What is the differential diagnosis of hypoglycemia?

Differential Diagnosis of Hypoglycemia

Primary Classification Framework

The differential diagnosis of hypoglycemia must first distinguish between medication-induced hypoglycemia in patients with diabetes versus spontaneous hypoglycemia in non-diabetic individuals, as these represent fundamentally different diagnostic pathways. 1

---

Medication-Induced Hypoglycemia (Diabetic Patients)

Iatrogenic Causes

• Insulin therapy (highest risk with intensive regimens including multiple daily injections, continuous subcutaneous infusion, or automated delivery systems) 1
• Sulfonylureas (second-line risk after insulin) 1
• Meglitinides (glinides) 1
• Combination therapy with insulin plus sulfonylureas markedly increases hypoglycemia risk 1

Exacerbating Risk Factors in Treated Diabetes

• Recent level 2 or 3 hypoglycemia within past 3-6 months 1
• Impaired hypoglycemia awareness (hypoglycemia-associated autonomic failure) 1
• End-stage kidney disease 1
• Cognitive impairment or dementia 1
• Age ≥75 years 1
• Food insecurity or low-income status 1
• Chronic kidney disease with eGFR <60 mL/min/1.73 m² or albuminuria 1

---

Spontaneous Hypoglycemia (Non-Diabetic Patients)

Endogenous Hyperinsulinism

Insulinoma is the classic cause, characterized by:

• Inappropriately elevated insulin concentrations during documented hypoglycemia 1, 2, 3
• Elevated proinsulin-to-insulin ratio (particularly suggestive of islet cell tumor) 2
• Elevated C-peptide during hypoglycemia 2, 3, 4
• Fasting hypoglycemia (not provoked by meals, distinguishing it from late dumping) 1
• Requires 72-hour supervised fast with simultaneous measurement of glucose, insulin, C-peptide, and proinsulin 1, 2, 5, 6

Post-bariatric/gastric surgery hypoglycemia (Late Dumping Syndrome):

• Occurs 1-3 hours postprandially (meal-provoked, not fasting) 1
• Results from exaggerated insulin response to rapid glucose absorption 1
• Distinguished from insulinoma by timing (postprandial vs. fasting) 1

Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS):

• Postprandial hypoglycemia with hyperinsulinism 7, 5, 6
• Diffuse beta-cell dysfunction rather than discrete tumor 5, 6

Genetic causes of hyperinsulinism:

• Glucokinase-activating gene mutations (postprandial hypoglycemia with major hyperinsulinism) 7
• Insulin receptor mutations 7
• SLC16A1 gene mutations (exercise-induced hyperinsulinism) 7
• Proinsulin processing enzyme mutations (high proinsulin with normal insulin) 2

Autoimmune Hypoglycemia

Insulin autoimmune syndrome (Hirata syndrome):

• Anti-insulin antibodies causing erratic insulin release 4, 7, 5
• Associated with Graves' disease 7
• Elevated insulin and C-peptide with positive insulin antibodies 4, 5

Type B insulin resistance syndrome:

• Antibodies against insulin receptor 4, 7
• Paradoxical hypoglycemia despite insulin resistance 4

Factitious Hypoglycemia

Surreptitious insulin administration:

• Elevated insulin with suppressed C-peptide (key distinguishing feature) 1, 2, 3
• Negative sulfonylurea screen 5, 6

Oral hypoglycemic agent ingestion:

• Elevated insulin and C-peptide 5, 6
• Positive sulfonylurea/meglitinide screen in plasma or urine 5, 6

Non-Islet Cell Tumor Hypoglycemia (NICTH)

• Large tumors secreting IGF-2 (Big-IGF2) 7
• Low insulin, low C-peptide, low IGF-1 during hypoglycemia (distinguishes from insulinoma) 7
• Typically mesenchymal tumors, hepatocellular carcinoma, or adrenal carcinoma 7

Critical Illness and Organ Failure

• Sepsis (impaired gluconeogenesis and increased glucose utilization) 3, 7, 6
• Hepatic failure (depleted glycogen stores, impaired gluconeogenesis) 3, 7, 6
• Renal failure (impaired renal gluconeogenesis, decreased insulin clearance) 3, 7, 6

Hormonal Deficiencies

• Primary adrenal insufficiency (cortisol deficiency impairs gluconeogenesis) 7, 5, 6
• Hypopituitarism (combined growth hormone and cortisol deficiency) 7, 5, 6
• Isolated glucagon deficiency (rare, post-pancreas transplantation) 7

Inborn Errors of Metabolism (IEM)

Fasting hypoglycemia patterns:

• Glycogen storage diseases (types 0, I, III) 7
• Fatty acid oxidation disorders 7
• Gluconeogenesis disorders 7
• Associated with rhabdomyolysis after fasting/exercise, hepatomegaly, or cardiac disease 7

Postprandial hypoglycemia pattern:

• Hereditary fructose intolerance 7

Alcohol-Related Hypoglycemia

• Ethanol inhibits hepatic gluconeogenesis 7, 5
• Occurs with depleted glycogen stores (fasting state) 7, 5

Medications (Non-Diabetes Drugs)

• Quinolone antibiotics 7, 6
• Pentamidine 7, 6
• Quinine 7, 6
• Beta-blockers (mask hypoglycemia symptoms) 6
• Salicylates in overdose 6

---

Diagnostic Algorithm

Step 1: Confirm True Hypoglycemia (Whipple's Triad)

1. Documented low plasma glucose (<70 mg/dL or <3.9 mmol/L) 1, 5, 6
2. Symptoms consistent with hypoglycemia (adrenergic: sweating, tremor, palpitations; neuroglycopenic: confusion, altered consciousness) 1, 8, 6
3. Resolution of symptoms with glucose administration 5, 6

Step 2: Obtain Critical Laboratory Panel During Hypoglycemic Episode

• Plasma glucose 5, 6
• Insulin 2, 3, 5, 6
• C-peptide 2, 3, 5, 6
• Proinsulin 2, 5, 6
• Beta-hydroxybutyrate (suppressed in hyperinsulinemic states) 5, 6
• Plasma and urine sulfonylurea/meglitinide screen 5, 6

Step 3: Interpret Insulin/C-Peptide Pattern

High insulin + High C-peptide:

• Insulinoma (check proinsulin-to-insulin ratio) 2, 3, 4
• Post-bariatric hypoglycemia (postprandial timing) 1
• Insulin autoimmune syndrome (check insulin antibodies) 4, 7
• Sulfonylurea/meglitinide ingestion (positive drug screen) 5, 6

High insulin + Low C-peptide:

• Exogenous insulin administration (factitious) 1, 2, 3

Low insulin + Low C-peptide:

• Non-islet cell tumor hypoglycemia (check IGF-2) 7
• Critical illness 3, 7, 6
• Hormonal deficiency 7, 5, 6
• Alcohol-induced 7, 5
• Inborn errors of metabolism 7

Step 4: Provocative Testing if Initial Evaluation Non-Diagnostic

72-hour supervised fast:

• For suspected fasting hypoglycemia (insulinoma, hormonal deficiency) 1, 2, 5, 6
• Measure glucose, insulin, C-peptide, proinsulin every 6 hours and when symptomatic 5, 6

Mixed-meal test:

• For predominantly postprandial symptoms (post-bariatric, NIPHS, reactive hypoglycemia) 1, 5, 6

---

Critical Diagnostic Pitfalls

• Do not diagnose insulinoma without elevated insulin AND C-peptide during documented hypoglycemia; normal C-peptide definitively excludes endogenous hyperinsulinism 2, 3
• Timing matters: fasting hypoglycemia suggests insulinoma, while postprandial (1-3 hours) suggests late dumping or NIPHS 1, 7
• Always screen for sulfonylureas before diagnosing insulinoma, as factitious ingestion mimics the biochemical profile 5, 6
• Measure C-peptide to distinguish exogenous insulin (suppressed C-peptide) from endogenous sources (elevated C-peptide) 1, 2, 3
• Asymptomatic low glucose readings do not constitute hypoglycemia; symptoms must be present and resolve with glucose correction 5, 6, 9
• Proinsulin-to-insulin ratio >0.2 is particularly suggestive of insulinoma 2