Overview
Definition:
Persistent neonatal hypoglycemia refers to abnormally low blood glucose levels (< 45 mg/dL or 2.5 mmol/L) in a newborn that continues despite adequate nutritional support and treatment, often requiring prolonged or intensive glucose administration
Hyperinsulinism is a state where the pancreas secretes excessive insulin, inappropriately suppressing hepatic glucose production and promoting glucose utilization, leading to recurrent or persistent hypoglycemia.
Epidemiology:
Neonatal hypoglycemia affects 1-15% of newborns, with persistence seen in a smaller subset
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in term infants, with an incidence of approximately 1 in 2500 to 50,000 live births, varying with genetic subtypes
Premature infants, infants of diabetic mothers, and SGA infants are at higher risk for transient hypoglycemia.
Clinical Significance:
Untreated or prolonged neonatal hypoglycemia can lead to irreversible neurological damage, including cognitive deficits, developmental delays, seizures, and cerebral palsy
Early identification and management of persistent hypoglycemia, particularly when caused by hyperinsulinism, are crucial for optimizing neurodevelopmental outcomes and preventing long-term morbidity in neonates.
Clinical Presentation
Symptoms:
Jitteriness
Irritability
Lethargy
Poor feeding
Vomiting
Apnea
Tachypnea
Cyanosis
Temperature instability
Seizures (generalized or focal)
Pallor
Hypotonia
High-pitched cry.
Signs:
Often non-specific
Tremors
Exaggerated Moro reflex
Hypotonia
Weak cry
Signs of underlying etiology (e.g., macrosomia in infants of diabetic mothers)
Vital sign instability (hypotension, bradycardia in severe cases).
Diagnostic Criteria:
Plasma glucose < 45 mg/dL (2.5 mmol/L) in any neonate
Persistent hypoglycemia is defined by recurrence despite standard glucose therapy (e.g., requiring >12 mg/kg/min continuous infusion) or recurrence after discontinuation of therapy
In the context of hyperinsulinism workup, demonstration of inappropriately high insulin levels for the given glucose concentration is key.
Diagnostic Approach
History Taking:
Gestational age and birth weight
Maternal diabetes or GDM
Infant of diabetic mother (IDM)
Sepsis
Asphyxia
Intrauterine growth restriction (IUGR) or small for gestational age (SGA)
Congenital anomalies
Family history of hypoglycemia, consanguinity, sudden infant death, or known genetic syndromes
Duration and severity of symptoms
Response to previous glucose boluses or infusions.
Physical Examination:
Assess for signs of dysmorphism suggestive of genetic syndromes (e.g., Beckwith-Wiedemann syndrome)
Evaluate for sepsis
Assess neurological status for signs of encephalopathy or seizures
Check for hepatomegaly or splenomegaly
Assess hydration status and perfusion.
Investigations:
Initial: Blood glucose (fingerstick, followed by lab confirmation)
Serum electrolytes, calcium, magnesium, CBC, blood gas
If hypoglycemia persists despite intensive therapy: Simultaneous measurement of plasma glucose, insulin, C-peptide, cortisol, GH, IGF-1, free fatty acids, ketones, and lactate
Urine for organic acids and amino acids
Genetic testing for common CHI genes (ABCC8, KCNJ11, HADH, SCH9A, GLUD1, GCK, HNF4A, UCP2, UCP3, EIF2AK3)
Imaging: Abdominal ultrasound to assess pancreatic size and exclude masses
Dynamic MRI or PET scan in select cases for focal CHI localization.
Differential Diagnosis:
Transient hypoglycemia (e.g., IDM, SGA, prematurity, sepsis, asphyxia, polycythemia)
Ketotic hypoglycemia
Non-ketotic hypoglycemia
Inborn errors of metabolism (e.g., fatty acid oxidation defects, glycogen storage diseases, amino acid disorders)
Hormonal deficiencies (e.g., adrenal insufficiency, hypopituitarism)
Hyperinsulinism (congenital, transient, or secondary)
Sepsis
Hypothermia
Red blood cell transfusion reactions.
Workup For Hyperinsulinism
When To Suspect Hyperinsulinism:
Persistent hypoglycemia requiring high glucose infusion rates (> 12-15 mg/kg/min)
Recurrent hypoglycemia after discontinuation of infusions
Hypoglycemia with inappropriately high insulin levels (e.g., insulin > 3-5 mU/L at glucose < 50 mg/dL)
Hypoglycemia with suppressed ketone and free fatty acid levels
Family history of hypoglycemia or consanguinity
Dysmorphic features suggestive of syndromes associated with CHI (e.g., Beckwith-Wiedemann).
Diagnostic Testing Strategy:
The key is to measure glucose and insulin levels simultaneously
A provocative test (e.g., oral glucose challenge, glucagon challenge, or mixed meal tolerance test) may be considered in stable infants to assess insulin response, but is often not necessary if spontaneous hypoglycemia with high insulin is documented
A "critical sample" should be drawn at the time of documented hypoglycemia, ideally while the infant is symptomatic or during a period of low glucose
This sample should include glucose, insulin, C-peptide, cortisol, GH, IGF-1, free fatty acids, and ketones.
Interpretation Of Results:
Inappropriately high insulin level for the blood glucose concentration is the hallmark of hyperinsulinism
For example, a plasma insulin > 3-5 mU/L when plasma glucose is < 50 mg/dL (2.8 mmol/L) suggests CHI
Suppressed ketones and free fatty acids also support hyperinsulinism as they should normally rise when glucose is low
A high C-peptide level generally correlates with insulin production
Genetic testing confirms the diagnosis and identifies specific subtypes which can guide management.
Localization Of Lesions:
For diffuse CHI, medical management is typically the first line
For focal CHI, surgical resection of the affected pancreatic segment offers a cure
Localization can be challenging and may involve arterial calcium stimulation with hepatic venous sampling, endoscopic ultrasound, MRI, or 18F-FDOPA PET/CT scans
Accurate localization is crucial for surgical planning.
Management
Initial Management:
Aggressive glucose administration via IV infusion (starting at 6-8 mg/kg/min and titrating up to 12-15 mg/kg/min or higher)
Frequent blood glucose monitoring (every 15-30 minutes initially, then hourly)
Correction of any precipitating factors (e.g., sepsis treatment).
Medical Management Of Hyperinsulinism:
Diazoxide (loading dose 1-5 mg/kg/dose, then maintenance 5-15 mg/kg/day divided every 8-12 hours)
Somatostatin analogs (octreotide) (IV infusion 1-2 mcg/kg/hr, titrating up to 10 mcg/kg/hr
or subcutaneous 1-5 mcg/kg every 6-8 hours)
Nifedipine (for diazoxide non-responders)
Glucagon therapy may be used intermittently to prevent rebound hypoglycemia
Dietary management: frequent small feeds, high carbohydrate content, avoidance of prolonged fasting.
Surgical Management:
Subtotal (90-95%) pancreatectomy is the definitive treatment for persistent hyperinsulinism refractory to medical management
In cases of focal CHI identified by imaging, surgical enucleation or resection of the specific affected area is performed
Preoperative management focuses on stabilizing glucose levels and optimizing the infant for surgery
Postoperative monitoring for hypoglycemia and pancreatic insufficiency (exocrine and endocrine) is essential.
Supportive Care:
Continuous cardiorespiratory monitoring
Neurological assessment for seizures
Nutritional support with adequate caloric intake
Parental education and support regarding long-term management and follow-up
Regular monitoring of growth and development.
Complications
Early Complications:
Neurological damage (seizures, cognitive impairment, developmental delay)
Persistent hypoglycemia requiring very high glucose infusion rates
Pancreatic fistula post-surgery
Necrotizing pancreatitis.
Late Complications:
Diabetes mellitus (if extensive pancreatectomy leads to loss of insulin-producing cells)
Exocrine pancreatic insufficiency (malabsorption, steatorrhea)
Growth restriction
Long-term neurodevelopmental deficits
Recurrent hypoglycemia if not fully controlled.
Prevention Strategies:
Prompt recognition and management of risk factors for hypoglycemia
Close monitoring of blood glucose in at-risk neonates
Early and aggressive treatment of persistent hypoglycemia
Careful selection of medical and surgical management strategies
Adequate parental education for home management and follow-up.
Prognosis
Factors Affecting Prognosis:
Severity and duration of hypoglycemia
Age at diagnosis and treatment initiation
Response to medical therapy
Extent of pancreatectomy
Presence of underlying genetic syndrome
Severity of neurological involvement.
Outcomes:
With timely and appropriate management, many infants with transient hypoglycemia and even some with hyperinsulinism can achieve normal neurodevelopmental outcomes
Infants with CHI requiring subtotal pancreatectomy may develop diabetes mellitus or pancreatic insufficiency, requiring lifelong management
Early diagnosis and treatment of CHI are critical for preventing severe neurological sequelae.
Follow Up:
Regular neurological assessments
Growth monitoring
Endocrine evaluation for diabetes mellitus and pancreatic insufficiency
Developmental assessments at appropriate intervals
Genetic counseling for families
Continued monitoring for recurrence or complications.
Key Points
Exam Focus:
Definition of hypoglycemia (< 45 mg/dL)
Critical glucose levels for investigation
Key hormones in glucose regulation (insulin, glucagon)
Diagnostic triad for hyperinsulinism (low glucose, high insulin, low ketones/FFA)
Initial management (IV glucose, frequent monitoring)
Medical agents for hyperinsulinism (diazoxide, octreotide)
Surgical option (pancreatectomy)
Genetic basis of congenital hyperinsulinism.
Clinical Pearls:
Always check a lab glucose for confirmation after a fingerstick reading < 45 mg/dL
Draw a critical sample with glucose, insulin, and C-peptide when hypoglycemia is documented
Suspect hyperinsulinism in any neonate with persistent, difficult-to-manage hypoglycemia
Consider genetic testing early in persistent cases
Differentiate between focal and diffuse CHI for surgical planning.
Common Mistakes:
Delayed diagnosis due to relying solely on fingerstick glucose values
Inadequate glucose infusion rates for persistent hypoglycemia
Not obtaining simultaneous glucose and insulin levels when suspecting hyperinsulinism
Inappropriate use of empiric medications without confirmed diagnosis
Over-reliance on medical therapy for focal CHI without appropriate localization and surgical consideration.