Rare diseases: congenital hyperinsulinism

By Cristiano Antonino On Nov 9, 2022

Congenital hyperinsulinism is a rare disease. It is the most frequent cause of recurrent hypoglycaemia and may depend on genetic or acquired causes

Early diagnosis is essential to reduce the risk of neurological damage.

What is congenital hyperinsulinism

Congenital hyperinsulinism is a rare disease caused by a hyperplasia of the pancreatic β-cell that results in uncontrolled and excessive insulin secretion relative to contemporary plasma glucose levels.

It is the most frequent cause of severe and persistent hypoglycaemia in infants and early childhood.

It can, however, begin at any age of life.

Recurrent hypoglycaemia places patients at risk of permanent neurological damage.

The signs and symptoms of congenital hyperinsulinism are an expression of glucose deficiency in the central nervous system

Based on glycaemic levels, one distinguishes between neurogenic and neuroglycaemic symptoms.

Neurogenic symptoms are vegetative symptoms that appear when blood glucose levels fall below 60 mg/dl and are characterised by pallor, algid sweating, hyporeactivity, drowsiness, headache, palpitations, anxiety, dizziness, or tremors, paresthesias, hunger, irritability. The infant may present with faint crying, hypotonia, cyanosis, pallor, hypovalid sucking, hypothermia.

Neuroglycopenic symptoms appear when blood glucose falls below 50 mg/dl, manifest as sensory disturbances, convulsions and coma, and are an expression of cerebral dysfunction due to energy deficiency.

Genetic causes:

Congenital, monogenic hyperinsulinism;
Hyperinsulinism associated with genetic syndromes.

Acquired causes:

Transitional hyperinsulinism (first 48-72 hours of life, related to adaptation to extrauterine life);
Transient hyperinsulinism (from perinatal stress):
Asphyxia;
Intrauterine growth retardation;
Maternal diabetes;
Toxaemia.

The diagnosis is based on the finding of non-ketotic hypoglycaemia, with suppressed NEFA (non-esterified fatty acids), inappropriately responding to glucagon.

The analysis is performed on a critical sample, taken at the time of spontaneous hypoglycaemia or at the end of a fasting test.

Another important element, particularly in the neonatal period, is the high glucose requirement needed to maintain normoglycaemia.

Treatment of congenital hyperinsulinism

Emergency therapy aims to rapidly restore blood glucose values to normal (70-100 mg/dl) and is based on the administration of intravenous glucose solution in combination with a carbohydrate-rich diet.

In severe cases, it is necessary to place a central venous access to deliver highly concentrated glucose solutions, insert a naso-gastric tube or perform a gastrostomy to ensure hyperglucidic feeding.

Intravenous administration of glucagon may also be necessary to reduce the glucose requirement, thereby reducing water overload.

Long-term therapy is aimed at preventing brain damage and promoting normal psychomotor development of the child, encouraging normal eating behaviour, ensuring adequate fasting tolerance, and maintaining the best possible quality of life.

It is based on drugs that reduce insulin secretion: diazoxide is the drug of first choice, orally. In case of non-responsiveness to diazoxide, somatostatin analogues (subcutaneous octreotide, slow-release LAR octreotide by intramuscular injection) are used in combination with a hyperglucidic diet, often with the addition of maltodextrins or maize starch.

The diagnostic algorithm involves the interpretation of biochemical, genetic and imaging analyses (18Fluoro-DOPA PET/TC) to differentiate focal and diffuse forms of congenital hyperinsulinism.

Focal forms are an elective indication for partial pancreas resection surgery, which definitively cures the disease.

In contrast, for diffuse forms of hyperinsulinism, subtotal pancreasectomy surgery is only indicated in severe cases that do not respond to pharmacological and nutritional therapy.

This is a demolitive operation, with up to 98% of the pancreas removed, which does not guarantee recovery from hyperinsulinism and puts patients at high risk of developing insulin-dependent diabetes and exocrine pancreatic insufficiency.

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Diffuse forms are treated conservatively with pharmacological and nutritional therapy

In some severe non-responsive cases caused by mutations in the glucokinase gene, the ketogenic diet has proved effective in recovering intellectual disability and epilepsy.

The follow-up of patients involves serious checks with the intermittent use of continuous home blood glucose monitoring by means of a glycaemic holter, a very useful tool in personalising medical and nutritional therapy.

Patients also undergo periodic neuropsychological assessments to verify the effects of treatment on the development of the central nervous system, the early detection of any disabilities, and the timely initiation of rehabilitation courses.

Congenital hyperinsulinism, if not diagnosed and treated early, can cause permanent neurological damage, resulting in intellectual disability, epilepsy, cortical blindness and cerebral palsy.

Rapid diagnosis and the implementation of timely and specific normoglycaemic therapy can effectively prevent neurological damage, ensuring a good quality of life for the patient and family.

Therefore, the identification of at-risk individuals, early diagnosis and referral of patients to multidisciplinary referral centres is crucial.

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