Congenital Hyperinsulinism

Congenital hyperinsulinism (CHI) is the most frequent cause of persistent hypoglycemia in newborn babies, infants, and children. ^[1] Although it was initially thought to affect only infants and children, numerous cases have been reported in adults but at a much lower incidence.

CHI is defined by severe, recurrent hypoglycemia associated with an inappropriate elevation of serum insulin, C-peptide, and proinsulin levels. If left untreated, CHI can lead to brain damage or death.

The causes of CHI are largely genetic. ^{[2, 3, 4]} Mutations in at least 12 genes that play a role in regulating beta-cell insulin secretion have been implicated in the pathogenesis of HI. ^[5]  Genetic forms are sometimes classified into the following seven subtypes ^[6] :

• K _ATP-hyperinsulinism (diffuse or focal)
• GDH-hyperinsulinism
• GK-hyperinsulinism
• SCHAD-hyperinsulinism
• UCP2-hyperinsulinism
• HNF4A and HNF1A-hyperinsulinism
• MCT1-Hyperinsulinism

Approximately 50% of diazoxide-responsive cases and 10% of diazoxide-unresponsive cases of CHI have unknown etiology, suggesting that additional genes may be identified. ^[6]  Several syndromic genetic forms of CHI have also been identified (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes). However, in these cases, CHI is only one of the features that characterize the clinical picture. ^[5]

The histology of CHI has been divided into focal and diffuse categories. Approximately 40% of cases can be classified as focal, 50% of cases as diffuse, and 10% of cases are considered atypical. ^[7]  In the focal form, the focal lesion contains isletlike cell clusters with ductuloinsular complexes, hypertrophic cells, and giant nuclei. A well-developed endoplasmic reticulum and prominent Golgi complex are present, suggesting a high level of protein synthetic activity. Immunohistochemical staining shows an increased proportion of insulin-containing cells.

In the diffuse form of CHI, findings throughout the pancreas are similar to those found within a focal lesion. Again, isletlike cell clusters with ductoinsular complexes, hypertrophic cells, and enlarged, hyperchromatic nuclei are observed; endocrine cells also occur individually. The endoplasmic reticulum is well developed, and Golgi complexes are prominent. Results of macroscopic examination are normal.

Genetic mutation testing is now well established as the standard of care to define best approaches to treatment of CHI. New methods make it possible to obtain results in less than a week, preferably within 2 or 3 days. Rapid turnaround time for genetic tests is required because treatment decisions need to be made within a few days for severely ill infants. ^[5]

Fluorine-18L-3,4-hydroxyphenylalanine positron emission tomography (¹⁸F-DOPA-PET) is considered the gold standard for preoperative differentiation of focal from diffuse disease and localization of the focal lesion. ^{[7, 8]}  CHI is often poorly responsive or unresponsive to medical management, necessitating 95% or near-total pancreatectomy.

In congenital hyperinsulinism (CHI), the histologic abnormalities in pancreatic structure are heterogeneous but can be grouped into the following two 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 one 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, intellectual disability, and focal CNS deficits. Therapy should be aimed at prevention of hypoglycemia to prevent morbidity and mortality.

Congenital hyperinsulinism (CHI) is a clinically, pathologically, and genetically heterogeneous disease. Most cases are sporadic, although rare familial forms have been documented. ^[9] In approximately 50% of cases, no known genetic abnormality is found. Genes that have been identified as etiologic factors in CHI include the following ^[10] :

• ABCC8, also known as SUR1: Beta-cell high-affinity sulfonylurea receptor gene

• KCNJ11, also known as Kir6.2: Inwardly rectifying potassium channel gene

• GCK, also called GK: Glucokinase gene

• GLUD1, also called GUD1: Glutamate dehydrogenase gene, which is associated with hyperinsulinism with hyperammonemia

• HADH: 3-hydroxyacyl-coenzyme A dehydrogenase

• SLC16A1: Solute carrier family 16, member 1

• HNF4A: Hepatocyte nuclear factor 4-alpha

• HNF1A: Homeobox A

• UCP2: Uncoupling protein 2

• HK1: Hexokinase 1

• PGM1: Phosphoglucomutase 1

• PMM2: Phosphomannosmutase 2

Some data have helped elucidate the mechanism of the focal form of CHI. In the focal form of K_ATP-hyperinsulinism, 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. ^[11]

High rates of consanguinity have been noted in some series. No known genetic abnormalities have been found in approximately half of the patients studied, suggesting the existence of other mutations that have not yet been described. 

Adult-onset hyperinsulinemic hypoglycemia  has been reported in adults following Roux-en-Y gastric bypass surgery. ^[12] The relation between the operative procedure and the pancreatic disease remains poorly understood. Hypoglycemia due to hypersecretion of insulin may be related to excess production of gut-derived incretin hormones. Post-RYGB hypoglycemia has also been ascribed to an ill-defined reactive process leading to, or unmasking, a defect in beta-cell function. The view that postbypass hyperinsulinemia and hypoglycemia may result from altered nutrient delivery rather than hyperfunction of beta-cells is supported by a report of successful management of such cases with a gastrostomy tube. ^[12]  

Hyperinsulinemia (HI) is estimated to occur in 1 in 30,000-50,000 live births. ^[6] In Japan, the incidence of transient neonatal HI is estimated at 1 in 17,000 births and that of persistent hypoglycemia at 1 in 35,400 births. ^[13]  Estimates of the incidence of congenital HI (CHI) range from 1 in 50,000 births in Holland to as high as 1 in 2500 in Saudi Arabia (due to high rates of consanguinity). Among Ashkenazi Jews, the incidence, based on the carrier frequency for two recessive KATP-HI founder mutations, has been estimated to be 1 in 10,816. However, these incidence rates likely underestimate the prevalence of CHI because they do not include other forms of the disorder. ^[5]

More the half of cases of CHI are diagnosed during the first month of life and up to 90% before the infant is one year old. However, the risk of permanent brain injury in infants with HI is as high as 25–50% because of delays in diagnosis and inadequate treatment. ^[5] 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.

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. ^[14] 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. ^[14]

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. ^[15] 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 intellectual disability, 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 congenital hyperinsulinism (CHI) has not been fully excluded. Other series, usually in conjunction with medication studies, have shown normal developmental progress in patients with CHI.

In a study of 121 individuals who underwent pancreatectomy for HI between 1960 and 2008, neurobehavioral problems were reported in 48% (58 of 121). Psychiatric/behavioral problems and speech delay were the most common abnormalities reported. Learning disabilities and seizures were also apparent. Patients with diffuse CHI had worse outcomes on the neurobehavioral measures than those with focal disease. ^[14]

Permanent neurologic dysfunction (eg, seizures, developmental delay, focal neurologic deficits) or death secondary to severe, prolonged hypoglycemia may occur if CHI 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.