Falsely Elevated HbA1c in a Patient With Euglycemia

• Research Article
• Florence Awosika
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A 63-year-old White woman presents to an endocrine clinic for evaluation of a glycated hemoglobin A1c (HbA1c) level of 10% in April 2019. The patient has no prior medical history of diabetes, predi

A 63-year-old White woman presents to an endocrine clinic for evaluation of a glycated hemoglobin A1c (HbA1c) level of 10% in April 2019. The patient has no prior medical history of diabetes, prediabetes, or gestational diabetes and is asymptomatic. She is not on any antihyperglycemic agents. The patient is otherwise healthy with no other pertinent medical issues and no past surgical history. There is no family history of diabetes. She is not taking any medications or supplements other than an over-the-counter multivitamin. She denies using alcohol, illicit drugs, or tobacco products. The patient is asymptomatic and the physical examination is normal.

A review of laboratory reports shows a normal HbA1c level of 5.5% at a visit 6 months prior. There are no other HbA1c tests in her medical record and fasting serum glucose levels were always <100 mg/dL.

In June 2019, blood work is ordered and her HbA1c is 9.8%. The measure is repeated 1 month later in July 2019 and remains elevated at 9.8%. A comprehensive laboratory evaluation follows to assess for an underlying cause of her elevated HbA1c. This workup includes the following measurements, all of which are within normal limits: iron, salicylates, lipids, vitamin B12, folate panel, lead, vitamin E, thyroid function, complete blood count with differential, and comprehensive metabolic panel.

A fructosamine level is obtained and shows a result of 220 µmol, which is in the normal range. This measure provides an estimate of long-term glycemic control. Her fructosamine level is equivalent to an HbA1c value of <6%, which is inconsistent with the patient’s HbA1c laboratory value of 10% in November 2019. Hemoglobin electrophoresis/hemoglobin fractionated reveals a possible case of alpha thalassemia.

The patient returns to the clinic with the results of her home blood glucose testing but was only checking the fasting level, which is well within the normal range (<100 mg/dL). As there are no random or postprandial glucose readings and to further evaluate her glycemic patterns the patient agrees to wear a 14-day continuous glucose monitor. The results show that the daily average blood glucose over the 11 days of wear was 99 mg/dL, which indicates an HbA1c of 5.1%.

The patient returns for follow-up 11 months later in October 2020. The continuous glucose monitor test is repeated and shows a similar result with a normal 14-day average blood glucose level (82 mg/dL, indicating an HbA1c of 4.5%); however, her HbA1c remains elevated at 10.2% (Table).

Table 1: Review of HbA1c With Corresponding Fasting Serum Glucose Level

Discussion

Diabetes mellitus remains one of the major causes of illness and death worldwide. The prevalence of diabetes is rising at an alarming rate in the United States. According to the Centers for Disease Control and Prevention National Diabetes Statistics Report for 2020, the prevalence of diabetes in the United States has risen to an estimated 34.2 million people (or 10.5% of the US population).1 In 2018, an estimated 26.8 million adults aged 18 years and older (or 10.2% of the US population) had diagnosed diabetes and approximately 7.3 million people had undiagnosed diabetes.1

In 2017, diabetes was the seventh leading cause of death in the United States.1 Diabetes can affect many parts of the body and is associated with serious complications including heart disease, stroke, blindness, kidney failure, lower-limb amputation, and death.1

The most widely used clinical test to estimate mean blood glucose level is HbA1c measurement. Since its first introduction into clinical use in the 1970s, HbA1c has remained the standard biomarker of long-term glycemic control and its role broadened in 2010 when the American Diabetes Association (ADA) added it as a diagnostic criterion.2,3 In the 2020 ADA guidelines, the diagnostic criteria for diabetes in asymptomatic adults include the following:

• Fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L);
• 2-hour plasma glucose values ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT); or
• A1C value ≥6.5% (48 mmol/mol)

The HbA1c measurement reflects the mean blood glucose over the entire 120-day lifespan of the red blood cell.3,5,6 Because of the integral role of HbA1c in diagnosis and treatment, it is important for clinicians in practice to quickly recognize clinical scenarios and interfering factors that may yield false results. Falsely elevated HbA1c can be detrimental and potentially fatal if insulin is administered in a patient with euglycemia.

A strict quality control program has improved the precision and accuracy of assays in the United States and many international assays. The National Glycohemoglobin Standardization Program (NGSP)’s standardization of HbA1c test results to pivotal trials like the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) established the direct relationship between HbA1c levels and disease outcomes in patients with diabetes.5-8 Although the international standardization of the HbA1c assay has greatly decreased the potential for technical errors in interpreting HbA1c results, biologic and patient-specific factors may cause misleading results.  

Certain hemoglobin variants and conditions have been shown to affect red cell lifespan and hence may lead to false HbA1c results. Conditions linked to falsely elevated HbA1c levels include anemias associated with decreased red blood cell turnover, asplenia, uremia, severe hypertriglyceridemia (>1750 mg/dL), severe hyperbilirubinemia (>20 mg/dL), lead poisoning, and chronic ingestion of alcohol, salicylates, and opioids.3

Conversely, conditions that could lead to a falsely decreased HbA1c include anemia from acute or chronic blood loss, splenomegaly, pregnancy, and red blood cell transfusion. Additionally, ingestion of vitamin E, ribavirin, and interferon-alpha may be associated with falsely lowered HbA1c.3 Hemoglobin variants and vitamin C ingestion can falsely increase or decrease HbA1c depending on method and assay used.3,8,9

As the HbA1c depends on the lifespan and morphology of red blood cells, a hemoglobin fractionation was performed for this patient, which revealed mild alpha thalassemia. Alpha thalassemia is one of the hemoglobin variants that may falsely elevate or reduce HbA1c measurement depending on the method and assay used due to analytical, biochemical, and biologic factors.3

Thus, while the HbA1c is a generally well-accepted parameter used for diagnosis of diabetes mellitus and to estimate the degree of glycemia, there are factors that can falsely increase or decrease the test result. Fortunately, as this patient’s glucose levels were not elevated despite the high HbA1c result, the patient did not receive any oral or injectable antihyperglycemic medications. The use of continuous glucose monitoring devices can make the identification of within-day and between-day glycemic variations easier and allow for identification of falsely elevated HbA1c results such as those presented in this clinical case.

Intensive insulin therapy effectively delays the onset and slows the progression of microvascular complications in patients with diabetes.5,8,10 Although the international standardization of the HbA1c assay has decreased the potential for technical errors in interpreting HbA1c results, other biologic and patient-specific factors may cause misleading results. These factors should continually be kept in mind as falsely elevated HbA1c or lowered HbA1c result could lead to underuse or misuse of antihyperglycemic medications.

1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2020.
2. Bunn HF, Haney DN, Kamin S, Gabbay KH, Gallop PM. The biosynthesis of human hemoglobin A1c. Slow glycosylation of hemoglobin in vivo. J Clin Invest. 1976;57(6):1652-1659. doi:10.1172/JCI108436
3. Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med. 2014;29(2):388-394. doi:10.1007/s11606-013-2595-x
4. American Diabetes Association. Standards of Medical Care in Diabetes – 2020. Accessed March 4, 2020. https://care.diabetesjournals.org/content/43/Supplement_1
5. King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol. 1999;48(5):643-648. doi:10.1046/j.1365-2125.1999.00092.x
6. National Glycohemoglobin Standardization Program (NGSP). HbA1c and Estimated Average Glucose (eAG). Accessed March 3, 2021. http://www.ngsp.org/A1ceAG.asp
7. Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37(1):9-16. doi:10.2337/dc13-2112
8. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86. doi:10.1056/NEJM199309303291401.
9. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ; A1c-Derived Average Glucose Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31(8):1473-1478. doi:10.2337/dc08-0545
10. Nathan DM, Bayless M, Cleary P, Genuth S, Gubitosi-Klug R, Lachin JM, Lorenzi G, Zinman B; DCCT/EDIC Research Group. Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes. 2013;62(12):3976-3986. doi:10.2337/db13-1093