What Is Congential Hyperinsulinism?

Congenital hyperinsulism (CHI), otherwise referred to as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and familial hyperinsulinism is a rare genetic disorder in which the pancreas produces too much insulin, resulting in hypoglycemia (low blood sugar). On average, it occurs once every 50,000 births.

According to the National Organization of Rare Disorders, about 60% of babies with CHI are diagnosed during the first month of life. An additional 30% will be diagnosed later in the first year and the remainder after that. There are few centers in the United States dedicated to treating this disorder.

There are different types of congenital hyperinsulinism as well as differing levels of severity. The disease can be characterized by hypoglycemia that ranges from severe neonatal (newborn stage) onset to childhood onset with mild symptoms

In some instances, babies may need to have surgery after birth to remove part of the affected pancreas. Oftentimes this cures the disease, however, depending on the type of congenital hyperinsulinism, this is not always the case. In other instances, medications can control the disease.

Types of Congenital Hyperinsulinism

The pancreas is the organ that is affected in hyperinsulinism. A normal functioning pancreas will secrete insulin in response to glucose in the bloodstream so that it can bring glucose to the cells to use for energy and normalize the amount of glucose in the blood.

When a person is in a fasting state and not eating, insulin secretion is turned off. However, in people with congenital hyperinsulinism, insulin is secreted from beta cells regardless of the amount of glucose present in the blood, and whether or not the person has eaten or is fasting. This causes low blood sugar.

Extra insulin secretion prevents the typical protective responses to prevent hypoglycemia such as the release of glycogen from the liver, conversion of protein to glucose, and conversion of fat to ketones. Deprivation of these important fuels can cause the brain cells to stop working. Prolonged lack of fuel to the brain can result in seizures, learning disabilities, death of brain cells or even death.

Claudia Boucher-Berry, MD, pediatric endocrinologist of UI Health says, "At least eight different mutations have been identified that lead to congenital hyperinsulinism. Each mutation leads to a different defect in the beta cell that causes insulin to be released regardless of the blood sugar. Even though the mutations are different, the end result is the same—the blood sugars will drop low due to the elevated insulin levels."

However, not all forms of hyperinsulinism are caused by gene mutations.

Transient Hyperinsulininism

Transient hyperinsulinism is a temporary state of hyperinsulinism that usually goes away in a few days to a few weeks. This type of hyperinsulinism can be apparent in babies that are born prematurely or small for gestational age.

Sometimes, babies who are born to mothers who have diabetes with chronically elevated blood sugar may have transient hyperinsulinism because their body was accustomed to making extra insulin to compensate for the glucose they were receiving from their mother. Once they are born their body continues to make extra insulin temporarily, which can result in low blood sugar.

KATP-HI Diffuse or Focal Disease

This is a genetic form of CHI due to defects in two genes that make up the potassium channel, called the ATP channel in the beta cells of the pancreas. The genes of defect are the SUR1 gene and the Kir6.2 gene which causes inappropriate insulin secretion that results in hypoglycemia.

There are two different types of KATP-HI—diffuse and focal. Children with either have the same signs and symptoms. They tend to have significant low blood sugar in the first few days of life and require large amounts of glucose to keep their blood sugar normal.

These children may have seizures due to hypoglycemia. Oral medication is often an ineffective treatment for these children. It's important to differentiate between the two types because focal disease can often be cured with surgery.

Diffuse congenital hyperinsulinism is seen when abnormal beta cells throughout the entire pancreas produce too much insulin. This is the most common form of hyperinsulinism and is typically inherited in an autosomal recessive pattern.

The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In the fetus, both copies of the gene in each cell have mutations.

Focal congenital hyperinsulinism occurs when only some of the beta cells in a restricted area of the pancreas over-secrete insulin. This type of hyperinsulinism is harder to explain. Mutations in the genes are not active for all cells, therefore, only some of the beta cells secrete excess insulin.

The good news is that focal hyperinsulinism is often curable with surgery. Identification of the abnormal part of the pancreas will be critical to determining surgery.

GDH-HI

This type of hyperinsulinism is caused by a mutation in the enzyme glutamate dehydrogenase (GDH). It is inherited in either an autosomal dominant manner or can arise sporadically in a child with no family history.

Children with GDH-HI typically develop hypoglycemia after eating a high protein meal. This occurs because GDH plays an important role in regulating insulin secretion stimulated by protein or amino acids, such as leucine.

This type of hyperinsulinism is also associated with elevated blood levels of ammonia, which is derived from protein. Most children with GDH-HI have symptoms later in infancy, when they are weaned from low protein-containing breast milk to infant formula. Sometimes this is not recognized until they go for longer periods without eating, such as overnight.

There is less frequency of hypoglycemia with this type of hyperinsulinism and it is usually treated successfully with medication and avoidance of pure protein meals.

GK-HI

This type of hyperinsulinism occurs because of mutations of the enzyme glucokinase. Glucokinase is an enzyme that gives the pancreatic beta cells direction- it alerts the beta cells as to how high blood glucose is and when to secrete insulin.

When there is a mutation in the enzyme, beta cells secrete insulin at a lower when the blood glucose is lower than normal. Usually, this type of hyperinsulinism can be treated with medication.

HNF4A/HNF1A HI

This type of hyperinsulinism is caused by mutations in HNF4A and HNF1A which are transcription factors that play an important role in the beta-cells. These mutations cause hyperinsulinism in infancy and familial diabetes. Children with this type of hyperinsuilnism are generally responsive to oral medications and may present with ketones during a hypoglycemic episode.

Other Types

Other types of hyperinsulinism include short-chain 3-hydroxyacyl-CoA dehydrogenase hyperinsulinism (SCHAD-HI), insulinomas (insulin-secreting tumors of the pancreas) can cause hyperinsulinism, as well as Nissen fundoplication, MCT1, hexokinase, and UCP1.

There are other types of hyperinsulinism that are related to other diseases, such as Beckwith Wiedemann syndrome, Kabuki syndrome, and Turner syndrome among others. In these instances, hyperinsulinism is just one of the symptoms.

Congenital Hyperinsulinism Symptoms

Symptoms of congential hyperinsulinism include hypoglycemia or low blood sugar and "will differ depending on the age of the child," says Boucher-Berry.  Sometimes this can be a difficult symptom to identify in newborns and infants because common symptoms such as lethargy, sleepiness, and irritability can mimic typical newborn behaviors.

Dr. Boucher-Berry tells us, "When the blood sugar is low in an infant, they may be excessively sleepy or irritable." However, sometimes, babies may have more atypical symptoms such as a fever, lack of color, and difficulty feeding.

Reoccurring episodes of low blood sugar can result in serious complications such as seizures, brain damage, vision loss, intellectual disability, and coma.

"In the milder forms, the hypoglycemia may not be picked up until the child is older," says Boucher-Berry. "Older children can also present with irritability or increased fatigue, but they will also experience excessive hunger, headaches, dizziness, feeling shaky, rapid pulse, or confusion. Extremely low blood sugars can lead to loss of consciousness, seizures or coma," she warns.

Children are usually diagnosed before 2 years of age.

Causes

Most of the time, congenital hyperinsulinism is caused by mutations in the genes that regulate insulin. Mutations in different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital hyperinsulinism.

Dr. Claudia Boucher-Berry says, "Even though the mutations are different, the end result is the same—the blood sugars will drop low due to the elevated insulin levels."

Sometimes, if a fetus is born to a woman who has diabetes during pregnancy that is not controlled properly, they can have a form of temporary hyperinsulinism, which typically goes away. In roughly half the cases, the cause is unknown.

Diagnosis

If there is suspicion of hyperinsulinism, most children can be diagnosed with blood and urine samples. The tests should be done during a spontaneous episode of hypoglycemia. These tests include things such as c-peptide, free fatty acid, low β-hydroxybutyrate, inappropriately low acetoacetate, etc.

Dr. Boucher-Berry says, "Genetic testing can be done to identify the cause of the hyperinsulinism. However, the diagnosis can be made based on laboratory testing during the time of hypoglycemia."

Other tests that may be done to determine a diagnosis include a glucagon stimulation test. If a child requires a certain amount of glucose daily to keep blood sugars normal, this is also suggestive of hyperinsulinism.

In instances where the hyperinsulinism is severe, the presence of symptomatic hypoglycemia and elevated insulin levels can often confirm a diagnosis.

Imaging is used when there is suspicion of focal disease. Dr. Boucher-Berry says, "(18F-DOPA) PET/CT is an imaging study used to identify the abnormal areas of the pancreas. The scan is useful to identify if the affected areas of the pancreas are limited to a small section or if the whole pancreas is affected."

Fluoro-DOPA positron emission tomography (F-DOPA-PET) has been used successfully for the preoperative localization of focal lesions.

Treatment

The first priority is to treat the hypoglycemia. Dr. Boucher-Berry warns, "Hypoglycemia in a child is very dangerous and can lead to severe brain damage. It is imperative to identify hypoglycemia in a child and start them on treatment immediately. Medical therapy can have side effects, so it is important to weigh the risks/benefit ratio and do what is in the best interest of the child."

Lack of glucose to the brain can cause brain damage if not treated promptly and, because the body is unable to use alternative sources of energy, administration of glucose will be necessary. For most infants this will mean giving glucose via intravenous infusion. Older infants and children can be given a glucose containing drink.

Getting the baby to feed regularly will be important for development as well as preventing low blood sugar. Sometimes, even before differentiating a specific type of hyperinsulinism, babies will be put on certain medications to attempt to stop insulin secretion. This can work for certain types of hyperinsulinism, but not for all.

Boucher-Berry says, "Treatment for congenital hyperinsulinism includes medical treatment and surgical options. If a child does not respond to medical therapy (meaning they continue to have low blood sugar), then surgery should be considered for management. Surgery entails removal of a portion of the pancreas, so that the insulin levels will drop."

One of the first medicines given is called diazoxide. Diazoxide is medication that acts on the KATP channel to prevent insulin secretion. This medication is generally given a few times daily and is works best in children who have certain types of hyperinsulinism, usually not in children with KATP-HI.

Like all medications, it does have some side effects. According to the Children's Hospital of Philadelphia, the main side effects include fluid retention (increased swelling of the feet, hands, and face), increased weight gain from excessive water being stored in the body and in small infants, this can cause heart failure due to fluid overload.

A later side effect is the increased growth of hair on the body including not only the head, but also on the face, arms, legs, and back. Most children will be on diazoxide for many years.

Octreotide is another drug that is used to treat hypoglycemia by inhibiting insulin secretion. It can be given throughout the day subcutaneously via injection or delivered via infusion through a pump.

A pump is a type of vehicle of administration that is commonly used for people with type 1 diabetes who use insulin therapy via pump. This medication is often very effective, but can become ineffective as time goes on.

Side effects include alteration of gut motility which may result in poor feeding. Other side effects include gallstones, short stature and very rarely hypothyroidism. It is contraindicated in infants at risk for necrotizing enterocolitis.

Glucagon injections can be given in emergency situations when a child has a low blood sugar and cannot be feed. This medication stimulates the release of glucose from the liver and is often used in people with Type 1 diabetes when they have severe hypoglycemia. Sometimes it is given in the hospital via vein through continuous infusion when a child is being prepared for surgery.

In children who have focal hyperinsulinism, surgery can cure the disease. Children with diffuse KATP hyperinsulinism often require 95-99% pancreatectomies. Unfortunately, these surgeries do not cure hyperinsulinism and therefore children will still need frequent feedings and medication to stop low blood sugar. Sometimes they also need multiple surgeries.

Prognosis

Early detection and aggressive treatment and prevention of hypoglycemia can prevent brain damage. The long-term prognosis is greatly influenced by the type and severity of hyperinsulinism that the child has. If the condition is not recognized or ineffective in treating hypoglycemia, brain damage can occur.

It is difficult to predict or determine learning disabilities in these children because it depends on the frequency of low blood sugar as well as how long the episodes of low blood sugar occur. Children with frequent low blood sugar are also at risk for increased risk of developing other neurological problems, including motor delays, cognitive delays, or cerebral palsy.

Genetic defects, feeding difficulties, and long-term tube feeding and intravenous fluids can cause feeding problems. One of the most important parts of treatment is getting a child to feed by mouth early in life. Early intervention with a feeding therapist will be critical to achieving this goal.

Children with focal lesions that are successfully resected with partial pancreatectomy are cured of their disease and are not anticipated to have an increased risk of diabetes mellitus or of food malabsorption.

In children with diffuse disease who have a 95-99% pancreatectomy may still be at risk of hypoglycemia even after their pancreas is removed. Sometimes additional surgeries will be required. These children are at increased risk of developing diabetes and can have issues with absorption of certain goods because of the loss of pancreatic enzymes, in which case they may require enzyme replacement.

Despite these difficulties, the good news is that with the right medical treatment, the ability to maintain normal glucose levels becomes easier with time. In fact, the Cook Children's hyperinsulinism center says, "Fortunately, most of the long-term forms become easier to treat as your child gets older."

Most individuals treated medically enter clinical remission after several months or years of treatment. In addition, most children who respond well to medical treatment can be treated without long-term complications. Sometimes long-term treatment can result in glucose intolerance which can be effectively managed with mild dietary restrictions.

Coping

Having a child with hyperinsulinism can be very overwhelming, especially during the initial phases when physicians are figuring out specifics of the disease and parents are trying to prevent hypoglycemia with frequent feedings and medications. Prolonged hospital stays and complicated medical regimes can also be taxing for the family.

A pediatric endocrinologist with be an integral part of the treatment team. Dr. Boucher-Berry says, "I tend to start the medical treatment and if the child responds to the medical therapy, then I will continue to manage them. When I have children who are unresponsive to medical therapy, then I will transfer them to a special center (CHOP) for further management."

There are several special centers across the U.S. that specialize in hyperinsulinism and they have so many success stories and additional support for families and loved ones. These centers have a special team of doctors, including, pediatric endocrinologists, surgeons, neurologists, neonatologists, gastroenterologists, nutritionists, social workers, and speech and feeding specialists.

Support of family, friends, and medical staff will be critical for helping parents and siblings. Education and current research will also be an important part of dealing with and coping with the disease.

Congenital Hyperinsulinism International often holds educational family conferences. They had their first virtual conference in July 2020 which included topics such as, infants and toddlers with hyperinsulinism, developmental delays, managing hyperinsulinism at school, hyperinsulinism in teenagers, living with hyperinsulinism as an adult, feeding, and nutrition, etc.

You may also want to consider joining a congenital hyperinsulinism global registry to help fuel new research as well as to be considered for any clinical trials.

A Word From Verywell

Congenital hyperinsulinism is a complex and complicated disease that poses many challenges for children and their families. It is very rare and each treatment plan, medication and feeding schedule is to be individualized. Treatment and prevention of hypoglycemia as well differentiating between types of hyperinsulinism can help to prevent complications.

Centers that specialize in congenital hyperinsulinism can assist parents and children with the disease and can serve as a source of essential support and knowledge. The good news is that the disease is treatable, and often gets easier to manage as children get older.