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Joslin’s Diabetes Deskbook, A Guide for Primary Care Providers, Updated 2nd Ed., Excerpt 2: Do You Know the Conditions that May Cause Inaccurate Results from the A1C Test?

Mar 23, 2012

By Richard S. Beaser, M.D.



Chapter 3: Monitoring Diabetes
The Importance of Self-Monitoring of Blood Glucose and Glycohemoglobin Measurements
The Glycohemoglobin Measurement (A1C)


One of the functions of the red blood cells is to carry oxygen to the cells throughout the body. Hemoglobin within the red blood cells is the substance that carries this oxygen. The most vital part of the hemoglobin molecule is a fraction called hemoglobin A.

Glucose binds to many molecules through a process referred to as “glycosylation.” When the blood glucose level is elevated, more glycosylation occurs. Within red blood cells, the hemoglobin molecule becomes glycosylated. A small, measurable subfraction of hemoglobin A known as hemoglobin A1 forms when hemoglobin A is glycosylated. A further subfraction of the glycosylated hemoglobin A1 known as the hemoglobin A1c can also be measured. It is this fraction, the hemoglobin A1c, that is now most commonly measured as a reflection of glucose control. These glycosylated hemoglobin molecules are commonly referred to as “glyco-“(for glucose) hemoglobin: “glycohemoglobin.” Technically, the term glycohemoglobin refers to hemoglobin A1, not hemoglobin A1c, although most use this term to refer to this latter measurement as well….

Recently, the ADA recommended shortening the terminology for the HbA1c to just “A1C” although the older terminology is still occasionally used. Both refer to the same entity, hemoglobin A1c. Further, most labs now measure the Hemoglobin A1c, and treatment targets are based on this measurement. Although methodology does still vary, the normal range in most labs for people who do not have diabetes is between 4% and 6% (or values very close to this range), making comparison easier. This number represents the percent of hemoglobin molecules that have been glycosylated. Alternatively, if the normal ranges of two values are quite different, one can calculate the percent above the upper limit of normal to make a crude comparison.

On average, red blood cells live for about 120 days, after which time they die and are removed from the circulation. New red blood cells are manufactured to replace them. At any given time, there are red blood cells that have just been born and those that are about to die. Thus, the average age for all the red blood cells present in the human body at a given time is about 2 months old, or half the total lifespan. Glycosylation occurs continually throughout the life span of the red blood cell. The amount of glycosylation of the hemoglobin depends on the level of blood glucose — the higher the blood glucose level, the more glycosylation will occur. Therefore, the glycosylated hemoglobin or A1C measurement is dependent on the average blood glucose level. As the average age of the total pool of red blood cells is 2 months, the A1C measured represents predominantly the level of control during the previous 2-month period.

The higher the result of the A1C level, the poorer the diabetes control during the past two months. (Tables 2-4, 2-5 and 2-6 in Chapter 2 show various groups’ recommended goals for A1C levels.) As part of routine care, the American Diabetes Association recommends that the A1C level be measured 4 times per year for people with type 1 diabetes, and at least twice per year for those with type 2 diabetes, though more frequent monitoring is helpful to provide feedback to healthcare professionals and patients. The target A1C is less than 7.0%, with anything 7.0% or higher suggesting the need for treatment adjustment (see Chapter 2).

Conditions that May Cause Inaccurate Results

The A1C measurement, like many tests in medicine, is not perfect. People with unusual hemoglobin molecules, such as those with sickle cell anemia, may have invalid test results. It may also be in error in early stages of pregnancy because the fetus produces its own red blood cells. Also, be alert to patients who have recently had transfusions, as some of the hemoglobin that is being measured has not been in them for the requisite period of time. Anemias can render the glycohemoglobin measurement inaccurate as well, as the average age of a red blood cell is usually younger when some cause for premature red cell removal is present. Anything that causes red cells to live longer, such as a splenectomy, can also affect hemoglobin A1C measurement.

With respect to the testing methodology, when HPLC laboratory techniques are used to perform measurements, the number of things that can affect the test results is limited. Using this methodology, the most common factors that can affect A1C measurements are:

  • Hemolytic anemias
  • Carbamylated and acetylated hemoglobins (rare)
  • “Fast” migrating hemoglobins, most commonly hemoglobins D, J, and N, can lower readings
  • Fetal hemoglobin greater than 25% interferes with hemoglobin A1c measurement and cannot be corrected for
  • True beta-thalassemia will interfere with some HPLC methods, but the patient has to be symptomatic at the time for the effect to be significant
  • Severe lipemia in some patients can interfere with measurements. Interference can be reduced by washing red cells and making an offline dilution to report out the A1C value
  • Taking medications such as salicylates can have an effect, though rarely

Despite these limitations, the use of the glycohemoglobin measurement is still a powerful tool! Many studies have correlated the A1C level with the risk of developing complications. Many such complications may even result from the glycosylation of various tissues of the body in a manner similar to the glycosylation of hemoglobin. Thus, the glycosylation of hemoglobin may represent a surrogate of what is occurring to other tissues, and the measurement of glycohemoglobin may actually measure one of the processes that leads to the complications of diabetes.

As noted in Chapter 2, at the time of this writing, a recommendation has been made by an expert international committee that the A1C test be used as the primary approach for diagnosis and screening of diabetes, as fasting is not required for an A1C. The proposed cutoff for diagnosis of diabetes is an A1C > 6.5 %. Readers are advised to monitor the literature, and, if the recommendation is accepted, to read usage guidelines carefully.  

Copyright © 2010 by Joslin Diabetes Center. All rights reserved. Reprinted with permission. Neither this book nor any part thereof may be reproduced or distributed in any form or by any means without permission in writing from Joslin. Note: Joslin does not endorse products or services.

For Excerpt #1 from the Joslin Diabetes Deskbook, 2nd, in this series, just click here.

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