HbA1c is the imperfect diagnosis of diabetes

HbA1c is the imperfect diagnosis of diabetes

When diabetes is not controlled, higher percentages of hemoglobin become glycosylated, causing elevated HbA1c and glucose levels to rise within the body.

Purpose of HbA1c as a clinical marker of diabetes

Hemoglobin A1c (HbA1c) is an accepted measure for both the diagnosis and chronic treatment of diabetes.1 Hemoglobin is the protein responsible for transporting oxygen throughout the body.

HbA1c assesses the percentage of hemoglobin proteins that are glycosylated, which is a direct measure of how well controlled glucose levels are within the body.1 If insulin is not properly released in response to rising glucose levels, complications involving both the macrovascular and microvascular systems can occur.

When diabetes is not controlled, higher percentages of hemoglobin become glycosylated, causing elevated HbA1c and glucose levels to rise within the body, leading to the aforementioned complications.1.2

HbA1c can measure trends in glycosylated hemoglobin over the previous 3 months because the average lifespan of a red blood cell (RBC) is approximately 90 to 120 days.1 Although this lab test can be helpful in evaluating diabetes control, it is also important to be aware of conditions that may affect these readings.

Conditions Affecting HbA1c Values

There are some conditions that could cause an increase in HbA1c levels despite a patient’s blood glucose levels (BGL) being well controlled. Some of the more common conditions are described in Table 1. One of them is iron deficiency anemia which leads to a decrease in the production of red blood cells.3.4

Table 1: Conditions that cause falsely inflated HbA1c.5

As production declines, the average age of red blood cells increases, leading to higher levels of HbA1c (Figure 1). In general, any condition that increases the lifespan of a red blood cell can cause a falsely elevated HbA1c value.

Figure 1: Iron deficiency anemia and mechanism of HbA1c.

In addition, there are conditions that can decrease the lifespan of a red blood cell, leading to an imprecise decrease in the HbA1c value. Conditions that can falsely lower the HbA1c value are described in Table 2.

Table 2: Conditions that cause falsely low HbA1c.5

*Low HbA1c values ​​are expected during the second trimester, but may increase during the third trimester

**More common to raise than lower HbA1c

Keep in mind that red blood cell transfusions can raise or lower HbA1c values. The change in HbA1c values ​​depends on the donor’s blood glucose levels, as they can have a diluting or concentrating effect. Higher HbA1c values ​​are seen more often as most blood transfusions are stored in dextrose solutions.6

Alternative Methods for Assessing Glucose Control

Alternative laboratories may be considered for cases where the accuracy of HbA1c is in question; one option includes fructosamine. This is a measure of circulating proteins such as albumin, globulins, and lipoproteins that have become glycated over the previous 7 to 21 days (Figure 2).7

Figure 2. Glycosylated albumin as a measure of fructosamine.

Ultimately, albumin will play the largest role in this value because it is the most abundant protein circulating throughout the body. Albumin levels can be affected by multiple conditions, including nephrotic syndrome, advanced liver disease, and thyroid disease, adding complexity when considering the use of fructosamine as a marker of diabetes control.8

Furthermore, there is no clear equation for the interpretation of fructosamine in relation to HbA1c. Situations where it would be reasonable to measure a fructosamine level include discordant blood glucose and AbA1c levels, when it is not feasible to wait 3 months to measure HbA1c, or if the HbA1c value is suspected to be inaccurate.

Under the 2022 ADA and 2017 AACE guidelines, there are limitations to fructosamine, such as a lack of specific guidance on when or how to use it in diabetes.9.10

How to proceed in case of inaccurate HbA1c

If inaccurate HbA1c is suspected, it would be reasonable to consider relying on blood glucose levels or continuous glucose monitor (CGM) data to guide diabetes therapeutic adjustments. Before relying entirely on blood glucose values, consider ensuring that the patient’s fingerstick meter provides accurate readings by using control solution.

An additional HbA1c value can be obtained in 3 months, time permitting, and if it still seems inaccurate, then consider using CGM data, glucose levels, or fructosamine.5.11

Although the exact deviations from actual HbA1c values ​​for each of these conditions are unknown, clinical judgment should be used to assess whether there are discrepancies in patients’ HbA1c and other clinical signs of diabetes control.

Author: Micaela Den Hartog, PharmD Candidate, University of Minnesota, Class of 2023
Preceptor: Kristina Thurber, PharmD, clinical pharmacist, Mayo Clinic Division of Community Internal Medicine

References

  1. Eyth E, Naik R. Hemoglobin A1C. [Updated 2022 Mar 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK549816/
  2. Sherwani SI, Khan HA, Ekhzaimy A, Masood A, Sakharkar MK. Importance of the HbA1c test in the diagnosis and prognosis of diabetic patients. Biomark Perspectives. July 3, 2016; 11:95-104. doi: 10.4137/IMC.S38440. PMID: 27398023; PMID: PMC4933534.
  3. Mehdi U, Toto RD. Anemia, diabetes and chronic kidney disease. Diabetes care. 2009 July; 32 (7): 1320-6. doi: 10.2337/dc08-0779. PMID: 19564475; PMCID: PMC2699743.
  4. “Diabetes and Chronic Kidney Disease”. Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, May 7, 2021, https://www.cdc.gov/diabetes/managing/diabetes-kidney-disease.html.
  5. Radin, Michael S. “Hemoglobin A1c Pitfalls: When Results Can Be Misleading.” Journal of General Internal Medicine Vol. 29.2 (2014): 388-94. doi:10.1007/s11606-013-2595-x
  6. Sugimoto, Takeshi et al. “HbA1c alterations derived from autologous blood donation for elective surgery in patients with diabetes mellitus”. Blood transfusion = Trasfusione del sangue vol. 12 Supplement 1, Supplement 1 (2014): s209-13. doi:10.2450/2013.0271-12
  7. Gounden V, Ngu M, Anastasopoulou C, et al. Fructosamine. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK470185/
  8. Danese, Elisa et al. “Advantages and dangers of fructosamine and glycosylated albumin in the diagnosis and treatment of diabetes”. Journal of diabetes science and technology vol. 9.2 (2015): 169-76. doi:10.1177/1932296814567227
  9. Professional Practice Committee of the American Diabetes Association et al. “16. Diabetes Care in Hospital: Standards of Medical Care in Diabetes-2022.” Diabetes Care Vol. 45, Supplement 1 (2022): S244-S253. doi:10.2337/dc22-S016
  10. Rodbard, Helena W et al. “American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus.” Endocrine Practice: Official Publication of the American College of Endocrinology and the American Association of Clinical Endocrinologists Vol. 13 Supplement 1 (2007): 1-68. doi:10.4158/EP.13.S1.1
  11. Henderson, Wendy O et al. “How should you assess glycemic control if hemoglobin A1c is inaccurate or cannot be interpreted?” Cleveland Clinic Journal of Medicine Vol. 88.2 81-85. February 1, 2021, doi:10.3949/ccjm.88a.19135

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