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Clinical Chemistry 43: 511-517, 1997;
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(Clinical Chemistry. 1997;43:511-517.)
© 1997 American Association for Clinical Chemistry, Inc.

Articles

Comparative evaluation of three assay systems for automated determination of hemoglobin A1c

Gabriele Halwachs-Baumann1,a, Susanne Katzensteiner1, Wolfgang Schnedl1, Peter Pürstner2, Thomas Pieber1 and Martie Wilders-Truschnig1

Departments of
1 Laboratory Medicine and
2 Gynaecology, Karl Franzens University, Graz, Austria.
a Address correspondence to this author, at: Blocklabor II, Auenbruggerplatz 15, 8036 Graz, Austria. Fax 0316/385/3430.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We evaluated three newly introduced systems for automated determinations of hemoglobin (Hb) A1c, which allow the processing of large amounts of samples in a routine clinical laboratory. We compared these methods—the Variant HPLC, the Hi-Auto A1c analyzer system, and the Roche immunoassay—with the Diamat HPLC system. All showed good precision and good concordance with the Diamat HPLC. The reference range for Hb A1c has to be determined by the laboratory for each assay system. Interference study showed no statistically significant influence of anemia, polycythemia, rheumatoid factor, or chronic hemodialysis, although individual Hb A1c values can be influenced by polycythemia (when measured with the Hi-Auto A1c analyzer) and by chronic hemodialysis (when measured with the Variant HPLC). HPLC was not suitable for measuring Hb A1c in the examined cases of hemoglobin variants; assaying fructosamine seems to be better for monitoring these patients.


Key Words: indexing terms: chromatography, liquid • immunoassay • intermethod comparison • variation, source of • hemoglobin variants


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Quantification of glycohemoglobin (gHb) in the form of Hb A1c or Hb A1 is recommended by the American Diabetes Association and others for monitoring diabetic patients (1). Routine determination of gHb is now widely used in clinical practice to monitor glycemia in persons with diabetes (2)(3)(4). However, measurement of gHb places a great demand on the clinical laboratory: The method of choice should measure this marker highly precisely; should be economical, automatable, and simple to perform; and should yield results that are comparable between different laboratories (1). Former methods showed many analytical problems: They were time-consuming and technically demanding (5)(6), and different assays measured different proportions of Hb A1c (2). In recent years, new assay systems have been introduced, allowing fully automated testing of large amounts of samples (7)(8)(9). These assays can be broadly divided into two categories, according to the principle used to separate glycated from nonglycated Hb components: (a) charge differences, e.g., in ion-exchange chromatography, and (b) structural characteristics of the carbohydrate groups on the Hb, e.g., in immunoassay (10). The kind and degree of interferences depend on the principles of gHb detection (11)(12)(13).

Besides method-dependent interferences, interlaboratory standardization and harmonization present problems, since no stable standards exist for use with different types of assays. Accordingly, multicenter studies are difficult to carry out, and direct comparison of results from different locations is not reliable (14)(15).

Here we describe the evaluation of three newly introduced Hb A1c assay systems, in comparison with the Diamat HPLC (Bio-Rad Labs., Hercules, CA) method (15).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients
We investigated 77 nondiabetic subjects, whose %Hb A1c values were within the reference interval as determined by Diamat Hb A1c (7). To check for possible interferences with Hb A1c analysis, we also investigated samples from 170 diabetic patients (insulin- and non-insulin-dependent) submitted routinely for Hb A1c analysis and 88 selected samples from patients undergoing chronic hemodialysis (n = 22) or with anemia (n = 33), polycythemia (n = 16), high concentrations of rheumatoid factor (n = 10), or known Hb variants (n = 7). Characteristics of these patient groups are summarized in Table 1 . Five patients had Hb Graz (16), one had Hb Sherwood Forest (17)(18), and one had Hb O-Padova (19)(20). For these patients we also quantified fructosamine in serum and preprandial blood glucose to define whether diabetic metabolism was present or absent (21)(22)(23). In all, samples from 335 patients were included in the study.


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  		Table 1. Characteristics of 81 patients in interference study.

procedures
Venous blood was collected into EDTA-containing evacuated collection tubes and kept at 4 °C until analysis (within 5 days after collection). All Hb A1c analyses were performed at the University of Graz Department of Laboratory Medicine (II) with use of the Diamat HPLC, the Variant HPLC (Bio-Rad Labs.), the Hi-Auto A1c analyzer system HA-8140 (Menarini Diagnostics, Florence, Italy), and a Roche immunoassay (UNIMATE Hb A1c reagents used with a COBAS MIRA analyzer system; Hoffmann-La Roche, Basel, Switzerland).

Fructosamine was determined in serum by a nitroblue tetrazolium colorimetric procedure (Hoffmann-La Roche) on the COBAS MIRA. The reference interval, determined in our laboratory, is <285 µmol/L.

Preprandial serum glucose concentrations were determined by a hexokinase/glucose-6-phosphate dehydrogenase assay without deproteinization, performed with a Hitachi 747 (all from Boehringer-Mannheim, Mannheim, Germany). The reference interval is 3.92–7.28 mmol/L in our laboratory.

hb a1c assays
Diamat HPLC.
Whole-blood samples are hemolyzed in a borate-containing buffer, which promotes dissociation of labile Hb A1c. This reaction is enhanced by a 30-min incubation at 37 °C. Further sample processing is performed automatically. For chromatographic separation, a step gradient of three phosphate buffers with increasing ionic strengths is used. Results are generated as %Hb A1c or as %Hb A (a+b+c). Analysis time is 5 min per sample. The reference interval is 4.3–6.1%, determined in our laboratory (7).

Variant HPLC.
This fully automated Hb analyzer, developed specifically for determining Hb A1c in human blood, uses ion-exchange HPLC. First, samples are diluted with lysing reagent (citrate solution, pH 5.0, containing <0.5 g/L sodium azide as preservative) and then incubated at room temperature for 10 min to hemolyze the blood and remove labile Hb A1c. Further sample processing is performed automatically. The samples are injected into the analytical flow path and applied to a cation-exchange column that binds Hb. The Hb components are chromatographically separated by programed washing with a buffer gradient of increasing ionic strength. The separated Hb then passes through the flow cell of the filter photometer, which measures absorbance at 415 nm and monitors the changes in absorbance; background variations are corrected by use of an additional filter at 690 nm. Labile Hb A1c does not interfere, and analysis time is 3 min per sample.

Hi-Auto A
1c analyzer system. The principle of the analysis is cation-exchange and reversed-phase chromatography. The whole sample processing is performed automatically. The analyzer is equipped with a cap-piercing system for direct sampling of whole blood from a closed primary tube. The Autosampler makes it possible to test a virtually unlimited number of samples in the same test session. The system can run whole-blood samples or prehemolyzed samples alternately without operator adjustment of the instrument. Samples of whole blood are first diluted by the Autosampler with hemolysis wash solution, which chemically removes the labile Hb A1c component. The hemolysate is transferred to a column, where it is separated by HPLC into Hb Alab, Hb F, Hb A1c, Hb A0, and various pathological fractions. Hb A1c is expressed as a percentage of the summed physiological hemoglobins only. These Hb fractions are separated by electrostatic interactions with the gel. The hard gel packed in the column consists of porous beads of copolymers of methacrylic acid and methacrylate ester; thus, the surface of the gel has hydrophobic groups and ion-exchange groups. The Hb fractions are eluted by varying the pH of the mobile phase and are measured photometrically (main wavelength 415 nm, reference wavelength 500 nm). Analysis time is 4 min per sample.

Roche immunoassay.
The whole sample processing is performed automatically. The test system combines a latex-enhanced competitive turbidimetric immunoassay for determining Hb A1c in whole blood with a colorimetric assessment of total Hb. First, erythrocytes are lysed by exposure to low osmotic pressure, after which the Hb is proteolytically transformed to make the ß-N-terminal available for the competitive immunoassay. The ß-N-terminal of Hb binds the monoclonal antibody carried by nonagglutinating latex particles. Free (residual unbound to Hb) latex-bound antibodies agglutinate with a synthetic polymer that carries copies of the ß-N-terminal, and the turbidity of these agglutinates is measured. This competitive immunoassay gives nonlinear results; i.e., the differences in absorbance are smaller than the increases in Hb A1c concentrations. Total Hb concentrations are measured in a cyanide-free colorimetric assay, according to the formation of alkaline hematin in basic detergent solution. Concentrations of total Hb are measured by their absorbance at 550 nm. The test result is then calculated from the Hb A1c/Hb ratio. The formula for calculation of %Hb A1c contains a conversion factor to make the results comparable with those by HPLC; this factor is installed (as a default) by the manufacturer but can be changed by the user. Analysis time is 2 min per sample.

control materials
To assess within-run imprecision, we prepared whole-blood pools with low, medium, and high Hb A1c contents and analyzed the pools (14–16 replicates) in 1 day. Total imprecision was determined with commercially available control blood (supported or recommended by the manufacturers) of low and high Hb A1c content by repeated analysis on 20 operating days. The control materials used were: Recipe level 1 and level 2 for Diamat HPLC; Lyphochec Glycated Hemoglobin Control (whole blood) level 1 and 2 for Variant HPLC; Glyco Hb Control level 1 and level 2 for HI-Auto A1c; and Hb A1c Control N and P for Roche immunoassay.

statistical methods
The between-methods correlations of Hb A1c values were determined by linear regression analysis. Differences were compared by Wilcoxon Sign Rank Test. P <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Data from the within-run and total imprecision studies are summarized in Table 2 . The %Hb A1c values of nondiabetic and diabetic patients are summarized in Table 3 .


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  		Table 2. Precision of the methods investigated.


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  		Table 3. %Hb A1c values determined in nondiabetic and diabetic patients.

For method comparison, we assayed all 335 samples with all four methods. In the nondiabetic patients group, the three new analyzers gave results significantly different from the results obtained with Diamat HPLC (P <0.001); in addition, the values determined with the Variant HPLC and Hi-Auto A1c analyzer were similar. In the diabetic patients, the three analyzer systems gave significantly lower Hb A1c values than the Diamat HPLC results (P <0.03) but did not vary significantly among themselves. To determine the correlations between the different analyzer systems, we used the results for all samples except those with hemoglobin variants. The correlation coefficients from comparing Variant HPLC, Hi-Auto A1c analyzer system, and Roche immunoassay with the Diamat HPLC were 0.97, 0.98, and 0.97, respectively (Fig. 1 ).



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  		Figure 1. Comparison of Hb A1c results (n = 335) assayed by the three new methods (y) vs Diamat HPLC (x): (A) Diamat HPLC vs Variant HPLC; (B) Diamat HPLC vs Hi-Auto A1c; (C) Diamat HPLC vs Roche immunoassay.

(... . . ) Line of identity.

To detect possible interferences, we analyzed selected samples with anemia (n = 33), polycythemia (n = 25), or high titers of rheumatoid factor (n = 10) and samples from patients undergoing hemodialysis because of end-stage renal failure (n = 22). To detect systemic effects, we calculated the mean residual value of each data pair, i.e., the y-axis distance from the point delineated by the data pair to the regression line. No statistically significant interferences were evident (Fig. 2 ).




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  		Figure 2. Box and whisker plots showing residuals of linear regression fit of (A) Variant HPLC, (B) Hi-Auto A1c analyzer, and (C) Roche immunoassay vs Diamat HPLC results for Hb A1c, plotted for five different patient subgroups.

Group 1, all investigated patients (n = 247) who were not members of groups 2-5 and not patients with Hb variants; 2, patients undergoing chronic hemodialysis because of end-stage renal failure (n = 22); 3, patients with anemia (n = 33); 4, patients with high titers of rheumatoid factor (n = 10); 5, patients with polycythemia (n = 16). The lower and upper limits of each box represent the 25th and 75th percentiles, respectively, and the line in the box shows the mean. Whiskers are drawn from each box to the lowest and highest observed values (that were not outside values or far-outside values). ({circ}), outside values: >1.5 times the box height away from the mean; (*), far-outside values: >3 times the box height away for the mean.

Results for the samples containing Hb variants (Table 4 ) were as follows:


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  		Table 4. Hb A1c results for samples containing Hb variants.

Hb Graz (n = 5).
In the three HPLC assay systems, all five cases of this Hb variant gave extremely high Hb A1c values. Only the Hi-Auto A1c analyzer declared the chromatogram as showing "abnormal separation." The Roche immunoassay analyzer gave results within or below the reference interval. In two of the five Hb Graz cases, fructosamine concentrations exceeded the reference interval; the concentrations in the other three were normal. HPLC chromatograms of a representative patient with Hb Graz are shown in Fig. 3 .



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  		Figure 3. Chromatograms from the (A) Diamat HPLC, (B) Variant HPLC, and (C) Hi-Auto A1c analyzer of a patient with Hb Graz.

Hb Sherwood Forest (n = 1).
This Hb variant gave an extremely high Hb A1c result in the Diamat assay system. The Variant HPLC divided the peak into two parts labeled "Unknown 1" and "Unknown 2." The Hi-Auto A1c analyzer system remarked "Abnormal separation," as with Hb Graz. The Hb A1c value obtained with the Roche immunoassay analyzer was within the reference interval, which was in accordance with the fructosamine concentration.

Hb O-Padova (n = 1).
This Hb variant ordinarily elutes within the A0 fraction by HPLC. Both Diamat HPLC and the Hi-Auto A1c analyzer divided the A0 peak into two parts, but only the Hi-Auto A1c analyzer declared this to be a Hb variant; no warning was given by the Variant HPLC. The values obtained by HPLC were within the reference interval in two cases (Diamat HPLC and Variant HPLC) and above-normal in one case (Hi-Auto A1c). The Hb A1c proportion measured by the Roche immunoassay analyzer system was high, as was the fructosamine concentration.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
All of the tested analyzer systems showed a good correlation with the Diamat HPLC, although the reference intervals varied greatly according to the type of procedure used. Precision was also good on all tested assay systems—all falling within the medically allowable CV (i.e., 5% of the Hb A1c value (24)). Diamat HPLC showed significantly greater %Hb A1c values in diabetic and nondiabetic persons than did all other methods. The well-known assay dependency of Hb A1c results (1)(2)(14)(15) still is not solved, despite the latest analytical improvements. Thus, clinicians must keep in mind that variations of Hb A1c values can arise from the use of different assay systems.

An explanation for this discrepancy might be that "gHb" contains various distinct molecules (6), which are measured differently by different methods (11). In addition, negatively charged Hb can interfere more or less (13), and uremia, anemia, and polycythemia can result in falsely high or falsely low values for Hb A1c (11)(13)(25). In our study we saw no significant influence of rheumatoid factor, anemia, polycythemia, or chronic hemodialysis on the Hb A1c values in any of the assay systems investigated, although Hb A1c values measured by Variant HPLC showed a wider range of the residuals for the samples from patients needing chronic hemodialysis than did the other methods. In the Hi-Auto A1c analyzer system a wider range of the residuals of Hb A1c values was observed in samples from patients with polycythemia. This difference was not statistically significant, but it still exceeded the medically allowable error, 1%Hb A1c (e.g., from 9.5% to 10.5% Hb A1c (24)), and in individual patients could cause interpretative problems for clinicians. Thus, in an individual case, the %Hb A1c value might change by >2%Hb A1c because of these interferences. This might result in a wrong diagnostic classification of the patient and cause unnecessary therapeutic interventions (24).

That various methods for Hb A1c measurements show different values for Hb variants is well known (22)(25) and can cause problems in the monitoring of diabetic patients. To overcome this, one should use a method that meets the following conditions: The Hb variant should be recognized; and Hb A1c, Hb A0, and Hb variants should be separated and quantified reliably (25). In HPLC methods, most investigated Hb variants can be recognized by looking at the chromatogram. Only the Hi-Auto analyzer system denotes all such chromatograms as abnormal separations or as showing a Hb variant. The Diamat HPLC showed an abnormal chromatogram, but gave no warning. The Variant HPLC, which characterized only Hb Sherwood Forest as "Unknown," showed an abnormal chromatogram of samples with Hb Graz without warning; its chromatogram for the sample with Hb O-Padova appeared normal and no warning was given. This could lead to problems in cases where the Hb variant gives plausible %Hb A1c values.

As is known for immunoassays (25), the Roche immunoassay analyzer system does not recognize Hb variants. The user of such systems thus has no possibility of controlling the accuracy of the measured %Hb A1c values. According to the corresponding fructosamine concentrations, the Hb A1c values given by the Roche immunoassay analyzer system would be falsely low in two of five cases of Hb Graz. Hb Sherwood Forest is a mutation in position 104 of the ß-chain (17). Because the Hb is proteolytically degraded in the first step of the immunoassay and the ß-N-terminal structure does not differ from that for normal Hb (17), no interference of Hb A1c determination in the Roche immunoassay analyzer system would be expected, as was the case in our patient. The accordance of the %Hb A1c value given by this system with fructosamine values support this hypothesis. Also, Hb O-Padova, an {alpha}-chain variation (19), gave %Hb A1c values within the reference intervals for two analyzer systems (Diamat, Variant) and above-normal values in the Hi-Auto and the Roche immunoassay analyzer systems. These latter two results corresponded with the sample's fructosamine values. Finally, because %Hb A1c values in patients with Hb variants may be influenced by several nonanalytical factors (22) that also can hamper interpretation of results, it is not surprising that interpretations of test results are often erroneous. Measurement of fructosamine may be a suitable alternative for patients with Hb variants (22).


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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