Extremely low HbA1c levels as a marker of hemolysis and indicator of severe hemolytic anemia
Editors:
- Dr. Praful B. Godkar (Ph.D)
Eminent Author, Medical Biochemist and Scientist, Technical Education consultant. AGD Biomedicals (Pvt) LTD. - Dr. Gauri Kulkarni MD (Pathology)
Vice President, AGD Biomedicals (Pvt) LTD.
Multiple studies have reported unexpectedly low values in various hemolytic disorders, which may be considered spurious or misleading(3-6). In clinical laboratories, the most frequently seen cases of hemolytic anemia include hemoglobinopathies such as Sickle Cell disease and Thalassemia, Glucose-6-phosphate Dehydrogenase (G6PD) deficiency, drug-induced anemia, and hemolytic reactions caused by blood transfusion incompatibility(7). To ensure accurate glycemic assessment, concurrent analysis of a full blood count is vital for validating results. AGD Biomedicals offer a fifth-generation technology-based hematology analyzers and diagnostic kit for HbA1c determination, providing precise, NGSP-compliant measurements for reliable clinical management(7).
Q1. Why does the glycation percentage of glucose with hemoglobin decrease significantly in cases of hemolytic anemia?
ANS(1): Normal life span of red blood cells (RBCs) is average 120 days. In hemolytic anemia. In hemolytic anemia, RBC lifespan drops below 70–90 days. Early RBC destruction decreases overall blood glucose exposure time. Compensatory reticulocytosis (increase in reticulocytes) induced by hemolysis results in a younger erythrocyte population, which limits the time available for hemoglobin glycation and leads to falsely low HbA1c levels.
Q2. Why is it important to conduct a complete blood count before carrying out an HbA1C test?
ANS(2): To ensure accurate glycemic assessment, concurrent analysis of a full blood count is vital for validating results.
CASE STUDY
A thirteen-year-old girl was admitted to a hospital since she was suffering from weakness, anorexia, recurrent fever, yellow coloration of eyes and skin, and loss of weight. Her case history indicates that she was non-diabetic. Her complete hemogram report was as follows:
COMPLETE BLOOD COUNT
| PARAMETER | RESULT | NORMAL RANGE |
| Hemoglobin | 4.5 g/dl | 13–18 g/dl |
| Total erythrocyte count | 2.1 X 1012 /l | 5.0 ± 0.5 X 1012 /l |
| Total leukocyte count | 5.6 X 109/l | 7.0 ± 3.0 X 109/l |
| Differential leukocyte count: | ||
| Neutrophils | 67% | 40–75% |
| Lymphocytes | 24% | 20–45 % |
| Eosinophils | 3% | 1–4 % |
| Monocytes | 2% | 2–8 % |
| Hypochromia | +++ + | Normal cells |
| Microcytosis | + ++ | Normal cells |
| Poikilocytes | +++ | Normal cells |
| Target cells | ++ | |
| PCV | 18% | 36–48% |
| MCV | 66.0 fL | 82–92 fL |
| MCH | 18.8 pg | 27–32 pg |
| MCHC | 32.0% | 32–36 % |
| RDW- CV | 32 | 12–14 |
| Platelet count | 155 X 109/l | 150–400 X 109/l |
STAINED BLOOD SMEAR :
Microscopic observations:
Presence of large number of microcytes, hypochromic cells, anisocytes, target cells and poikilocytes.
HEMOGLOBIN FRACTIONATION BY HPLC
| PARAMETER | RESULT | NORMAL RANGE |
| HbA | 11% | 95-98% |
| HbA2 | 6% | 2.0-3.5% |
| HbF | 79% | < 2% |
INTERPRETATION:
Based on markedly reduced hemoglobin levels, total RBC count, MCV, MCH, and PCV, along with the presence of microcytes, poikilocytes, and target cells, as well as a significant decrease in HbA and elevations in HbF and HbA2, the findings are indicative of Thalassemia Major.
TESTS TO CONFIRM GLYCEMIC CONTROL
| PARAMETER | RESULT | NORMAL RANGE |
| Blood glucose (fasting) | 95 mg/dl | 70-110 mg/dl |
| Blood glucose (PP) | 116 mg/dl | Up to 140 mg/dl |
| HbA1c | 1.8% | 4-7% |
INTERPRETATION
Based on her Case history and blood glucose readings, it seems she was not diabetic, and on any hypoglycemic treatment. Hence, her HbA1C report was expected to fall within the normal range. However, it is significantly low.
ADDITIONAL TESTS TO CONFIRM JAUNDICE AND HEMOLYTIC ANEMIA
LIVER FUNCTION TESTS
| PARAMETER | RESULT | NORMAL RANGE |
| Serum Total bilirubin | 9.3 mg/dl | Up to 1.0 mg/dl |
| Serum Direct bilirubin | 0.5 mg/dl | Up to 0.5 mg/dl |
| Serum indirect bilirubin | 8.8 mg/dl | Up to 0.5 mg/dl |
| SGPT | 40 IU | 5–35 IU |
| SGOT | 110 IU | 8-40 IU |
| Serum alkaline phosphatase | 65 IU | 20-80 IU |
| Serum LDH | 490 | 7—240 IU |
INTERPRETATION:
A total bilirubin level exceeding 2 mg/dl is indicative of jaundice. The presence of normal direct bilirubin combined with significantly elevated indirect bilirubin suggests a diagnosis of hemolytic jaundice. These biochemical findings, corroborated by the complete blood count (CBC), indicate that the patient is suffering from hemolytic anemia. Furthermore, the patient’s HbA1C value of 1.8% is inconsistent with her normal blood glucose readings and the established reference range (4-6%). Because this HbA1C result is likely invalid due to a significantly reduced red blood cell lifespan caused by the severe hemolysis, it is not a valid marker of long-term glycemic control in this scenario.
References
(1) NGSP. HbA1c and Estimated Average Glucose (eAG). http://www.ngsp.org/A1ceAG.asp (accessed 2 May 2013).
(2) Goldstein DE, Little RR, Lorenz RA, et al. American Diabetes Association technical review on tests of glycemia. Diabetes Care 1995;18:896–909.
(3) Kutter D, Thoma J. Hereditary spherocytosis and other hemolytic anomalies distort diabetic control by glycated hemoglobin. Clin Lab 2006;52:477–81.
(4) Debard A, Charmion S, Ben Ameur S, et al. Inappropriate low glycated hemoglobin and hemolysis. Rev Med Internet 2009;30:525–7.
(5) Danzig JA, Moser JT, Belfield P, et al. Glucose-6-phosphate dehydrogenase deficiency diagnosed in an adolescent with type 1 diabetes mellitus and HbA1c discordant with blood glucose measurements. J Padiatr 2011;158:849–51.
(6) Jandrić Balen M, Lukenda V, Jandrić I, et al. HbA1C—overall glycemia marker and hemolytic anemia indicator. Med Glas (Zenica) 2012;9:406–8.
(7) Godkar PB, Godkar DP. Textbook of Medical laboratory technology (4th edition, 2024), Bhalani Publishers, Mumbai. India.
