From Diagnosis to Emerging Therapies: A Clinical Q&A on Congenital Hyperinsulinism with Dr. Diva D. De León-Crutchlow

Here at Children’s Hospital of Philadelphia (CHOP), we continue to build our reputation as one of the world leaders in treating hyperinsulinism (HI). In addition to answering key questions about diagnosis and management, Diva D. De León-Crutchlow, MD, MSCE, Chief of the Division of Endocrinology and Diabetes and Director of the Congenital Hyperinsulinism Center, recently sat down to discuss how advances in imaging, genetics and emerging therapies are reshaping care for children with hyperinsulinism.  

Question: How can clinicians differentiate between hyperinsulinism and other causes of persistent hypoglycemia in neonates and infants?  

Dr. De Léon-Crutchlow: The diagnosis of hyperinsulinism is based on the demonstration that insulin secretion and insulin actions are inappropriately active during a spontaneous or provoked episode of hypoglycemia. This includes evidence that insulin secretion is not turned off during hypoglycemia as shown by a measurable insulin concentration in plasma when the plasma glucose is low (< 50 mg/dL). In addition, we look for evidence that insulin actions are suppressing the normal physiologic responses to fasting and hypoglycemia, which includes activation of lipolysis, fatty acid oxidation/ketogenesis and glycogenolysis. This is demonstrated by low plasma levels of free fatty acids (<1.7 mmol/L) and beta hydroxybutyrate (<1.8 mmol/L), and a glycemic response to glucagon (> 30 mg/dL).

What are the current best practices for acute and long-term management of patients with hyperinsulinism, particularly those unresponsive to diazoxide?

The management of children with hyperinsulinism requires a stepwise approach that starts with the stabilization of plasma glucose levels and prevention of further episodes of hypoglycemia. In infants with hyperinsulinism, this frequently requires administration of intravenous dextrose.

For infants who require high glucose infusion rates, fluid overload is a concern. In these cases, we utilize a continuous intravenous infusion of glucagon, which we have demonstrated effectively reduces the glucose requirement and therefore reduces the risk of fluid overload.

Once the plasma glucose has been restored to the normal range, the emphasis should be on completing the diagnostic evaluation, and once the diagnosis of hyperinsulinism is confirmed, the next step is to start the first line of pharmacologic treatment for hyperinsulinism, which is diazoxide. Because treatment with diazoxide can result in fluid retention, diuretics should be initiated concomitantly.

A very important step in the management of children with hyperinsulinism is the demonstration that treatment with diazoxide is effective. This requires a fasting test to demonstrate that the cardinal feature of hyperinsulinism, hypoketotic hypoglycemia, has been reversed by diazoxide treatment.

For diazoxide-unresponsive children, the priority is to identify those that may have focal hyperinsulinism. Genetic testing to sequence the genes that encode the ATP-sensitive potassium channel is essential to determine the likelihood of focal hyperinsulinism. The finding of a monoallelic recessive pathogenic variant in either one of these two genes encoding the channel, ABCC8 and KCNJ11, have a sensitivity of 97% for focal hyperinsulinism. Children suspected of having focal hyperinsulinism should be referred to a center with capability to do advanced imaging for localization of the lesion. The treatment of choice for focal hyperinsulinism is surgical resection of the lesion.

For children with non-focal diazoxide-unresponsive hyperinsulinism, treatment options are limited and include the off-label use of somatostatin analogues alone or in combination with continuous dextrose through a gastrostomy. When medical treatment attempts fail, near-total pancreatectomy may be required. 

How do imaging modalities (such as ^18F-DOPA PET) guide surgical decision making in focal vs. diffuse HI? 

18FDOPA PET is a specialized imaging technique used for localization of focal lesions. This technique is almost 100% accurate for localization. The approach is always to do genetic testing first to guide the decision of doing 18FDOPA PET because the sensitivity of the 18FDOPA PET for focal hyperinsulinism is lower than the sensitivity of the genetic testing. The 18FDOPA PET is done in combination with a CT scan, and this allows the radiologist to give very precise coordinates about the localization of the lesion to the surgeon. The use of 18FDOPA PET has drastically changed hyperinsulinism management, making it possible to cure those with the disease's focal form. 

What are the latest advancements in genetic testing for hyperinsulinism, and how do they influence clinical decision making? 

Genetic testing has advanced significantly in the last 10 to 15 years, both in the ability to test for different genetic changes simultaneously, and in the turnaround time to get results. Currently, we can sequence the genes that are associated with focal hyperinsulinism and have results within a week; this has changed the management of children suspected to have focal hyperinsulinism in a very dramatic way. In addition, the ability to identify the underlying genetic cause of hyperinsulinism has allowed us to get a better understanding of the different phenotypes, natural histories and outcomes associated with different genetic types of hyperinsulinism. However, there is still more to be discovered; in about 40% of cases with hyperinsulinism we are unable to identify the underlying genetic cause with current testing techniques. 

What emerging therapies or research directions hold the most promise for improving outcomes in patients with hyperinsulinism?

We have made tremendous advances in improving the outcomes of patients with focal hyperinsulinism; however, there are several new exciting research directions that promise to improve the outcomes of all children with hyperinsulinism. One of them is research efforts that we and others are undertaking to develop novel approaches to identify babies with hyperinsulinism before they experience symptoms. We are also working on novel ways of identifying the underlying genetic mechanisms of children for whom traditional genetic testing has failed to reveal the cause. Finally, there are great advances in the development of new therapeutics for hyperinsulinism. This a very exciting new era where we have several drug development programs at different stages, from the preclinical stage to phase three clinical trials, so there is the promise that in a few years we will have new medications that would prevent the need to do a near-total pancreatectomy for children with diazoxide-unresponsive non-focal hyperinsulinism.

To discuss a challenging case or learn more about our approaches for treating HI, please reach out to us at hyperinsulin@chop.edu.