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.
|Date of Award||1 Aug 2020|
- The University of Manchester
|Supervisor||Donald Ward (Supervisor), Mark Dunne (Supervisor), Karen Cosgrove (Supervisor) & Indraneel Banerjee (Supervisor)|