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Hyperinsulinism

 



Congenital Hyperinsulinism

Paul S Thornton
Clinical Director of the Hyperinsulinism Programme
Children's Hospital of Philadelphia


Congenital Hyperinsulinism is the most frequent cause of severe, persistent hypoglycaemia 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 hyperinsulinism develop hypoglycemia 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 hypoglycaemia, brain damage can be prevented. However, brain damage can occur in up to 50% of children with hyperinsulinism if their condition is not recognized or if treatment is ineffective in the prevention of hypoglycaemia. This article will explain the different forms of hyperinsulinism. The mechanisms of each type of hyperinsulinism will be outlined and will include the genetic defects responsible and their mode of inheritance. Treatment options and recent advances in diagnosis will be presented.

Mechanisms of Disease

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 the blood glucose in the normal range. Insulin acts by driving glucose into the cells of the body. This action of insulin has two effects 1) maintaining blood glucose between 3.3mmol/L to 5mmol/L (60 to 90 mg/dl) and 2) storing glucose particularly as glycogen in the liver. Once feeding is completed and the 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 starved (fasted), blood glucose levels remain in the normal range and the body has access to energy at all times.
With hyperinsulinism, however, this close regulation of blood glucose and insulin secretion is lost. The pancreas, which is responsible for insulin secretion, is blind to the blood glucose level and makes insulin regardless of the blood glucose concentration. As a result, the child with hyperinsulinism can develop hypoglycaemia at any time but particularly when fasting. In the most severe form of hyperinsulinism this glucose blindness causes frequent, random episodes of hypoglycaemia. With one of the rarer forms of hyperinsulinism, hypoglycaemia is related to protein ingestion.

Hyperinsulinism causes a particularly damaging form of hypoglycaemia 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 hypoglycaemia, 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 can not make the energy they need to work and so they stop working. This loss of function may result in seizures and coma and if prolonged may result in death of the cells. It is this cell demise which causes the damage which manifests as learning disabilities, cerebral palsy, blindness or even death.

Causes of Hyperinsulinism

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 hyperinsulinism do not go away, but in some cases, may become easier to treat as the child gets much older.

Transient hyperinsulinism

Babies who are born small for gestational age, or prematurely, may develop hypoglycaemia due to excessive insulin secretion. In addition, infants in whom fetal distress occurred due to lack of oxygen to the brain may also have hypoglycaemia from hyperinsulinism. The cause of this inappropriate insulin secretion is unclear, but it can last a few days to months. Once recognized, this form of hyperinsulinism is usually easy to treat. Many affected infants will not have hypoglycaemia once they are fed every 3-4 hours. In the more severely affected children, intravenous glucose is needed to prevent hypoglycaemia. Rarely, drug therapy is required; in which case, diazoxide is usually a very effective treatment. Children with this form of hyperinsulinism should have a fasting study done whilst off all medications , to prove that the hyperinsulinism was transient.

A small number of babies born to mothers with diabetes mellitus may have hyperinsulinism. This hyperinsulinsim 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 hypoglycaemia 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 of intensive intravenous drip feeding of glucose. Once the hypoglycaemia resolves, it should never recur.


Persistent Hyperinsulinism

Although the persistent forms of hyperinsulinism are uncommon, a number of different genetic defects causing hyperinsulinism have recently been recognized. In the past, before the different genetic forms of hyperinsulinism were recognized, hyperinsulinism was referred to by many names, including nesidioblastosis, islet cell dysregulation syndrome, idiopathic hypoglycaemia of infancy, Persistent Hyperinsulinaemic Hypoglycemia of Infancy (PHHI) and Congenital Hyperinsulinism. With the identification of the genes responsible for these disorders, the naming of the different forms of hyperinsulinism has become more exact.


KATP -HI Diffuse or Focal Disease

The KATP form of HI is considered the classic form of hyperinsulinism and previously was known as "nesidioblastosis" or "PHHI". It is usually found in newborns who have larger than normal birth weights (many weigh above 9lbs) and occurs 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 and the Kir6.2 gene. Normally, when the beta cell senses that glucose levels are elevated, the KATP channel commences 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 causes disease and whichever parent has the mutation will also have the disease) have been found in the KATP channel and also 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. The beta-cells of the focal lesion have lost the mother's normal KATP channel and are only able to express the father's defective KATP channel.

Children with either form of KATP-HI are identical in their appearance and behavior. They tend to have significant hypoglycaemia 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 hypoglycaemia. Diazoxide is usually an ineffective treatment for these children because diazoxide works on the broken KATP channel and it cannot fix the broken channels. Other drugs have been used to treat KATP-HI but are also usually poorly effective. Octreotide given by injection every 6 to 8 hours or by continuous infusion and nifedipine may be successful in the short term. Glucagon may be given by intravenous infusion to stabilize the blood sugar as a temporizing measure. Some centres advocate a very intensive regimen of feeding every two hours and four to six injections a day of octreotide or continuous octreotide by subcutaneous pump. We 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

GDH-HI has also been known as the Hyperinsulinism/Hyperammonaemia Syndrome (HI/HA), leucine-sensitive hypoglycaemia, and diazoxide-sensitive hypoglycaemia. 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 hypoglycaemia after eating a high protein meal. GDH-HI affected individuals can have significant hypoglycaemia 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. These high ammonia levels, however, do not appear to be harmful in GDH-HI.

Patients with GDH-HI often present later that 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 hypoglycaemia until they sleep overnight without a middle of the night feed or after they start higher protein-containing solid foods such as yoghurt. The frequency of hypoglycaemia 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.

GK-HI

Three families are now known with mutations of the enzyme glucokinase. This defect was inherited in an autosomal dominant fashion but likely can 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 hyperinsulinism 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. Genetic tests for the GK gene are available in only a few centers.

Others

Other forms of hyperinsulinism are known to exist, but the genetic mutations responsible have yet to be identified. Their clinical features and response to therapy vary.

Diagnosis

The diagnosis of hyperinsulinism may be quite difficult if one relies on demonstrating an elevated blood insulin concentration at the time of hypoglycaemia because insulin levels fluctuate widely over time in patients with hyperinsulinism. Other signs and chemical markers must be used to provide clues to excess insulin action and are often easier to demonstrate. Hypoglycaemia 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 hypoglycaemia. 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 hypoglycaemia is a sensitive marker for hyperinsulinism. Ketones, free fatty acids, and the glucagon stimulation test may all be performed if a random episode of hypoglycaemia occurs. A fasting study is sometimes required to provoke hypoglycaemia and confirm the diagnosis of HI.

The identification of genetic defects responsible for hyperinsulinism and the improved understanding of the mechanism of abnormal insulin secretion have permitted the development of insulin secretion studies aimed at identifying the specific type of hyperinsulinism a child may have. The acute insulin response studies (AIRs) are performed by serially administering intravenous injections of glucose and drugs (calcium, tolbutamide which stimulates insulin secretion through SUR1 and leucine, an amino acid) over a short period of time. Insulin measurements are taken just prior to and for 5 minutes after the infusions. The specific pattern of insulin responses to these agents can help delineate the genetic defect affecting the beta-cell.

If a focal lesion is suspected based upon the acute insulin response studies, an attempt to identify the location of the lesion in the pancreas can be undertaken. Localization of the lesion helps the surgeon identify the lesion in the pancreas and may avoid subjecting needlessly an infant with a focal lesion to a 95% pancreatectomy. One of the localization studies available is called pancreatic arterial stimulation venous sampling (ASVS). ASVS involves placement of a catheter (a long intravenous line) into the artery of the leg. Through this catheter the radiologist injects calcium into each of the three arteries that supplies blood to the various regions of the pancreas (head, body, and tail). Through an intravenous line inserted into the child's neck, blood samples are obtained to measure the insulin coming out of the pancreas. An increase in insulin secretion, after injection of calcium into one of the three arteries, suggests the location of the focal lesion (head, body, or tail).

Transhepatic Portal Venous Sampling (THPVS) is another procedure designed to localize the site of a focal lesion. A catheter is inserted through the skin, into the liver, and into the veins of the pancreas. Blood samples for insulin are obtained throughout the various regions of the pancreas. The location of the focal lesion is suggested by the region of the pancreatic venous system with the highest insulin concentrations.


Treatment

Prompt treatment of hypoglycaemia due to hyperinsulinism is essential to prevent brain damage. Unlike other hypoglycaemia-causing conditions in which alternative fuels, such as ketones or lactate, may be available for the brain during periods of hypoglycaemia, hyperinsulinism prevents the production of these fuels and leaves the brain without a source of energy. Hypoglycaemia 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 hypoglycaemia 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 hyperinsulinism include diazoxide, octretide, and glucagon:

Diazoxide. 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 rarely works in children KATP-HI.
Side effects of diazoxide include fluid retention, a particular problem for the newborn which has received large amounts of intravenous glucose to maintain the blood glucose in the normal range. A diuretic medication (hydrochlorthiazide or chlorthiazide) is sometimes used with diazoxide in anticipation of such a problem. Diazoxide also causes a cosmetic problem of excessive hair growth of the eyebrows, forehead, and back. This hair growth resolves several months after diazoxide therapy is stopped. Shaving the hair occasionally may be necessary and does not intensify hair growth.

Nifedipine. This is an oral medication, used to treat high blood pressure, that blocks calcium entry into the cells. In theory, it should work well to prevent hypoglycaemia, however in practice it rarely does. There are several publications indicating its success but overall most people who treat larger groups of children with HI say that it works in less than 10 % of patients.

Octreotide. 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 its initial effectiveness may wane with time and it becomes less effective. In addition more is not always better as the higher the dose (higher than 20 -40 microgramms/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.

Glucagon. 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 hyperinsulinism has low blood glucose 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.

Surgery

Children with diffuse KATP-HI commonly require 95-99% pancreatectomies. These surgeries are not always 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 hypoglycaemia.
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, pathologists and surgeons, specialized in this procedure. Therefore it is generally only available in the major centres treating patients with hyperinsulinism. 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.

Focal lesions can be cured with surgery. The difficulty, however, is that many focal lesions 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.


Outcome

Prognosis is greatly influenced by the form (severity) of hyperinsulinism an affected child has. The most severe long term complication is brain damage. Even in the centres most experienced in treating children with hyperinsulinism, rates of up to 20% of the children suffer permanent damage. For all children, the development of permanent learning disabilities is difficult to predict and depends not only on the frequency of low blood glucose but also the duration of a hypoglycemic episode. In addition to learning disabilities, stroke like symptoms or cerebral palsy can occur. Strabismus (turned in eye) or blindness may also be caused by hypoglycaemia.

Children with diffuse disease who have a 95-99% pancreatectomy will continue to be at risk for hypoglycaemia. Occasionally a second or third surgery may be required. The hypoglycemia post surgery is usually easier to control than prior to surgery. Diabetes in both the immediate post-operative period and in the long term is a greater risk in patients with diffuse disease. Failure to absorb the food from the gut may be a problem due to loss of the enzymes produced by the pancreas for digestion of food. This may require enzyme replacement.

Children with focal lesions that are successfully resected with partial pancreatectomies are cured of their disease and are not anticipated to have an increased risk of diabetes mellitus or of food mal-absorption

Technically less disabling, but a very serious problem, are feeding difficulties. There is a lot of debate about the cause of these difficulties. The two main theories currently discussed are a primary problem in abnormal gut motility due to the genetic defect responsible for hyperinsulinism. This in theory should only therefore be found in patients with diffuse disease. Because it is found in both diffuse and focal disease, the second possibility is that feeding difficulties commonly occur as a result of the therapy of the hyperinsulinism. Long term tube feeds and the use of intravenous fluids without oral feeding, designed to prevent hypoglycaemia, may hinder the child from learning how to feed by mouth during the critical first two to three months of life. Later, excessive weight associated with forced tube feeding to prevent hypoglycemia may suppress the appetite and thus prevent the child from developing the desire to eat. Attempts should be made to encourage the child to feed by mouth from birth in addition to whatever other therapies are required, and early intervention by a feeding specialist should be implemented, to decrease the risk of development of feeding problems. In this manner, feeding difficulties will be reduced dramatically.

Children with HI/HA and other forms of hyperinsulinism which are diazoxide responsive tend to do well long-term but will need occasional in-hospital monitoring of home regimens to insure safety and for dose adjustments. The elevated blood ammonia concentrations do not seem to cause problems in GDH-HI.

Finally, but equally important, are the stresses for the family. Prolonged hospitalizations requiring parents to be away from home or work, and intense home medical regimens can be quite taxing for the family. Support of family, friends, and medical staff is critical for helping the parents and siblings through the difficulties. A medical regimen and a feeding schedule which are manageable for the families without compromising the safety of the child are also important so as to decrease the burden on the family.

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