Abnormally Low Hemoglobin A1c as Harbinger of Hemoglobinopathy

Discussion

Hemoglobin A1c became available to clinicians in 1978 and was first recommended for clinical use by the American Diabetes Association a decade later in 1988.¹ Various studies over the years have demonstrated the utility of hemoglobin A1c in predicting diabetes-related outcomes and complications.^2,3 Since 2010, hemoglobin A1c has been recommended as one of the criteria that may be used for the diagnosis of diabetes,³ further expanding its clinical utility. Despite these benefits, a number of clinical scenarios may contribute to false results of this lab test. An excellent review by Radin⁴ reviews these potential conditions as noted in Table 1.

Since hemoglobin A1c is a product of the glycosylation of hemoglobin A, its use in patients with hemoglobinopathies may be less accurate for predicting disorders of glucose metabolism.⁵ This is particularly impactful on those hemoglobinopathies that demonstrate an abnormal quantity of hemoglobin A. In the case of our patient, her hemoglobin electrophoresis demonstrated 0% hemoglobin A, which explains her A1c value of <3.5%. Other reviews have demonstrated that A1c seems to be most inaccurate in the case of homozygous hemoglobinopathies,⁶ which was also the case with our patient.

Since hemoglobin A1c cannot be used in these patients to screen for or monitor diabetes mellitus, clinicians may use another of the American Diabetes Association's recommended screening approaches; fasting plasma glucose ≥ 126 mg/dL, random plasma glucose ≥ 200 mg/dL with classic symptoms of hyperglycemia, or plasma glucose ≥ 200 mg/dL 2 hours after a 75-g glucose load.⁹ In terms of monitoring glycemic control, clinicians may consider either following a glucose log of both fasting and postprandial values or using other markers such as fructosamine.⁴

Of particular interest in this case was the presentation of co-occurring hemoglobinopathies with mitigating effects on one another. Our patient was homozygous for hemoglobin SS (sickle-cell disease) with 59.8% hemoglobin S on her electrophoresis. The usual morbidity and mortality of this condition, as well as the usual finding of profound anemia, were mitigated by the presence of hereditary persistence of hemoglobin F, a coinherited hemoglobinopathy whose effects protect erythrocytes from hemoglobin S polymer-induced damage.⁷ Both of these conditions are found at higher incidence in the patient's home country⁸ and in this case were revealed by her abnormally low hemoglobin A1c.