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Letters |
1
Queen Beatrix Hospital, Beatrix Park 1, 7101 BN Winterswijk, The Netherlands
2 Hospital De Weezenlanden, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands
a Author for correspondence. Fax 31 543 524265; e-mail cweykamp{at}skbwinterswijk.nl
To the Editor:
Glycohemoglobin is widely accepted as a valuable indicator for long-term diabetic control (1). The in vivo reaction of hemoglobin with urea-derived isocyanate and the possible interference of the resulting carbamylated hemoglobin in uremic patients have been described (2). Since our earlier studies (3)(4), conflicting results have been reported (5)(6)(7) and methods have been modified or newly introduced.
We recently revisited carbamylated hemoglobin as part of the educational program of the European Reference Laboratory for Glycohemoglobin (ERL). We investigated the interference of carbamylated hemoglobin by comparing HbA1c results in lyophilized specimens from a uremic patient and a nonuremic volunteer, both being nondiabetic, in the 1998 ERL program. The first sample was prepared from the blood of a 50-year-old man with a mean urea during the preceding month of 27.9 mmol/L. According to a previous study (3), which concluded that 0.063% carbamylated hemoglobin is associated with each mmol/L of urea, a carbamylated Hb percentage of 27.9 x 0.063% = 1.8% was expected. Using capillary electrophoresis, our group separated carbamylated hemoglobin from HbA1c (8), and a value of 2.0% was found in this specimen. The second sample was chosen on the basis of having an equal HbA1c percentage as the first sample and a carbamylated hemoglobin concentration of 0.3%, which is within the health-related reference range (with both HbA1c and carbamylated hemoglobin measured with National Glycohemoglobin Standardization Program-certified capillary electrophoresis).
This specimen was analyzed by 24 laboratories of the ERL program (in 17
countries) using 14 methods, and the results were compared with those
for the sample from the nonuremic volunteer (Table 1
). The results on the two samples agreed within 0.5% by
immunologic, affinity chromatographic, capillary electrophoresis, and
IMx methods. All HPLC methods based on ion-exchange chromatography
showed higher HbA1c percentages in the sample of the uremic patient.
The mean difference for all 21 HPLC users was 1.6%, quite near the
calculated value of 1.8% and the observed value of 2.0% for
carbamylated hemoglobin with capillary electrophoresis. This is not
entirely unexpected because urea reacts with the hemoglobin molecule at
the same site as does glucose, and the isoelectric point of
carbamylated hemoglobin is thus similar to that of HbA1c. As a
consequence carbamylated hemoglobin might be assayed as HbA1c in
methods based on differences in electrical charge. In the immunoassays
(+0.1%) and capillary electrophoresis (-0.1%), hardly any difference
was seen. Interestingly, HPLC based on affinity chromatography (+0.5%)
and Abbott IMx (+0.4%) showed a small but significant difference.
Conclusions, based on results from a single sample, should be made with
caution: even between two nonbiased methods differences up to 1% might
occur because of scatter in individual patients. The mean difference of
1.6% as seen with ion-exchange methods seems too large to be explained
by individual scatter, but the 0.5% seen with affinity methods might
be attributed to this phenomenon. The persistence of carbamylated
hemoglobin interference will be investigated in the next ERL program
with a specimen from another uremic patient. An additional
problem, although not directly related to carbamylated
hemoglobin, is the frequent occurrence of shortened erythrocyte
life-span in renal failure, which might obscure correct interpretation
of HbA1c outcome.
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We believe that carbamylated hemoglobin gives rise to falsely high HbA1c in all HPLC methods based on ion-exchange chromatography.
References
The following articles in journals at HighWire Press have cited this article:
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  R. M. Cohen, Y. R. Holmes, T. C. Chenier, and C. H. Joiner Discordance Between HbA1c and Fructosamine: Evidence for a glycosylation gap and its relation to diabetic nephropathy Diabetes Care, January 1, 2003; 26(1): 163 - 167. [Abstract] [Full Text] [PDF]
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 L. Bry, P. C. Chen, and D. B. Sacks Effects of Hemoglobin Variants and Chemically Modified Derivatives on Assays for Glycohemoglobin Clin. Chem., February 1, 2001; 47(2): 153 - 163. [Abstract] [Full Text] [PDF]
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C. A. Krone and J. T.A. Ely Vitamin C and Glycohemoglobin Revisited Clin. Chem., January 1, 2001; 47(1): 148 - 148. [Full Text] [PDF]
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