Overview
Definition:
Congenital hyperinsulinism (CHI) is a severe form of persistent hypoglycemia in neonates and infants characterized by inappropriate insulin secretion from pancreatic beta-cells
Pancreatectomy, specifically subtotal or total pancreatectomy, is a definitive surgical intervention reserved for cases unresponsive to maximal medical management.
Epidemiology:
CHI affects approximately 1 in 30,000 to 50,000 live births
It is the most common cause of persistent hypoglycemia in newborns
Genetic mutations are identified in about 60-70% of cases, with dominant mutations in KCNJ11 ( Kir6.2) and ABCC8 (SUR1) being the most frequent.
Clinical Significance:
Untreated CHI can lead to severe neurological sequelae, including seizures, developmental delay, and intellectual disability, due to recurrent or prolonged hypoglycemia
Pancreatectomy is a life-altering procedure aimed at normalizing glucose homeostasis and preventing long-term neurodevelopmental deficits in selected patients.
Clinical Presentation
Symptoms:
Hypoglycemia presenting as irritability, lethargy, poor feeding, tremors, pallor, sweating, apnea, and seizures
Symptoms typically manifest within the first few days of life
Neonatal hypoglycemia is often defined as blood glucose < 40 mg/dL (2.2 mmol/L).
Signs:
Physical examination may reveal signs of hypoglycemia such as tachypnea, grunting, hypotonia, and abnormal neurological status
Macrosomia may be present in some genetic forms (e.g., HNF4A mutations)
Persistent hypoglycemia despite adequate feeding is the hallmark.
Diagnostic Criteria:
Diagnosis is confirmed by demonstrating hypoglycemia (< 40 mg/dL or < 2.2 mmol/L) with hyperinsulinemia (elevated plasma insulin levels) and an elevated insulin-to-glucose ratio (typically > 0.4 or > 0.5) during hypoglycemic episodes
The suppression of ketones and free fatty acids also supports the diagnosis.
Diagnostic Approach
History Taking:
Detailed birth history, including gestational age, birth weight, and maternal diabetes
Family history of hypoglycemia, consanguinity, or sudden infant death
Nutritional history, including feeding patterns and response to glucose administration
Previous attempts at medical management and their efficacy.
Physical Examination:
Thorough assessment for neurological deficits
Evaluation for dysmorphic features that may suggest specific genetic syndromes
Assessment of signs of hypoglycemia
Measurement of vital signs to detect instability.
Investigations:
Laboratory tests: Blood glucose, plasma insulin, C-peptide, free fatty acids, beta-hydroxybutyrate, growth hormone, cortisol, and ACTH
Genetic testing for known CHI-associated genes (KCNJ11, ABCC8, GLUD1, HNF4A, GCK, HGD, SLCA10)
Imaging: Abdominal ultrasound to evaluate pancreatic size and morphology
Arterial stimulation with calcium and amino acids (ASPAC) or sequential intra-arterial calcium stimulation and venous sampling ( IAVS) for precise localization of focal CHI lesions, though less commonly used for diffuse disease requiring pancreatectomy.
Differential Diagnosis:
Other causes of neonatal hypoglycemia including transient neonatal hypoglycemia, ketotic hypoglycemia, endocrine deficiencies (e.g., adrenal insufficiency, growth hormone deficiency), metabolic disorders (e.g., galactosemia, glycogen storage diseases), and sepsis
Distinguishing between focal and diffuse CHI is crucial as focal lesions may be amenable to enucleation rather than pancreatectomy.
Management
Initial Management:
Immediate administration of intravenous glucose infusion to maintain normoglycemia
Frequent blood glucose monitoring
Identification of the underlying cause (genetic testing).
Medical Management:
First-line therapy: Diazoxide, an ATP-sensitive potassium channel opener, which inhibits insulin release
Dosage is titrated to maintain blood glucose > 50 mg/dL
Second-line agents: Octreotide (somatostatin analog) via continuous subcutaneous infusion or glpagon
Nifedipine may be used as an adjunct
Medical management is typically maximal before considering surgery.
Surgical Management:
Indications: Persistent, severe hypoglycemia refractory to maximal medical therapy, requiring excessively high glucose infusion rates (>15 mg/kg/min), and significant risk of neurological damage
Procedure: Subtotal pancreatectomy is the preferred surgical approach, aiming to preserve endocrine and exocrine function while removing the majority of hypersecreting tissue
Typically, 80-95% of the pancreas is resected
Total pancreatectomy is reserved for extreme cases where subtotal pancreatectomy fails to control hypoglycemia.
Supportive Care:
Continuous glucose monitoring
Nutritional support to meet caloric needs and prevent catabolism
Management of potential complications such as pancreatitis and diabetes mellitus post-operatively
Long-term endocrine and exocrine insufficiency management.
Complications
Early Complications:
Postoperative hypoglycemia (due to residual hyperinsulinism or impaired glucagon reserve)
Pancreatitis
Infection
Fluid and electrolyte imbalances
Bleeding.
Late Complications:
Diabetes mellitus (type 1 or type 3c) due to loss of beta-cell function
Pancreatic exocrine insufficiency (malabsorption, steatorrhea)
Growth retardation
Recurrent hypoglycemia in rare instances.
Prevention Strategies:
Careful preoperative medical optimization
Meticulous surgical technique to preserve as much pancreatic tissue as possible
Aggressive postoperative glucose monitoring and management
Timely initiation of enzyme replacement therapy and insulin therapy if indicated.
Prognosis
Factors Affecting Prognosis:
The underlying genetic mutation, the extent of pancreatectomy, the development of postoperative diabetes or exocrine insufficiency, and the presence of neurological deficits prior to surgery
Early and effective intervention is critical for optimal neurodevelopmental outcomes.
Outcomes:
Successful pancreatectomy can lead to normoglycemia and resolution of symptoms
However, the risk of developing long-term complications like diabetes mellitus remains significant
Patients undergoing subtotal pancreatectomy have a better chance of preserving some pancreatic function.
Follow Up:
Lifelong monitoring for glucose homeostasis (risk of hypoglycemia and hyperglycemia)
Regular assessment of pancreatic exocrine function (e.g., fecal elastase)
Monitoring for growth and development
Genetic counseling for families.
Key Points
Exam Focus:
Differentiating focal vs
diffuse CHI
Medical management options (diazoxide, octreotide) and their mechanisms
Surgical indications and extent of resection (subtotal vs
total)
Postoperative complications, especially diabetes and exocrine insufficiency
Genetic basis of common CHI subtypes.
Clinical Pearls:
The insulin-to-glucose ratio is a critical diagnostic marker
Persistent hypoglycemia despite high glucose infusion rates in a neonate should raise suspicion for CHI
Subtotal pancreatectomy aims for 80-95% resection to balance efficacy and morbidity
Consider lifelong management of diabetes and exocrine insufficiency post-surgery.
Common Mistakes:
Delaying surgical intervention when maximal medical therapy fails
Inadequate pancreatic resection, leading to persistent hyperinsulinism
Over-resection, leading to immediate or early onset of diabetes
Underestimating the need for lifelong follow-up and management of pancreatic insufficiency.