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Veronica A Preda and Ashley B Grossman

We appreciate the letter from of Dr Soh et al. regarding our review on the use of etomidate in the treatment of Cushing's syndrome. We note that in their experience, our recommended dose regimen of 2.5 mg/h or thereabouts appears to be a safe and effective starting dose in most patients, and we note the utility and ease of use of the lipid formulation and its relative freedom from side effects compared with the more commonly used propylene glycol formulation; these are very helpful comments. Their experience in treating a further four patients is indeed further evidence of the usefulness of this agent.

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Veronica A Preda, Jonathan Sen, Niki Karavitaki and Ashley B Grossman

The authors apologise for the publication of an error in Table 2 of this article published in the European Journal of Endocrinology 167 137–143. They wish to make clear in Table 2 that they are stipulating the dose of etomidate and that the corresponding dose of hydrocortisone for complete blockade should be 0.5–1.0 mg/h. The correct table is published in full below.

Table 2

Treatment of hypercorticolism with etomidate: Recommendations.

Infusion rate optionsBlockadeCortisol levelBiochemical monitoringOther
Etomidate (IV) 0.04–0.05 m/kg per h=2.5–3.0 mg/hPartial to complete depending on clinical circumstance of the patientTitrate to serum cortisol 500–800 nmol/l in physiologically stressed patient, 150–300 nmol/l in non-physiologically stressed patientPotassium level Cortisol levelSedation scoring initially every two hours then every 12 hours after first 24 hours
Hydrocortisone IV 0.5–1.0 mg/hComplete (will need steroid replacement)<150 nmol/lPotassium level Cortisol level

This table could now be used as a practical guide for clinicians commencing infusions on the ward of etomidate and required hydrocortisone replacement.

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Veronica A Preda, Jonathan Sen, Niki Karavitaki and Ashley B Grossman

This review addresses the practical usage of intravenous etomidate as a medical therapy in Cushing's syndrome. We reviewed the relevant literature, using search terms ‘etomidate’, ‘Cushing's syndrome’, ‘adrenocortical hyperfunction’, ‘drug therapy’ and ‘hypercortisolaemia’ in a series of public databases. There is a paucity of large randomised controlled trials, and data on its use rely only on small series, case study reports and international consensus guideline recommendations. Based on these, etomidate is an effective parenteral medication for the management of endogenous hypercortisolaemia, particularly in cases with significant biochemical disturbance, sepsis and other serious complications such as severe psychosis, as well as in preoperative instability. We suggest treatment protocols for the safe and effective use of etomidate in Cushing's syndrome.

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Agata Juszczak, Avinash Gupta, Niki Karavitaki, Mark R Middleton and Ashley B Grossman

Ipilimumab (Yervoy; Medarex and Bristol-Myers Squibb) is a human MAB against cytotoxic T-lymphocyte antigen 4, which enhances co-stimulation of cytotoxic T-lymphocytes, resulting in their proliferation and an anti-tumour response. It is licensed for the treatment of unresectable or metastatic malignant melanoma, while multiple clinical trials using this medication in the treatment of other malignancies are ongoing. As a clinical response to ipilimumab results from immunostimulation, predictably it generates autoimmunity as well, causing immune-related adverse events in the majority of patients. Of those, endocrinopathies are frequently seen, and in particular, autoimmune lymphocytic hypophysitis with anterior panhypopituitarism has been reported a number of times in North America. We present a case of a male referred to our department with manifestations of anterior panhypopituitarism after his third dose of ipilimumab for metastatic malignant melanoma, and we discuss the management of his case in the light of previous reports. We also review the published literature on the presenting symptoms, time to presentation, investigations, imaging, treatment and follow-up of ipilimumab-induced autoimmune lymphocytic hypophysitis.

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Veronica Preda, Márta Korbonits, Simon Cudlip, Niki Karavitaki and Ashley B Grossman

Aim

To study the prevalence of germline mutations of the aryl-hydrocarbon receptor interacting protein (AIP) gene in a large cohort of patients seen in the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), UK, with apparently sporadic pituitary adenomas, who were either diagnosed or had relevant clinical manifestations by the age of 40 years.

Patients

We prospectively investigated all patients who were seen at Oxford University Hospital, OCDEM, and a tertiary referral centre, between 2012 and 2013, and presented with pituitary tumours under the age of 40 years and with no family history: a total of 127 patients were enrolled in the study.

Methods

Leukocyte-origin genomic DNA underwent sequence analysis of exons 1–6 and the flanking intronic regions of the AIP gene (NM_003977.2), with dosage analysis by multiplex ligation-dependent probe amplification.

Results

AIP variants were detected in 3% of the 127 patients, comprising four of 48 patients with acromegaly (8%), 0 of 43 with prolactinomas, 0 of the 20 patients with non-functioning adenomas, 0 of 15 with corticotroph adenomas and 0 of one with a thyrotroph adenomas. Definite pathogenetic mutations were seen in 2/4 variants, comprising 4.2% of patients with acromegaly.

Conclusions

This prospective cohort study suggests a relatively low prevalence of AIP gene mutations in young patients with apparently sporadic pituitary adenomas presenting to a tertiary pituitary UK centre. Those with somatotroph macroadenomas have a higher rate of AIP mutation. These findings should inform discussion of genetic testing guidelines.

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Emilia Sbardella, Robin N Joseph, Bahram Jafar-Mohammadi, Andrea M Isidori, Simon Cudlip and Ashley B Grossman

Context

Disease processes that affect the pituitary stalk are broad; the diagnosis and management of these lesions remains unclear.

Objective

The aim was to assess the clinical, biochemical and histopathological characteristics of pituitary stalk lesions and their association with specific MRI features in order to provide diagnostic and prognostic guidance.

Design and methods

Retrospective observational study of 36 patients (mean age 37years, range: 4–83) with pituitary stalk thickening evaluated at a university hospital in Oxford, UK, 2007–2015. We reviewed morphology, signal intensity, enhancement and texture appearance at MRI (evaluated with the ImageJ programme), along with clinical, biochemical, histopathological and long-term follow-up data.

Results

Diagnosis was considered certain for 22 patients: 46% neoplastic, 32% inflammatory and 22% congenital lesions. In the remaining 14 patients, a diagnosis of a non-neoplastic disorder was assumed on the basis of long-term follow-up (mean 41.3months, range: 12–84). Diabetes insipidus and headache were common features in 47 and 42% at presentation, with secondary hypogonadism the most frequent anterior pituitary defect. Neoplasia was suggested on size criteria or progression with 30% sensitivity. However, textural analysis of MRI scans revealed a significant correlation between the tumour pathology and pituitary stalk heterogeneity in pre- and post-gadolinium T1-weighted images (sensitivity: 88.9%, specificity: 91.7%).

Conclusions

New techniques of MRI imaging analysis may identify clinically significant neoplastic lesions, thus directing future therapy. We propose possible textural heterogeneity criteria of the pituitary stalk on pre- and post-gadolinium T1 images with the aim of differentiating between neoplastic and non-neoplastic lesions with a high degree of accuracy.

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Emilia Sbardella, Carlotta Pozza, Andrea M Isidori and Ashley B Grossman

Introduction

The transition age is the period between childhood to adulthood; it refers to a broad set of physical, cognitive and sociocultural modifications, arbitrarily defined as starting in late puberty and ending with full adult maturation. Pituitary disorders in adolescence represent a challenge that requires careful management during the transition to adult care.

Methods

Given the complexity of care of pituitary disorders in the transition age, we have reviewed the relevant medical literature focusing on aetiology, clinical manifestations, treatment strategies of GH deficiency (GHD), hypogonadotrophic hypogonadism (HH) in male and female adolescents, central hypothyroidism (CH), central adrenal insufficiency (CAI) and cranial diabetes insipidus (CDI) at this time. The objective of the present review is to provide an up-to-date evaluation of the transition period to evaluate the specific needs of adolescents with chronic pituitary disease in order to optimise their management.

Results

We provide an overview of current clinical management of GHD, HH, CH, CAI and CDI in the transition age.

Conclusions

Specific changes occur in pituitary function during the transition period. A holistic approach including discussion of patients’ concerns and emotional support should constitute a key component of managing pituitary disorders in adolescence. Special transition clinics where paediatric and adult endocrinologists work together, should be increasingly created and strengthened to bridge care, to promote continuity and adherence to treatment and to limit potential negative development, metabolic, skeletal and cardiovascular sequelae of discontinuity of care among adolescents with pituitary disorders.

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Andrea M Isidori, Marianna Minnetti, Emilia Sbardella, Chiara Graziadio and Ashley B Grossman

Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin–antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis.

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Sarah J Larkin, Francesco Ferraù, Niki Karavitaki, Laura C Hernández-Ramírez, Olaf Ansorge, Ashley B Grossman and Márta Korbonits

Objective

The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas.

Design

Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study.

Methods

The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern.

Results

No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns.

Conclusions

It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out.

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Michel Procopiou, Hazel Finney, Scott A Akker, Shern L Chew, William M Drake, Jacky Burrin and Ashley B Grossman

Objective

To define the test characteristics of an enzyme immunoassay (EIA) for plasma-free metanephrines (metanephrine and normetanephrine) in the diagnosis of pheochromocytoma and paraganglioma.

Design

Prospective observational design from a single University Hospital. Twenty-four hour urine for catecholamines and plasma for free metanephrines were collected from patients with a clinical suspicion of pheochromocytoma or paraganglioma. Patient records were reviewed for clinical data, follow-up, imaging and laboratory results to establish or exclude the diagnosis of pheochromocytoma.

Patients and methods

Out of 178 consecutive patients, 10 had a paraganglioma and 12 had a pheochromocytoma: 156 were finally judged not to harbour active tumors and were therefore considered as controls. The main outcome measure was the diagnosis or exclusion of paraganglioma or pheochromocytoma and test characteristics of plasma-free metanephrines measured by EIA.

Results

Urinary epinephrine had a sensitivity of 45.5% and norepinephrine a sensitivity of 75% (98.8% specificity) for the diagnosis of pheochromocytoma. Plasma-free metanephrine and normetanephrine both had a sensitivity of 66.7% and a specificity of 100%, but when combined (either positive) they demonstrated a 91.7% sensitivity with a preserved specificity of 100%. For the diagnosis of paraganglioma, urinary norepinephrine gave slightly better results than plasma-free metanephrines, but combined testing was of no additional value.

Conclusions

Plasma-free metanephrines measured by EIA have better diagnostic test characteristics than urinary catecholamines in the diagnosis of pheochromocytoma. The EIA offers a simple and effective measurement of plasma-free metanephrines.