Overview
Definition:
Hyperinsulinism (HI) is a condition characterized by inappropriately high insulin secretion relative to blood glucose levels, leading to recurrent, severe hypoglycemia
It is the most common cause of persistent hypoglycemia in neonates and infants
Genetic defects in various pancreatic beta-cell proteins involved in insulin secretion are the underlying cause.
Epidemiology:
Congenital hyperinsulinism (CHI) affects approximately 1 in 30,000 to 50,000 live births
The prevalence can be higher in consanguineous populations due to the predominantly autosomal recessive inheritance patterns of many CHI genes
There is no clear gender predilection.
Clinical Significance:
Untreated or poorly managed hyperinsulinism can lead to severe, life-threatening hypoglycemia, causing significant morbidity including neurodevelopmental impairment, seizures, coma, and death
Early diagnosis and appropriate management are crucial for optimal outcomes and preventing long-term neurological sequelae, making its understanding vital for pediatricians and endocrinologists preparing for DNB and NEET SS examinations.
Clinical Presentation
Symptoms:
Hypoglycemia symptoms manifest as irritability, poor feeding, lethargy, pallor, diaphoresis, tremors, and tachypnea
In severe cases: seizures, apnea, hypotonia, and coma
Symptoms often present within the first days or weeks of life
A key feature is the failure of hypoglycemia to resolve with typical glucose infusions or feeds.
Signs:
Physical examination may reveal signs of hypoglycemia like pallor and diaphoresis
Macrosomia may be present in some genetic subtypes (e.g., GCK mutations)
Evidence of neurological compromise such as hypotonia or seizures may be observed in advanced stages.
Diagnostic Criteria:
Diagnosis is suspected in neonates and infants with recurrent hypoglycemia unresponsive to standard management, typically below 2.2 mmol/L (40 mg/dL) in term infants or 1.7 mmol/L (30 mg/dL) in preterm infants or neonates, accompanied by inappropriately high insulin levels and low ketone/fatty acid levels during the hypoglycemic episode
An elevated insulin-to-glucose ratio (e.g., >0.3-0.4) is suggestive.
Diagnostic Approach
History Taking:
Detailed birth history (birth weight, gestational age, maternal diabetes)
History of recurrent episodes of hypoglycemia, including age of onset, frequency, duration, precipitating factors (e.g., fasting), symptoms, and response to interventions
Family history of consanguinity or unexplained neonatal deaths or hypoglycemia is critical.
Physical Examination:
Complete physical examination focusing on neurological status, hydration, signs of infection, and any dysmorphic features
Assess for macrosomia or intrauterine growth restriction
Monitor vital signs closely, especially heart rate and respiratory rate during hypoglycemic episodes.
Investigations:
Initial investigations during a hypoglycemic episode: blood glucose, serum insulin, C-peptide, cortisol, growth hormone, free fatty acids, and ketones (beta-hydroxybutyrate)
Persistent hyperinsulinism is confirmed by inappropriately high insulin levels (>3-5 mIU/L) and a low insulin-to-glucose ratio when glucose is <2.8 mmol/L
Ketosis resistance is also a key indicator
Genetic testing is essential for definitive diagnosis and to identify specific subtypes.
Differential Diagnosis:
Other causes of neonatal hypoglycemia: transient HI, impaired gluconeogenesis (e.g., due to fatty acid oxidation defects, glycogen storage diseases), endocrine deficiencies (hypopituitarism, adrenal insufficiency), hyperinsulinism secondary to other conditions (e.g., sepsis, erythroblastosis fetalis), or macrosomia related hypoglycemia.
Genetic Testing
Importance:
Genetic testing is crucial for confirming the diagnosis of congenital hyperinsulinism, identifying the specific gene mutation, predicting disease severity, guiding management, and providing genetic counseling
It helps differentiate between diffuse and focal forms of CHI, which have implications for surgical management.
Common Genes:
Key genes involved include KCNJ11 (Kir6.2, SUR1 subunits of KATP channel), ABCC8 (SUR1 subunit of KATP channel), GCK (glucokinase), HADH (3-hydroxyacyl-CoA dehydrogenase), UGCG (UDP-glucose ceramide glucosyltransferase), SLC16A1 (monocarboxylate transporter 1), and others
Mutations in KCNJ11 and ABCC8 account for the majority of cases, typically presenting with diffuse disease.
Testing Methodology:
Next-generation sequencing (NGS) panels designed for hyperinsulinism or hypoglycemia are the standard of care
This allows for simultaneous analysis of multiple genes
Sanger sequencing may be used for confirmation or targeted analysis of specific mutations
Molecular karyotyping and methylation studies may be needed for specific genetic loci.
Interpretation:
Positive genetic findings confirm the diagnosis and can predict the likelihood of responsiveness to diazoxide
Specific mutations may correlate with focal versus diffuse disease, severity, and potential need for pancreatectomy
Variants of unknown significance require careful interpretation in the clinical context.
Diazoxide Response
Mechanism Of Action:
Diazoxide is a potassium channel opener
By opening ATP-sensitive potassium (KATP) channels in pancreatic beta-cells, it hyperpolarizes the cell membrane, preventing calcium influx and thereby inhibiting insulin secretion.
Indications:
Diazoxide is the first-line medical therapy for diazoxide-responsive forms of hyperinsulinism, particularly those caused by mutations in KCNJ11 and ABCC8 genes
It is used to control hypoglycemia when medical management is preferred or as a bridge to surgery.
Dosing And Administration:
Typical starting dose is 3-5 mg/kg/day, divided into 2-3 doses
The dose is titrated upwards based on glycemic control, usually up to a maximum of 10-15 mg/kg/day
It is usually given orally with food to minimize gastrointestinal upset and maximize absorption
Monitoring blood glucose levels frequently is essential during titration.
Predicting Responsiveness:
Genetic testing is the most reliable predictor
Mutations in KCNJ11 and ABCC8 are generally associated with diazoxide responsiveness
Patients with mutations in GCK, HADH, or other genes are typically unresponsive to diazoxide
A trial of diazoxide can also empirically assess responsiveness if genetic results are pending or inconclusive, but this should be guided by expert opinion.
Side Effects And Monitoring:
Common side effects include hypertrichosis (excessive hair growth), hyperglycemia, nausea, vomiting, and fluid retention
Less common but serious side effects include neutropenia, thrombocytopenia, and cardiac abnormalities
Regular monitoring of blood glucose, blood pressure, and complete blood count is recommended
Hyperglycemia should be managed cautiously.
Management Principles
Initial Management:
Immediate stabilization with intravenous glucose infusion (often requiring high rates, >10 mg/kg/min) to maintain blood glucose levels above 2.2 mmol/L
Frequent glucose monitoring is paramount.
Medical Management:
Diazoxide is the mainstay for responsive forms
Other medications like octreotide or nifedipine may be used as adjuncts or in unresponsive cases, but are generally less effective and have more significant side effects
Glucagon therapy may be used for severe, refractory hypoglycemia
Surgical pancreatectomy (near total or subtotal) is reserved for diazoxide-unresponsive cases, particularly focal forms after localization via imaging and intraoperative assessment.
Surgical Considerations:
Surgical pancreatectomy is indicated for diazoxide-unresponsive CHI, especially if focal disease is identified
Focal lesions (adenomatous hyperplasia) can be surgically resected with a high chance of cure
Diffuse disease may require near-total pancreatectomy, leading to iatrogenic diabetes mellitus and exocrine insufficiency, necessitating lifelong management.
Nutritional Support:
Frequent feeds (every 2-3 hours) are crucial, often requiring nasogastric or gastrostomy tube feeding, especially at night, to prevent fasting-induced hypoglycemia
A high carbohydrate diet is generally recommended.
Prognosis
Factors Affecting Prognosis:
The prognosis depends heavily on the underlying genetic cause, severity of hypoglycemia, responsiveness to treatment, and the presence of neurological complications
Early diagnosis and effective management are key to preventing long-term sequelae.
Outcomes:
Patients with diazoxide-responsive HI, especially focal forms, have an excellent prognosis
Those with diffuse disease requiring pancreatectomy have a guarded prognosis due to the risk of diabetes and exocrine insufficiency
Neurological outcomes are significantly impacted by the duration and severity of untreated hypoglycemia.
Follow Up:
Long-term follow-up by a pediatric endocrinologist is essential to monitor glycemic control, growth, neurodevelopment, and manage potential complications such as diabetes, exocrine insufficiency, and developmental delays
Regular genetic and endocrine assessments are crucial.
Key Points
Exam Focus:
Recognize hyperinsulinism as the most common cause of persistent hypoglycemia in neonates/infants
Understand the role of insulin-C-peptide ratio in diagnosis
Differentiate genetic subtypes based on clinical presentation and diazoxide responsiveness
Know the mechanism and side effects of diazoxide.
Clinical Pearls:
Always consider hyperinsulinism in a hypoglycemic infant who requires high glucose infusion rates
Family history and consanguinity are important clues
Genetic testing is pivotal for guiding management and predicting diazoxide response
Remember hypertrichosis as a classic diazoxide side effect.
Common Mistakes:
Misinterpreting insulin levels in the context of hypoglycemia
Failing to consider HI in infants with unexplained neurological symptoms
Initiating pancreatectomy without thorough investigation and failed medical management, especially without localizing focal disease
Not considering diazoxide responsiveness based on genetic results.