Congenital Hyperinsulinaemic Hypoglycaemia

Congenital hyperinsulinaemic hypoglycaemia is a rare genetic condition where the pancreas produces too much insulin, causing dangerously low blood sugar levels that can lead to serious brain damage if not treated promptly.

Table of contents

• What is congenital hyperinsulinaemic hypoglycaemia?
• How common is this condition?
• Signs and symptoms
• Causes and genetics
• Different forms of the condition
• How is it diagnosed?
• Treatment options
• Long-term outlook

CHI, congenital hyperinsulinism, hyperinsulinaemic hypoglycaemia, HH, persistent hyperinsulinemic hypoglycemia of infancy, PHHI

What is congenital hyperinsulinaemic hypoglycaemia?

Congenital hyperinsulinaemic hypoglycaemia is a condition that causes the body to have abnormally high levels of insulin (a hormone that helps control blood sugar levels).^[2] In this condition, the pancreas (an organ below the stomach that produces insulin) releases too much insulin, even when blood sugar levels are normal or already low.^[8]

Normally, the body’s insulin-producing cells, called beta cells, carefully regulate how much insulin they release based on the amount of sugar in the blood. When blood sugar rises after eating, beta cells release more insulin. When blood sugar is low, they release less or even stop producing insulin entirely.^[8] In people with congenital hyperinsulinaemic hypoglycaemia, this control system does not work properly. The beta cells release insulin inappropriately all the time, regardless of blood sugar levels.^[16]

This excessive insulin causes blood sugar to drop to dangerously low levels, a condition called hypoglycaemia.^[2] The brain relies on blood sugar as its primary source of energy, so when sugar levels become too low, the brain cannot function properly. High insulin levels also prevent the body from making ketone bodies, which are alternative fuels the brain normally uses when blood sugar is low.^[16] This means that people with this condition are constantly dependent on having adequate blood sugar levels to maintain normal brain function.^[8]

• Pancreas
• Beta cells
• Brain

How common is this condition?

Congenital hyperinsulinaemic hypoglycaemia is the most common cause of persistent hypoglycaemia in infants and children, but it is relatively rare.^[1] The condition affects approximately 1 in 50,000 newborns in most populations.^[2] However, in certain communities, it is more common, affecting up to 1 in 2,500 newborns.^[2]

About 60 percent of infants with congenital hyperinsulinaemic hypoglycaemia experience their first episode of low blood sugar within the first month of life, while others develop symptoms during early childhood.^[2]

Signs and symptoms

The symptoms of congenital hyperinsulinaemic hypoglycaemia are mainly related to low blood sugar levels and typically appear in early infancy and the neonatal period.^[1] In infants and young children, episodes of low blood sugar are characterized by a lack of energy (lethargy), irritability, or difficulty feeding.^[2]

The symptoms can range from non-specific signs to more serious complications. Common symptoms in newborns and infants include:^[1][12]

• Poor feeding
• Lethargy
• Irritability
• Breathing problems (apnoea)
• Hypothermia (abnormally low body temperature)
• Pallor (lack of normal skin color)
• Cyanosis (blue discoloration of the face, typically around the mouth)
• Fast breathing
• Shaking

More serious symptoms include seizures and coma.^[1] During clinical examination, newborns may also present with cardiomyopathy (a condition affecting the heart muscle) and hepatomegaly (an enlarged liver).^[1]

In older children, symptoms may include hunger, shaking, and other signs of low blood sugar.^[12] Unlike typical episodes of hypoglycaemia, which usually occur after periods without food or after exercising, episodes in people with congenital hyperinsulinaemic hypoglycaemia can also occur after eating.^[2]

Repeated episodes of low blood sugar increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and even coma.^[2] If the condition is left untreated or improperly managed, it can lead to permanent brain damage or death.^[3]

Causes and genetics

Congenital hyperinsulinaemic hypoglycaemia is caused by changes (mutations) in genes that control how insulin is released from beta cells in the pancreas.^[2] These genetic mutations lead to over-secretion of insulin, causing blood sugar levels to drop dangerously low.^[2]

Mutations in at least 12 different genes have been identified as causes of this condition.^[3][9] The most commonly affected genes are ABCC8 and KCNJ11. Mutations in the ABCC8 gene are responsible for approximately 40 percent of cases, while KCNJ11 mutations are less common.^[2] Other genes associated with this condition include GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, and PMM2.^[9]

The genetic mutations can occur spontaneously (not inherited from parents) or can be inherited from one or both parents.^[12] The condition can follow different inheritance patterns. Most commonly, the diffuse form is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell have mutations. In this case, parents typically carry one copy of the mutated gene but do not show symptoms themselves.^[2] Less frequently, the condition is inherited in an autosomal dominant pattern, where one copy of the altered gene is sufficient to cause the disorder.^[2]

In approximately half of people with congenital hyperinsulinaemic hypoglycaemia, the genetic cause remains unknown, suggesting that additional genes may yet be identified.^[2][3]

Several genetic syndromes can also include congenital hyperinsulinaemic hypoglycaemia as one feature, including Beckwith-Wiedemann syndrome, Kabuki syndrome, and Turner syndrome.^[3]

Different forms of the condition

The condition can be classified into different forms based on how much of the pancreas is affected.^[3][12]

Diffuse disease occurs when all the beta cells throughout the pancreas are affected and produce too much insulin. Approximately 50 percent of cases are classified as diffuse.^[3] In this form, findings similar to those seen in focal lesions are present throughout the entire pancreas.^[3]

Focal disease occurs when only some beta cells are affected, usually in the form of a small, non-cancerous lesion in a localized area of the pancreas. The remainder of the pancreas is normal.^[6][12] About 40 percent of cases can be classified as focal.^[3] In focal lesions, the affected area contains islet-like cell clusters with specific characteristics visible under microscopic examination.^[3]

Transient disease is a form where the low blood sugar resolves with age. This form can last from a few weeks up to several months and is associated with prematurity, maternal diabetes during pregnancy (especially if not well controlled), heart disease, and severe infections in the pregnant mother.^[12]

About 10 percent of cases are considered atypical, meaning they do not fit neatly into the focal or diffuse categories.^[3]

How is it diagnosed?

The diagnosis of congenital hyperinsulinaemic hypoglycaemia is based on specific laboratory findings during an episode of low blood sugar. The key diagnostic criteria include plasma glucose levels less than 54 mg/dL (3.5 mmol/L) with detectable serum insulin and C-peptide (a substance made when insulin is produced), accompanied by suppressed or low serum ketone bodies and free fatty acids.^[1][9]

For the purpose of diagnosis, hypoglycaemia in this condition is defined as blood glucose concentration below 3.5 mmol/litre.^[8][16] In the absence of ketone bodies, infants with this condition are constantly reliant on circulating blood glucose as fuel for normal neurological functioning, which is why maintaining blood glucose concentration above this level is so important.^[16]

Genetic mutation testing is now considered standard of care to help determine the best treatment approach.^[3] Modern methods can provide results within less than a week, and rapid turnaround time is essential because treatment decisions need to be made quickly for severely ill infants.^[3]

The gold standard test for determining whether the condition is focal or diffuse is fluorine-18-dihydroxyphenyloalanine PET scanning (18F-DOPA PET).^[1][3] This specialized imaging test can identify and locate focal lesions in the pancreas, which is crucial for planning treatment.^[3]

Treatment options

Treatment for congenital hyperinsulinaemic hypoglycaemia aims to prevent episodes of low blood sugar and avoid neurological complications.^[10] The approach depends on the severity of the condition and how well it responds to medication.

Medical treatment is always tried first. The first-line medication is diazoxide, which is the only FDA-approved drug for treating this condition.^[10][13] Diazoxide works by reducing insulin secretion from the pancreas. However, patients with certain genetic mutations, particularly those with diffuse forms of the condition caused by homozygous or compound heterozygous recessive mutations, often remain resistant to this therapy.^[1] A medication called chlorothiazide is sometimes used together with diazoxide for a synergistic effect.^[10]

The second-line medication is octreotide, a somatostatin analogue that also helps reduce insulin secretion.^[1][10] Other therapeutic options include lanreotide (another somatostatin analogue), glucagon, acarbose, sirolimus, everolimus, and nifedipine.^[1][10]

In emergency situations, if low blood sugar is unresponsive to oral feeding, glucose must be administered intravenously. Maintaining normal blood sugar in patients with this condition often requires very high glucose infusion rates. Glucagon may also be given as emergency treatment.^[10]

Surgical treatment is required when medication does not adequately control blood sugar levels.^[1] For patients with focal disease where a specific lesion can be identified, surgery to remove just that area (focal lesionectomy) can cure the condition.^[1] For patients with diffuse disease who do not respond to medication, a near-total pancreatectomy (removal of most of the pancreas) may be necessary.^[1] International guidelines recommend that surgery be considered for children in whom a removable focal lesion is suspected.^[10]

Dietary measures are also an important part of management. Patients may need frequent feedings to maintain blood sugar levels, and some may require continuous feeding through a tube.^[7]

Long-term outlook

The severity of congenital hyperinsulinaemic hypoglycaemia varies widely among affected individuals, even among members of the same family.^[2] The long-term outlook depends largely on how quickly the condition is diagnosed and how effectively blood sugar levels are maintained.

The most significant risk is brain damage from repeated or prolonged episodes of low blood sugar. This can lead to long-term neurological complications including epilepsy, cerebral palsy, neurodevelopmental deficits, intellectual disability, and vision loss.^[9] Therefore, prompt diagnosis and immediate management are essential to prevent hypoglycaemic brain injury.^[9]

With early diagnosis and proper treatment, hypoglycaemia can be managed effectively, and neurological disorders may be avoided.^[7] Children who undergo successful focal lesionectomy for focal disease can often be cured completely. However, even with optimal medical and surgical treatment, episodes of low blood sugar may still occur, making ongoing glucose monitoring and patient and family education essential.^[10]

Surgical treatment has its own risks and challenges. Despite many years of experience, rates of initial failure to control hypoglycaemia remain high, and there is a paradoxically high rate of subsequent development of diabetes mellitus after near-total pancreatectomy.^[10]

Because of the complexity and rarity of this condition, it is important for affected children to receive care from experienced treatment centers that specialize in congenital hyperinsulinaemic hypoglycaemia.^[6][15]