Can occult infections or malignancies elevate Hemoglobin A1c (HbA1c) levels despite good Self-Monitoring of Blood Glucose (SMBG) readings?

Occult Infections and Malignancies Can Elevate HbA1c Despite Normal SMBG Readings

Yes, occult infections and malignancies can cause elevated HbA1c levels despite good self-monitoring blood glucose (SMBG) readings, primarily through mechanisms that affect red blood cell lifespan and turnover. 1

Mechanisms of HbA1c Elevation in Occult Disease

• Any condition that slows erythropoiesis or prolongs red blood cell lifespan can increase HbA1c values independent of actual glycemic control 2
• Occult malignancies, particularly those affecting bone marrow function, can alter red blood cell production and lifespan, leading to falsely elevated HbA1c 1
• Chronic infections may cause inflammatory responses that affect red blood cell turnover, potentially resulting in higher HbA1c values than would be expected based on blood glucose levels 1
• Iron deficiency anemia, which can be associated with occult malignancies (especially gastrointestinal), prolongs erythrocyte lifespan and can cause falsely elevated HbA1c 2, 3

Common Causes of Discrepancy Between HbA1c and SMBG

• Conditions affecting red blood cell lifespan:
  • Prolonged RBC lifespan (iron deficiency anemia, aplastic anemia) increases HbA1c 2, 3
  • Shortened RBC lifespan (hemolytic anemia, recovery from blood loss) decreases HbA1c 2
• Limited SMBG testing frequency may miss significant glycemic excursions, particularly postprandial hyperglycemia 1
• Operator-related errors in SMBG technique (improper calibration, poor hand washing, dirty meters) 1

Clinical Implications

• HbA1c should be interpreted with caution when there is a discrepancy with SMBG readings, especially in patients with suspected occult disease 2
• For approximately 20% of people with diabetes, HbA1c levels are substantially higher or lower than would be predicted from mean blood glucose levels 4
• When HbA1c values seem discordant with clinical presentation or SMBG results, consider occult conditions as potential confounding factors 1, 5

Evaluation Steps for Discrepant HbA1c and SMBG

1. Evaluate the patient's monitoring technique and frequency 1
2. Consider testing during different times of day, including postprandial periods 1
3. Investigate for conditions that might affect red blood cell lifespan:
   • Complete blood count to assess for anemia 3
   • Iron studies to evaluate for iron deficiency 2, 3
   • Evaluation for occult infection or malignancy when clinically suspected 1

Management Recommendations

• When HbA1c is suspected to be unreliable due to occult disease, consider alternative measures of glycemic control 1:
  • Fructosamine or glycated albumin measurements 6
  • Continuous glucose monitoring (CGM) to better understand glycemic patterns 1, 5
  • Structured SMBG testing at various times of day 1
• A hemoglobin variant or interference should be suspected if the HbA1c reading is surprisingly high or low, or significantly changed coincident with a change in laboratory method 2
• In cases of suspected interference, correlation with other glycemic measures (fasting glucose, post-prandial glucose) is essential to establish true glycemic status 7

Pitfalls and Caveats

• Relying solely on HbA1c without considering potential confounding factors can lead to inappropriate treatment intensification 2
• Sequential HbA1c values that are within 0.5% do not statistically differ from one another unless the assay coefficient of variation is less than 3% 2
• Comparing HbA1c tests performed in different clinical laboratories introduces another source of error 2
• Point-of-care HbA1c testing is not subject to systematic quality oversight and may be less reliable 2

Understanding these factors is crucial for accurate interpretation of glycemic control in patients with suspected occult disease and for making appropriate treatment decisions.