Hemoglobin Variants, Diabetes, and False Positive A1C Levels

Red blood cells, SEM

Hemoglobin and diabetes have an ongoing relationship. Glucose collects on hemoglobin in your red blood cells and stays there for up to three months. The amount of glucose attached to your hemoglobin is tested in the hemoglobin A1c test and reported as the EAG number. That number, however, is affected by more than your average blood sugar, and to understand your levels it's important to understand a few concepts. How are hemoglobin and diabetes related, and when might your A1c test be inaccurate?

What Is Hemoglobin?

Hemoglobin is a protein molecule in your red blood cells that carries oxygen from your lungs to all parts of your body. Nearly all of the oxygen in your blood is carried on hemoglobin, so it is vitally important. It contains iron and it is what makes red blood cells red in color. When you have "iron-poor blood" it is due to not having enough hemoglobin in your red cells.

How Hemoglobin Is Used to Test for Diabetes

When you eat, your body breaks down larger carbohydrates into the glucose or sugar that it uses for energy. It eventually ends up in your bloodstream so that it can be carried to all parts of your body. Some of the sugar that ends up in your bloodstream attaches to the hemoglobin on your red blood cells and stays there for up to three months. Most of your red cells are recycled after four months, so your cells show only the past three month's history.

If you have elevated levels of sugar in your blood, as many people with diabetes do, then more of that sugar will attach to your red blood cells. The higher the concentration of sugar in your blood, the more sugar attaches to your hemoglobin.

Hemoglobin A1c Test

Daily blood glucose testing is critically important in the overall management of diabetes. But, these tests give only a snapshot of the level of glucose in the bloodstream at the time of the test. One hour later, the result may be different. A test called hemoglobin A1c (or glycohemoglobin test) gives a longer view of glucose levels by measuring how much glucose has attached to hemoglobin over the life of the red blood cell, which is about three months. It is considered the gold standard test to understand longer-term glucose levels in the blood and is recommended by the American Diabetes Association. It is also used as a screening test for diabetes.

Hemoglobin Variants Affect the A1C Test

The A1c test is not accurate in people with variant forms of hemoglobin. These tests are designed for people with hemoglobin A, the most common type of hemoglobin. These variant forms of hemoglobin are more common (are inherited) in many people of African, Mediterranean, and Southeast Asian heritage. There are also abnormal forms of hemoglobin A. Normal hemoglobin is made up of two A chains or two B chains. When either of these chains is missing (an inherited condition) the resultant condition is referred to as thalassemia.

Types of hemoglobin include:

  • Hemoglobin S (found with sickle cell trait)
  • Hemoglobin C
  • Hemoglobin E
  • Hemoglobin F - Hemoglobin F is seen during pregnancy, in the fetus and sometimes in the pregnant.
  • Many less common variants such as Hb D or G trait, Hb J, and more
  • Carbamylated hemoglobin (found in people with kidney failure)

Not all variants of hemoglobin lead to health problems, as they do with sickle cell disease, but they can cause false positive results with the A1c test. For example, people who have the sickle cell trait are carriers of sickle cell disease but do not have symptoms of the disease. They will, however, have inaccurate readings on an A1c test.

If you have a hemoglobin variant, chances are that you will get a false positive reading on a HbA1c test telling you and your doctor that your blood sugar is too high, even if it is not. In response to this, your diabetes medications or insulin dose may be increased, to attempt to bring your diabetes under better control. Unfortunately, this increase could result in low blood sugar (hypoglycemia) which can at times be very dangerous and is a medical emergency.

A false positive reading may also make you and your doctor believe you have diabetes even if you do not. Medications or insulin may then be started, which, as above, could result in hypoglycemia. Emotionally, a wrong diagnosis can also be very traumatic, having you believe you have a condition which you don't.

Who Might Have a Hemoglobin Variant? 

Who should be tested to see if they have a hemoglobin variant? People more likely to have a variant hemoglobin include those who:

  • Are of African, Mediterranean, or Southeast Asian heritage
  • Have a family history of someone having a hemoglobin variant
  • If you are surprised by the results of your A1c test (for example, if it is high and your readings have been good)
  • If your A1c reading is extremely high
  • If your A1c readings change significantly with a change in the lab that performs these tests

If you have a hemoglobin variant, you can still have HbA1c tests. Not all tests are affected by hemoglobin variants, and your doctor will need to have your test performed where this is taken into consideration.

In one large study of a multiethnic North American population, 3.77 percent of individuals were found to have a hemoglobin variant. Of these, variants included:

  • HbS (sickle cell trait) - 2.85 percent
  • HbSS (sickle cell disease) - 0.03 percent
  • HbC trait - 0.61 percent
  • HbCC disease - 0.01 percent
  • HbSC - 0.04 percent
  • HbE - 0.13 percent
  • HbD or G trait - 0.6 percent
  • HbS B-thalasemia - 0.1 percent
  • Persistent HbF - 0.01 percent
  • HbMontgomery - 0.01 percent

Alpha thalassemia was also present in 3.82 percent of those with hemoglobin variants.

Other Factors Which May Give False Readings

Since hemoglobin A1c levels are dependent on the red blood cells, anything which interferes with (shortens) the life of red blood cells may cause abnormal results. For example, blood loss due to surgery or heavy menstrual periods or a condition such as hemolytic anemia may result in falsely low readings. Iron deficiency anemia may result in lower readings, whereas iron replacement therapy may result in high levels. If you have had a blood transfusion, your levels may also be inaccurate. Hemoglobin A1c levels can be difficult to interpret in people with kidney failure for a number of reasons.

Bottom Line

The hemoglobin A1c level is very important in determining the average level of blood sugar over a longer period of time. Unfortunately, hemoglobin variants can make this test inaccurate, thereby reducing the accuracy.

If your A1c levels do not seem to be consistent with your daily glucose checks, especially if you are of African, Mediterranean, or Southeast Asian heritage, talk to your doctor about doing a simple blood test to see if you have a hemoglobin variant. Knowing that you have a variant, your doctor can then make sure your blood is tested at a lab which used procedures which are not affected by these variants.

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