supporting the role of ACTH, but not luteinizing hormone, in regulating tumor-specific steroid excess. Conclusion: We report bilateral testicular tumors occurring in a patient with recurrent Cushing disease 12 years after bilateral adrenalectomy. Using mRNA expression analysis and steroid metabolome profiling, the tumors demonstrated both adrenocortical and gonadal steroidogenic properties, similar to testicular adrenal rest tumors found in patients with congenital adrenal hyperplasia, suggesting the presence of pluripotent cells even in patients without congenital adrenal hyperplasia.

Secondary hypertension occurs in a significant proportion of adult patients (~10%). In young patients, renal causes (glomerulonephritis) and coarctation of the aorta should be considered. In older patients, primary aldosteronism, obstructive sleep apnoea and renal artery stenosis are more prevalent than previously thought. Primary aldosteronism can be screened by taking morning aldosterone and renin levels, and should be considered in patients with severe, resistant or hypokalaemia-associated hypertension. Symptoms of obstructive sleep apnoea should be sought. Worsening of renal function after starting an angiotensin-converting enzyme inhibitor suggests the possibility of renal artery stenosis. Recognition, diagnosis and treatment of secondary causes of hypertension lead to good clinical outcomes and the possible reversal of end-organ damage, in addition to blood pressure control. As most patients with hypertension are managed at the primary care level, it is important for primary care physicians to recognise these conditions and refer patients appropriately.

Item does not contain fulltext Adrenal crisis is a life-threatening medical emergency, associated with a high mortality unless it is appropriately recognized and early treatment is rendered. Despite it being a treatable condition for almost 70 years, failure of adequate preventive measures or delayed treatment has often led to unnecessary deaths. Gastrointestinal illness is the most common precipitant for an adrenal crisis. Although most patients are educated about "sick day rules," patients, and physicians too, are often reluctant to increase their glucocorticoid doses or switch to parenteral injections, and thereby fail to avert the rapid deterioration of the patients' condition. Therefore, more can be done to prevent an adrenal crisis, as well as to ensure that adequate acute medical care is instituted after a crisis has occurred. There is generally a paucity of studies on adrenal crisis. Hence, we will review the current literature, while also focusing on the incidence, presentation, treatment, prevention strategies, and latest recommendations in terms of steroid dosing in stress situations.

Item does not contain fulltext CONTEXT: Patients with pheochromocytomas and paragangliomas (PGLs) may have brown adipose tissue (BAT) activation induced by catecholamine excess. (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) can be used for the localization of both PGLs and BAT. It is unknown whether BAT is specifically affected by altered cellular energy metabolism in patients with SDHx- and VHL-related PGLs. OBJECTIVE: The objective of the study was to determine endocrine and paracrine effects of catecholamine excess on BAT activation in patients with PGLs as detected by (18)F-FDG PET/CT, taking into account genetic variation. DESIGN: Patients with PGLs who were fully genetically characterized underwent presurgical (18)F-FDG PET/CT imaging for tumor localization and to quantify BAT activation. SETTING: The study was conducted at a single Dutch tertiary referral center. PATIENTS AND INTERVENTION: Seventy-three patients, aged 52.4 +/- 15.4 years, with a body mass index of 25.2 +/- 4.1 kg/m(2), mean +/- SD, were grouped into sporadic, cluster 1 (SDHx, VHL) and cluster 2 (RET, NF1, MAX) mutations. MAIN OUTCOME MEASURES: (18)F-FDG mean standard uptake values were assessed in predefined BAT locations, including perirenal fat. RESULTS: Twenty-one of 73 patients (28.8%) exhibited BAT activation. BAT activation was absent in all six patients with nonsecreting PGLs. No difference in (18)F-FDG uptake by perirenal fat on the side of the pheochromocytoma and the contralateral side was observed (mean standard uptake value of 0.80 vs 0.78, respectively, P = .42). The prevalence of BAT activation did not differ between sporadic (28.9%), cluster 1 (40.0%), and cluster 2 patients (15.4%, P= .36). CONCLUSION: Patients with PGLs exhibit a high prevalence of BAT activation on (18)F-FDG PET/CT. This is likely due to systemic catecholamine excess. BAT activation is not associated with specific germline mutations.

To determine whether tight glycemic control is associated with greater risk of hip fractures in individuals being treated for type 2 diabetes mellitus.Case-control study.Tertiary hospital.Cases were selected from all individuals with diabetes mellitus admitted between 2005 and 2010 to Changi General Hospital for hip fracture (N = 932). Cases were included if their glycosylated hemoglobin (HbA1c) had been measured within 3 months of the fracture and they were undergoing treatment with oral hypoglycemic medications or insulin. Each case was matched with one control for sex, age, race, duration of diabetes mellitus, and comorbidities.Information on baseline characteristics, HbA1c, and use of diabetic medications was obtained. The likelihood of hip fracture was determined comparing four different values of HbA1c [6%, 6.1-7.0%, 7.1-8.0%,8% (reference group)] and use of diabetic medications.The mean age of cases was 77.3 ± 7.7, and 73.3% were female. After adjusting for age, sex, race, comorbidities, and other covariates, participants with tighter glycemic control (HbA1c6% and 6.1-7.0%) were more likely to have a hip fracture than those with HbA1c8% (odds ratio (OR) = 3.01, 95% confidence interval (CI) = 2.01-4.51, P.001; and OR = 2.34, 95% CI=1.71-3.22, P.001, respectively). The use of insulin and sulfonylurea was similar between cases and controls.The present study found an association between tight glycemic control (when HbA1c7%) and greater risk of hip fracture in individuals being treated for type 2 diabetes mellitus. Greater caution needs to be exercised in treating older patients with diabetes mellitus.

a b s t r a c t Occupational driving may increase cardiovascular events. We studied the risk of overall cardiovascular events in occupational professional drivers against matched controls in a cohort of people with diabetes (N = 6563). There was an increase in overall cardiovascular events in occupational drivers despite similar risk factors. This particular occupational risk factor may need to be addressed.