HbA1c Below the Reportable Range

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Abstract and Introduction

Abstract

This case report concerns a 71 year old female patient who had a very low glycosylated hemoglobin (HbA1c) despite having a high level of fasting blood glucose. The patient had a decreased erythrocyte count, elevated red blood cell indices, and a reticulocyte count with no evidence of hemoglobinopathy. She reported receiving hydroxychloroquine treatment for systemic lupus erythematosus. Subsequent laboratory investigations revealed hemolysis with formation of cold agglutinin. Because cold agglutinins can interfere with HbA1c assays, the specimens were reanalyzed after warming. The complete blood count results improved, but the HbA1c result did not change. In patients in whom medications and/or medical conditions may interfere with HbA1c levels, alternative measures of glycemic control, such as fructosamine, could be beneficial.

Introduction

Glycosylated hemoglobin (HbA1c) is extensively used for the screening, diagnosis, and monitoring of diabetes mellitus. It reflects an individual's glycemic control over the past 8 to 12 weeks and correlates with the development of diabetic complications. The measurement of HbA1c does not require patients to be fasting, and it has high preanalytical stability. In addition, it is more convenient in clinical practice than other measures such as fasting blood glucose or a glucose tolerance test.

Research has shown that HbA1c is formed from the posttranslational addition of glucose to the N-terminal valine of the beta chain of hemoglobin A through an Amadori rearrangement.^[1] Application of HbA1c as a glycemic control indicator relies on glycation efficiency, which is determined by the integrity of globin chains and the life span of erythrocytes. Therefore, HbA1c may give false results in certain conditions (Table 1), thus warranting alternative methods to diagnose and monitor diabetes.

Apart from the hematologic and genetic conditions mentioned in Table 1, the use of certain drugs affecting the red blood cells (RBCs) may also cause a false HbA1c result (Table 2). This report highlights the limitations of using HbA1c as a diagnostic tool in a patient with hemolytic anemia further complicated by the formation of cold agglutinin. Furthermore, this report indicates that an HbA1c finding needs to be interpreted in the context of a clinical situation.

Table 1. Conditions in Which HbA1c Is Not A Reliable Indicator of Glycemic Status
Scenario	Conditions	Mechanism
False decrease in HbA1c level	Pregnancy	Increased erythropoietin/decreased RBC survival^2,3
	Erythropoietin use	Reticulocytosis⁴
	Hemolytic anemia	Decreased erythrocyte survival⁵
	Chronic kidney disease	Anemia, use of erythropoietin, uremia, and transfusion⁶
	Liver cirrhosis/chronic hepatitis and alcoholic liver disease	Anemia of chronic disease, low albumin, gastrointestinal bleed, and hypersplenism⁷
	Acute/chronic blood loss	Reduction in life span of RBCs
	Hemoglobinopathies	Reduction in life span of RBCs
	Myelodysplastic syndrome	Reduction in life span of RBCs, frequent blood transfusion⁸
False increase in HbA1c level	IDA	Malondialdehyde (increased in IDA) enhances glycation of hemoglobin^9,10
	Folate/vitamin B₁₂ deficiency	Prolonged life span of erythrocytes¹¹
	Postsplenectomy	Prolonged life span of erythrocytes¹¹
	Chronic alcohol consumption	Formation of HbA1-AcH compound¹²

HbA1-AcH, hemoglobin-acetaldehyde; HbA1c, glycosylated hemoglobin; IDA, iron deficiency anemia; RBCs, red blood cells.

Table 2. Drugs Affecting RBCs Where HbA1c Is Not A Reliable Indicator of Glycemic Status
Scenario	Name of Drugs	Mechanism
False decrease in HbA1c level	Dapsone	Oxidation of hemoglobin to methemoglobin, reduced erythrocyte survival, and increased erythrocyte destruction¹³
	Ribavirin/interferon-α	Shortened survival of erythrocytes^14,15
	Nucleoside analogue antiretroviral agents	Subclinical hemolysis¹⁶
	High dose of vitamins C and E	Competitive inhibition of glycosylation¹⁷
	Hydroxyurea	Shift in hemoglobin pattern from HbA to HbF¹⁸

HbA, hemoglobin A; HbA1c, glycosylated hemoglobin; HbF, hemoglobin F; RBCs, red blood cells.

Table 3. Laboratory Results
Parameters	Result		Reference Interval/Unit
Parameters	Before Incubation	After Incubation	Reference Interval/Unit
Hemoglobin	8	8.4	13.5–16.9 g, %
RBC count	190	220	440–560 G/L
MCV	115.5	110.9	81.8–95.5 fL
MCH	43.3	37.6	27–32.3 pg
MCHC	37.5	33.9	32.4–35 g/dL
Platelet count	161	161	150–450 G/L
Reticulocyte count	…	4.8	Up to 2%
PCV	22.4	25.4	42%–52%
ESR	6		0–22 mm/h
Total bilirubin	39.33		5.13–32.49 μmol/L
Direct bilirubin	4.68		0.0–5.13 μmol/L
AST	25		17–59 U/L
ALT	32		10–45 U/L
ALP	348		98–279 U/L
LDH	393		100–210 U/L
FBG	5.8		3.89–5.55 mmol/L
Fructosamine	311		205–285 μmol/L
Vitamin B₁₂	301.2		138.01–614.75 pmol/L
Vitamin D	56.41		74.88–249.6 nmol/L
Iron	16.3		13–31 μmol/L
Ferritin	269.2		21.81–274.66 μg/L
Serum folate	22.66		6.25–45.32 nmol/L

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BG, fasting blood glucose; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PCV, packed cell volume; RBC, red blood cell.

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HbA1c Below the Reportable Range

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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