International Guidelines for the Diagnosis and Management of Hyperinsulinism

Abstract

Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI, however; there have been almost no new therapeutic modalities since the development of diazoxide. Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in ‘developed’ countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an “essential medicine” by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.

Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome

“…Diagnosis of HI was based on biochemical evidence of inappropriate insulin action at the time of hypoglycemia (plasma glucose <50 mg/dL [2.8 mmol/L]), as previously described [ 21 ]. Diazoxide is the first-line treatment for HI [ 22 ]. Given the risk of diazoxide-associated fluid retention and pulmonary hypertension, our Center's practice is to concomitantly treat with diuretic and consult cardiology before initiating diazoxide in children with congenital heart disease.…”

“…Given the risk of diazoxide-associated fluid retention and pulmonary hypertension, our Center's practice is to concomitantly treat with diuretic and consult cardiology before initiating diazoxide in children with congenital heart disease. Diazoxide responsiveness was defined as the ability to maintain plasma glucose concentration >70 mg/dL (3.9 mmol/L) for at least 12 hours of fasting and/or generate appropriate hyperketonemia (plasma β-hydroxybutyrate >1.8 mmol/L) before development of plasma glucose <50-60 mg/dL (2.8-3.3 mmol/L) [ 22 , 23 ]. Resolution of HI was defined as demonstration of the development of hyperketonemia (β-hydroxybutyrate >1.8 mmol/L) before development of plasma glucose <50 mg/dL (2.8 mmol/L) during a controlled inpatient fast performed off treatment [ 22 ].…”

Diagnosis and treatment of a newborn with congenital hyperinsulinemia:Case report and literature review

“…We conducted fasting diagnostic and glucagon tests before her discharge from the hospital (3,4). The fasting test was initiated immediately after a meal, with the glucose infusion rate reduced by 1 mg/kg/min per hour.…”

Commentary on studies investigating low‐dose diazoxide in hyperinsulinism

“…Diazoxide, utilised in hyperinsulinism since the 1960s, 1 is the recommended first-line pharmacological therapy for children with hyperinsulinism. 2 It blocks the sulfonylurea receptor 1 (SUR1) subunit of K ATP -channel on pancreatic beta cells, increasing the permeability to potassium ions leading to hyperpolarization of the cells and inhibition of calcium-dependent insulin secretion. 3 The recently published International Guidelines for the Diagnosis and Management of Hyperinsulinism 2 recommends therapeutic diazoxide doses of 5-15 mg/kg/day aiming for plasma glucose concentration targets of 3.9-5.6 mmol/L (70-100 mg/dl).…”

“…A lower hypoglycaemia threshold (3.5 mmol/L or 63 mg/dl) may be acceptable in children with severe forms of hyperinsulinism-where the recommended plasma glucose concentration targets may be difficult to achievedepending on the severity and frequency of hypoglycemia and the availability other therapeutic options. 2 Malhotra et al and Ng et al advocate for a shift to this paradigm, presenting their experience with the initial use of low-dose diazoxide (2-5 mg/kg/day)escalating the dose if necessary-and adopting a plasma glucose concentration threshold for treatment of 3.5 mmol/L (63 mg/dl) as standard practice. These consensus parameters have been adopted in the UK.…”