Congenital Hyperinsulinism - Causes, Symptoms, Diagnosis, and Treatment

What Is Congenital Hyperinsulinism?

Hyperinsulinism or hyperinsulinaemic glycemia is a genetically inherited and morphologically developed heterogeneous group of disorders related to irregular and over secretion of insulin, leading to conditions like hypoglycemia or low blood sugar. Among newborns and infants, it is the most typical cause of hypoketotic hypoglycemia, and in severe conditions, it leads to brain impairment. Moreover, there are other complications that are associated with the condition, like cerebral palsy and neurodevelopmental defects.

Insulin controls the glucose levels in the blood, and this makes it an essential hormone in the human body. After food consumption, the blood glucose levels increase, and the pancreas releases insulin to balance the glucose level in the blood. After food consumption or during the fasting period, glucose level falls, which also stops the secretion of insulin and releases the glycogen from glucose into the bloodstream. Furthermore, in the same condition, the body is forced to use the fat and protein stored in the body to use as a source of energy. In either eating or fasting conditions, the body’s normal cycle always balances the glucose levels in the blood.

If the metabolic action and metabolism process of insulin is disturbed or stopped, it increases the intake and stimulates glycogen synthesis, glycogenolysis, and gluconeogenesis in the body. Moreover, its anabolic effect on fat tissue stimulates lipogenesis, the release of free fatty acid, and ketone body formation by the beta-oxidation process. The hypoketotic state reduces the availability of the alternative fuels required for normal brain activity. However, infants have a more elevated level of glucose consumption than adults, and this makes them more vulnerable to brain damage. It is normally seen at the time of birth or can develop in late childhood as well.

What Are the Etiological Factors Behind Congenital Hyperinsulinism?

Almost in half of the people with hyperinsulinism, the main etiology behind this condition is unknown. However, there are a few factors affecting this process, such as:

• Genetic mutation.

• Premature birth.

• Islet cell dysregulation syndrome.

• Idiopathic hypoglycemia.

• Insulin gene receptor mutation.

• Drug-Induced.

• Dumping syndrome.

• Central hypoventilation syndrome.

• Perinatal asphyxia.

• Maternal diabetes mellitus.

• Intrauterine growth restriction.

What Are the Signs and Symptoms of Congenital Hyperinsulinism?

• Low plasma sugar level.

• Irritability.

• Crying or constantly cranky.

• Lethargy.

• Increased appetite.

• Increased heart rate.

• Seizures.

• Pallor.

• Excessive sweating.

How to Diagnose Congenital Hyperinsulinism?

It is the first and very important step in treating the condition. In the same way, there are other diagnostic measures that are taken into account for diagnosing the condition, such as:

• History:

  • Since it is very difficult to diagnose a child and ask for the symptoms, asking about their prenatal and postnatal history to their caregivers is very important.

  • Usually, paediatricians ask for family history, length of the gestation period, and any sudden infant deaths, seizures, or low plasma sugar that runs in the family.

• Laboratory Tests:

  • When plasma sugar level drops to less than 50 mg/dl, the suppressed ketones and free fatty acids and elevated insulin level is seen.

  • It is important that the sample should be obtained in a controlled environment with an experienced person, as a long time with low plasma sugar can be life-threatening to the child.

• Genetic Tests:

  • The DNA testing at the commercial laboratory on the child as well as parents is done in order to check for any abnormality that a child might inherit from parents.

How to Treat Congenital Hyperinsulinism?

Congenital hyperinsulinism causes brain damage. It is the most common complication of congenital hyperinsulinism, and providing prompt treatment plays an essential part in the treatment. Additionally, due to low blood sugar and excess insulin level, it is important to balance sugar levels if it is more than 70 mg/dL, and the treatment is done according to the severity in the following ways:

• Emergency Management:

  • Parental Glucose Infusion: In the case where there is no option for feeding orally, intravenous 2 ml/kg glucose administration is required. If necessary, the patient can repeat the administration. However, an excessive dose can be fatal as it triggers insulin release. Normally, the patient requires less than 25 mg/kg/min of glucose infusion to balance the need.

  • Glucagon Administration: Usually, when oral feed or intravenous administration is not easy to obtain, glucagon can be a very important treatment option. It is a crucial counter-regulatory hormone and, within a few minutes of administration, induces the glycogenolysis, gluconeogenesis, and lipolysis cycle. The advised dosage of the treatment is 0.5 to 1 mg and is injected intramuscularly or subcutaneously. However, excessive usage can cause rebound hypoglycemia in some patients.

  • Frequent Feeding: It is a treatment without any side effects. A high-calorie diet with carbohydrates is recommended as it decreases hypoglycemia in patients. Although some patients who are on Diazoxide are seen with loss of appetite and for them, gastrectomy is recommended to continue with frequent feeding.

• Long-Term Management:

Patients with congenital hyperinsulinism are recommended this option as per the severity of the condition and also the age and physical condition of the patient. With the regular observation of adverse effects, drug therapy is recommended. Some of the commonly used drugs are:

• Diazoxide: It is usually effective in all patients except for dominant KATP-Hchannel mutation. The administration of the drug is oral with 5 to 20 mg/kg/day in 3 doses. There are some side effects seen with this drug, like water and salt retention, hypertrichosis (excessive hair growth), and loss of appetite.

• Chlorothiazide: It is a Thiazide diuretic drug, usually administered orally with Diazoxide to newborns in order to control fluid retention. It is 7 to 10 mg/kg/day given in two divided doses. The adverse effects of these drugs are hypokalemia and hyponatremia.

• Nifedipine: It is used for long-term use in patients with congenital hyperinsulinism orally, with a dose of 0.25 to 2.5 mg/kg/day in two to three divided doses. It has only one side effect when the dose exceeds 0.5 mg/kg/day; hypotension.

• Diet (Ketogenic Diet): Glucose and ketone bodies are essential for normal brain function, but in congenital hyperinsulinism, the patient is deprived of these two. During the breastfeeding phase, ketone bodies are the main source of energy, and in adulthood, glucose. A ketogenic diet has proved very effective in patients with epilepsy and ischemia. Although the treatment is still in the research phase, there are many cases that show promising results.

• Surgical Therapy: In the cases of KATP-HI,almost 99% of the time, pancreatectomies are required along with continuous, frequent feed and medications. Moreover, due to the removal of only a small part of the pancreas, sometimes they might have to go with a second pancreatectomy. Sometimes due to the inclusion of the bile duct and duodenum at the head of the pancreas, it is impossible to do surgery without harming them.

Conclusion

Children with congenital hyperinsulinism require prolonged hospitalization and continuous care, and it is difficult for caregivers and families to provide constant support. However, with a medical regime and a balanced diet suggested by a paediatrician, the disorder can be managed.