Abstract
Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in children, which if unrecognized may lead to development delays and permanent neurologic damage. Prompt recognition and appropriate treatment of HI are essential to avoid these sequelae. Major advances have been made over the past two decades in understanding the molecular basis of hyperinsulinism and mutations in nine genes are currently known to cause HI. Inactivating KATP channel mutations cause the most common and severe type of HI, which occurs in both a focal and a diffuse form. Activating mutations of glutamate dehydrogenase (GDH) lead to hyperinsulinism/hyperammonemia syndrome, while activating mutations of glucokinase (GK), the “glucose sensor” of the beta cell, causes hyperinsulinism with a variable clinical phenotype. More recently identified genetic causes include mutations in the genes encoding short-chain 3-hydroxyacyl-CoA (SCHAD), uncoupling protein 2 (UCP2), hepatocyte nuclear factor 4-alpha (HNF-4α), hepatocyte nuclear factor 1-alpha (HNF-1α), and monocarboyxlate transporter 1 (MCT-1), which results in a very rare form of HI triggered by exercise. For a timely diagnosis, a critical sample and a glucagon stimulation test should be done when plasma glucose is < 50 mg/dL. A failure to respond to a trial of diazoxide, a KATP channel agonist, suggests a KATP defect, which frequently requires pancreatectomy. Surgery is palliative for children with diffuse KATPHI, but children with focal KATPHI are cured with a limited pancreatectomy. Therefore, distinguishing between diffuse and focal disease and localizing the focal lesion in the pancreas are crucial aspects of HI management. Since 2003, 18 F-DOPA PET scans have been used to differentiate diffuse and focal disease and localize focal lesions with higher sensitivity and specificity than more invasive interventional radiology techniques. Hyperinsulinism remains a challenging disorder, but recent advances in the understanding of its genetic basis and breakthroughs in management should lead to improved outcomes for these children.
Highlights
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children, which if unrecognized may lead to development delays and permanent neurologic damage
A failure to respond to maximum dose of diazoxide (15 mg/kg/day) after at least 5 days of treatment, suggests a ATP-sensitive potassium channel (KATP) channel defect as the most likely cause of hyperinsulinism
Congenital hyperinsulinism is one of the most complicated and challenging disorders faced by pediatric endocrinologists
Summary
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children, which if unrecognized may lead to development delays and permanent neurologic damage. A failure to respond to maximum dose of diazoxide (15 mg/kg/day) after at least 5 days of treatment, suggests a KATP channel defect as the most likely cause of hyperinsulinism Such children are potential surgical candidates and require referral to a specialized HI center with 18fluoro L-3,4-dihydroxyphenylalanine positron emission tomography (18 F-DOPA PET) scan availability [Figure 2]. The benefit of surgery in this group is that their hypoglycemia is often easier to manage following a pancreatectomy, but this must be weighed against the risks of a surgical procedure and long-term complications, such as diabetes Those children with diffuse disease who have very limited fasting tolerances (less than 2–3 h) and very high glucose infusion requirements will most likely require a pancreatectomy. In the largest published series, 91% of children who had undergone a near-total pancreatectomy in infancy required insulin therapy for diabetes by the age of 14 years [53]
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