Factors that Interfere with HbA1c Test Results
More about hemoglobin variants and HbA1c can also be found at the NIDDK web site:
Sickle Cell Trait and Other Hemoglobinopathies and Diabetes: Important Information for Physicians
For People of African, Mediterranean, or Southeast Asian Heritage: Important Information about Diabetes Blood Tests
Factors that Interfere with HbA1c Measurement: Genetic variants (e.g. HbS trait, HbC trait), elevated fetal hemoglobin (HbF) and chemically modified derivatives of hemoglobin (e.g. carbamylated Hb in patients with renal failure) can affect the accuracy of HbA1c measurements. The effects vary depending on the specific Hb variant or derivative and the specific HbA1c method. Table 1 contains information for most of the commonly used current HbA1c methods for the four most common Hb variants, elevated HbF and carbamylated Hb. Interferences from less common Hb variants and derivatives are discussed in Bry, et al . All entries in Table 1 are based on published information. In addition, if a product insert indicates clearly that there is inference from a particular factor, then the interference is entered as “yes” and the product insert is cited. When selecting an assay method, laboratories should take into consideration characteristics of the patient population served, (e.g. high prevalence of hemoglobinopathies or renal failure).
Factors that affect interpretation of HbA1c Results: Any condition that shortens erythrocyte survival or decreases mean erythrocyte age (e.g., recovery from acute blood loss, hemolytic anemia) will falsely lower HbA1c test results regardless of the assay method used . HbA1c results from patients with HbSS, HbCC, and HbSC must be interpreted with caution given the pathological processes, including anemia, increased red cell turnover, and transfusion requirements, that adversely impact HbA1c as a marker of long-term glycemic control. Alternative forms of testing such as glycated serum protein or glycated albumin should be considered for these patients.
Iron deficiency anemia, a major public health problem in developing countries, is associated with higher HbA1c and higher fructosamine . Consistent with these observations, iron replacement therapy lowers both HbA1c and fructosamine concentrations in diabetic and non-diabetic individuals [3-5]. HbA1c , but not glycated albumin, is increased in late pregnancy in nondiabetic individuals owing to iron deficiency . Insight into the mechanism was recently obtained by the observation that malondialdehyde, which is increased in patients with iron deficiency anemia , enhances the glycation of hemoglobin . Alternative measures of glycemic assessment (e.g., glucose monitoring) must be used in the presence of significant iron deficiency anemia, at least until the iron deficiency has been successfully treated.
Chronic renal failure develops in many diabetic patients. The role of glycemic control and the value of HbA1c in diabetic subjects with renal disease are controversial. While interference from carbamylated Hb can be evaluated, the role of renal anemia, erythropoietin intake, and other factors in chronic renal failure is more difficult to evaluate. Recent reports suggest HbA1c underestimates glycemic control in diabetic patients on dialysis and that glycated albumin is a more robust indicator of glycemic control [8-11]. Further studies are needed to clarify the role of HbA1c in diabetic patients with chronic renal failure.
Some interferences for some methods are highlighted in gray indicating that they have been tested using a new stricter criterion of >7% difference at 6 and 9% HbA1c to define clinical significance (13). The other methods were tested using either criteria of >10% at 6 and 9% HbA1c or some other criteria.
@ In the absence of specific method data, it can generally be assumed that immunoassay methods do not have clinically significant interference from HbE and HbD because the E and D substitution are distant from the N-terminus of the hemoglobin beta chain (16).
Yes/No indicates that there is conflicting data in the literature. The indicator in bold is the opinion of the NGSP based on review of the literature cited.
- Many other publications have been reviewed. Only those with conclusions that are reasonably supported by data are included.
- For ion-exchange HPLC methods, interference from Hb variants and adducts may be dependent on the lot of reagents used (33).
- Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycated hemoglobin. Clin. Chem. 2001;47:153-63. REVIEW
- Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Peterson CM: American Diabetes Association Technical Review on Tests of Glycemia. Diabetes Care 1995;18:896-909.
- Sundaram RC, Selvaraj N, Vijayan G et al.: Increased plasma malondialdehyde and fructosamine in iron deficiency anemia: effect of treatment. Biomed Pharmacother 2007; 61:682-5.
- Tarim O, Kucukerdogan A, Gunay U, Eralp O, Ercan I. Effects of iron deficiency anemia on hemoglobin A1c in type 1 diabetes mellitus. Pediatr Int 1999;41:357-62.
- Coban E, Ozdogan M, Timuragaoglu A: Effect of iron deficiency anemia on the levels of hemoglobin A1c in nondiabetic patients. Acta Haematol 2004;112:126-8.
- Hashimoto K, Noguchi S, Morimoto Y et al.: A1C but not serum glycated albumin is elevated in late pregnancy owing to iron deficiency. Diabetes Care 2008;31:1945-8.
- Selvaraj N, Bobby Z, Sathiyapriya V: Effect of lipid peroxides and antioxidants on glycation of hemoglobin: an in vitro study on human erythrocytes. Clin Chim Acta 2006;366:190-5.
- Peacock TP, Shihabi ZK, Bleyer AJ et al.: Comparison of glycated albumin and hemoglobin A(1c) levels in diabetic subjects on hemodialysis. Kidney Int 2008;73:1062-8.
- Inaba M,Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J am Soc Nephrol 2007;18:896-903.
- Freedman BI, Shenoy RN, Planer JA, Clay KD, Shihabi ZK, Burkart JM, Cardona CY, Andries L, Peacock TP, Sabio H, Byers JR, Russell GB, Bleyer AJ. Comparison of glycated albumin and hemoglobin A1c concentrations in diabetic subjects on peritoneal and hemodialysis. Peritoneal Dialysis International. 2008;30:72-9.
- Freedman BI, Shihabi ZK, Andries L, Cardona CY, Peacock TP, Byers JR, Russell GB, Stratta RJ, Bleyer, AJ. Relationship between assays of glycemia in diabetic subjects with advanced chronic kidney disease. Am J Nephrol 2010;31:375-9.
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- Beckman Coulter, HbA1c (Hemoglobin A1c) product insert
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- Randox Laboratories Ltd, Haemoglobin A1c product insert
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- Siemens Advia, product insert
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