A-027 The Clinical Indications of Low or Non-reportable HbA1c Results
Authors: Lu S , Neibauer T , Saylor E , Dewasse B , Straub M , Zhu Y 
Published: September 2023

Abstract

Background
Hemoglobin A1c (HbA1c) is the major non-enzymatic glycation product of hemoglobin A (HbA) and usually measured as a percentage of total hemoglobin. It is widely used in the screening, diagnosis, and monitoring of diabetes because HbA1c correlates with the average blood glucose level over the past 8–12 weeks in patients with a normal RBC lifespan. However, many factors can cause inaccurate HbA1c measurements or invalidate this correlation. While a high HbA1c raises the concern of inadequate glycemic control, a low or non-reportable HbA1c may also indicate diverse clinical conditions or technical issues. This study analyzes the pathophysiological conditions and technical limits leading to a low or non-reportable HbA1c value and discusses the use of other lab values in HbA1c result interpretation.

Methods
HbA1c was measured by cation exchange HPLC (Tosoh G8, v5.24F). 37 cases with a low or non-reportable HbA1c (&lt;4.0%) from January 1, 2022 to November 30, 2022 were reviewed. The relevant diagnoses, medical history, medications, and recent (±1 week from the HbA1c test) lab results (CBC, blood glucose, fructosamine, haptoglobin, LDH) were examined to identify the causes of low HbA1c values. The causes were grouped by pathological mechanisms or technical issues to calculate the frequency, and the association with other lab values was also explored.

Results
Low or non-reportable HbA1c cases accounted for 0.1% of total HbA1c tests (37/42 771), and about 30% (11/37) had been diagnosed with diabetes by the end of the review period. From the chart, 41% (15/37) cases had elevated blood glucose (&gt;109 mg/dL), 73% (27/37) were anemic (Hb &lt; 13.0 or 11.7 g/dL for male or female), and 46% (17/37) showed a high MCV (&gt;96 fL). Among those cases, a minor portion was caused by method-specific technical issues (8%, 3/37) or unknown reasons (5%, 2/37). The majority (86%, 32/37) was attributed to the following mechanisms: intravascular hemolysis (51%, 19/37), hepatosplenic RBC destruction (27%, 10/37), and increased erythropoiesis (8%, 3/37). For those cases with intravascular hemolysis (51%), the causes were categorized as inherited RBC disorders (19%, 7/37, including hemoglobinopathy and G6PD deficiency), acquired hemolytic diseases (19%, 7/37, including autoimmune hemolytic anemia), and adverse effects of medications (13%, 5/37, including dapsone and hydroxychloroquine). For those cases with hepatosplenic RBC destruction (27%), most of them were caused by cirrhosis (19%, 7/37). In addition, increased erythropoiesis (8%) was observed in patients with recent hemorrhage or EPO treatment. Some hemoglobin variants like homozygous HbE resulted in non-reportable HbA1c (8%), which represented a technical limit of the HPLC method.

Conclusion
Although low or non-reportable HbA1c cases are rare (0.1%), a significant portion (30%) of them are diabetic patients, and their HbA1c results can be misleading. The majority of low HbA1c cases (86%) are associated with clinical conditions causing a shortened RBC lifespan, and the most common causes include inherited RBC diseases (19%), cirrhosis (19%), medication adverse effects (14%), and autoimmune diseases (11%). Because increased RBC destruction and compensatory erythropoiesis are the underlying mechanisms, hemoglobin, MCV, and markers assessing hemolytic anemia (haptoglobin, LDH, reticulocyte%) can aid in HbA1c interpretation.