NORD gratefully acknowledges Julie Raskin, Executive Director, Congenital Hyperinsulinism International, Diva D. De Leon-Crutchlow, MD, Professor of Pediatrics, Chief, Division of Endocrinology and Diabetes, and Director, Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Susan A. Becker, Nurse Coordinator, RN, BSN, Congenital Hypeirnsulinism Center, The Children's Hospital of Philadelphia, and Paul Thornton, MD, Medical Director, Cook Children’s Endocrine and Diabetes Program, for the preparation of this report.
Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies, infants, and children. In most countries it occurs in approximately 1/25,000 to 1/50,000 births. About 60% of babies with HI are diagnosed during the first month of life. An additional 30% will be diagnosed later in the first year and the remainder after that. With early treatment and aggressive prevention of hypoglycemia, brain damage can be prevented. However, brain damage can occur in children with HI if the condition is not recognized or if treatment is ineffective in the prevention of hypoglycemia.
Insulin is the most important hormone for controlling the concentration of glucose in the blood. As food is eaten, blood glucose rises and the pancreas secretes insulin to keep blood glucose in the normal range. Insulin acts by driving glucose into the cells of the body. This action of insulin maintains blood glucose levels and stores glucose as glycogen in the liver. Once feeding is completed and glucose levels fall, insulin secretion is turned off, allowing the stores of glucose in glycogen to be released into the bloodstream to keep blood glucose normal. In addition, with the switching off of insulin secretion, protein and fat stores become accessible and can be used instead of glucose as sources of fuel. In this manner, whether one eats or is fasting blood glucose levels remain in the normal range and the body has access to energy at all times.
This close regulation of blood glucose and insulin secretion does not occur normally in people who have HI. The beta cells in the pancreas, which are responsible for insulin secretion, are blind to the blood glucose level and secrete insulin regardless of the blood glucose concentration. As a result, the baby or child with HI can develop hypoglycemia at any time but particularly when fasting. In the most severe form of HI this glucose blindness causes frequent, random episodes of hypoglycemia.
HI causes a particularly damaging form of hypoglycemia because it denies the brain of all the fuels on which it is critically dependent. These fuels are glucose, ketones, and lactate. The usual protective measures against hypoglycemia, such as release of glycogen stores from the liver (called glycogenolysis), conversion of protein to glucose (called gluconeogenesis) and conversion of fat into ketones (called fatty acid oxidation and ketogenesis) are prevented by insulin. Once the brain cells are deprived of these important fuels, they cannot make the energy they need to work and so they stop working. The lack of appropriate fuel to the brain may result in seizures and coma and if prolonged may result in death of the brain cells. It is this cell damage which can manifest as a permanent seizure disorder, learning disabilities, cerebral palsy, blindness or even death.
It is often difficult to identify symptoms of HI because they are often confused with typical behaviors of newborns and infants. Common symptoms include irritability, sleepiness, lethargy, excessive hunger and rapid heart rate. More severe symptoms, such as seizures and coma, can occur with a prolonged or extremely low blood sugar level. Common symptoms of low blood sugar in older children and adults include feelings of shakiness, weakness, or tiredness, confusion and rapid pulse. More severe symptoms include seizures or coma.
A number of causes exist. Some forms will resolve and are considered transient. Others arise from genetic defects and persist for life. These genetic forms of HI do not go away, but in some cases, may become easier to treat as the child gets much older.
Babies born small for gestational age, or prematurely, may develop hypoglycemia due to excessive insulin secretion. In addition, infants who experience fetal distress due to lack of oxygen to the brain may develop hypoglycemia. The cause of this inappropriate insulin secretion is unclear, but it can last a few days to months. Once recognized, this form of hypoglycemia is usually easy to treat. Many affected infants will not have hypoglycemia once they are fed every 3-4 hours. In the more severely affected children, intravenous glucose is needed to prevent hypoglycemia. Occasionally, drug therapy is required; in which case, diazoxide is usually a very effective treatment. Children with this form of hyperinsulinism have a fasting study done when medications have been weaned, to prove that the hyperinsulinism has resolved and therefore was transient. A small number of babies born to mothers with diabetes mellitus may have transient hypoglycemia. This tends to occur if the mother’s diabetes was not under good control. The mother’s high blood glucose levels are transmitted across the placenta to the fetus. The fetus compensates by secreting extra insulin. This step-up in insulin secretion does not cause hypoglycemia while the fetus is inside the mother, but after birth, the constant supply of high glucose from the placenta is gone and the blood sugar in the newborn falls precipitously. This form of hyperinsulinism should resolve within a few days with frequent feeding or in some cases intensive intravenous drip of glucose. Once the hypoglycemia resolves, it should never recur.
A number of different genetic defects causing HI have been identified. In the past, before the different genetic forms of HI were recognized, HI was referred to by many names, including nesidioblastosis, islet cell dysregulation syndrome, idiopathic hypoglycemia of infancy, and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). With the identification of the genes responsible for these disorders, the naming of the different forms of HI has become more exact.
KATP-HI Diffuse or Focal Disease
The KATP form of HI was formerly known as “nesidioblastosis” or “PHHI”. Neonates with this form of hyperinsulinism are frequently, although not always, larger than normal birth weight (many weigh above 9lbs) and present in the first days of life. It is called KATP-HI because its genetic cause is due to defects in either of two genes that make up the potassium channel (called KATP channel) in the insulin secreting beta-cells of the pancreas. These two genes are the SUR1 gene (known as ABCC8) and the Kir6.2 gene (known as KCNJ11). Normally, when the beta cell senses that glucose levels are elevated, closure of the KATP channel triggers insulin secretion. When the KATP channel is defective, inappropriate insulin secretion occurs and causes hypoglycemia. Two forms of KATP-HI exist: diffuse KATP-HI and focal KATP-HI. When these mutations are inherited in an autosomal recessive manner (one mutation in the gene inherited from each parent, neither of whom is affected) they cause diffuse disease, meaning every beta-cell in the pancreas is abnormal. Recently autosomal dominant mutations (a mutation in a single copy of the gene) have been found to cause diffuse disease. When a recessive mutation is inherited from the father and loss of heterozygosity for the maternal copy of the gene (loss of the mother’s unaffected gene from a few cells in the pancreas) occurs, a focal lesion arises. Abnormal beta cells are limited to this focal lesion and are surrounded by normal beta-cells.
Children with either form of KATP-HI are identical in their appearance and behavior. They tend to have significant hypoglycemia within the first few days of life and require large amounts of glucose to keep their blood glucose normal. They may have seizures due to hypoglycemia. Diazoxide is often an ineffective treatment for these children because diazoxide works on the KATP channel and it cannot fix the broken channels. Octreotide given by injection every 6 to 8 hours or by continuous infusion may be successful (sometimes only in the short term). Glucagon may be given by intravenous infusion to stabilize the blood sugar as a temporary measure in the hospital setting. Some centers prefer the surgical approach. With the recent discovery of diffuse and focal KATP-HI, attempts to differentiate these two forms are very important: surgical therapy will cure focal HI but not diffuse HI (see below).
GDH-HI has also been known as the hyperinsulinism/hyperammonemia syndrome (HI/HA), leucine-sensitive hypoglycemia, and protein-sensitive hypoglycemia. GDH-HI is caused by a mutation in the enzyme glutamate dehydrogenase (GDH). It is inherited in either an autosomal dominant manner or may arise as a sporadically new mutation in a child with no family history. GDH plays an important role in regulating insulin secretion stimulated by amino acids (especially leucine). Individuals with GDH-HI develop hypoglycemia after eating a high protein meal or after fasting. GDH-HI affected individuals can have significant hypoglycemia if they eat protein (for instance eggs or meat) without eating carbohydrate containing foods such as bread, juice or pasta. GDH-HI is also associated with elevated blood concentrations of ammonia, which is derived from protein. Patients with GDH-HI often present later than KATP channel HI, typically, not until three to four months of age when they wean from low protein containing breast milk to infant formula. Others do not have recognizable hypoglycemia until they sleep overnight without a middle of the night feed or after they start higher protein-containing solid foods. In addition, GDH-HI can be successfully treated with diazoxide and the avoidance of protein loads without carbohydrates. Most children with GDH-HI will do very well once recognized, but if the diagnosis is delayed, they may also suffer brain damage from untreated hypoglycemia.
This defect is inherited in an autosomal dominant fashion but can also arise sporadically. Glucokinase is the “glucose sensor” for the beta-cell. It tells the beta-cell how high the blood glucose is and when to secrete insulin. Glucokinase mutations that cause HI instruct the beta-cell to secrete insulin at a lower blood glucose than is normal. Like GDH-HI, GK-HI can be treated with diazoxide, but sometimes, it may be severe and unresponsive to diazoxide.
Other forms of HI, responsive to diazoxide include: 1) HI due to mutations in SCHAD, an enzyme that regulates GDH. Children with SCHAD HI, are also protein-sensitive. 2) HNF4A and HNF1A HI are caused by mutations in HNF4A and HNF1A, transcription factors that play an important role in the beta-cells. These mutations cause hyperinsulinism in infancy and familial diabetes (also known as MODY, or maturity onset diabetes of the young) later in life. 3) Exercise-induced hyperinsulinism is a rare form of HI in which hypoglycemia is triggered by exercise.
Other forms of HI are known to exist, but the genetic mutations are not yet well described. Their clinical features and response to therapy vary. HI can also be associated with syndromes such as Beckwith Wiedemann syndrome, Kabuki syndrome, and Turner syndrome among others. In these cases, HI is only one of the features that characterize the clinical picture.
HI affects both males and females and has been reported in many countries. In most countries it occurs in approximately 1/25,000 to 1/50,000 births.
The diagnosis of HI may be quite difficult if one relies on demonstrating a detectable blood insulin concentration at the time of hypoglycemia because insulin levels fluctuate widely over time in patients with HI. Other signs and chemical markers must be used to provide clues to excess insulin action and are often easier to demonstrate.
Hypoglycemia which occurs while an infant is on a glucose infusion is strongly suggestive of HI. Other clues to excess insulin action are low free fatty acids and ketones at the time of hypoglycemia. Another indicator of excess insulin can be demonstrated by the glucagon stimulation test. Glucagon is a hormone that opposes insulin action and stimulates release of glucose from liver glycogen stores. A rise in blood glucose after glucagon administration at the time of hypoglycemia is a sensitive marker for hyperinsulinism. Ketones, free fatty acids, and the glucagon stimulation test may all be performed if a random episode of hypoglycemia occurs. A fasting test done in a safe setting in an experienced hospital is sometimes required to provoke hypoglycemia and confirm the diagnosis of HI.
Distinguishing between focal and diffuse disease is an important aspect of diagnosis. Genetic testing is the most useful test in determining the likelihood of focal hyperinsulinism. Special radiologic testing is used in some centers to help localize focal lesions. The 18-F-DOPA PET scan which involves use of a radioactive drug is the most effective way to localize focal lesions. 18-F-DOPA is not yet approved by the FDA, so this work is being done under research protocols in the U.S. The 18-F-DOPA PET scan is more widely available in some centers in Europe. Other imaging modalities such as ultrasound, CT scans, or MRIs are not useful to localize these lesions.
Prompt treatment of hypoglycemia due to HI is essential to prevent brain damage. Unlike other hypoglycemia-causing conditions in which alternative fuels, such as ketones or lactate, may be available for the brain during periods of hypoglycemia, HI prevents the production of these fuels and leaves the brain without a source of energy. Hypoglycemia can be treated by giving a carbohydrate-containing drink by mouth or if severe, by giving glucose through the vein or by injecting glucagon. A child with a feeding tube can have glucose given through the tube. The goal of treatment is to prevent hypoglycemia while the child has a normal feeding pattern for age with a little extra safety built in, e.g., a one year old who normally would not eat overnight for 10-12 hours should be able to fast for at least 14 -15 hours on a successful medical regimen. Medications used to treat HI include diazoxide, octreotide, and glucagon.
Diazoxide is given by mouth 2-3 times per day. The dose varies from 5 to 15mg/kg/day. Usually, if 15 mg/kg/day does not work, higher doses will not work. Diazoxide acts on the KATP channel to prevent insulin secretion. It is generally effective for infants with stress-induced hyperinsulinism, infants with GDH-HI or GK-HI, and in a subgroup of infants whose basic defect is not known. Diazoxide often does not work in children with KATP-HI. Side effects of diazoxide include fluid retention, a particular problem for the newborn who is receiving large amounts of intravenous glucose to maintain the blood glucose in the normal range. A diuretic medication is sometimes used with diazoxide in anticipation of such a problem. Diazoxide also causes excessive hair growth of the eyebrows, forehead, and back (referred to medically as hypertrichosis). This hair growth resolves several months after diazoxide therapy is stopped. Some patients choose to shave the hair occasionally and this does not intensify hair growth.
Octreotide is a drug that also inhibits insulin secretion. It is administered by injection. It can be given periodically throughout the day by subcutaneous injection or may be administered continuously under the skin by a pump that is commonly used for insulin therapy in individuals with diabetes. Octreotide is often very effective initially, but it may become less effective over time. In addition, more is not always better as the higher the dose (higher than 20 micrograms/kg/day), the less effective it may become. Side effects include alteration of gut motility, which may cause poor feeding. It may also cause gallstones and very rarely may produce hypothyroidism, and short stature. As with any injection, risks of pain, infection, and bruising exist. Additionally, octreotide is not currently recommended in neonates already at risk for NEC (necrotizing enterocolitis). There other drugs similar to octreotide that have a longer duration of action and can be used once a month, these include octreotide LAR and lanreotide. These longer acting preparations are reserved for use in those patients that have responded to the short acting octreotide and are on a stable regimen.
Glucagon stimulates release of glucose from the liver. It is given through a vein or by injection under the skin or into the muscle. Glucagon can be used in cases of emergency when a child with HI has low blood glucose levels and cannot be fed. It can also be given in the hospital as a continuous infusion through a vein. It is most effective as a holding therapy while the child is prepared for surgery.
Children with diffuse KATP-HI often require 95-99% pancreatectomies. These surgeries are not curative and KATP-HI children who have undergone such surgeries may continue to require frequent feeds and medications to prevent hypoglycemia. They also may need repeat surgeries. The hope with such surgery is to lessen the intense medical regimen that otherwise would be needed to protect the child from recurrent, severe hypoglycemia.
In children with focal KATP channel HI, surgery to remove only the small part of the pancreas that is affected is the procedure of choice. This requires a multidisciplinary team of endocrinologists, radiologists, pathologists and surgeons, specialized in the treatment of these children. Therefore it is generally only available in the major centers treating patients with HI. The majority of patients with focal HI will be cured or will not require any medical therapy after the surgery. This is in stark contrast to those with diffuse disease in whom medical therapy after surgery is the rule.
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