Introduction: Congenital hyperinsulinism (CHI) is a disesase of severe hypoglycaemia, often due to in mutations in ABCC8/KCNJ11. Sirolimus, an mTOR inhibitor, has been reported to be successful in CHI patients, but the evidence is limited. We have aimed (i) to review the efficacy and safety profile of sirolimus, (ii) to assess the role of mTOR signalling pathways in CHI, (iii) to assess the impact of sirolimus in CHI pancreatic tissue.
Methods: Patients with CHI unresponsive to medical treatment were recruited (June 2014 to June 2016) with informed consent. Sirolimus efficacy was ascertained by cessation of intravenous dextrose and achievement of adequate fasting tolerance with sustainable euglycaemia. Patients were monitored for drug efficacy and side effects; treatment was withdrawn if persistent hypoglycaemia or serious side effects occurred. In silico analysis was used to assess the relationship between mTOR signaling pathways and CHI. Post-operative examination of pancreatic tissue was used to assess rates of cell proliferation using Ki67 expression.
Results: Four patients with severe CHI were included; 3 patients had homozygous ABCC8 mutations and in one patient no mutations were identified. Sirolimus was effective in one patient with euglycaemia sustained following discharge from hospital. Two patients showed an initial response; however, treatment effect was reversed with increasing hypoglycaemia. In the patient without mutations, no response was observed. One patient had stomatitis, two patients developed exocrine pancreatic insufficiency and three patients had sepsis. Subtotal pancreatectomy was performed in 2 patients. Differential gene expression between CHI and age-matched control revealed that 1960 genes had significant changes (P=<0.01, paired t-test). However, mTOR gene expression was unchanged (P=<0.98) and there was borderline association of the mTOR signaling with CHI (P=<0.03). To verify this, we examined cell proliferation in pancreatic tissue from 2 children following continuous sirolimus treatment. We found incidence of proliferation showed no reduction following sirolimus, indeed it was increased by 7.3- (n=18,053) and 2.6-fold (n=30,144) over control values.
Conclusion: Sirolimus remains of doubtful efficacy in the treatment of severe CHI and can be complicated by side effects in young infants. mTOR inhibition is unlikely to cause clinically relevant loss of insulin effect in CHI.
23 - 25 Nov 2016
British Society for Paediatric Endocrinology and Diabetes