Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients

Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. Design: This was designed as a retrospective, multicenter study. Setting: Thirteen University hospitals were studied. Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS

Calcimimetic and calcilytic therapies for inherited disorders of the calcium-sensing receptor signalling pathway

The calcium-sensing receptor (CaS receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss-of-function and gain-of-function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS receptor signal transduction in the parathyroid glands is probably regulated by G-protein subunit α11 (Gα11) and adaptor-related protein complex-2 σ-subunit (AP2σ), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS receptor, Gα11 or AP2σ proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient-based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS receptor signalling pathway

A nationwide study of adults admitted to hospital with diabetic ketoacidosis or hyperosmolar hyperglycaemic state and COVID‐19

AimsTo investigate characteristics of people hospitalized with coronavirus-disease-2019 (COVID-19) and diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS), and to identify risk factors for mortality and intensive care admission.Materials and methodsRetrospective cohort study with anonymized data from the Association of British Clinical Diabetologists nationwide audit of hospital admissions with COVID-19 and diabetes, from start of pandemic to November 2021. The primary outcome was inpatient mortality. DKA and HHS were adjudicated against national criteria. Age-adjusted odds ratios were calculated using logistic regression.ResultsIn total, 85 confirmed DKA cases, and 20 HHS, occurred among 4073 people (211 type 1 diabetes, 3748 type 2 diabetes, 114 unknown type) hospitalized with COVID-19. Mean (SD) age was 60 (18.2) years in DKA and 74 (11.8) years in HHS (p < .001). A higher proportion of patients with HHS than with DKA were of non-White ethnicity (71.4% vs 39.0% p = .038). Mortality in DKA was 36.8% (n = 57) and 3.8% (n = 26) in type 2 and type 1 diabetes respectively. Among people with type 2 diabetes and DKA, mortality was lower in insulin users compared with non-users [21.4% vs. 52.2%; age-adjusted odds ratio 0.13 (95% CI 0.03-0.60)]. Crude mortality was lower in DKA than HHS (25.9% vs. 65.0%, p = .001) and in statin users versus non-users (36.4% vs. 100%; p = .035) but these were not statistically significant after age adjustment.ConclusionsHospitalization with COVID-19 and adjudicated DKA is four times more common than HHS but both associate with substantial mortality. There is a strong association of previous insulin therapy with survival in type 2 diabetes-associated DKA

Recurrent pancreatitis in a patient with familial hypocalciuric hypercalcaemia treated successfully with cinacalcet.

UNLABELLED: A 22-year-old female student presented with a history of recurrent pancreatitis. The commonest causes of pancreatitis, including drugs, gallstones, corticosteroids, excess alcohol and hypertriglyceridaemia, were excluded. She was found to have an elevated serum calcium level that was considered to be the cause of her pancreatitis, with a detectable serum parathyroid hormone (PTH). An initial diagnosis of primary hyperparathyroidism was made. However, two neck explorations failed to reveal a parathyroid adenoma. She was referred to our unit three years later as her episodes of pancreatitis were becoming more frequent and her calcium level remained persistently elevated. Her investigations were as follows: elevated adjusted calcium level of 2.79 mmol/l (2.2-2.58), PTH level of 4.2 pmol/l (0.6-6.0), low 24 h urine calcium of 0.3 mmol/l and a urine calcium:creatinine ratio of A mutation in the calcium-sensing receptor gene. Although the hypercalcaemia of FHH is usually without sequelae due to the generalised changes in calcium sensing, in the presence of this complication she was started on cinacalcet 30 mg daily. She had one further episode of pancreatitis with calcium levels ranging between 2.53 and 2.66 mmol/l. Her cinacalcet was gradually increased to 30 mg three times daily, maintaining her calcium levels in the range of 2.15-2.20 mmol/l. She has not had a further episode of pancreatitis for more than 2 years. FHH is usually a benign condition with minimal complications from hypercalcaemia. Pancreatitis has been reported rarely, and no clear management strategy has been defined in these cases. Cinacalcet was successfully used in treating recurrent pancreatitis in a patient with FHH by maintaining calcium levels in the lower part of the reference range. Whether or not this is an effective long-term treatment remains yet to be seen. LEARNING POINTS: FHH is an important differential diagnosis for hypercalcaemia.FHH can rarely cause pancreatitis.No clear strategy is available to help in the management of patients with pancreatitis due to FHH.Cinacalcet was effective in lowering serum calcium levels and reducing the frequency of pancreatitis in our patient with FHH

Recurrent pancreatitis in a patient with familial hypocalciuric hypercalcaemia treated successfully with cinacalcet.

UNLABELLED: A 22-year-old female student presented with a history of recurrent pancreatitis. The commonest causes of pancreatitis, including drugs, gallstones, corticosteroids, excess alcohol and hypertriglyceridaemia, were excluded. She was found to have an elevated serum calcium level that was considered to be the cause of her pancreatitis, with a detectable serum parathyroid hormone (PTH). An initial diagnosis of primary hyperparathyroidism was made. However, two neck explorations failed to reveal a parathyroid adenoma. She was referred to our unit three years later as her episodes of pancreatitis were becoming more frequent and her calcium level remained persistently elevated. Her investigations were as follows: elevated adjusted calcium level of 2.79 mmol/l (2.2-2.58), PTH level of 4.2 pmol/l (0.6-6.0), low 24 h urine calcium of 0.3 mmol/l and a urine calcium:creatinine ratio of &lt;0.003. A clinical diagnosis of familial hypocalciuric hypercalcaemia (FHH) was made and confirmed on genetic testing that showed a c.1703 G&gt;A mutation in the calcium-sensing receptor gene. Although the hypercalcaemia of FHH is usually without sequelae due to the generalised changes in calcium sensing, in the presence of this complication she was started on cinacalcet 30 mg daily. She had one further episode of pancreatitis with calcium levels ranging between 2.53 and 2.66 mmol/l. Her cinacalcet was gradually increased to 30 mg three times daily, maintaining her calcium levels in the range of 2.15-2.20 mmol/l. She has not had a further episode of pancreatitis for more than 2 years. FHH is usually a benign condition with minimal complications from hypercalcaemia. Pancreatitis has been reported rarely, and no clear management strategy has been defined in these cases. Cinacalcet was successfully used in treating recurrent pancreatitis in a patient with FHH by maintaining calcium levels in the lower part of the reference range. Whether or not this is an effective long-term treatment remains yet to be seen. LEARNING POINTS: FHH is an important differential diagnosis for hypercalcaemia.FHH can rarely cause pancreatitis.No clear strategy is available to help in the management of patients with pancreatitis due to FHH.Cinacalcet was effective in lowering serum calcium levels and reducing the frequency of pancreatitis in our patient with FHH

Acute hyperglycaemic crisis after vaccination against COVID-19: A case series.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the most important component of the global response to the COVID-19 pandemic. Although most adverse reactions observed have been mild, the emergence of more serious vaccine-associated adverse events is being closely monitored

Phaeochromocytoma and Paraganglioma Excision Involving the Great Vessels

: Objective/background: Phaeochromocytomas and paragangliomas are vascular neuroendocrine tumours distributed between the neck and the pelvis and may be associated with catecholamine secretion. The aim of the study was to describe the complex surgical management required to excise these tumours when in close proximity to the great vessels (aorta and vena cava). Methods: This was a retrospective case series. Patients included those undergoing surgical excision of a phaeochromocytoma or paraganglioma involving the great vessels. Data on clinical presentation; genetic mutations; tumour location; catecholamine/metanephrine secretion; surgical strategy; pre-, intra-, and post-operative course were collated. Results: Five patients (age range 16–60 years) were identified; three had thoracic paragangliomas located under the arch of the aorta, one had an abdominal paraganglioma invading the aorta, and one had a massive phaeochromocytoma invading the inferior vena cava via the adrenal vein. Three patients had predisposing germline mutations. All patients had adrenergic blockade prior to surgery. A diverse range of complex surgical techniques were employed to excise tumours, including cardiopulmonary bypass, aortic resection, grafting and venotomy of the vena cava. Early post-operative complications were limited. Conclusions: Excision of phaeochromocytomas and paragangliomas involving the great vessels is high risk surgery optimally undertaken within a multidisciplinary setting in a tertiary referral centre. Comprehensive radiological and biochemical assessment, meticulous pre-operative preparation and close intra- and post-operative monitoring are essential. Radiological imaging may be unable to resolve the tumour extent and anatomy pre-operatively and direct visualisation of the tumour may be the only way to clarify the surgical strategy. Pre-operative knowledge of the genetic predisposition may influence surgical management. Keywords: Aorta, Paraganglioma, Phaeochromocytoma, Surgery, Vena cav