NORD gratefully acknowledges Julie Raskin, Executive Director, Congenital Hyperinsulinism International, Diva De Leon, MD, Assistant Professor of Pediatrics and Pediatric Endocrinologist, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Susan A. Becker, Nurse Coordinator, RN, BSN, 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 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 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 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 while off all medications, to prove that the hyperinsulinism is 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.
Although the persistent forms of HI are uncommon, a number of different genetic defects causing HI have recently been recognized. 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”. It is often although not always found in newborns with larger than normal birth weight (many weigh above 9lbs) and presents 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, the KATP channel begins 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 loss of heterozygosity (inheritance of a mutation from the father and loss of the mother’s good 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. 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 diazoxide-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. GDH-HI affected individuals can have significant hypoglycemia if they eat protein (for instance eggs or meat) without eating sugar 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. The frequency of hypoglycemia is usually less than that associated with KATP-HI. In addition, GDH-HI can be successfully treated with diazoxide and the avoidance of pure protein loads. 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.
A few families are now known with mutations of the enzyme glucokinase. 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.
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 HI is caused by mutations in HNF4A. These mutations cause hyperinsulinism in infancy and familial diabetes later in life. 3) Exercise-induced hyperinsuinism 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 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. Special radiologic testing is used in some centers to help identify focal lesions. The 18-F-DOPA PET Scan which involves use of a radioactive drug is the most effective way to identify focal lesions. 18-F-DOPA is not yet approved by the FDA, so this work is being done under a research protocol in the U.S. The PET scan is more widely available in some centers in Europe.
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 20mg/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 has received 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. The French are researching long acting octreotide given once every three weeks or month. 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 20-40 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).
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 a small part of the pancreas is the procedure of choice. This requires a team of endocrinologists, radiologists, pathologists and surgeons, specialized in this procedure. 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.
While focal lesions can be cured with surgery, the difficulty is that many are found in the head of the pancreas. The immediate surroundings of the pancreatic head include important structures such as the bile ducts and duodenum. Successfully resecting a lesion in the head of the pancreas without harming these other important structures may sometimes be impossible.
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Stanley, CA, De León, DD, Monogenic Hyperinsulinemic Hypoglycemia. In: Frontiers in Diabetes, Vol 21., Porta and Matschinsky, editors. 2012 Krager, Philadelphia, PA.
Davidson BJ, Burman KD. Cancer of the Thyroid and Parathyroid. In: Head and Neck Cancer: A Multidisciplinary Approach, 3rd ed. Harrison LB, Sessions RB, Hong WK, editors. 2009 Lippincott, Williams & Wilkins. Philadelphia, PA. pp. 690-742.
Porterfield SP, White BA, Endocrine physiology. 2007 Mosby. Philadelphia, PA.
Li C, Allen A, et al. Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. J Biol Chem 2006;281:10214-10221.
Mikhailov MV, Campbell JD, et al. 3- D structural and functional characterization of the purified KATP channel complex Kir6.2- SUR1. EMBO J 2005; 24:4166-4175.
Sharma N, Crane A, et al. Familial hyperinsulinism and pancreatic beta- cell ATP- sensitive potassium channels. Kidney Int 2005;57:803-808.
Stanley CA. Hyperinsulinism in infants and children. Ped Clin of North Am 1997;44(2):363-374.
GENETIC TYPES OF HI:
Loechner, KJ, et al. Congenital hyperinsulinism and glucose hypersensitivity in homozygous and heterozygous carriers of Kir6.2 (KCNJ11) mutation V290M mutation: K(ATP) channel inactivation mechanism and clinical management. Diabetes;2011;60(1):209-17.
Henquin JC, et al. In vitro insulin secretion deviates from model predictions in infants with diazoxide- resistant congenital hyperinsulinism. J Clin Invest 2011;121:3932-3942.
Shimomura K, et al. Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism. EMBO Mol Med 2009 1(3):166-77.
Marthinet E, et al. Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function. J Clin Endocrinol Metab 2005;90(9)5401-6.
Henwood MJ, Kelly A, et al. Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate- sensitive potassium channel genes. J Clin Endocrinol Metab 2005;90:789-794.
Flanagan SE, et al. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 2003 30(2):170-80.
Hussain K et al. The diagnosis of ectopic focal hyperinsulinism of infancy with [18F] dopa positron emission tomography. J Clin Endocrinol Metab 2006;91:2839-2842.
Suchi M, MacMullen CM, Thornton PS, Adzick NS, Ganguly A, Ruchelli ED, Stanley CA: Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Mod Pathol. 2006;1: 122-9.
Suchi M, MacMullen CM, et al. Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Mod Pathol 2006;19:122-129.
Giurgea I, Sempoux C, et al. The Knudson’s two- hit model and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism. J Clin Endocrinol Metab 2006;91:4118-4123.
Mohnike K, et al. [18F]-DOPA positron tomography for preoperative localization in congenital hyperinsulinism. Horm Res. 2008;70(2):65-72.
Ribeiro MJ, et al. The added value of [18F]fluoro-L-DOPA PET in the diagnosis of hyperinsulinism of infancy: a retrospective study involving 49 children. Eur J Nucl Med Mol Imaging 2007;34:2120-21128.
Hardy OT, et al. Accuracy of [18F]fluoro-L-DOPA positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin endocrinol Metab 2007;92:4706-4711.
de Lonlay P, et al. Congenital hyperinsulinism: pancreatic [18F] fluoro-L-dihydroxyphenylalanine (DOPA) positron emission tomography and immunohistochemistry study of DOPA decarboxylase and insulin secretion. J Clin Endocrinol Metab 2006;91:933-940.
Otonkoski T, et al. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]- DOPA positron emission tomography. Diabetes 2006;55;13-18.
Ludwig A, Ziegenhorn K, et al. Glucose metabolism and neurological outcome in congenital hyperinsulinism. Semin Pediatr Surg 2011;20:45-49.
Mazor- Aronovitch K, et al. Long- term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol 2007;157:491-497.
Steinkrauss L, et al. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism. J Pediatr Nurs 2005;20:109-118.
Meissner T, et al . Long- term follow- up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol 2003;149:43-51.
Menni F, et al. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476-479.
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