MON-595 - Severe Hyperglycemia with A Normal HbA1c: Unmasking Hb Raleigh as A Cause of HbA1c Discordance

Background: Hemoglobin A1c (HbA1c) is a cornerstone metric for assessing long-term glycemic control. However, hemoglobin variants can interfere with glycation and produce falsely low or high HbA1c values. Hb Raleigh is a rare β-chain hemoglobin variant associated with reduced glycation, leading to underestimation of true hyperglycemia. Early recognition is essential to prevent misclassification of diabetes severity and undertreatment.

Case Presentation: A 41-year-old woman with hypertension, type 2 diabetes mellitus (T2DM), hyperlipidemia, recurrent gallstone pancreatitis, status post cystgastrostomy, obstructive sleep apnea, and nephrolithiasis presented for evaluation of uncontrolled diabetes. She was diagnosed with T2DM in April 2023 during hospitalization for pancreatitis, at which time her serum glucose levels were persistently in the 400 mg/dL range despite an HbA1c of 5.2%. Treatment history included metformin intolerance and progression to basal–bolus insulin therapy (Basaglar 36 units daily; lispro 4 units with meals plus sliding-scale correction). Despite intensive insulin therapy, her continuous glucose monitoring (CGM) for >72 hours revealed: mean glucose 267 mg/dL, glycemic variability 62%, 58% time >250 mg/dL, and only 8% time in range (70–180 mg/dL). Surprisingly, her HbA1c in May 2024 was 6.9%, discordant with severe hyperglycemia and absence of hypoglycemia. Further evaluation showed an abnormal hemoglobin pattern: hemoglobin electrophoresis (4/2023) demonstrated Hb Raleigh 48.4% and HbA 49.3%, confirming a hemoglobin variant known to cause reduced glycation and artifactually low HbA1c. Fructosamine was elevated at 402 µmol/L but interpretation was limited by concurrent diabetic nephropathy and proteinuria.

Discussion: This case highlights that discordance between HbA1c and CGM/Self-monitoring of blood glucose values should prompt evaluation for hemoglobinopathies. Hb Raleigh reduces glycation of hemoglobin, rendering HbA1c unreliable for monitoring glycemic control. Alternative markers including fructosamine and glycated albumin may also be influenced by renal disease and protein turnover, making CGM the most reliable tool in these patients. HbA1c should be avoided for diagnosis or treatment decisions in individuals with Hb Raleigh.

Conclusion: Clinicians should suspect hemoglobin variants when HbA1c does not correlate with glucose data. In patients with Hb Raleigh, HbA1c significantly underestimates glycemia, risking undertreatment of diabetes. CGM-based metrics should be the primary method of monitoring in such cases. Increased awareness of hemoglobin variants can prevent misdiagnosis and improve management of patients with atypical glycemic profiles.

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