What is the management and diagnosis of a non-diabetic patient with an Hemoglobin A1c (HbA1c) level of 2.8 and recurrent hypoglycemia?

Investigation of Non-Diabetic Patient with HbA1c 2.8 and Recurrent Hypoglycemia

Critical First Step: Verify HbA1c Accuracy

An HbA1c of 2.8% is physiologically implausible and indicates a laboratory error or hemoglobin variant interference—immediately repeat HbA1c testing using a different methodology and consider hemoglobin electrophoresis to identify variants that falsely lower HbA1c values. 1, 2

Why This HbA1c is Suspect

• Normal HbA1c range is 4-6%, and values below this are typically seen only with conditions affecting red blood cell turnover 3
• Hemoglobin variants (HbS, HbC, HbE, HbJ, and 893+ other variants) can cause falsely low or high HbA1c measurements depending on the assay methodology used 1
• Hemolytic anemia shortens erythrocyte lifespan, resulting in falsely low HbA1c values that do not reflect true glycemic control 2
• The combination of extremely low HbA1c with recurrent hypoglycemia suggests either severe measurement error or a hemoglobinopathy masking the true glucose status 1

Diagnostic Workup for Recurrent Hypoglycemia

Immediate Laboratory Evaluation

• Document hypoglycemia during symptoms with Whipple's triad: symptoms of hypoglycemia, documented low plasma glucose (<3.9 mmol/L or <70 mg/dL), and relief of symptoms with glucose administration 3
• Complete blood count with reticulocyte count to assess for hemolytic anemia 2
• Hemoglobin electrophoresis to identify variants affecting HbA1c measurement 1
• Fructosamine or glycated albumin as alternative glycemic markers unaffected by red cell turnover 2, 4

Supervised Fasting Test (72-hour if needed)

• Measure plasma glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate at time of hypoglycemia 3
• Screen for sulfonylureas and meglitinides to exclude factitious hypoglycemia
• Insulin >3 μU/mL with glucose <55 mg/dL suggests endogenous hyperinsulinism (insulinoma or nesidioblastosis)
• Suppressed insulin and C-peptide suggests non-insulin-mediated hypoglycemia (IGF-2 secreting tumor, adrenal insufficiency, or other causes)

Additional Investigations Based on Initial Results

• Imaging studies (CT/MRI pancreas, chest/abdomen CT) if insulinoma or IGF-2 secreting tumor suspected
• Cortisol and ACTH stimulation test to exclude adrenal insufficiency
• Liver function tests and renal function as hepatic or renal failure can cause hypoglycemia
• Medication review for drugs causing hypoglycemia (quinolones, pentamidine, quinine) 3

Management Priorities

Immediate Safety Measures

• Prescribe glucagon emergency kit and train family members on administration, as this is essential for patients at risk for severe hypoglycemia 3
• Educate on hypoglycemia recognition and treatment: 15-20 grams of rapid-acting glucose (pure glucose preferred), recheck in 15 minutes, repeat if needed 3
• Avoid fasting states and ensure frequent small meals until diagnosis established 3

Addressing the Glycation Gap

• The discrepancy between measured HbA1c (2.8%) and clinical hypoglycemia represents a "glycation gap" that may have clinical significance 4
• Use alternative glycemic markers (fructosamine, glycated albumin, continuous glucose monitoring) until hemoglobin variant issue resolved 2, 4
• Do not rely on HbA1c alone when there is clinical-laboratory discordance 3

Common Pitfalls to Avoid

• Never dismiss an implausible HbA1c value—always investigate for hemoglobin variants or hemolytic conditions before accepting the result 1, 2
• Do not assume the patient is non-diabetic based solely on the low HbA1c; the true glycemic status is unknown until accurate testing is performed 1
• Avoid delaying the diagnostic workup for recurrent hypoglycemia, as severe episodes can cause cognitive impairment and require assistance from others (definition of severe hypoglycemia) 3
• Do not overlook medication-induced hypoglycemia even in "non-diabetic" patients—review all medications including over-the-counter and herbal supplements 3

Definitive Diagnosis Algorithm

1. Repeat HbA1c with different methodology + hemoglobin electrophoresis
2. If hemoglobin variant identified: Use fructosamine/glycated albumin for glycemic assessment going forward 2, 4
3. If hemolytic anemia identified: HbA1c is unreliable; use alternative markers and treat underlying hemolysis 2
4. Proceed with supervised fasting test to establish cause of hypoglycemia
5. Based on insulin/C-peptide results: Pursue imaging for insulinoma vs. evaluate for other causes of hypoglycemia