ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Endocr Soc. 2019 Feb 7;3(4):699–713.

This paper describes a retrospective study of patients with congenital hyperinsulinism (CHI) who were treated with mammalian target of rapamycin (mTOR) inhibitor, sirolimus, in a tertiary service, and reviews the 15 publications reporting CHI patients treated with sirolimus.

The diffuse forms of CHI can present with severe hypoglycemia usually unresponsive to therapy with diazoxide and needing a near total pancreatectomy. These patients are a real challenge to manage clinically as the hypoglycemia can be so severe. The therapeutic options for these patients with diffuse forms of hyperinsulinism are limited.

Sirolimus has been successfully used in patients with severe diffuse HH, unresponsive to maximum doses of diazoxide and octreotide. However, the therapeutic response to sirolimus has been variable with some studies reporting good responses and other studies reporting poor responses. In this largest study to date, 22 patients who were treated with sirolimus, virtually all showed some response with the best responses observed in those patients with either compound or heterozygous ABCC8/KCNJ11 gene mutations. As expected, the limiting factors for continuation of treatment were the side effects of sirolimus. However, it is difficult to know if all the side effects reported can be attributed solely to treatment with sirolimus. For example, newborns with severe HH have multiple other risk factors (such as central venous lines for delivering concentrated dextrose infusions) for infections.

The exact mechanism/s how sirolimus ameliorates HH is unclear. In clinical practice, sirolimus should be used as a last resort in patients with diffuse HH to avoid pancreatectomy. In some patients, the combination of sirolimus, diazoxide and or octreotide might be more effective in preventing a near total pancreatectomy. Sirolimus can also be used as a short-term treatment until the underlying HH becomes milder and then an alternative form of treatment can be started. Patients on sirolimus should be carefully monitored for possible side effects. Understanding the impact of mTOR inhibitors on beta-cell function in patients with diffuse HH might give further insights into their action. There is an urgent need to develop novel therapies for the diffuse form of CHI so that a near total pancreatectomy can be avoided.