When A1c Isn't Accurate

There are several ways to evaluate someone for possible insulin resistance and the conditions that often accompany it. One of the most common tools is the hemoglobin A1c, more commonly called simply A1c. Let’s review what A1c represents, how it came to be named, and when the number may not tell the full story.

His astute physician recognizes that he has macrocytic anemia and is concerned that his A1c may be falsely low, appearing normal despite underlying issues.

A Brief History of the A1c

Historically, this test was known as hemoglobin A1c. The result is expressed as a percentage, reflecting the amount of glucose attached to red blood cells—hence the word hemoglobin in its original name.

Over time, “hemoglobin” was dropped, and the shorter term A1c became the norm. This change, which took hold in the 1990s–2000s, made the term easier to remember and more relatable for patients as diabetes self-management and education became a major focus in healthcare.

No one should have an A1c of 0%. The lowest reported values ever documented are around 2.8% to 3.3%, depending on the validity of the data. These values are extremely rare and often reflect special conditions or laboratory interference rather than true physiology.

Normal and Abnormal A1c Ranges

• Normal: A1c ≤ 5.6%

• Prediabetes: A1c 5.7%–6.4%

• Type 2 Diabetes Mellitus (T2DM): A1c ≥ 6.5%

These cutoffs are established by the American Diabetes Association (ADA) and are used worldwide to help screen, diagnose, and monitor metabolic health.

Red Blood Cell Size and A1c Accuracy

During residency, I was taught that anemia causes a falsely low A1c because less hemoglobin is available for glucose binding. That’s not entirely accurate. The type and size of the red blood cells (RBCs) matter much more than anemia alone.

On a CBC (complete blood count), the MCV—mean corpuscular volume—reflects the average size of your red blood cells.

• Normal range: 80–99 fL

• Low (<80): Microcytosis (smaller RBCs)

• High (≥100): Macrocytosis (larger RBCs)

Microcytic anemia—in which red blood cells are smaller—can cause a false elevation in A1c.1 Common causes include:

• Iron deficiency

• Anemia of chronic disease (from ongoing inflammation or illness)

• Sideroblastic anemia (e.g., lead poisoning)

• Thalassemia traits (genetic)

These elevations are usually slight and do not typically push results into the prediabetic or diabetic range but can create confusion if A1c is near diagnostic cutoffs.

In contrast, macrocytic anemia—with larger RBCs (MCV ≥100 fL)—can cause a false lowering of A1c.1 Studies have found that if anemia is present and the MCV is >90 fL, A1c may be falsely elevated even though an MCV of 90-99 is still considered normal.1 This type of anemia is most commonly due to:

• Vitamin B12 deficiency

• Folic acid deficiency

• Heavy alcohol consumption

However, this effect is only seen when true anemia (low hemoglobin and/or hematocrit) is present.

For example:

• Someone with normal hemoglobin, an MCV of 95, and an A1c of 5.7% should not assume the A1c is inaccurate.

• But if someone has anemia (low hemoglobin), an MCV of 105, and an A1c of 5.6%, the value may be falsely low, and the anemia should be investigated and treated before assuming that A1c is normal.

Anyone with an A1c near the diagnostic cutoffs for prediabetes or type 2 diabetes who also has any type of anemia should have the anemia evaluated and corrected first. This ensures the A1c reflects true glucose control rather than altered red blood cell physiology.

What About Wayne?

An interesting and very rare finding is Hemoglobin Wayne—a benign hemoglobin variant that can interfere with A1c measurements.2 When present, it can cause falsely elevated A1c results, often in the uncontrolled diabetic range (e.g., ≥10%) even though the person’s fasting glucose and insulin tests are entirely normal.

Hemoglobin Wayne occurs in fewer than 1 in 100,000 individuals and typically appears in family clusters. It is harmless on its own but can lead to major confusion if clinicians rely solely on A1c without corroborating glucose data.

In Summary

• A1c is a valuable marker for assessing average glucose control.

• The term “hemoglobin” was dropped from its name to make it more approachable for patients.

• Red blood cell size and lifespan can influence A1c accuracy.

• Heavy alcohol consumption can result in a falsely low A1c.

• Anemia should be corrected before diagnosing prediabetes or diabetes based solely on A1c or before assuming an A1c near the end of the normal range is in fact normal.

• Rare variants like Hemoglobin Wayne can dramatically distort A1c results.

References:

1. Sakamoto N, Hu H, Nanri A, Mizoue T, Eguchi M, Kochi T, Nakagawa T, Honda T, Yamamoto S, Ogasawara T, Sasaki N, Nishihara A, Imai T, Miyamoto T, Yamamoto M, Okazaki H, Tomita K, Uehara A, Hori A, Shimizu M, Murakami T, Kuwahara K, Fukunaga A, Kabe I, Sone T, Dohi S. Associations of anemia and hemoglobin with hemoglobin A1c among non-diabetic workers in Japan. J Diabetes Investig. 2020 May;11(3):719-725. doi: 10.1111/jdi.13159. Epub 2019 Nov 3. PMID: 31605656; PMCID: PMC7232301.

2. Bejcek A, Wenkert D. Hemoglobin Wayne causing a falsely elevated hemoglobin A1c. Proc (Bayl Univ Med Cent). 2021 Oct 15;35(1):84-85. doi: 10.1080/08998280.2021.1984792. PMID: 34970045; PMCID: PMC8682848.