What are the differential diagnoses for a patient with hypoglycemia?

Differential Diagnoses for Hypoglycemia

The differential diagnosis for hypoglycemia must distinguish between medication-induced causes (insulin, sulfonylureas), endogenous hyperinsulinism (insulinoma, insulin autoimmune syndrome), post-surgical dumping syndrome, and factitious hypoglycemia, with the diagnostic approach fundamentally different for fasting versus postprandial presentations.

Primary Diagnostic Framework

Medication-Related Hypoglycemia

• Exogenous insulin administration is the most common cause in hospitalized patients, with insulin dosing errors occurring frequently and accounting for 13.9% of diabetes-related hospitalizations in elderly patients 1
• Sulfonylurea-induced hypoglycemia accounts for 10.7% of medication-related hospitalizations and is biochemically indistinguishable from insulinoma 1, 2
• Somatostatin analogs (octreotide) can cause hypoglycemia in 4% of treated patients through inhibition of counter-regulatory hormones 3
• Insulin secretagogues and oral hypoglycemic agents must be excluded via plasma/urine sulfonylurea screening 1, 4

Endogenous Hyperinsulinemic Hypoglycemia

Insulinoma should be considered the primary diagnosis until proven otherwise when fasting hypoglycemia occurs with inappropriately elevated insulin and C-peptide levels 1, 2. Key distinguishing features include:

• Fasting hypoglycemia (not meal-provoked) is the classic presentation, though rare postprandial cases exist 1, 5
• A supervised 72-hour fast (typically 48 hours) demonstrates hypoglycemia with pathological failure to suppress insulin secretion 1, 4
• Elevated insulin and C-peptide during documented hypoglycemia with negative sulfonylurea screen 4, 5

Insulin autoimmune syndrome (IAS) presents with:

• Markedly elevated insulin autoantibodies (>50 kU/L) 6
• Extremely high insulin levels (>7,000 μIU/mL) with elevated C-peptide and insulin-to-C-peptide molar ratio >13 6
• Recurrent postprandial hypoglycemia in individuals without prior exogenous insulin exposure 6
• Increasingly recognized in non-Asian populations despite being the third leading cause of spontaneous hypoglycemia in Japan 6

Post-Surgical Hypoglycemia

Late dumping syndrome occurs 1-3 hours postprandially after upper GI, gastric, or bariatric surgery 1:

• Results from reactive hyperinsulinemia following rapid glucose absorption 1
• Distinguished from insulinoma by temporal relationship to meals and surgical history 1
• Vegetative symptoms accompany hypoglycemia (sweating, palpitations, weakness) 1

Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) should be considered in post-gastric bypass patients with postprandial hypoglycemia 4

Factitious Hypoglycemia

Surreptitious insulin use is detected by 1, 2:

• Insulin-to-C-peptide ratio >1.0 during hypoglycemia 2
• Inappropriately low C-peptide levels (<0.6 ng/mL) with elevated insulin 1
• Critical caveat: Most commercial insulin immunoassays only detect human insulin and cannot identify synthetic analog insulin, potentially leading to misdiagnosis 7

Sulfonylurea abuse presents with 1, 4:

• Elevated insulin and C-peptide during hypoglycemia
• Positive plasma/urine sulfonylurea screen
• Important limitation: Common detection methods for sulfonylureas have low diagnostic value, and negative screens do not definitively exclude abuse 7

Factitious hypoglycemia is associated with higher incidence of suicide, depression, and personality disorders, with generally poor prognosis 2

Other Endocrine Causes

Non-islet cell tumor hypoglycemia from mesenchymal, epithelial, or hematopoietic tumors 8, 4:

• Diagnosed via CT or MRI of chest, abdomen, and pelvis 8
• Typically presents with fasting hypoglycemia 4

Primary adrenal insufficiency and hypopituitarism cause hypoglycemia through loss of counter-regulatory hormones 4

Post-Surgical Complications Mimicking Dumping

In patients with upper GI surgery history, consider 1:

• Stenosis or anastomotic complications: dysphagia with fullness after meals, confirmed by gastroscopy or contrast studies 1
• Internal herniation: colicky pain, fullness after meals, possible ileus without vegetative symptoms, diagnosed by CT or diagnostic laparoscopy 1
• Marginal ulcer or gastritis: pain during meals, acid reflux, nausea confirmed via gastroscopy 1

Critical Diagnostic Pitfalls

• Postprandial syncope may mimic loss of consciousness from hypoglycemia, especially in elderly patients, making differentiation difficult 1
• In correctional settings, hypoglycemia symptoms (altered mental status, agitation, diaphoresis) are frequently confused with intoxication or withdrawal 1
• Acute kidney injury is an important risk factor for hypoglycemia through decreased insulin clearance 1
• Recurrent hypoglycemia increases risk of subsequent severe episodes through impaired counter-regulation, with 84% of severe hypoglycemic events preceded by prior hypoglycemia during the same hospitalization 1

Diagnostic Algorithm Priority

For fasting hypoglycemia: 72-hour supervised fast with simultaneous measurement of glucose, insulin, C-peptide, pro-insulin, beta-hydroxybutyrate, and sulfonylurea screen 4. If insulin and C-peptide are elevated with negative sulfonylurea screen, proceed to imaging for insulinoma 4, 5.

For postprandial hypoglycemia: Mixed meal test is preferable, with same biochemical measurements during symptomatic hypoglycemia 4. Consider dumping syndrome in post-surgical patients, IAS if insulin antibodies are markedly elevated, and rare postprandial insulinoma if other causes excluded 1, 6, 5.

In all cases: Clinical suspicion remains the best diagnostic strategy for factitious hypoglycemia given laboratory limitations in detecting analog insulin and sulfonylureas 7, 2.