Congenital hyperinsulinism (HI or CHI) is a condition causing severe hypoglycemia (low blood sugar) in newborns due to the overproduction of insulin. 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 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.

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. and 1:2000.

  • Lethargy (excessive sleepiness)
  • Abnormal breathing patterns/apnoea

More severe symptoms, such as seizures (fits or convulsions), can occur with a prolonged or extremely low blood sugar level.

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.

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

thumb|130 px|Ketone-group (low levels are additional indication of the condition)

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.

Treatment

thumb|DiazoxideThe 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: