A 55-year-old man comes to the office to establish care after relocating to the area. The patient has a 6-year history of type 2 diabetes mellitus for which he takes metformin monotherapy. He feels well and has no other medical conditions. The patient does not use tobacco or alcohol. He consumes a balanced diet and jogs for 40 minutes every morning. Review of his blood glucose journal over the last few months shows fasting glucose levels of 150-180 mg/dL. Laboratory analysis shows a hemoglobin A1c level of 4%. Further evaluation with hemoglobin electrophoresis shows a hemoglobin A2 level of 7.5% (normal: 1.5%-3.5%). Which of the following is the most likely explanation for this patient's lower-than-expected hemoglobin A1c level?

Question

A 55-year-old man comes to the office to establish care after relocating to the area.  The patient has a 6-year history of type 2 diabetes mellitus for which he takes metformin monotherapy.  He feels well and has no other medical conditions.  The patient does not use tobacco or alcohol.  He consumes a balanced diet and jogs for 40 minutes every morning.  Review of his blood glucose journal over the last few months shows fasting glucose levels of 150-180 mg/dL.  Laboratory analysis shows a hemoglobin A1c level of 4%.  Further evaluation with hemoglobin electrophoresis shows a hemoglobin A2 level of 7.5% (normal: 1.5%-3.5%).  Which of the following is the most likely explanation for this patient's lower-than-expected hemoglobin A1c level?

Quizplus · Accepted Answer

Hemoglobin A1c is produced by irreversible nonenzymatic glycosylation of the N-terminal of the hemoglobin molecule. The degree of glycosylation (ie, hemoglobin A1c level) directly correlates with average blood glucose levels over the life span of circulating erythrocytes, which is normally approximately 3 months. Higher glucose levels and increased exposure time of red cells to glucose increase hemoglobin A1c values. As such, conditions that alter red blood cell survival time also affect hemoglobin A1c levels. This patient has an elevated hemoglobin A2, which suggests comorbid beta-thalassemia minor. Hemoglobin A2 is elevated in beta-thalassemia to compensate for beta-globin-chain underproduction, but results in microcytic red cells that are prone to hemolysis. Increased erythrocyte turnover results in a misleadingly low hemoglobin A1c level. In such cases, measurement of glycated serum proteins (ie, fructosamine) is sometimes used to estimate glycemic control. (Choices B and C) Deficiencies of iron, folate, and vitamin B₁₂ can reduce production of new red cells, leading to a preponderance of older erythrocytes and falsely elevated hemoglobin A1c. In contrast, treatment of vitamin deficiencies causes young red cells to be rapidly released into circulation, falsely lowering hemoglobin A1c. (Choice D) Advanced diabetic nephropathy may cause reduced erythropoietin production. The resulting decrease in production of new red cells may lead to falsely high hemoglobin A1c (similar to nutrient deficiencies). (Choice E) Chronically elevated blood glucose (ie, poor glycemic control) is the primary cause of increased hemoglobin A1c in patients with diabetes. (Choice F) Sickle cell trait is characterized by heterozygous carriage of hemoglobin S. Some patients with sickle cell trait can have slightly reduced hemoglobin A1c level due to increased red cell turnover (homozygous individuals with sickle cell disease have rapid red cell turnover and very low A1c). However, hemoglobin A2 percentage remains near normal in patients with sickle cell mutations. Educational objective: Hemoglobin A1c is produced by nonenzymatic glycosylation of the hemoglobin molecule. A hemoglobin A1c assay provides an estimate of chronic glycemic control over the life span of circulating erythrocytes (~3 months). However, rapid erythrocyte turnover (eg, hemolytic anemia) can give a misleadingly low hemoglobin A1c in relation to glycemic status. __________ References: Limitations of A1c interpretation. (http://www.ncbi.nlm.nih.gov/pubmed/26630892)

A 55-Year-Old Man Comes to the Office to Establish Care