Congenital hyperinsulinism (HI or CHI) is a condition causing severe hypoglycemia (low blood sugar) in newborns due to the overproduction of insulin. There are various causes of HI, some of which are known to be the result of a genetic mutation. Sometimes HI occurs on its own (isolated) and more rarely associated with other medical conditions (as a syndrome).
Congenital forms of hyperinsulinism can be transient (short-term) or persistent (long-term) and mild or severe. It can be the result of a defect in the entire pancreas (diffuse HI) or in just part of the pancreas (focal HI). Irrespective of the form, cause, or type, HI is a medical emergency that must be managed from its onset. There is no other hypoglycemic condition in the newborn period as dangerous as HI. Left untreated, hypoglycemia from HI can cause developmental disorders, seizures, permanent brain damage, and even death.
For those with focal HI, there is the potential for a cure with surgery. For those with diffuse HI, diazoxide is the only approved medication to treat hypoglycemia. For those who do not respond to diazoxide, the condition is often managed with continuous carbohydrates delivered through a feeding pump and a gastrostomy tube, and off-label use of medications such as octreotide given by injection. In the most severe cases, surgery may be necessary to remove most of the pancreas. New and more effective treatments are in development for those who continue to have hypoglycemia on existing therapies and treatments, and those who experience adverse effects of current treatments.
The incidence of persistent HI has been found to range from 1:2,500 to 1:50,000 births depending on the region or country. The incidence of transient forms of HI has been estimated to be between 1:1200 and 1:2000.
Signs and symptoms As HI is a congenital condition, an infant usually starts to show signs and symptoms within the first few days of life, although very occasionally symptoms may appear later in life. It is often difficult to identify signs and symptoms of HI because they are often confused with the typical behaviours of newborns and infants. About 60% of babies with HI develop hypoglycemia during the first month of life. An additional 30% will be diagnosed later in the first year and some later in life.HI may present in several ways; common symptoms of hypoglycemia include: Irritability Lethargy (excessive sleepiness) Jitteriness/tremors Tachycardia or bradycardia Abnormal breathing patterns/apnoea Hypothermia Abnormal feeding behaviour (not waking for feeds, not sucking effectively, appearing unsettled and demanding very frequent feeds, especially after a period of feeding well) High-pitched cry Hypotonia (Loose/floppy muscles) Pale/pallor/cyanosis (bluish coloured skin) Sweating
Older children and adults' symptoms may also include headaches, confusion, and dizziness.
Parents often describe initial concerns or symptoms such as their infants "not feeding well, being sleepy and jittery".More severe symptoms, such as seizures (fits or convulsions), can occur with a prolonged or extremely low blood sugar level. If the blood sugar level is not corrected, it can lead to loss of consciousness and potential brain injury.A simple blood sugar measurement is essential if there are any symptoms of hypoglycaemia.
Cause Hyperinsulinism or congenital hyperinsulinism can be a genetic or acquired condition. Acquired HI may be secondary to factors around birth, such as growth restriction of the fetus, less oxygen to the baby, or maternal diabetes. Together, these are often called perinatal stress-induced HI. They are typically present in the first 24 hours of life but often resolve by two weeks of age.
In contrast to the resolving perinatal stress-induced low blood sugars, HI can also be due to a genetic cause. Therefore, genetic testing should be considered in children in whom acquired HI is unlikely. This typically includes those not responding to first-line medication diazoxide. A genetic cause is also possible in children responding to diazoxide but where low sugars persist beyond the first 4 months of life.There are many different genetic forms of HI which can be present in isolation or as part of a wider condition, called a syndrome.
Isolated forms Isolated hyperinsulinism occurs in the majority of individuals with HI. The most common genetic cause is a change in one or both copies of a gene that instructs the building of the potassium channel (ABCC8 and KCNJ11). This channel normally regulates insulin production from the β-cell in the pancreas in response to sugar levels in the blood. A change or fault in the channel leads to uncontrolled and excessive production of insulin. These changes in the ABCC8/KCNJ11 genes can be inherited in a dominant or recessive manner. In the dominant form, a single (monoallelic) change inherited from one parent (or arising spontaneously) causes diffuse HI. In diffuse HI, the whole pancreas is affected. Dominant HI may be mild and respond to diazoxide or severe and diazoxide unresponsive. Some changes in the ABCC8 and KCNJ11 genes are not inherited dominantly but are inherited recessively. In these families, each parent carries one copy of a faulty gene, but are themselves unaffected. A child will develop HI if they inherit two copies of the faulty ABCC8/KCNJ11 gene, one from each parent. Recessively inherited changes in the ABCC8/KCNJ11 genes cause diffuse HI which typically does not respond to diazoxide. In some cases, a paternal copy of the faulty gene is inherited by the child which occurs in combination with a loss of the mother's normal copy of the gene in the pancreas. This gives rise to focal HI where only one part of the pancreas (called a focal lesion) produces excess insulin.
If HI is severe and not responsive to medicines, rapid testing of the ABCC8 and KCNJ11 genes is recommended. This helps to identify the possibility of focal HI early in the course of the illness. Following a genetic finding, specialised positron emission tomography (PET) scanning using the radiotracer 18-fluoro-dopa can be used to localise the focal abnormality (lesion) for surgical removal. Genetic testing is also helpful to determine if two copies of faulty ABCC8/KCNJ11 genes are inherited – these indicate a diagnosis of diffuse HI that may not respond to diazoxide. Such cases require treatment with alternative medications such as octreotide and may need surgical removal of most of the pancreas. Therefore, early rapid genetic testing is important to guide the medical and surgical management of children with severe HI. Results from HI genetic testing are preferably analysed by molecular genetics laboratories experienced and specialised in HI.
Another common genetic cause of HI results from changes in the gene for the enzyme glutamate dehydrogenase (GDH). This genetic form of HI is also known as GDH-CHI or GLUD1-CHI. These gene changes are inherited dominantly but may also arise spontaneously. In this condition, ammonia levels in the blood are mildly raised. Children and adults with GDH-CHI often respond to diazoxide. An excess of proteins in the diet can bring about low sugars, so a good carbohydrate-to-protein ratio is advisable. There are many other genetic causes of isolated HI. Examples include changes in the genes that make the enzymes hydroxyacyl-CoA dehydrogenase gene (SCHAD-CHI) and glucokinase (GCK-CHI). More recently, changes in hexokinase 1 (HK1), another enzyme similar to glucokinase have been identified to cause both mild and severe forms of illness.
Syndromic forms Syndromic HI is less common than isolated HI. Data from patient registries suggest a prevalence of less than 1% among reported cases. In syndromic HI, genetic causes are common. Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome is a well-recognized form of syndromic HI. Other syndromes that commonly feature HI include Kabuki syndrome and Turner syndrome. Most individuals with syndromic HI respond to treatment with diazoxide and HI may resolve over time. However, HI with BWS can be severe and be unresponsive to usual therapy.
Diagnosis
HI is due to dysregulation of the secretion of the hormone insulin from beta-cells in the pancreas. Insulin is present in the blood at the time of hypoglycemia rather than being suppressed. This can be difficult to measure due to fluctuation in insulin levels. The diagnosis of HI is made based on increased insulin action and/or inadequate suppression of plasma insulin during a time of hypoglycemia. Increased insulin action can be demonstrated by increased glucose requirement (e.g., > 8 mg/kg/minute in a newborn compared to normal of 4-6 mg/kg/minute. Another sign of excess insulin action is suppressed blood levels of free fatty acids and ketones (beta-hydroxybutyrate) during hypoglycemia. The clinical diagnosis is also supported by a large blood glucose rise after glucagon administration at the time of hypoglycemia. Glucagon is another hormone secreted from the pancreas that opposes insulin action and stimulates the release of glucose from liver glycogen stores. Measurement of insulin, c-peptide (which is co-secreted with insulin) free fatty acids and ketones together with a glucagon stimulation test can be performed during the spontaneous time of hypoglycemia or during hypoglycemia induced by a period of supervised and monitored fasting. In newborn infants, there is a time of transitional hypoglycaemia due to hyperinsulinism for the first after birth 72 hours. Hence the clinical diagnosis is best established after 72 hours of age. Assessing blood ammonia and acylcarnitine profile, urinary metabolic profiles, in addition to provocative responses to protein and amino acids (leucine) may be helpful in defining the subtype of HI.
Treatment The goal of treatment in hyperinsulinism is to prevent hypoglycemia-induced brain damage, thus, the goal of therapy is to maintain the blood sugar level in the normal range [>70 mg/dL (3.9 mmol/L)]. The first step is the restoration of blood sugar level to the normal range after acute hypoglycemia, followed by the prevention of recurrent episodes of hypoglycemia, which is common in congenital hyperinsulinism. This is best accomplished with intravenous dextrose initially.
Once the diagnosis of HI has been established, including determination of the genotype and phenotype, whenever possible, specific treatment should be initiated. Some of the following measures are often tried: