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2019 María A. Salomón Estébanez Conservative Management and Neurodevelopment in patients with Congenital Hyperinsulinism A Thesis Submitted To The University Of Manchester For The Degree Of Master of Philosophy In The Faculty Of Biology, Medicine And Health 2019 María A. Salomón Estébanez THE SCHOOL OF MEDICAL SCIENCES LIST OF CONTENTS LIST OF FIGURES ……………………………………………………………………………….. 4 LIST OF TABLES ………………………………………………………………………………… 5 ABSTRACT ………………………………………………………………….……………………. 6 DECLARATIONS AND COPYRIGHT STATEMENT......................................................... 7 Declaration and copyright statement ..................................................................... 7 Thesis in Journal Format ………………………………………………..……………… 8 Publications and presentations generated from this thesis ……..……..…………… 9 Research projects and funding generated from this thesis …………………………. 11 ACKNOWLEDGEMENTS ..……………………………………………………………………… 12 CHAPTER 1. INTRODUCTION …………………………………………..…………………….. 13 1.1 Congenital Hyperinsulinism (CHI) ……………………………….………………... 13 1.2 Aetiology ………………………………………………………………..…………… 13 1.3 Histological forms of CHI …………………………………………….…………….. 15 1.4 Diagnosis and initial management ………………………..………………………. 16 1.5 Medical treatment ……………………………………………………….………….. 18 1.6 Outcomes of CHI …………………………………………………………………… 21 1.6.1 Natural history of the disease ………………..………………………….. 21 1.6.2 Neurodevelopmental outcomes ………….……………………………… 22 1.7 References …………..……………………………………………………………… 23 CHAPTER 2. PROJECT AIMS AND OBJECTIVES .…..……………………………...…... 27 CHAPTER 3. Conservatively treated Congenital Hyperinsulinism (CHI) due to KATP channel gene mutations: reducing severity over time ..…………………………………. 30 3.1 Abstract ………………………………………………………………………………. 31 3.2 Background ………………………………………………………………………….. 32 3.3 Aims ………………………………………………………………………………….. 33 3.4 Methods ……………………………………………………………………………… 33 3.5 Results ……………………………………………………………………………….. 36 3.6 Discussion …………………………………………………………………………… 48 3.7 Conclusion …………………………………………………………………………… 50 2 3.8 References ………………………………………………………………...………… 52 CHAPTER 4. mTOR inhibitors for the treatment of severe Congenital Hyperinsulinism: perspectives on limited therapeutic success ………………………... 56 4.1 Abstract ………………………………………………………………………….…… 57 4.2 Background ……………………………………………………………………….…. 58 4.3 Methods …………………………………………………………………………...…. 59 4.4 Results …………………………………………………………………………..…… 62 4.5 Discussion …………………………………………………………………………… 67 4.6 Conclusion …………………………………………………………………………… 69 4.7 References ……………………………………………………………………...…… 70 CHAPTER 5. Vineland adaptive behavior scales to identify neurodevelopmental problems in children with Congenital Hyperinsulinism (CHI) …………………………… 73 5.1 Abstract …………………………………………………………………………….… 74 5.2 Background ………………………………………………….………………….…… 75 5.3 Methods ……………………………………………………………………………… 75 5.4 Results ………………………………………………………………………..……… 79 5.5 Discussion …………………………………………………………………………… 85 5.6 Conclusion …………………………………………………………………..………. 87 5.7 References ………………………………………………………………………….. 89 CHAPTER 6. GENERAL DISCUSSION ……………………………………………………….. 93 6.1 Outcomes of medically treated CHI patients …………………………………….. 93 6.2 mTOR inhibitors in CHI …………………………………………………..………… 95 6.3 Neurodevelopment in CHI …………………………………………………………. 97 6.4 References …………………………………………………………………………... 99 Word count: 20. 522 3 LIST OF FIGURES Figure 1.1 Insulin secretion in the normal β-cell and the CHI β-cell due to KATP channel mutations …...………………………………………………….……...……….. 14 Figure 1.2 Management of patients with CHI based on diazoxide response …...………….. 17 Figure 3.1 Maximum and present doses of diazoxide in children with CHI represented as box and whisker plots ...…………………………….…………………..…………... 44 Supplementary Figure 3.A Mean blood glucose levels before and after prolonged fasting in patients with resolved CHI …….………………………….…….…….…….. 45 Supplementary Figure 3.B Mean blood ketone (3 hydroxybutyrate) levels before and after prolonged fasting in patients with resolved CHI …………………..………. 46 Figure 3.2 VABS-II scores as standard deviation scores for patients with persistent CHI and resolved CHI …………………………………………………………………… 47 Figure 4.1 Cell proliferation is not suppressed by sirolimus treatment ….………………….. 66 Figure 4.2 Quantification of proliferation in CHI tissue following sirolimus ………………… 67 Figure 5.1 VABS-II scores in Early and Late CHI …………………………………………….. 80 Figure 5.2 Scatterplot of VABS-II Total scores for age at presentation of hypoglycaemia .. 82 Figure 5.3 Clustered box and whisker plots of VABS-II Total scores in Early-CHI and Late-CHI ………………………………….………………………………………………. 83 Figure 5.4 Association of total behaviour scores with developmental delay ……………….. 84 4 LIST OF TABLES Table 1.1 Medical treatment in CHI …………………………………..…………….…………… 20 Table 3.1 Patients’ characteristics …………………………………………..………….………. 37 Table 3.2 Genetic characterisation of patients with medically treated KATP CHI ……..……. 40 Table 4.1 Patients’ characteristics and glycaemic support before mTOR inhibitors ...……. 60 Table 4.2 Medical therapy and supporting glucose requirement at study entry ..………..… 61 Table 4.3 mTOR inhibitor treatment, dose, trough levels and duration of treatment …….... 63 Table 4.4 Response to treatment, duration of fasting and clinical adverse events ………... 64 Table 4.5 Monitoring data in follow-up assessments after mTOR inhibitor treatment …..… 65 Table 5.1 Individual and total VABS-II domain correlations with developmental delay by objective assessment …..……………………………………………………………… 81 Appendix 5.A Clinical descriptors of patients ………………………...………………………… 90 5 ABSTRACT Patients with Congenital hyperinsulinism (CHI) are at high risk of permanent brain damage due to recurrent episodes of severe hypoketotic hypoglycaemia. In order to prevent adverse neurodevelopmental outcomes, some patients with the most severe forms of the disease will need subtotal pancreatectomy, which will cause lifelong consequences. In this thesis we demonstrate that conservatively treated patients with genetic forms of CHI due to KATP channel gene mutations (KATP CHI) show a reduction of severity over time and, in a significant proportion of patients, the disease is resolved including in patients with recessively inherited mutations. This supports conservative management in certain patients as opposed to subtotal pancreatectomy. Sirolimus, an mTOR inhibitor with immunosuppressive and antiproliferative effects has been reported to be successful in a limited number of CHI patients. However, in our experience sirolimus has limited efficacy and poor safety profile and should not routinely be used in the management of medically-unresponsive CHI. Furthermore, the rate of cell proliferation in pancreatic tissue from patients treated with sirolimus is not decreased, illustrating the lack of effect of sirolimus in the CHI pancreas. Assessing neurodevelopment is of paramount importance in CHI patients. The rate of adverse neurodevelopmental outcomes in our cohort of medically treated patients was no different to other cohorts and it was similar to cohorts of surgically treated patients. The use of Vineland Adaptive Behavior Scales Second Edition (VABS-II), a parent report questionnaire, has proved to be a reliable and specific tool to detect abnormal neurodevelopment in CHI patients. Male gender, later age at presentation and severity of disease are independent risk factors for worse neurodevelopment. These data expand our knowledge in this complex condition and provide important information on the natural history of the disease, repurposed therapeutic opportunities as well as highlighting the relevance of neurodevelopmental surveillance. 6 DECLARATIONS AND COPYRIGHT STATEMENT Declaration I declare that no portion of the work referred to in the thesis has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning. Copyright statement i. The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and s/he has given The University of Manchester certain rights to use such Copyright, including for administrative purposes. ii. Copies of this thesis, either in full or in extracts and whether in hard or electronic copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as amended) and regulations issued under it or, where appropriate, in accordance with licensing agreements which the University has from time to time. This page must form part of any such copies made. iii. The ownership of certain Copyright, patents, designs, trademarks and other intellectual property (the “Intellectual Property”) and any reproductions of copyright works in the thesis, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property and/or Reproductions. iv. Further information on the conditions under which disclosure, publication and commercialisation of this thesis, the Copyright and any Intellectual Property and/or Reproductions described in it may take place is available in the University IP Policy (see http://documents.manchester.ac.uk/DocuInfo.aspx?DocID=2442 0), in any relevant Thesis restriction declarations deposited in the University Library, The University
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