Case
A 29-year-old female without any past history before came to the outpatient clinic complaining about her recent chest tightness and palpitation. While electrocardiography showed normal sinus rhythm, other parameters were checked to rule out any underlying disease, including diabetes mellitus, dyslipidemia, uric acid, and cardiac echo. However, glycated hemoglobin (HbA1c) could not be detected by the ARKRAY HA-8180V A1c analyzer. Thus, the glycated albumin was tested and was found to be in a normal range (12.6%). When the hemoglobinopathy was tested, Hb electrophoresis showed low HbA1c, with high HbF and HbE/HbA2 ratio (Fig. 1). Notably, the patient denied any family history of anemia or hemoglobinopathy. She had no symptoms of anemia and was symptom-free after taking Propranolol 10 mg twice a day.
Discussion
HbA1c is broadly applied in long-term glycemic control. There are several ways of estimating HbA1c: ion-exchange high-performance liquid chromatography (HPLC), which separates HbA1c from other hemoglobin by net charge differences; immunoassays that use antibodies directed against the glucose-binding site of beta-globin to detect structural changes in the N-terminal amino acid of hemoglobin chains; boronate affinity assay that measures total glycated Hb and other enzymatic methods. However, there are some restrictions on HbA1c. For instance, it is unreliable in the acute phase, such as sepsis. It is also inaccurate, while Hb shows structural and metabolic disease, including hemoglobinopathy. Hemoglobinopathies that include thalassemia and structural Hb variants are estimated to affect nearly 8% of the world population. Weatherall and Clegg [1] predicted that the population of hemoglobin disorders would increase as a result of reduced childhood mortality due to infection and malnutrition, and more babies with hemoglobin disorders would survive to present for treatment. The most common Hb variants worldwide are HbS, HbE, HbC, and HbD. In addition, elevated HbF levels can occur in certain pathologic conditions or with hereditary persistence of fetal hemoglobin, which may result in an inaccurate HbA1c. In our case, high HbE/HbA2 and HbF ratios were detected, with low HbA1. Consequently, HbA1c was undetectable.
Lee et al. [2] reported a case of extremely high HbA1c, up to 54.6%, with a glucose level of 106 mg/dL, which was re-checked using a turbidimetric inhibition immunoassay, showing below the level of detection. Noteworthily, it is caused by hemoglobin Raleigh, a variant containing a valine --> alanine substitution at position 1 of the beta chain, increasing HbA1c in an automated ion-exchange HPLC method.
On the other hand, Hegde et al. [3] reported an undetectable HbA1c case, diagnosed as an HbD disease [3]. Nasir et al. [4] compared the HbA1c values measured on HPLC and immunoassay in patients who were detected to have a hemoglobin variant after HbA1c analysis. They concluded a significant difference in patients with HbE, HbS, and HbD variants. Meanwhile, our case emphasizes the importance of the need for awareness about Hb variants among physicians for proper interpretation of HbA1c results, especially in areas with a high prevalence of Hb disorders. Other alternative non-hemoglobin methods of measuring glycemic control, such as glycated serum albumin, fructosamine, or self-monitoring of blood glucose, may be more suitable than HbA1c in patients with hemoglobin variants and should be considered.