A few months ago, I was contacted by an endocrinologist who had a patient referred to her for a low hemoglobin A1c. The result was so low, in fact, that it was below the measurement range of the HPLC analyzer: <3.8%! She wasn’t sure if she should believe the result and asked me to verify the accuracy. After repeating the sample, I pulled historic data and discovered that we actually got over 10 A1cs <3.8% last year, and over 200 <4.5%, so apparently this isn’t as rare as I had expected. But what does it mean? Do these individuals have persistent hypoglycemia? Is there any impact on health as a result of such a low Hb A1c?
As it turns out, there’s not a lot of information in the medical literature on this subject. Nor is there a single, clear definition of what value of Hb A1c is considered low. In two studies, <4.0% is used as a cutoff (1, 2), and <5.0% was used in another.(3) In these three population-based studies, a low Hb Ab1 was associated with increased risk of mortality and liver disease, despite the fact the low values are more often observed in young, healthy individuals.(3) A stronger association has been shown between low Hb A1c and liver disease, presumably due to aberrant glucose and insulin metabolism, decreased erythropoiesis and protein synthesis, and/or decreased red cell survival.(4, 5)
In addition to liver disease, a low Hb A1C may be the result of any cause of increased red cell turnover/decreased survival, such as hemoglobinopathy, excessive bleeding, or red cell membrane defect. Consistent hypoglycemia is also a cause of how Hb A1c, either through extreme dietary control or overuse of antidiabetic medications. Finally, lab error may also result in inappropriately low Hb A1c. (6) In cases where Hb A1c is suspected to be unreliable, alternatives include fructosamine, 1,5-anhydroglucitol, or oral glucose tolerance tests.
Three case reports have described abnormally low hemoglobin A1c results(4, 6, 7). In one, the Hb A1c was <3.5%, and was ultimately determined to be the result of a hemoglobinopathy(7). In another, once most other causes of a low Hb A1c was ruled out, the result of 3.2% was attributed to a highly restrictive diet and anti-diabetes medication, and was confirmed by a low fructosamine.(6) Finally, in the third report, the low Hb A1c was attributed to advanced cirrhosis.(4) Case review of patients from my own lab didn’t reveal any clear tendencies, except that several of the patients were HIV positive, but the trend did not reach statistical significance. Another interesting observation is that several patients with an Hb A1c <4.0% had the same result obtained on more than one occasion, suggesting the phenomenon was persistent within an individual.
A low Hb A1c is a finding of unclear significance, and more work still needs to be done to determine both the causes and short- and long-term consequences of the issue. Ultimately, I didn’t have any particularly helpful information to share regarding the patient in question. She did have an oral glucose tolerance performed, and the results were normal, though not particularly near the low end of the range and she was released from the care of endocrinology.
- Carson AP, Fox CS, McGuire DK, Levitan EB, Laclaustra M, Mann DM, et al. Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. Circ Cardiovasc Qual Outcomes. 2010;3(6):661-7.
- Christman AL, Lazo M, Clark JM, Selvin E. Low glycated hemoglobin and liver disease in the U.S. population. Diabetes Care. 2011;34(12):2548-50.
- Aggarwal V, Schneider AL, Selvin E. Low hemoglobin A(1c) in nondiabetic adults: an elevated risk state? Diabetes Care. 2012;35(10):2055-60.
- Wang P. What Clinical Laboratorians Should Do in Response to Extremely Low Hemoglobin A1c Results. Lab Med. 2017;48(1):89-92.
- Lahousen T, Hegenbarth K, Ille R, Lipp RW, Krause R, Little RR, et al. Determination of glycated hemoglobin in patients with advanced liver disease. World J Gastroenterol. 2004;10(15):2284-.
- Joob B, Wiwanitkit V. Very low HbA1C, is it a problem? Iran J Pathol. 2018;13(3):379-80.
- St Louis J, Valdini A. Abnormally Low Hemoglobin A1c as Harbinger of Hemoglobinopathy. J Am Board Fam Med. 2019;32(6):923-4.