Congenital Hyperinsulinism 

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) represents the most common cause of hyperinsulinism in neonates; currently, many authors prefer the term congenital hyperinsulinism (CHI). It was first identified in 1938, when Laidlaw coined the term nesidioblastosis to describe the neodifferentiation of islets of Langerhans from pancreatic ductal epithelium (a term since replaced by PHHI and CHI).^[1]

Severe recurrent hypoglycemia associated with an inappropriate elevation of serum insulin, C-peptide, and proinsulin levels defines CHI. If left untreated, CHI can lead to brain damage or death secondary to severe hypoglycemia. Although it was initially thought to affect only infants and children, numerous cases have been reported in adults of all ages but at a much lower incidence. CHI is often poorly responsive or unresponsive to medical management, necessitating 95% or near-total pancreatectomy.

In CHI, the histologic abnormalities in pancreatic structure are heterogeneous but can be grouped into the following 2 broad categories:

• Focal adenomatous hyperplasia (found in one fourth to one third of cases)
• Diffuse abnormality of the islets

In the focal form, the histologically abnormal beta cells are limited to 1 or more focal areas, whereas in the diffuse form, the beta-cell abnormality is distributed throughout the pancreas.

Investigations into the molecular basis of CHI have led to the discovery of mutations in the sulfonylurea receptor and an inwardly rectifying potassium channel. However, approximately 50% of cases do not involve any currently known mutation.

Presumed structural or functional molecular abnormalities in the insulin secretory mechanism or glucose-sensing mechanism result in a failure to reduce pancreatic insulin secretion in the presence of hypoglycemia (serum glucose level < 60 mg/dL). Inappropriately high circulating insulin levels act to promote hepatic and skeletal muscle glycogenesis, causing a decrease in the amount of free glucose available in the bloodstream and suppression of the formation of free fatty acid (FFA), an alternative energy substrate for the brain.

The net effect is hypoglycemia, which results in physiologically appropriate adrenergic and neuroglycopenic symptoms, with severe neurologic dysfunction and frank seizure activity when central nervous system (CNS) glucose levels fall below 20-30 mg/dL.

Prolonged hypoglycemia causes death. Repeated episodes of severe, prolonged, sublethal hypoglycemia can result in permanent neurologic damage, including developmental delay, mental retardation, and focal CNS deficits. Therapy should be aimed at prevention of hypoglycemia to prevent morbidity and mortality.

CHI is a clinically, pathologically, and genetically heterogeneous disease. Most cases are sporadic. In approximately 50% of cases, no known genetic abnormality is found. Familial forms of CHI are rare but well documented. These cases involve autosomal recessive or dominant defects in the following 4 genes:

• Beta-cell high-affinity sulfonylurea receptor gene (ABCC8, also known as SUR1)
• Inwardly rectifying potassium channel gene (KCNJ11, also known as Kir6.2)
• Glucokinase gene (GCK, also called GK) - Only 5 persons have been described with this mutation
• Glutamate dehydrogenase gene (GLUD1, also called GUD1) - This gene is associated with hyperinsulinism with hyperammonemia; it is unclear whether GLUD1 mutation is a variant of CHI or a distinct clinical entity

Some data have helped elucidate the mechanism of the focal form of CHI. In the focal form, data have shown that a specific loss of maternal alleles occurs in the imprinted chromosome region 11p15 in the cells of the hyperplastic area, but no loss occurs in the normal pancreatic cells. This loss of heterozygosity results in a reduction to hemizygosity or homozygosity of the remaining paternal alleles that carry a mutation of ABCC8 (SUR1) or KCNJ11 (Kir6.2).

This abnormality occurs during embryonic development in a single pancreatic cell, resulting in a proliferative monoclonic lesion. However, other pancreatic cell lines not derived from this cell, as well as all other cells of the body, do not carry this genetic defect. The result is similar to uniparental disomy, but it occurs only in a clonal cell line and not constitutionally. This is a nonmendelian mechanism. This abnormality has not been observed in patients with the diffuse form of CHI.

High rates of consanguinity have been noted in some series. No known genetic abnormalities have been found in approximately half (in some series, the majority) of the patients studied, suggesting the existence of other mutations that have not yet been described. More detailed treatments of the genetics of hyperinsulinism have been published by Glaser et al^[2] and Fournet et al.^[3]

Adult-onset hyperinsulinemic hypoglycemia with pancreatic beta cell hypertrophy has been reported in adults undergoing Roux-en-Y gastric bypass surgery.^[4] The relation between the operative procedure and the pancreatic disease remains poorly understood. Service et al theorize that gastric bypass may increase activity of beta-cell trophic factors.^[4]

Few data are available on CHI. An estimated incidence of 1 in 50,000 live births in a random-mating US population has been reported. Worldwide, the incidence may be as high as 1 in 2500 live births in populations with high rates of consanguineous unions.

Age- and sex-related demographics

Patients with CHI usually present between birth and age 18 months, with most cases diagnosed shortly after birth. Cases of adult-onset forms of CHI are rare but well documented.

The diffuse form of CHI has a male-to-female ratio of 1.2:1. Focal lesions are found in a 1.8:1 male-to-female ratio. The overall male-to-female ratio is 1.3:1.

Cure

If a solitary focal lesion can be identified and excised, the patient usually maintains blood glucose levels within the reference range without the need for medication or continuous feedings.

Hypoglycemia often persists even after a 95-98% pancreatectomy. Hypoglycemia may be easier to control after partial pancreatectomy and may resolve months or years later or persist throughout life.

In a study of 101 patients, 50% of patients who underwent a 95% or greater pancreatectomy were cured (ie, they did not require medical or dietary treatment to maintain normoglycemia within the follow-up period of the study). The mean time from surgery to cure was 4.7 years.^[5] However, in some series, 40-63% of patients managed with medical therapy alone had late remission of hypoglycemia. Later onset of disease is correlated with a higher likelihood of being able to discontinue medical therapy.

Future development of diabetes mellitus

Patients who undergo partial pancreatectomy are at high risk for developing diabetes mellitus later in life. The risk of diabetes mellitus appears to increase with the extent of pancreatic resection; however, the risk is significant even with conservative surgical procedures.

In one series, 14% of children with diffuse lesions developed diabetes mellitus, regardless of the surgical procedure performed. The mean time from surgery to development of diabetes mellitus was 9.6 years.^[5] Because most series are limited by relatively short follow-up times, the lifetime incidence of diabetes mellitus is not well understood. Islet cell preservation and autotransplantation remain promising but untested therapies for patients who develop diabetes mellitus.

Diabetes mellitus is extremely rare after resection of focal lesions.

In a series of 3 patients treated without pancreatic resection, 2 developed impaired glucose tolerance, and one developed diabetes mellitus.^[6] All 3 patients had mutations of the ABCC8 (SUR1) gene. The significance of this small series is uncertain, but the results suggest that development of impaired glucose tolerance may be part of the underlying disease process and not solely due to surgical reduction in islet cell mass.

Education of the patient and family and long-term follow-up are essential to prevent delays in the diagnosis of disease recurrence, glucose intolerance, or diabetes mellitus.

Neurodevelopmental outcome

In some series, a high frequency of mental retardation, developmental delay, and nonhypoglycemic seizures has been observed. These findings are generally attributed to minimal brain damage from early hypoglycemic events, although the existence of these disorders as inherent comorbid conditions with CHI has not been fully excluded. Other series, usually in conjunction with medication studies, have shown normal developmental progress in patients with PHHI.

Some data suggest that patients with early, severe disease treated with early, aggressive surgery have a better neurodevelopmental outcome. No comprehensive long-term studies of neurodevelopmental outcomes in patients with PHHI are available, and the heterogeneity of the disease likely confounds many neurodevelopmental studies.

Permanent neurologic dysfunction (eg, seizures, developmental delay, focal neurologic deficits) or death secondary to severe, prolonged hypoglycemia may occur if PHHI goes untreated or is inadequately treated.

A nutritionist should provide dietary education and meal-planning assistance. Patients (if old enough) and family members should be taught how to use a home blood glucose monitor. They should also understand the signs and symptoms of hypoglycemia and how to treat this condition with rapid-acting oral carbohydrates and subcutaneous glucagon.

Family members must understand the importance of prompt treatment of hypoglycemia to prevent severe complications or death. Family members should be instructed to call the local emergency medical service (EMS) if they are unable to treat a hypoglycemic episode or if the patient does not respond to treatment promptly. Family members should know the local emergency phone number if 911 service is not available in their area. Patients should wear a medical identification bracelet.

Patients and family members should be reminded to carry medications, a glucose meter, a rapid-acting carbohydrate source, and glucagon when traveling. Families should carry sufficient supplies for several extra days in case of unexpected travel delays.

Patients who have undergone surgery, as well as their family members, should be reminded of the risk of future development of diabetes mellitus and the importance of long-term follow-up. Failure to educate families about this potential late complication could result in a delay of diagnosis of diabetes mellitus if it occurs.

Genetic counseling with regard to risk of recurrence may be appropriate. Techniques for prenatal diagnosis are currently limited to investigational use but may be available at some medical centers.