Hyperinsulinemic Hypoglycemia

Diagnosis

Indications for Testing

• Glucose <60 mg/dL with symptoms and without other evident etiology

Laboratory Testing

• Random blood sugar – expect decreased level
  • Patient may need to be fasting to detect blood glucose decline
  • Confirm low levels with at least two more tests
• Insulin (random or fasting; fasting preferred) – >6 µL/ml (elevated)
• Based on clinical scenario, other tests to consider
  • C-peptide – elevated
    • Low peptide and elevated insulin suggest surreptitious insulin administration
    • Elevated insulin and C-peptide may also be seen with insulinoma and surreptitious use of sulfonylureas, metformin
      • Rule out sulfonylurea- or metformin-induced hypoglycemia with serum or urine sulfonylurea testing
• Beta hydroxybutyrate – normal
• Free fatty acids – normal
  • If high, consider fatty acid oxidation disorders
• Consider genetic testing in infantile forms
  • Treatment response is often dependent on gene
    • GLUD1, HADH, and HNF4A mutations – good response to diazoxide
    • KCNJI1, ABCC8 – often require surgery 

Differential Diagnosis

• Postprandial hyperinsulinemic hypoglycemia
  • Dumping syndrome
  • Post-gastric bypass surgery
  • Insulin autoimmune syndrome
• Insulinoma
  • Sporadic
  • Multiple endocrine neoplasias subtype 1
• Surreptitious use of oral antihyperglycemics or insulin
• Adrenal insufficiency
• Unusual (generally transient)
  • Maternal DM
  • Perinatal asphyxiation
  • Intrauterine growth restriction
  • Rhesus isoimmunization

Clinical Background

Hypoglycemia may constitute a medical emergency because it can result in permanent neurologic defects.

Epidemiology

• Incidence of hypoglycemia
  • Newborns – 1-3/1,000 live births
  • Familial forms – 1/50,000 in sporadic populations (high in Ashkenazi Jews)
  • Diabetic patients
    • Type 1 – 10-30% annually
    • Type 2 – 1-2% annually
• Age
  • Neonatal forms – infancy
  • Adult forms – 25-45 years; depends on risk factors
• Definition of hypoglycemia
  • Glucose <50 mg/dL
  • Glucose <60 mg/dL plus signs and symptoms of hypoglycemia

Risk Factors

• Infants or newborns
  • Previous hyperinsulinemic hypoglycemia
  • Genetic
    • Defects in genes (7 identified) – ABCC8, KCNJ11, GLUD1, CAK, HADH, SLC16A1, HNF4A
    • Beckwith-Wiedemann syndrome (BWS)
  • Intrauterine growth retardation
  • Maternal diabetes mellitus (DM)
• Children
  • DM – higher risk in patients receiving insulin
  • Medication abuse
    • Insulin
    • Oral hypoglycemic agents
• Adults
  • DM – higher risk in patients receiving insulin
  • Medication abuse
    • Insulin
    • Oral hypoglycemic agents
  • Insulinoma
  • Insulin autoantibodies
  • Autoimmune diseases
  • Post bariatric surgery patients (gastric bypass procedures)
  • Diffuse nesidioblastosis

Pathophysiology

• Dysregulated insulin secretion with defects in glucose counter-regulatory hormones
• Insulin drives glucose into sensitive tissues (liver, adipose, skeletal muscle), which can cause profound hypoglycemia
• Simultaneous inhibition of glycogenolysis, gluconeogenesis, lipolysis and ketogenesis
• Nesidioblastosis (abnormally enlarged islets, hypertrophic beta cells, and periductal cells in the pancreas) is the likely explanation for pathology in gastric bypass patients

Clinical Presentation

• Adults and children
  • Lethargy, confusion, anxiety, sweating
  • Nausea
  • Focal neurologic defects
  • Seizures
  • Gastric bypass patients may experience symptoms as late as 1-2 years post procedure and usually 1-3 hours postprandially
• Infants and newborns
  • Lethargy, floppiness, sweating
  • Poor feeding, apnea, seizures, coma
  • Recurrent hypoglycemia can cause neurologic damage
  • BWS infants – omphalocele, gigantism, macroglossia, microcephaly, visceromegaly
    • 50% have hyperinsulinemic hypoglycemia  
  • Hypoglycemias associated with all but genetic defects tend to be transient and resolve spontaneously after several months

Treatment

• Treat hypoglycemia with intravenous glucose; prevention is best

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory