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Low HbA1c levels in a poorly controlled diabetic

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Q1: What do the data demonstrate?

The data demonstrate inappropriately low HbA1c values in a subject with symptomatic hyperglycaemia (weight loss, osmotic symptoms, and high plasma glucose values) and abundant glycosuria.

Q2: What is the differential diagnosis and what would you do next?

If a laboratory error can be ruled out (repeated samples need to be obtained), the main differential diagnosis is of an abnormal haemoglobin variant. Some causes of abnormal HbA1c values are listed in box 1. The next step is to perform haemoglobin electrophoresis. The following results were obtained in this patient:

Box 1: Causes of high/low HbA1c levels


  • Newly diagnosed diabetes mellitus.

  • Uncontrolled diabetes mellitus.

  • Non-diabetic hyperglycaemia: acromegaly, phaechromocytoma, thyrotoxicosis, Cushing’s syndrome.

  • Splenectomy.

  • Alcoholism.


  • Haemolytic anaemia: congenital (for example, spherocytosis and elliptocytosis), haemoglobinopathies, acquired haemolytic anaemias—for example, drug induced (dapsone, methyldopa).

  • Chronic blood loss.

  • Chronic renal failure (variable).

  • Alkali/acid elution: haemoglobin A + J (confirms the presence of abnormal haemoglobin J).

  • Globin: fast beta chain variant (abnormal beta chain).

  • Isoelectric focusing: haemoglobin A + J.

  • Abnormal haemoglobin: 48% (a high percentage of haemoglobin J)

  • Haemoglobin A2: 2.58% (normal <3%).

  • Sickledex: negative (no evidence of sickle cells).

  • Haptoglobin: 0.28 g/l (normal 0.7–3.19).

These tests are consistent with a diagnosis of haemoglobin beta chain variant: J trait.

Q3: What is the pathophysiological basis of the discrepancies observed and how would you assess this man’s long term glycaemic control?

Non-enzymatic binding of glucose to the valine residue of the beta chain of the haemoglobin molecule gives rise to glycated haemoglobin (HbA1a, HbA1b, and HbA1c). The level of HbA1c reflects ambient blood sugar concentrations during the life span of the patient’s red cells (half life about 6–8 weeks)—that is, uncontrolled hyperglycaemia results in high HbA1c levels. Current guidelines recommend HbA1c levels of less than 7% as a target for satisfactory control. HbA1c can be measured chemically, chromatographically, and electrophoretically.1 Most autoanalysers use the chromatographic method. Haemoglobin variants may affect chromatographically measured HbA1c levels either by inducing an abnormal peak and thereby making the estimation of the fraction of HbA1c unreliable, or by reducing time available for glycation as a result of reduced red cell survival. These two effects may coexist.2 Physicians should be aware of the potential pitfalls of HbA1c as a measure of long term diabetic control. Apparent discrepancies between glycaemic control reflected in day to day blood glucose concentrations, and HbA1c values should be noted. HbA1c levels are inappropriately affected by factors other than long term glycaemia as shown in boxes 1 and 2. Schnedl et al reported a prevalence of abnormal haemoglobin variants of 0.6% among 15 000 HbA1c estimations in a period of over six years.3 In such individuals a method unaffected by abnormal haemoglobin variants, such as a turbidimetric inhibition immunoassay4 or alternate methods of chromatography5 should be used.

Box 2: Abnormal haemoglobin variants and HbA1c

High HbA1c

  • HbF

  • HbE

  • HbD

  • HbJ Capetown

  • Hb Raleigh

Low HbA1c

  • HbS

  • HbC

  • HbJ

  • HbG

  • Hb Ramadan

Final diagnosis

Abnormal haemoglobin variant.


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