Congenital hyperinsulinism: Global and Japanese perspectives

Abstract

Over the past 20 years, there has been remarkable progress in the diagnosis and treatment of congenital hyperinsulinism (CHI). These advances have been supported by the understanding of the molecular mechanism and the development of diagnostic modalities to identify the focal form of ATP-sensitive potassium channel CHI. Many patients with diazoxideunresponsive focal CHI have been cured by partial pancreatectomy without developing postsurgical diabetes mellitus. Important novel findings on the genetic basis of the other forms of CHI have also been obtained, and several novel medical treatments have been explored. However, the management of patients with CHI is still far from ideal. First, state-of-the-art treatment is not widely available worldwide. Second, it appears that the management strategy needs to be adjusted according to the patient's ethnic group. Third, optimal management of patients with the diazoxideunresponsive, diffuse form of CHI is still insufficient and requires further improvement. In this review, we describe the current landscape of this disorder, discuss the racial disparity of CHI using Japanese patients as an example, and briefly note unanswered questions and unmet needs that should be addressed in the near future.Key words 18F-dihydroxyphenylalanine, congenital hyperinsulinism, potassium channel.Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants before weaning.Other terms for CHI, such as "nesidioblastosis" or "persistent hyperinsulinemic hypoglycemia in infancy," are currently less frequently used. "Nesidioblastosis" is a pathological term indicating the continuous proliferation of islet cells from the pancreatic ducts, which is a common finding in healthy newborns and in obese subjects, 1-4 and the term "persistent hyperinsulinemic hypoglycemia in infancy" is no longer favored because symptoms of CHI could develop after infancy or even in adulthood. 5Persistent severe hypoglycemia could lead to permanent brain damage, so appropriate and timely treatment is extremely important for the prognosis of patients with CHI.6-9 Patients resistant to medical treatment previously often underwent near-total pancreatectomy, which involves removal of more than 95% of the total volume of the pancreas. The results, however, were frequently unsatisfactory because many patients remained hypoglycemic after surgery and most patients without hypoglycemia eventually developed postsurgical insulin-dependent diabetes mellitus. 9-11Fortunately, during the past decade, there has been major progress in the understanding and treatment of CHI, and many cases are now curable without postsurgical complications. However, there are still unanswered questions about the cause of CHI and unmet needs of patients that need to be addressed. Importantly, current diagnostic and therapeutic strategies are not uniformly available and applicable throughout the world.We have studied CHI in Japan over the past several years and found that there are regional biological ...

Clinical practice guidelines for congenital hyperinsulinism

“… Includes both syndromic and nonsyndromic form ( Table 1 Table 1. Known causes of pediatric hyperinsulinemic hypoglycemia (including acquired causes) ( 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ). ) …”

“…Furthermore, oral administration of diazoxide, a pancreatic β cells K ATP channel opener, has been approved for the treatment of CHI. For patients with diazoxide unresponsive CHI, the following therapies have been attempted: off-label use of octreotide, as multiple daily injections or continuous infusion; glucagon, as a continuous infusion; intravenous injection of glucocorticoids; or oral administration of nifedipine ( 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ). When euglycemia cannot be maintained by medical treatment, pancreatectomy has been performed to avoid neurological sequelae.…”

Efficacy and safety of octreotide for the treatment of congenital hyperinsulinism: a prospective, open-label clinical trial and an observational study in Japan using a nationwide registry

“…neonates and infants caused by dysregulated excessive secretion of insulin from the pancreatic β cells. The incidence of persistent CHI is low and estimated at 1 in 35,400 live births in Japan (2011 National Survey) [1]. Nonetheless, appropriate treatment is critically important as profound and repeated episodes of hypoglycemia often cause severe psychomotor retardation [2,3].…”

Congenital hyperinsulinism: current status and future perspectives

“…The distinction between transient and persistent CHI is not possible on the basis of laboratory test results. In our national survey in Japan, only shorter gestational age and lighter birth weight were predictors of transient CHI20). The incidence of persistent CHI is generally estimated as 1 in 50,000 live births9) although the incidence could be higher in certain populations (e.g., 1 in 2,500 births in Saudi Arabia).…”