What are the differential diagnoses and investigations for hypoglycemia (low blood sugar)?

Hypoglycemia: Differential Diagnoses and Investigations

Definition and Clinical Significance

Hypoglycemia is defined as blood glucose <70 mg/dL (3.9 mmol/L), with clinically significant hypoglycemia occurring at <54 mg/dL (3.0 mmol/L), requiring immediate investigation to identify the underlying cause and prevent morbidity and mortality. 1

The classification system stratifies hypoglycemia into three levels 1:

• Level 1: Glucose <70 mg/dL but ≥54 mg/dL (3.9-3.0 mmol/L)
• Level 2: Glucose <54 mg/dL (3.0 mmol/L) - threshold for neuroglycopenic symptoms
• Level 3: Severe event with altered mental/physical status requiring assistance, irrespective of glucose level

Differential Diagnosis

Medication-Related Causes (Most Common)

Drug-related hypoglycemia is the most frequent cause, particularly in insulin-treated diabetic patients, but many other medications can be implicated. 2

Major medication culprits include 1:

• Insulin therapy (especially intensive regimens with multiple daily injections or continuous subcutaneous infusion)
• Sulfonylureas
• Meglitinides
• Other glucose-lowering agents in combination therapy

Endocrine Causes

Hormonal deficiencies must be systematically evaluated 2:

• Cortisol insufficiency including hypopituitarism
• Glucagon deficiency
• Growth hormone deficiency

Tumor-Related Causes

Insulinoma - functioning islet-cell tumor causing inappropriate insulin secretion 3, 2

Non-Islet Cell Tumor Hypoglycemia (NICTH) - large mesenchymal tumors secreting Big-IGF2, characterized by low insulin, C-peptide, and IGF-1 levels 4

Ectopic insulin secretion (rare) 4

Genetic and Metabolic Causes

Endogenous hyperinsulinism 4:

• Monogenic congenital hyperinsulinism
• Glucokinase-activating gene mutations (postprandial hypoglycemia with major hyperinsulinism)
• Insulin receptor mutations
• SLC16A1 gene mutations (exercise-induced hyperinsulinism)

Inborn errors of metabolism 4:

• Fasting hypoglycemia: Glycogen storage disorders (types 0, I, III), fatty acid oxidation disorders, gluconeogenesis disorders
• Postprandial hypoglycemia: Inherited fructose intolerance

Autoimmune Causes

Hirata syndrome - antibodies against insulin, especially associated with Graves' disease 4, 2

Insulin receptor antibodies 4, 2

Post-Surgical Causes

Post-bariatric or gastric surgery hypoglycemia 4

Post-pancreas transplantation 4

Post-gastrectomy reactive hypoglycemia 2

Organ Failure

Hepatic failure - decreased hepatic glycogen stores 2

Renal failure 2

Acute cardiac insufficiency 2

Toxic Causes

Alcohol is a major cause of toxic hypoglycemia 2

Multifactorial/Critical Illness

Underdiagnosed in hospitalized older patients with severe disease, sepsis, or underfeeding 2

Surreptitious/Factitious

Surreptitious insulin or sulfonylurea administration must be considered when other causes are excluded 4

Investigations

Initial Diagnostic Approach

The critical first step is documenting Whipple's triad during a spontaneous symptomatic episode 5:

1. Plasma glucose <70 mg/dL (3.9 mmol/L)
2. Specific symptoms: shakiness, confusion, tachycardia, sweating, irritability, hunger
3. Symptom resolution after glucose administration or food intake

Essential Laboratory Tests During Hypoglycemic Episode

Obtain the following simultaneously during documented hypoglycemia 5:

• Insulin level
• C-peptide level
• Proinsulin level

These help differentiate endogenous hyperinsulinism from exogenous insulin administration and other causes 5.

Additional Critical Laboratory Investigations

For suspected insulinoma or endogenous hyperinsulinism 4:

• Supervised 72-hour fast with serial glucose, insulin, C-peptide, and proinsulin measurements
• Beta-hydroxybutyrate levels (suppressed in hyperinsulinemic states)

For suspected NICTH 4:

• IGF-1 levels (low)
• IGF-2 levels
• Big-IGF2 measurement

For suspected hormonal deficiencies 2:

• Cortisol level
• ACTH stimulation test
• Growth hormone level
• Glucagon level

For suspected inborn errors of metabolism 4:

• Timing relationship to meals (fasting vs. postprandial)
• Lactate and pyruvate levels
• Urine organic acids
• Acylcarnitine profile
• Genetic testing for specific mutations

For suspected autoimmune causes 4, 2:

• Anti-insulin antibodies
• Insulin receptor antibodies
• Thyroid function tests (for associated Graves' disease)

Medication and Exposure History

Document all medications comprehensively 5:

• Prescription medications
• Over-the-counter drugs
• Supplements
• Alcohol use
• Access to insulin or sulfonylureas (for factitious hypoglycemia)

Imaging Studies

When tumor suspected 4:

• CT or MRI of pancreas for insulinoma
• Endoscopic ultrasound for small pancreatic lesions
• Whole-body imaging for large mesenchymal tumors causing NICTH
• Selective arterial calcium stimulation test for insulinoma localization

Risk Stratification for Diabetic Patients

Major clinical/biological risk factors requiring investigation 1:

• Recent (within 3-6 months) level 2 or 3 hypoglycemia
• Intensive insulin therapy
• Impaired hypoglycemia awareness (screen using Clarke, Gold, or Pedersen-Bjergaard scores) 1
• End-stage kidney disease
• Cognitive impairment or dementia

Major social/cultural/economic risk factors 1:

• Food insecurity
• Low-income status
• Homelessness
• Fasting for religious or cultural reasons

Other important risk factors 1:

• Age ≥75 years
• Female sex
• High glycemic variability
• Chronic kidney disease (eGFR <60 mL/min/1.73 m²)
• Cardiovascular disease
• Neuropathy, retinopathy
• Major depressive disorder
• Alcohol or substance use disorder

Continuous Glucose Monitoring

CGM is beneficial and recommended for individuals at high risk for hypoglycemia to detect patterns of asymptomatic hypoglycemia and nocturnal episodes 1, 6.

Common Pitfalls to Avoid

Do not diagnose hypoglycemia based solely on a low glucose level - many asymptomatic persons have levels below 50 mg/dL; diagnosis requires documented symptoms at glucose nadir that resolve with glucose administration 3.

Do not overlook multifactorial hypoglycemia in hospitalized older patients with severe illness, sepsis, or inadequate nutrition 2.

Do not miss surreptitious insulin or sulfonylurea use - always consider factitious disorder when investigations are otherwise unrevealing 4.

Do not forget to assess cognitive function - cognitive impairment increases hypoglycemia risk and may be both a cause and consequence of severe hypoglycemia 1.

Timing of hypoglycemia is diagnostically crucial 4:

• Fasting hypoglycemia suggests glycogen storage disorders, fatty acid oxidation defects, or insulinoma
• Postprandial hypoglycemia suggests inherited fructose intolerance, post-surgical states, or glucokinase mutations
• Exercise-induced suggests SLC16A1 mutations