Pearls of Wisdom: Elevated A1c With Well-Managed Fasting Glucose
Mary, a 52-year-old obese woman, has been treated for type 2 diabetes for 7 years.
In addition to diet and exercise, her treatment regimen includes appropriate doses of metformin, a sulfonylurea, pioglitazone, and insulin glargine. Her fasting glucose level has ranged from 110 to 140 mg/dL, according to the log on her portable glucometer.
She calibrates her glucometer at home with a control solution, and you have compared her office random glucose level (145 mg/dL) with that of her personal device (150 mg/dL). She doesn’t routinely check her postprandial or bedtime glucose level, but when she does, it is never more than 200 mg/dL. You check her hemoglobin A1c level in the office today, and it is 13.5%.
What is the explanation for Mary's markedly elevated hemoglobin A1c despite that her fasting blood glucose level (according to her glucometer) has been well managed?
A. She is having marked evening or overnight glucose elevations that have been missed, since she doesn’t routinely check at those times.
B. Her glucometer is broken.
C. She doesn’t know how to properly read her glucometer (eg, the units might be set to mmol/L instead of mg/dL).
D. She has a hemoglobinopathy.
What is the correct answer?
(Answer and discussion on next page)
Louis Kuritzky, MD, has been involved in medical education since the 1970s. Drawing upon years of clinical experience, he has crafted each year for almost 3 decades a collection of items that are often underappreciated by clinicians, yet important for patients. These “Pearls of Wisdom” often highlight studies that may not have gotten traction within the clinical community and/or may have been overlooked since their time of publishing, but warrant a second look.
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Answer: She has a hemoglobinopathy
When glucose monitoring results are discordant with hemoglobin A1c results, only a few explanations. Sometimes, the device itself is faulty, but this patient has had her technique reviewed, she calibrates her device, and the results of a random glucose test in the office and the results on her device are comparable. Had the glucometer been set to read in millimoles instead of milligrams, the numbers would have been much lower, since 1 mmol of glucose equals approximately 18.5 mg. Hence, if the device were inappropriately set to mmol/L, a glucose reading of 110 to 140 in the mornings would actually be equivalent to 2035 to 2590 mg/dL—not a likely scenario.
Although marked overnight glucose excursions would be a possible explanation, they would have to be quite dramatic to result in this much of an elevation of hemoglobin A1c. And even if that were the case, what could explain how the overnight hyperglycemia magically disappears by morning?
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Instead, hemoglobinopathy is the explanation, as described in an unusual article published in 2000.1
Adult Hemoglobin
Normal adult hemoglobin is constituted of hemoglobin A (96%), hemoglobin A2 (2%-3%), and hemoglobin F (also called fetal hemoglobin, 2%). Although hemoglobin F is the predominant form of hemoglobin at birth, it declines by about 3% to 4% per week such that hemoglobin F should comprise less than 2% of total hemoglobin by age 6 months.
High levels of hemoglobin F are seen in hemoglobinopathies, multiple myeloma, leukemia, anemia, and hereditary persistence of fetal hemoglobin (HPFH). Persons with homozygous HPFH have 100% hemoglobin F; heterozygotes have as much as 7% hemoglobin F.
Case Study
An example case in the article describes a 61-year-old woman with type 2 diabetes whose fasting glucose level consistently measured less than 110 mg/dL. Despite good fasting glucose control, her hemoglobin A1c level was 17.5%. Hemoglobin electrophoresis test results showed a hemoglobin F level of 7%, confirming a diagnosis of heterozygous HPFH.
Since hemoglobin A1c is not a useful measure of diabetes control in persons with HPFH, clinicians must rely on either simply measuring fasting and postprandial glucose levels or using a method that measures more short-term hyperglycemia, such as fructosamine testing. In this patient, despite a hemoglobin A1c level of 17.5%, the fructosamine level was normal, confirming the aberrant effect of hemoglobin F that resulted in a spurious hemoglobin A1c elevation.
What’s the "Take Home"?
Because hemoglobin F glycosylates very rapidly and co-elutes with hemoglobin A (the hemoglobin we measure when monitoring hemoglobin A1c for diabetes management), it markedly elevates glycosylated hemoglobin (hemoglobin A1c) if present in meaningful amounts.
Reference:
1. Egede LE, Obah E, Lorch T, Oussova T. Spurious elevation of hemoglobin A1c by hereditary persistence of fetal hemoglobin. South Med J. 2000;93(1):62-64.