When the A1c is Unreliable
Although hemoglobin A1c is usually the best test to estimate the average glycemic control in patients with diabetes, it is unreliable in some clinical circumstances. In select patient populations, measuring fructosamine and glycated albumin levels may also be useful.
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What is the A1c and why is it important?
A: A1c represents the percent of hemoglobin A with glucose bound to it. While the percent is normally low, in diabetics the higher glucose circulating in the blood causes more hemoglobin binding which results in a higher A1c level. It also can correlate with average glycemic control during the past 2 to 3 months. The American Diabetes Association recommends measuring A1c—≥ 6.5% (48mmol/mol)—as a diagnostic criterion for diabetes and quantifying A1c as the standard laboratory assessment to determine control of type 1 and type 2 diabetes.1 Since the publication of the Diabetes Control and Complications Trial in 1993, we know that A1c levels also directly correlate to the risk of developing diabetic complications such as retinopathy, neuropathy and nephropathy.2
When is the A1c unreliable?
A: For A1c standard test results to be reliable, normal adult hemoglobin A must be present for glucose binding. However, a number of clinically significant disorders alter hemoglobin either structurally or chemically thereby affecting the reliability of the A1c test (Table). These disorders can affect reliability in three ways: 1) altering the normal process by which hemoglobin A is glycosylated to A1c, 2) making the red blood cells more prone to breakdown so there is less time for glycosylation, or 3) causing an abnormal peak in the chromatography so that the estimation of A1c is unreliable.3
Several factors and comorbidities can affect the A1c independent of the plasma glucose concentration. To date, there are more than 700 disorders with abnormal hemoglobin, therefore, alternate forms of glucose monitoring should be considered in these conditions.3
For example, thalassemia, with Hb S-beta(+) instead of HbA, can shorten the erythrocyte lifespan, or sickle cell disease with HbF can lead to assay artifact, both making the A1c unreliable. However, other comorbidities can cause this same interference. Spherocytosis, acute blood loss, or hypersplenism can cause a shortened lifespan of red blood cells. Aspirin ingestion and chronic kidney disease both chemically alter hemoglobin and cause unreliable A1c results. Patients with HIV who receive antiretroviral therapy, those who receive vitamin E and C supplementation, and those with chronic liver disease will also have artificially lower A1c levels. Diseases such as hypertriglyceridemia and hyperbilirubinemia, or individuals of Afro-Caribbean ethnicity, can have artificially elevated A1c levels.4
Finally, studies show that patients receiving a large number of blood transfusions (eg, hemochromatosis) will have artificially high A1c levels because the donor blood was stored in a dextrose solution. This makes the A1c unreliable for 3 months following a blood transfusion.5
What is fructosamine and can it be used as an alternate to A1c testing?
A: Fructosamine is made when a protein, usually albumin, has a chemical reaction with glucose. After this chemical reaction, it undergoes another chemical change to distinguish it from other glycoproteins. Because glycation occurs during the entire life span of proteins, the amount of glycosylated protein reflects the average available quantity of blood glucose during this period. Its creation is dependent on serum protein glycation (instead of hemoglobin), so the results are unaffected by the presence of hemoglobinopathy. It is a measurement of the average blood glucose concentration for the past 2-3 weeks. Several clinical trials in patients with known hemoglobinopathies have shown a direct correlation between fructosamine and fasting blood sugar values.6,7
Fructosamine, like plasma glucose, reflects the physiology of glucose in the extracellular space; A1c reflects nonenzymatic glycation in the intracellular erythrocyte compartment. The difference between a measured A1c and the predicted A1c based on fructosamine is known as the glycation gap (GG). Some trials have shown that the GG statistically correlates to major complications of diabetic nephropathy, more strongly than just A1c alone.8
Unfortunately, fructosamine tests are not currently standardized and there are no definitive criteria to use the levels for diagnosis or titration of diabetes.
What is glycated albumin and can it be used as an alternate to A1c testing?
A: Glycated albumin, like fructosamine, is made when glucose interacts with albumin in the blood, but does not undergo the second chemical reaction that is required to make fructosamine. Glycated albumin reflects the average blood sugar for a 2-3 week period. There are many clinical studies that show its reliability in diagnosing diabetes and titrating therapy, especially in patients with chronic kidney disease on hemodialysis. If patients are on dialysis and/or receiving erythropoietin injections, the high hemoglobin turnover leads to significantly unreliable A1c. However, in those patients, glycated albumin was not affected by either the dialysis or the injections and it independently correlated with blood glucose concentrations.9
There are several limiting factors to the generalized use of glycated albumin. First, nephrotic patients can have a significant amount of proteinuria; therefore, it is important to use an enzymatic assay that relies on albumin-specific proteinase, which is independent of changes in albumin concentrations, instead of the more traditional HPLC assay that is more readily available. Second, although a glycated albumin level of ≥ 15.5% has been proposed as a great predictor for the diagnosis of diabetes, there are no definitive criteria yet available for the diagnosis or titration of diabetes.10 ■
1.American Diabetes Association. Standards of medical care in diabetes—2007 [Position Statement]. Diabetes Care. 2007;30 (Suppl. 1):S4-S41.
2.The DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
3.Smaldone A. Glycemic control and hemoglobinopathy: when A1C may not be reliable. Diabetes Spectrum. 2008;21:46-49.
4.Malkani S, DeSilva T. Controversies on how diabetes in diagnosed. Curr Opin Endocrinol Diabetes Obes. 2012;19:97-103.
5.Weinblatt ME, Kochen JA, Scimeca PG. Chronically transfused patients with increased hemoglobin A1C secondary to donor blood. Ann Clin Lab Sci. 1986;16:34-7.
6.Kosaryan M, Mahdavi MR, Aliasgharian A, et al. Credibility of measurement of fructosamine and hemoglobin A1C in estimating blood glucose level and diabetic patients with thalassemia major. Open J Hematol. 2012;3:1-7.
7.Guillausseau PJ, Charles MA, Goadard V, et al. Comparison of fructosamine with glycated hemoglobin as an index of glycemic control in diabetic patients. Diabetes Res. 1990;13:127-131.
8.Cohen RM, Holmes YR, Chenier TC, et al. Discordance between HbA1C and fructosamine. Diabetes Care. 2003;26:163-167.
9.Peacock TP, Shihabi ZK, Bleyer AJ, et al. Comparison of glycated albumin and hemoglobin A1C levels in diabetic subjects on hemodialysis. Kidney Int. 2008;73:1062-1068.
10.Furusyo N, Koga T, Ai M, et al. Utility of glycated albumin for the diagnosis of diabetes mellitus in a Japanese population study: results from the Kyusu and Okinawa Population Study (KOPS). Diabetologia. 2011;54:3028-3036.
11.Harmonizing Hemoglobin A1c Testing. National Glycohemoglobin Standarization Program. Available at www.ngsp.org. Accessed September 2013.
Neena A. Xavier, MD is a fellow in the Department of Internal Medicine, Division of Endocrinology, Metabolism, and Lipid Research at Washington University School of Medicine in St Louis, MO.
Kim A. Carmichael, MD is associate professor of medicine at the Department of Internal Medicine, Division of Endocrinology, Metabolism, and Lipid Research at Washington University School of Medicine in St. Louis, MO.