What does a low hemoglobin A1c (HbA1c) mean in a patient who also has a low alkaline phosphatase (ALP)?

Low Hemoglobin A1c: Clinical Significance

A low HbA1c (<4%) typically indicates either true hypoglycemia or, more commonly, conditions that shorten red blood cell lifespan, causing falsely low readings that underestimate actual glycemic control. 1

Primary Mechanisms Causing Low HbA1c

Shortened Red Blood Cell Survival (Most Common)

Any condition reducing erythrocyte lifespan will falsely lower HbA1c because glycation accumulates over the 120-day red cell lifespan, with younger cells having less accumulated glycation 1, 2:

• Hemolytic anemia of any etiology decreases HbA1c regardless of assay method used 1, 3
• Chronic lymphocytic leukemia causes hemolytic anemia or reduced red cell survival, leading to misleadingly low HbA1c values 2
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency lowers HbA1c by approximately 0.8% in homozygous men and 0.7% in homozygous women through increased red cell turnover 1, 3
• Recent blood loss or hemorrhage creates a younger red cell population with less glycation time 1, 3
• Recent blood transfusion decreases the average age of circulating red cells 1, 3
• Erythropoietin therapy stimulates production of younger red cells with less accumulated glycation 1, 3
• Hemodialysis and end-stage kidney disease can cause falsely low HbA1c 3
• Chronic liver disease with hypersplenism increases red cell turnover, as demonstrated in case reports of patients with splenomegaly showing HbA1c below 27 mmol/mol despite blood glucose readings of 8-15 mmol/L 4

True Hypoglycemia (Less Common)

• Congenital hyperinsulinism or other causes of recurrent hypoglycemia will genuinely lower HbA1c 5
• Excessive diabetes medication causing frequent hypoglycemic episodes 5

Clinical Context: Low HbA1c with Low Alkaline Phosphatase

When both HbA1c and alkaline phosphatase (ALP) are low, consider:

• Chronic liver disease with cirrhosis: Low ALP occurs in advanced hepatopathy, and associated hypersplenism causes increased red cell destruction, falsely lowering HbA1c 5
• Malnutrition or zinc deficiency: Can lower both ALP and potentially affect red cell parameters 5
• Hemolytic conditions: May present with low HbA1c; check for concurrent anemia and reticulocytosis 5

Diagnostic Algorithm

Step 1: Verify the Low HbA1c

• Repeat HbA1c using an NGSP-certified laboratory method to exclude measurement error 1
• Ensure the assay is standardized to the DCCT reference assay 1

Step 2: Assess for Red Cell Turnover Abnormalities

• Complete blood count: Look for anemia (hemoglobin <100 g/L) and reticulocytosis (>100 G/L), which suggest increased red cell turnover 5
• Peripheral smear: Evaluate for hemolysis, spherocytes, or other red cell abnormalities 1
• Hemoglobin electrophoresis: Screen for hemoglobin variants, particularly in African American patients 1
• G6PD testing: Especially in populations with higher prevalence 1, 3

Step 3: Evaluate for Underlying Conditions

• Liver function tests: Assess for hepatopathy, which can cause both low ALP and hypersplenism 5
• Spleen size: Imaging if hypersplenism suspected 4
• Kidney function: Check for end-stage renal disease or hemodialysis status 3
• Medication review: Identify erythropoietin therapy, drugs causing hemolysis, or medications known to interfere with HbA1c assays 1, 3

Step 4: Correlate with Direct Glucose Measurements

• Fasting plasma glucose: Should be measured to assess true glycemic status 1, 3
• Home blood glucose monitoring: Review patient's capillary glucose logs for pattern recognition 2, 4
• Continuous glucose monitoring: Provides thousands of measurements over weeks, offering superior correlation to actual glycemic exposure 6

Alternative Glycemic Monitoring When HbA1c is Unreliable

When conditions affecting red cell turnover are identified, the American Diabetes Association recommends using plasma glucose criteria alone for diagnosis and monitoring. 1, 3

• Fructosamine or glycated albumin: Reflect 2-4 weeks of glycemic control and are unaffected by red cell turnover 1, 2
• Self-monitoring of blood glucose (SMBG): Becomes the primary monitoring tool when HbA1c is unreliable 2, 4
• Continuous glucose monitoring: When available, provides comprehensive glycemic assessment independent of red cell lifespan 2

Critical Clinical Pitfalls

• Do not assume good glycemic control based solely on low HbA1c without correlating with direct glucose measurements, as this may represent falsely low values masking poor control 2, 7, 4
• Hemolytic anemia makes HbA1c a poor marker for both glycemia and hemolysis in diabetic patients, requiring alternative monitoring strategies 7
• Marked discordance between HbA1c and plasma glucose (e.g., HbA1c <4% with fasting glucose >126 mg/dL) mandates investigation for interfering conditions 1, 3
• In patients with hemoglobin variants (such as HbSS or HbEE), HbA1c cannot be measured and should not be reported; use glycated proteins instead 1
• Iron deficiency anemia paradoxically increases HbA1c by creating an older red cell cohort, the opposite effect of hemolytic conditions 1, 3

Race and Ethnicity Considerations

• African Americans may have HbA1c levels 0.3-0.8% higher than non-Hispanic whites at identical glucose levels, but the X-linked G6PD G202A variant (carried by 11% of African Americans) causes the opposite effect, lowering HbA1c 1, 3