Congenital Hyperinsulinism
Congenital Hyperinsulinism (CHI) is a rare genetic disorder of pancreatic β-cells that secrete excess amount of insulin causing severe persistent hypoglycemia (low blood glucose) in new-born babies and children.
Insulin, a hormone secreted by the β-cells of the islets of Langerhans of pancreas, is chiefly involved in the regulation of carbohydrate (glucose) metabolism. Any increase in blood glucose (sugar) concentration is the most important physiologic factor leading to insulin secretion. Insulin in turn leads to break down of glucose (glycolysis) into energy thereby decreasing glucose concentration in the blood. Additionally, insulin also prevents formation of new glucose (gluconeogenesis) conversion of fat into ketones (ketogenesis), which act alternative fuel for the body in absence of glucose.
Typically, child with hyperinsulinism will have detectable / raised insulin concentrations (hyperinsulinemic) with low ketone bodies (hypoketotic) and free fatty acids (hypofattyacidemic) at the time of low blood glucose concentration (hypoglycemia).
CHI causes repeated episodes of hypoglycemia because of dysregulated insulin secretion during low blood glucose concentrations in newborn babies and children. As a result, insulin suppresses ketone bodies formation and this unavailability of glucose and alternative fuels (ketone bodies) increase the risk of brain damage in these patients.
Previously used names of CHI:
- Hyperinsulinemic Hypoglycemia of Infancy
- Infancy Hyperinsulinemic Hypoglycemia
- Neonatal Hypoglycemia
- Persistent Hyperinsulinemic Hypoglycemia of Infancy
- Neonatal Nesidioblastosis/Neonatal Insulinoma
- Islet cell dysregulation syndrome
- Idiopathic hypoglycemia of infancy
Incidence:
In most countries it occurs in approximately 1 in 25,000 to 40,000 live-births in the general population. However, in countries with high rates of consanguineous marriages i.e. marriage between individuals who are closely related, the incidence is estimated up to 1 in 2500 live-births. In India so far there is no prevalence study undertaken but it is thought to be much commoner than in general population.
Sign & Symptoms:
Approximately 60% of the babies with CHI develop hypoglycemia during the first month of life, 30% develop it later in the first year and the remaining even after that.
The sign and symptoms of CHI are due to hypoglycemia and are non-specific during early period making its diagnosis difficult. It is also important to note that babies / children could be asymptomatic (no sign or symptoms) during hypoglycemia and is due to repeated episodes of hypoglycemia. Hence it is important to test blood glucose concentrations.
Common symptoms of hypoglycemia include:
- Irritability
- Sleepiness
- Lethargy
- Excessive hunger
- Rapid heart rate
More severe symptoms can occur with long periods of hypoglycemia and can lead to:
- Seizures
- Coma and Death
At later ages, the symptoms of CHI can be easier to recognize such as:
- Hunger
- Pallor
- Increased heart rate
- Tremor
- Excessive unusual sweating
- Tiredness
- Blurred vision
- Confusion
- Coma and Death
With early diagnosis and treatment to hypoglycemia, brain damage can be prevented.
Types of Hyperinsulinism
Hyperinsulinism is a broad classification that encompasses a heterogeneous group of disorders, including both transient and congenital forms of the disease.
Transient Congenital Hyperinsulinism
Although there is no precise definition of transient congenital hyperinsulinism, but if the hypoglycemia resolves by itself within the first few weeks to months of life then it can be considered as transient. This type of hyperinsulinism typically develops in newborns who have certain risk factors such as:
- maternal diabetes mellitus (mother having hyperglycemia / diabetes mellitus during pregnancy or hyperglycemia)
- maternal hyperglycemia caused by intravenous dextrose / glucose infusions before or during labor,
- babies born small for gestational age or prematurely
- infants who experience fetal distress due to lack of oxygen (perinatal asphyxia)
- hemolytic diseases of the newborn i.e. erythroblastosis fetalis
- Additionally, congenital transient hyperinsulinism may also develop in some newborns with no underlying risk factors.
Children with transient form of congenital hyperinsulinism undergo a fasting study with stopping of all medications, to prove that the hyperinsulinism is transient.
The cause of such inappropriate insulin secretion is not very clear, and can last a few days to months. Once recognized the initial management of this form of hyperinsulinism is target at maintaining adequate levels of blood glucose. This can be achieved through frequent feeding, providing increased glucose infusions either orally or intravenously. Occasionally it requires drug therapy, diazoxide or somatostatin analogs, in case of severe transient hyperinsulinism. Once resolved, this form of hyperinsulinism generally never recurs. There have been several studies published that suggest babies/children with transient hyperinsulinism are at equal risk of hypoglycemic brain injury when compared to persistent forms of CHI.
Persistent Congenital Hyperinsulinism
Persistent form of CHI involves fault in a number of genes that encode proteins involved in the regulation of insulin release from the β-cells of pancreas. Such defects disturb the insulin secretion stimulated by blood glucose levels leading to inappropriate insulin release. At present, 08 genes have been identified to cause CHI apart from other genes causing CHI along with syndromic disorders.
In approximately up to 50% of these patients the cause of hyperinsulinism remains unknown suggesting the role of additional genetic loci and unfortunately one-third to one-half of such cases report potential novel genetic mechanism. Diazoxide is traditionally used as a long-term therapy of many such cases, but diazoxide unresponsive cases require partial to near total pancreatectomy.
