A1C Versus Glucose Testing: A Comparison

DAVID B. SACKS 0 MB 0 CHB 0 FRCPATH 0 0 From the Department of Laboratory Medicine, National Institutes of Health , Bethesda, Maryland iabetes was originally identified by the use of A1C for diagnosis of diabetes D the presence of glucose in the urine. (4), a position that has been endorsed Almost 2,500 years ago it was (at the time of writing) by the American noticed that ants were attracted to the Diabetes Association (ADA) (1), the Enurine of some individuals. In the 18th docrine Society, and in a more limited and 19th centuries the sweet taste of urine fashion by American Association of Clinwas used for diagnosis before chemical ical Endocrinologists/American College methods became available to detect sugars of Endocrinology (5). This review will in the urine. Tests to measure glucose in the provide an overview of the factors that blood were developed over 100 years ago, influence glucose and A1C testing. and hyperglycemia subsequently became the sole criterion recommended for the FACTORS CONTRIBUTING TO diagnosis of diabetes. Initial diagnostic VARIATION IN RESULTS-Before criteria relied on the response to an oral addressing glucose and A1C, it is imporglucose challenge, while later measure- tant to consider the factors that impact the ment of blood glucose in an individual results of any blood test. While laboratory who was fasting also became acceptable. medicine journals have devoted some The most widely accepted glucose-based discussion to the sources of variability in criteria for diagnosis are fasting plasma results of blood tests, this topic has glucose (FPG) $126 mg/dL or a 2-h received little attention in the clinical plasma glucose $200 mg/dL during an literature. Factors that contribute to varoral glucose tolerance test (OGTT) on iation can conveniently be divided into more than one occasion (1,2). In a patient three categories, namely biological, prewith classic symptoms of diabetes, a sin- analytical, and analytical. Biological varigle random plasma glucose $200 mg/dL ation comprises both differences within is considered diagnostic (1). Before 2010 a single person (termed intraindividual) virtually all diabetes societies recom- and between two or more people (termed mended blood glucose analysis as the interindividual). Preanalytical issues perexclusive method to diagnose diabetes. tain to the specimen before it is measured. Notwithstanding these guidelines, over Analytical differences result from the the last few years many physicians have measurement procedure itself. The inbeen using hemoglobin A1C to screen for fluence of these factors on both glucose and diagnose diabetes (3). Although con- and A1C results will be addressed in more sidered the gold standard for diagnosis, detail below. measurement of glucose in the blood is subject to several limitations, many of GLUCOSE MEASUREMENT which are not widely appreciated. Measurement of A1C for diagnosis is appeal- FPG ing but has some inherent limitations. Measurement of glucose in plasma of These issues have become the focus of con- fasting subjects is widely accepted as a siderable attention with the recent publi- diagnostic criterion for diabetes (1,2). Adcation of the Report of the International vantages include inexpensive assays on Expert Committee that recommended automated instruments that are available c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c - in most laboratories worldwide (Table 1). Nevertheless, FPG is subject to some limitations. One report that analyzed repeated measurements from 685 fasting participants without diagnosed diabetes from the Third National Health and Nutrition Examination Survey (NHANES III) revealed that only 70.4% of people with FPG $126 mg/dL on the first test had FPG $126 mg/dL when analysis was repeated ;2 weeks later (6). Numerous factors may contribute to this lack of reproducibility. These are elaborated below. Biological variation. Fasting glucose concentrations vary considerably both in a single person from day to day and also between different subjects. Intraindividual variation in a healthy person is reported to be 5.78.3%, whereas interindividual variation of up to 12.5% has been observed (6,7). Based on a CV (coefficient of variation) of 5.7%, FPG can range from 112140 mg/dL in an individual with an FPG of 126 mg/dL. (It is important to realize that these values encompass the 95% confidence interval, and 5% of values will be outside this range.) Preanalytical variation. Numerous factors that occur before a sample is measured can influence results of blood tests. Examples include medications, venous stasis, posture, and sample handling. The concentration of glucose in the blood can be altered by food ingestion, prolonged fasting, or exercise (8). It is also important that measurements are performed in subjects in the absence of intercurrent illness, which frequently produces transient hyperglycemia (9). Similarly, acute stress (e.g., not being able to find parking or having to wait) can alter blood glucose concentrations. Samples for fasting glucose analysis should be drawn after an overnight fast (no caloric ingestion for at least 8 h), during which time the subject may consume water ad lib (10). The requirement that the subject be fasting is a considerable practical problem as patients are usually not fasting when they visit the doctor, and it is often inconvenient to return for phlebotomy. For example, at an HMO affiliated with an academic medical center, 69% (5,752 of 8,286) of eligible participants were screened for diabetes (11). Table 1FPG for the diagnosis of diabetes However, FPG was performed on only 3% (152) of these individuals. Ninety-five percent (5,452) of participants were screened by random plasma glucose measurements, a technique not consistent with ADA recommendations. In addition, blood drawn in the morning as FPG has a diurnal variation. Analysis of 12,882 participants aged 20 years or older in NHANES III who had no previously diagnosed diabetes revealed that mean FPG in the morning was considerably higher than in the afternoon (12). Prevalence of diabetes (FPG $126 mg/dL) in afternoon-examined patients was half that of participants examined in the morning. Other patient-related factors that can influence the results include food ingestion when supposed to be fasting and hypocaloric diet for a week or more prior to testing. Glucose concentrations decrease in the test tube by 57% per hour due to glycolysis (13). Therefore, a sample with a true blood glucose value of 126 mg/dL would have a glucose concentration of ;110 mg/dL after 2 h at room temperature. Samples with increased concentrations of erythrocytes, white blood cells, or platelets have even greater rates of glycolysis. A common misconception is that sodium fluoride, an inhibitor of glycolysis, prevents glucose consumption. While fluoride does attenuate in vitro glycolysis, it has no effect on the rate of decline (...truncated)