Hyperinsulinemic Hypoglycemia

Diagnosis

Indications for Testing

  • Demonstration of an inappropriate insulin level during an episode of hypoglycemia
  • Hypoglycemia with symptoms and without other evident etiology

Laboratory Testing

  • Classic lab finding is hypoketotic hypo-fatty-acidemic hypoglycemia
  • Random blood sugar – decreased level expected
    • Cutoffs used vary by guideline – glucose 50-60 mg/dL usually considered hypoglycemic
    • Patient may need to be fasting to detect hypoglycemia
    • Confirm hypoglycemia with at least two more tests
  • Insulin – random or fasting; fasting preferred
    • Inappropriate insulin level during episode of hypoglycemia
    • Low or undetectable insulin does not exclude diagnosis – most recently ATK2 mutation associated with this clinical presentation
    • Insulin alone may not be informative and should be considered in conjunction with C-peptide
  • C-peptide – usually ≥0.6 ng/mL
    • Low C-peptide with markedly elevated insulin level suggests surreptitious insulin administration
    • Elevated insulin and C-peptide levels also observed in insulinoma and surreptitious use of sulfonylureas, metformin
      • Rule out sulfonylurea- or metformin-induced hypoglycemia with serum/urine sulfonylurea and metformin testing
  • Beta hydroxybutyrate – typically normal
  • Free fatty acids – typically normal
    • If elevated, consider testing for fatty acid oxidation disorders
  • Glucagon response testing
    • Injection of 1 mg (IV or IM) of glucagon with pre- and post-glucose levels
    • Increase in plasma glucose >30 mg/dL post-glucagon administration confirms hyperinsulinemic hypoglycemia
  • Genetic testing for infantile forms – treatment response is often gene-dependent
    • GLUD1, HADH, and HNF4A mutations – good response to diazoxide
    • KCNJI1, ABCC8 – often require surgery

Differential Diagnosis

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 (higher incidence 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 (9 identified) – ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, UCP2, ATK2
        • ABCC8 and KCNJ11 most common
      • 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 nongenetic disorders 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
Test Name and Number Recommended Use Limitations Follow Up
Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Screen for hyperinsulinemic hypoglycemia

   
Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay

Aids in evaluation of hyperinsulinemic hypoglycemia

   
C-Peptide, Serum or Plasma 0070103
Method: Quantitative Chemiluminescent Immunoassay

Aids in evaluation of hyperinsulinemic hypoglycemia

   
Beta-Hydroxybutyric Acid 0080045
Method: Quantitative Enzymatic

Aids in evaluation of hyperinsulinemic hypoglycemia

   
Fatty Acids, Free 0080120
Method: Quantitative Spectrophotometry

Aids in evaluation of hyperinsulinemic hypoglycemia

   
Hypoglycemia Panel, Sulfonylureas Qualitative, Serum or Plasma 2010292
Method: Qualitative Liquid Chromatography-Tandem Mass Spectrometry

Quantitative test to evaluate if etiology of hypoglycemia is a result of sulfonylurea exposure

Drugs tested with analytical sensitivity

  • Glyburide – 5 ng/mL
  • Glimepiride – 5 ng/mL
  • Glipizide – 5 ng/mL
  • Repaglinide – 5 ng/mL
  • Nateglinide – 5 ng/mL
  • Acetohexamide – 100 ng/mL
  • Chlorpropamide – 100 ng/mL
  • Tolazamide – 100 ng/mL
  • Tolbutamide – 100 ng/mL

Cutoff concentrations vary by drug

 
Sulfonylurea Hypoglycemics Panel (Quantitative), Urine 0091100
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Quantitative test to evaluate if etiology of hypoglycemia is a result of sulfonylurea exposure

Drugs tested with analytical sensitivity

  • Glyburide – 5 ng/mL
  • Glimepiride – 5 ng/mL
  • Glipizide – 5 ng/mL
  • Repaglinide – 5 ng/mL
  • Nateglinide – 5 ng/mL
  • Acetohexamide – 100 ng/mL
  • Chlorpropamide – 100 ng/mL
  • Tolazamide – 100 ng/mL
  • Tolbutamide – 100 ng/mL

Cutoff concentrations vary by drug

 
Metformin Quantitation, Urine 2002928
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Quantitative test to evaluate if etiology of hypoglycemia is result of exposure to metformin

   
Proinsulin, Intact 0070112
Method: Quantitative Chemiluminescent Immunoassay

Screen for insulinoma