Euglycemia: Clinical Relevance/Discussion

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


Continue Reading

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.

Conclusion

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.

Florence O. Awosika, DNP, FNP-BC, CDCES, is an endocrinology nurse practitioner provider at the Walter Reed National Military Medical Center in Bethesda, Maryland.

References

  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