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Diabetes Discoveries & Practice Blog

Interpreting A1C: Diabetes and Hemoglobin Variants

Lab technician with a blood sample

Randie R. Little, PhD, explains what health care professionals need to know about factors that can interfere with A1C test results.

Health care professionals may use the A1C test to diagnose and manage patients with diabetes, but what are some factors that can affect the reliability and interpretation of A1C? In the second post of our Interpreting A1C blog series, Randie R. Little, PhD, discusses how hemoglobin variants can give falsely high or low readings with A1C testing methods, and how this can lead to the over-treatment or under-treatment of diabetes.

Q: What are hemoglobin variants and how can they affect the reliability of the A1C test used to diagnose and manage diabetes?

A: Normal human hemoglobin is made up of about 98% hemoglobin A (HbA). Some people have both HbA and another kind of Hb, such as hemoglobin S, C, D or E. These less common forms of hemoglobin are called hemoglobin variants, or hemoglobinopathies.

Some hemoglobin variants can affect some HbA1c methods, but not all of them. For instance, certain variants can cause falsely high or low A1C test results depending on the method used. The A1C blood test, also called the hemoglobin A1C test, HbA1c, or glycated hemoglobin test, reflects a person’s average blood glucose levels for the past 3 months.

Q: What are some common types of hemoglobinopathies?

A: There are hundreds of hemoglobin variants, but there are four that are the most common:

  • hemoglobin S (HbS or Sickle Cell);
  • hemoglobin E (HbE);
  • hemoglobin C (HbC); and
  • hemoglobin D (HbD).

S, E, C, and D is the order of worldwide prevalence, so sickle cell (S) is the most common hemoglobin variant. It’s easy to detect these if you test for them, but they are not usually tested because we see these variants in the heterozygous form. For example, with sickle cell trait (heterozygous HbS or HbAS), there is HbS and there is also HbA, so less than half of the hemoglobin is the variant. In this scenario, you have no disease and there is no reason to test for the variant, so you don’t always know that they are there in the heterozygous form.

About 7% of the world’s population has some heterozygous variant. Many of these people also have diabetes, so that’s why hemoglobin variants are discussed so much with regard to hemoglobin A1C testing.

Q: How would a health care professional know if their patient with diabetes has a hemoglobin variant?

A: Normally, health care professionals wouldn’t know if their patient has a hemoglobinopathy. The trait, which is what you see most commonly where a person has some hemoglobin A and some of the variant, is clinically silent. There’s no disease. There’s no reason to suspect that this person has a hemoglobin variant.

Some hemoglobinopathies (e.g. HbAS) are detected during pregnancy screening. For example, if two people suspect that they might have a hemoglobin variant, they might get tested to see if both have the trait, then there’s a chance that their baby will have, for example, sickle cell disease (HbSS).

More recently, variants have been identified during A1C testing for diabetes. But most people don’t know that they have a hemoglobin variant. Some hemoglobin variants are more common in different races, and in different parts of the world. For instance, a person might be more likely to have one of these Hb variants if they are of African, Mediterranean, or Asian heritage.

Q: What should health care professionals understand when it comes to interpreting “statistically” or “clinically” significant differences in A1C?

A: Health care professionals need to understand that they have to be careful about how they interpret very small differences or changes in hemoglobin A1C. They often don’t realize that every assay method has a certain degree of variability. On top of that, there can also be interferences with different methods in certain individuals. This isn’t just for hemoglobin A1C; this is for every laboratory test.

The NGSP (originally called the National Glycohemoglobin Standardization Program) provides a list of methods most often used to measure A1C and whether the method is affected by HbC, HbS, HbE or HbD trait, or by elevated fetal hemoglobin (HbF).

There is always a degree of variability and a possibility of interferences. Any time there is a discrepancy between an A1C result and the clinical impression based on other tests, health care professionals should verify the accuracy of the results. Doctors or patients interested in getting information about the accuracy of a particular A1C method for patients with hemoglobin variants should first find out which method their laboratory is using.

Q: Can other conditions also affect A1C test results?

A: There are several conditions that can affect A1C results because hemoglobin A1C is dependent on both the glucose levels over the last 2 to 3 months and the lifespan of the red blood cell. This is because glucose accumulates on hemoglobin as the red blood cells circulate. Red blood cells have a finite lifespan in the circulation. It’s not exactly the same for every person, but it’s close; there’s a certain degree of variability. In certain conditions – certain anemias or types of anemia, Sickle Cell (HbSS) or HbC (HbCC) disease, significant kidney disease, or liver failure – the red blood cell lifespan can be altered.

Q: What are your thoughts about point-of-care devices and A1C?

A: There are many point-of-care (POC) devices available worldwide and sold in the U.S. Many are NGSP-certified (PDF, 239.2 KB) , meaning that under ideal conditions – and in the hands of manufacturers – they perform with a high degree of accuracy and precision. Some of them can be as accurate as some lab methods.

The American Diabetes Association (ADA) states that POC testing provides an opportunity for more timely treatment changes because clinicians can get the results at the time of the visit. So, it’s certainly more convenient and it may help with routine diabetes care.

However, the ADA does not recommend POC for diagnosis because POC methods are generally categorized as waived tests – CLIA Waived category. What this means is that, unlike laboratory tests, CLIA Waived settings have much lower testing standards. The person performing the test can have very little education and training, and there is no oversight in terms of inspection of these sites or proficiency testing. In contrast, laboratories are required to participate in proficiency testing, meaning the labs are running samples three times a year to see if the results are accurate. That’s the biggest concern with POC.

Many of the POC methods are NGSP-certified, but because they are also CLIA Waived, they are often not performed in the same controlled setting as is done in a laboratory or for NGSP certification. I believe that’s why the ADA is hesitant to recommend these tests for diagnosis, and health care professionals should know that they should not be using these devices for diagnosis.

Q: What do health care professionals need to know when it comes to understanding or interpreting A1C?

A: I think the most important thing is that any test result – and A1C specifically – needs to be reviewed in the context of the whole patient. That includes the clinical impression and laboratory test results. For example, if a patient’s home glucose testing or continuous glucose test results indicate a certain average glucose, and that doesn’t correspond with the laboratory A1C results, then there might be some problem with one or the other test. This is important to investigate, and clinicians need to know that they can consult with their lab to find out what test the lab is using, what interferences may be associated with the test, and if there could be interferences in your particular patient.

What factors do you consider when selecting an assay method for HbA1c?

Stay tuned for the next and final post in this series, which discusses A1C and variability across ethnic and racial populations.


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