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Reviews |
1
Department of Pathology, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115.
a Address correspondence to this author at: Brigham & Women’s Hospital, Thorn 530, 75 Francis St., Boston, MA 02115. E-mail
dsacks{at}rics.bwh.harvard.edu.
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Abstract |
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 Top Abstract IntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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Approach: We conducted a review of the literature describing the effects of variant Hbs on gHb assay methods commonly used in clinical laboratories.
Content: This review summarizes the documented effects of both common and uncommon Hb variants and derivatives on the measurement of gHb. Where known, we discuss mechanisms of interference on specific assays and methodologies. We specifically address effects of commonly encountered Hbs, such as carbamyl-Hb, HbS, HbC, HbE, and HbF, on assays that use cation-exchange chromatography, immunoassays, or boronate affinity methods for measuring gHb.
Summary: A variety of patient- and laboratory-related factors can adversely affect the measurement of gHb in patients harboring Hb variants or derivatives. Identification of the variant or derivative Hb before or during testing may allow accurate measurement of gHb by the selection of a method unaffected by the given variant or derivative. However, laboratories should make available alternative, non-Hb-based methods for assessing long-term glycemic control in individuals with HbCC, HbSS, or HbSC disease, or with other underlying disorders where the concentration of gHb does not accurately reflect long-term glycemic control.
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Introduction |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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Hb Variants and Derivatives |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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,
ß, 
, or 
Hb chains. The widespread measurement of gHb has
identified new variants, many of which produce no phenotypic
abnormalities. Of the nearly 16 million diabetic patients in the United
States, estimates suggest that >150 000 carry one of these genetic Hb
variants (5)(6). HbS and HbC represent those
most commonly encountered. In other parts of the world, the prevalence
of variant Hbs has been demonstrated to be as high as one-third of all
diabetic patients undergoing testing (7). In addition to genetic variants, the measurement of gHb can be affected by chemical modifications of Hb, which may be chronically present in diabetic patients. These modifications may mimic gHb physically and chemically, leading to inaccurate determinations of gHb, particularly when separation methods based on charge differences are used. Carbamylated Hb, which is increased in uremic patients, represents the most frequently encountered derivative. High concentrations of acetylated Hb occur with uncommon mutations at the NH2 terminus of the ß-globin chain that enhance formation of acetyl-Hb in vivo. Although in vitro exposure of normal Hb to aspirin has been shown to produce acetylated Hb, no effects from in vivo exposure have been detected in patients chronically taking 1 g or less of aspirin a day (8).
Many hemoglobinopathies, including sickle cell disease, homozygous HbC disease, HbSC disease, and ß-thalassemia, frequently show increased amounts of minor Hb species, i.e., HbA2 and HbF, which interfere with some gHb methods. In addition, pathologic conditions affecting red cell half-life, including hemolysis (9), hemorrhage (9), iron deficiency anemia (10)(11), or red cell transfusion (12) affect gHb values.
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gHbs |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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97% HbA, 2.5%
HbA2, and 0.5% HbF (13).
Fractionation of HbA by chromatography identifies several minor peaks
referred to as HbA1, or fast Hbs, which include
the glycated forms HbA1a,
HbA1b, and HbA1c(13). These fast Hbs form as the result of a two-step
reaction. In the first step, a reversible reaction between the free
aldehyde group of glucose or other sugars and nonprotonated free amino
groups on the Hb molecule forms a Schiff base. This reversible reaction
is followed by an irreversible, nonenzymatic Amadori rearrangement that
produces gHb (13). The glycation alters the structure of the
Hb molecule and decreases its net positive charge. Many forms of
testing use one or both differences to separate gHb from nonglycated
Hbs.
The N-terminal valine of the ß chain provides the most common site of
glycation within the Hb tetramer, accounting for 80% of
HbA1 (13). The IFCC defines
HbA1c as Hb that is irreversibly glycated at one
or both N-terminal valines of the ß chains. The remaining gHbs have
glucose, glucose-6-phosphate, fructose-1,6-diphosphate, or pyruvic acid
bound to 1 of 44 additional sites occurring at 
-amino groups of
lysine residues or at the NH2 terminus of the chain
(13). Although all commercially available methods include
HbA1c in gHb measurements, they vary in their
ability to detect non-A1c gHb.
Current clinical recommendations of the American Diabetes Association suggest that gHb be maintained at 7%, consistent with a decreased risk for developing long-term complications from diabetes mellitus. A reevaluation of the treatment regimen should be undertaken in patients with repeated gHb values >8% (1).
In a healthy individual, gHb readings reflect the degree of
glycemic control over the preceding 2–3 months, reflecting the average
circulating life span of 120 days for red blood cells (1).
Pathophysiological conditions affecting red cell turnover, such as
sickle cell disease and HbCC and HbSC disease, thus limit the utility
of gHb testing in assessing long-term glycemic control. Alternative
tests, such as measurement of glycated serum proteins (GSPs) and
glycated serum albumin (GSA), should be performed when the
interpretation of gHb is confounded by variables affecting red
cell turnover or when Hb variants affect the ability of the Hb molecule
to be glycated. However, clinicians should be aware of two important
points concerning the use of GSPs or GSA as measures of long-term
glycemic control: (a) these tests assess the degree of
glycemic control over a period of 2 weeks, as opposed to 2–3 months
for gHb; and (b) neither test has been correlated with the
development of long-term complications from diabetes mellitus, as was
shown with gHb in the Diabetes Control and Complications Trial or with
the United Kingdom Prospective Diabetes Study (1).
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Laboratory Methods for Determining gHb |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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Methods of gHb Determination and Mechanisms by Which Hb Variants and Derivatives May Affect Results |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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Carriers of variant Hbs or Hb adducts or derivatives that elute
separately from HbA and HbA1c generally have
little effect on HbA1c measurements because they
do not factor into the above equation. Inaccurate
HbA1c values occur when the Hb variant, or its
glycated derivative, cannot be separated from HbA or
HbA1c. Fig. 1
illustrates three circumstances that produce inaccurate
determinations of HbA1c (Fig. 1, C–E
); variants
known to produce these patterns are shown in Tables 1
and 2
and are
discussed in the text. Interestingly, the same variant may
produce falsely increased or decreased HbA1c,
depending on the method used. In individuals homozygous for variant
Hbs, such as HbSS or HbCC, modifications to the HPLC protocol, the
algorithms used to calculate Hb A1c, and the use
of altered reference ranges have been proposed to provide more accurate
determinations of in vivo concentrations of HbX1c
(15). However, clinicians should consider methods other than
gHb for determining long-term glycemic control, given the multiple
factors confounding the interpretation of gHb results for these
individuals.
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The native Hb variant co-elutes with HbA1c
(Fig. 1C
and Table 1
). Many native Hb variants substitute a neutral amino acid
for a positively charged residue on the or ß chain. The
alteration decreases the retention time of the nonglycated variant
Hb, causing it to co-elute with HbA1c and
leading to a substantial overestimation of
HbA1c. Some patients have reported
HbA1c values as high as 54% (16).
Examples include Hb Raleigh (ß1Val
Ala) (16), Hb
Graz (ß2HisLeu) (17)(18), Hb
Sherwood Forest (ß104ArgThr)
(17)(18), Hb South Florida (ß1ValMet)
(19) and Hb Niigata [ßN-Methionyl-1(NA)ValLeu]
(20). In the cases of Hb Raleigh, Hb South Florida, and Hb
Niigata, the substitution at the NH2 terminus enhances the
formation of acetyl-Hb in vivo, providing a physiological basis for
spuriously increased HbA1c. Carbamyl-HbA has also
been found to produce false overestimation of
HbA1c in some methods by co-eluting with
HbA1c (8).
To confound matters, the co-elution of the variant Hb with HbA1c or its separation from HbA1c often depends on the method used. These inconsistencies arise from the distinct solvent mixture, column, and additional elution conditions, including temperature, pressure, flow rate, and program time, used in each system. The same Hb variant may thus yield very different results for HbA1c, depending on the method used. Furthermore, the algorithms used to calculate HbA1c can lead to inaccurate results if they do not recognize the presence of aberrant peaks and either provide warning flags or allow for corrections to make accurate determinations.
The glycated Hb variant co-elutes with HbA1c, whereas
the nonglycated Hb variant is resolved from HbA (Fig. 1D
).
This pattern overestimates the concentration of
HbA1c. The glycated Hb variant becomes
incorporated in the HbA1c peak, whereas the
denominator consists only of the area under the native HbA peak. This
effect occurs in the presence of Hb GPhiladelphia
on the Tosoh A1c 2.2+ system. Conversely, Hb
GPhiladelphia produces a falsely decreased value
on the Bio-Rad Variant system (21). The Bayer DCA-2000,
Roche TinaQuant, and Primus CLC 385 methods are not affected by this
variant (21).
The Hb variant co-elutes with HbA, whereas the glycated Hb variant
is resolved from HbA1c (Fig. 1E
and Table 2
). This elution pattern underestimates
HbA1c as the denominator includes both HbA and
the variant Hb, thus falsely decreasing the percentage of
HbA1c. Examples producing this pattern include
HbD, GPhiladelphia,
JBaltimore, and OPadova on
the Bio-Rad Variant system (21)(22) and Hb
Sherwood Forest and OPadova on the Hitachi L-9100
(22). Different platforms and systems may produce spurious
increases or decreases with the same Hb variants. On the Tosoh A1c
2.2+, HbE and JBaltimore generate this pattern,
but not D or GPhiladelphia(20)(21).
Electrophoresis
Agar gel electrophoresis is used infrequently to determine gHb in
clinical laboratories in the US. The method separates Hb species based
on charge differences (13). Scanning densitometry of the gel
allows quantification of Hb species in each sample. This method has
patterns of interference from Hb variants similar to those observed
with ion-exchange chromatography. However, minor variations in pH,
ionic strength, or temperature have little effect on the migration
pattern. In contrast to procedures involving cation-exchange
chromatography, interferences from individual Hb variants are expected
to be more consistent among different systems and platforms using gel
electrophoresis. Comigration of Hb variants or derivatives with either
HbA or HbA
1c interferes with HbA1c determinations. Comigration of HbF or carbamylated Hb with HbA1c produces spuriously increased HbA1c values (23).
Isoelectric focusing
Isoelectric focusing (IEF) is also used infrequently for
determining gHb. IEF uses a pH gradient gel to separate Hb species
based on their charge (13). After fixation of the gel,
quantification is performed by a high-resolution integrating
microdensitometer. Variants such as Hb Pavie (135ValGlu)
(24), Hb Hafnia (ß116HisGln) (25), and Hb
Fontainebleau (21AlaPro) (26) comigrate with
HbA
1c on IEF gels and can cause spuriously increased readings.
Immunoassays
Several commercial methods quantify HbA
1c using antibody-mediated inhibition of latex agglutination or immunoturbidimetric assays. Antibodies recognize the N-terminal glycated amino acid in the context of the first 4–10 amino acids of the Hb ß chain (27). These antibodies do not recognize the reversible Schiff base or other gHb species, including chemically modified derivatives. Of note, the most commonly encountered Hb mutations, HbS and HbC, fall within this susceptible region, and will be discussed subsequently.
HbF, Hb Graz, and Hb Raleigh are among those shown to cause decreased
HbA1c values by immunoassay
(16)(17). Other Hb variants with alterations in
the first 4–10 N-terminal amino acids could produce similar results.
In the case of Hb Raleigh, the ValAla substitution produces
substantial acetylation at the NH2 terminus, preventing the
formation of the gHb at this position and further decreasing results
obtained by immunoassay (16). gHb determinations in
this and other N-terminal variants, namely Hb Long Island
(28), Hb South Florida (19), and Hb Niigata
(20), are also of limited utility in assessing long-term
diabetic control because of the extensive acetylation of Hb in vivo.
Boronate affinity chromatography
Among commercially available methods, boronate affinity
chromatography tends to demonstrate the least interference from the
presence of Hb variants and derivatives
(5)(29)(30). The method determines
total gHb, including HbA1c and ketoamine
structures formed on lysines and N-terminal valine residues of both the
and ß chains. m-Aminophenylboronic acid, cross-linked
to agarose or glass beads, reacts specifically with cis-diol
groups of glucose bound to Hb to form a reversible five-member ring
complex, thus immobilizing gHb to the column. Addition of sorbitol
dissociates the complex and elutes the gHb (13). The gHb may
then be measured spectrophotometrically or by quenching of Hb
fluorescence with an added fluorophore.
Studies using the CLC 330 and CLC 385 (Primus Corporation) have reported no interference from common Hb variants or derivatives. Significant spurious increases in gHb values have been reported with the Quick Column method (Helena) in HbAC and HbCC samples (31). One study reported a positive bias in gHb readings from HbAC samples with the Abbott IMx® Glycated Hemoglobin assay, which uses a boronate/ion-capture method. Frank et al. (5) hypothesized that the bias may be attributable to the polyanion capture reagent, which may react with the Lys substitution at position 6 of nonglycated HbC.
Of the less common Hb variants that have been studied, only Hb Himeji
(ß140AlaAsp) has demonstrated falsely increased gHb results, which
were attributed to excessive glycation of Hb Himeji in vivo
(32). Accurate HbA1c values were
ultimately obtained by performing cation-exchange chromatography on the
eluate with Iso Glyc-affin GHb columns. This fractionation allowed
determination of HbA1c relative to HbA (Table 2
).
The authors hypothesized that the ß140AlaAsp substitution in Hb
Himeji may interact with the NH2 terminus of the ß chain,
enhancing the in vivo formation of Hb Himeji1c
(32).
Electrospray mass spectrometry
Electrospray mass spectrometry (ES-MS) appears to provide a means
of measuring total gHb that is unaffected by the presence of genetic or
chemical modifications to the Hb molecule. The IFCC has proposed using
ES-MS and capillary electrophoresis as candidate reference methods for
the determination of gHb. ES-MS is also frequently used to characterize
variant Hbs, including those identified by gHb testing
(33)(34). Hb prepared from samples of whole
blood is denatured and injected into the ES-MS instrument. Multiple
positive ions are generated for each protein in the sample, including
individual Hb chains, glycated forms, or chains containing other
chemical modifications. A mass spectrometer separates the ions based on
their mass-to-charge ratio (35). The profile gives an
accurate indication of total gHb as well as proportions of carbamylated
and variant forms. In patients with Hb variants, the same profile can
also provide information concerning the nature of the variants
(35)(36). Despite these attributes, the
prohibitive cost of ES-MS and the complicated nature of its
installation and operation make it unlikely that it will be used
in most clinical laboratories in the near future (36).
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Effect of Commonly Encountered Chemical Derivatives and Genetic Variants on gHb Methods |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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. We have opted to present data from studies where
(a) unless indicated, multiple samples with the given
variant were studied, (b) measurements were performed on
samples covering a range of expected gHb values, and (c) the
comparison method is known to be unaffected by the variants under
study.
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Carbamyl-Hb
Urea spontaneously dissociates in vivo to form ammonia and
cyanate. Protonation of cyanate leads to the formation of isocyanic
acid, which reacts with the and amino groups on proteins,
forming a carbamyl moiety (37). The N-terminal valine of the
Hb ß chain is particularly reactive with isocyanic acid, leading to
the stable formation of carbamyl-Hb. Previous studies have demonstrated
that 1 mmol/L urea is associated with the formation of 0.063%
carbamyl-Hb in vivo (8). Uremic patients may have
carbamyl-Hb concentrations as high as 3% of total Hb. In addition,
clinicians should be aware of additional factors in uremic patients
that impact red cell turnover, such as shortened red cell life span in
hemodialysis patients, which in turn affect the accuracy of gHb
readings.
Carbamyl-Hb has an isoelectric point similar to HbA1c and can thus interfere with charge-based methods of measuring gHb. In vitro carbamylation of Hb, to concentrations as high as 5.4% carbamyl-Hb, has been shown to produce significant spurious increases in HbA1c values in multiple cation-exchange methods, including the Bio-Rad Variant and Diamat, and the Tosoh A1c 2.2+ (38). However, studies assessing in vivo effects of carbamyl-Hb have shown differences that range from insignificant to significant. For example, effects of carbamyl-Hb on the Bio-Rad Diamat system demonstrated discrepancies ranging from 0.02% (39) and 0.47% increases in HbA1c values (39) to spurious increases of 1.1% (40). Immunoassay and boronate affinity methods, including the Roche TinaQuant II, Bayer DCA-2000, and Primus CLC 385, have been shown to be unaffected by concentrations of carbamyl-Hb encountered in uremic patients (38)(40).
Sickle trait
HbS (ß6GluVal) is the most commonly encountered variant Hb in
the United States; 7.8% of African Americans carry the sickle trait,
whereas homozygous sickle cell disease afflicts nearly 50 000
Americans (41). In parts of sub-Saharan Africa, the
prevalence of HbAS has been shown to be as high as one-third of all
patients undergoing HbA1c testing (7).
Commonly used boronate affinity methods have demonstrated accurate gHb readings in the presence of HbS (5)(15). Effects of HbS on cation-exchange chromatographic assays vary, depending on the method and platform used. A recent study found overestimation of HbA1c in the Bio-Rad Diamat or Variant HPLC systems, especially in the lower HbA1c range. The interference from HbS varied in the Diamat system, depending on the lot of columns used (5). Studies with the Tosoh gHb 2.2Ac+ and Menarini 8140 platforms showed no effect as HbS and HbS1c were readily separable from HbA and HbA1c(42)(43). The epitopes recognized by the antibodies used in the DCA-2000 and TinaQuant fall within the first four and six amino acids and are not affected by the mutation in HbS (8)(27). However, a significant spurious increase has been noted with the Roche Unimate immunoassay, which uses the same antibody as the Bayer DCA-2000 (44). The Unimate assay differs from the DCA-2000 in that it uses pepsin to cleave the ß chain near the NH2 terminus, and thus measures glycation on the peptide fragments. One study hypothesized that the antibody may have a higher affinity for the peptide fragments of HbS1c and HbC1c, leading to the spurious increases in gHb (44).
HbC TRAIT
HbC trait (ß6GluLys) has a prevalence of 2.3% among African
Americans and a prevalence as high as 30% in parts of sub-Saharan
Africa (41). HbC trait behaves similarly to HbS trait with
regard to many, but not all, assay systems. As discussed above, false
increases have been reported with the boronate affinity/cation-capture
method used in the Abbott IMx Glycated Hemoglobin method
(5), with the Quick Column method from Helena
Laboratories (31) and with the Roche Unimate immunoassay
(44). Use of the 3-min elution program on the Tosoh A1c 2.2+
has been recommended to fully separate HbC from HbA and allow for
accurate readings (43)(45). The shorter Tosoh
2.2 program is available only on instruments in use in Japan and in
Europe.
HbE TRAIT
HbE (ß26GluLys) is most commonly encountered in regions of
Southeast Asia where the prevalence can be as high as 30% of the
indigenous population (41).
HbE1c frequently elutes as a shoulder to
HbA1c in most HPLC or cation-exchange
chromatographic methods (46). Unless corrected, these
methods lead to inaccurate determinations of
HbA1c that may be spuriously increased or
decreased, depending on the method used
(15)(21)(32). As the mutation falls
outside regions of recognition of most antibodies, the mutation has
little effect on immunoassay methods (8)(46),
although one study reported that a correction was required to determine
accurate gHb values with the Dako Novoclone immunoassay (8).
Boronate affinity methods are also unaffected; results incorporate gHb
on both HbA and HbE.
HbSS DISEASE
gHb readings from patients with sickle cell disease must be
interpreted with caution given the pathological processes, including
anemia, increased red cell turnover, transfusion requirements, and
increased HbF, that adversely impact gHb as a marker of long-term
glycemic control. Corrections to some HPLC and cation-exchange methods
allow accurate, analytical determination of HbS1c
(8), although the values have limited utility in assessing
long-term glycemic control. Other platforms, including the Menarini
8140 and Tosoh gHb 2.2Ac+, do not report results, although the
Menarini 8140 flags the abnormal peaks (42)(43).
Although Weykamp et al. (15) have advocated the use of
alternative reference ranges to account for the shortened half-life of
red cells in these patients, additional measures of glycemic control,
such as GSA and GSPs, should be considered (1).
HbCC AND HbSC DISEASE
Both HbCC and HbSC disease share the same confounding factors in
the determination of gHb as HbSS disease, although both entities
produce a less severe anemia than sickle cell disease. The prevalence
of HbCC disease in the US is approximately 1 in 1800, whereas that of
HbSC disease is 1 in 1100 (41). Alternative forms of
testing, as described above, should be considered for the determination
of long-term glycemic control in these individuals.
HbF
At birth, HbF comprises 70% of all Hb, and falls to <5% by 6
months of age (47). Individuals with hereditary persistence
of HbF may have concentrations up to 30% of total Hb, whereas
ß-thalassemia and sickle cell patients commonly demonstrate
concentrations ranging from 2% to 20% of total Hb (48).
Slight increases occur during pregnancy, with severe anemias, and in
certain leukemias. Approximately 1.5% of the US population has
HbF concentrations >2%, although the number of patients hospitalized
in tertiary medical centers with HbF >2% has been found to be as high
as 12% (49). As indicated in Table 3
, HbF concentrations
<5% of total Hb have no significant effect on the majority of gHb
methods. Most cation-exchange chromatographic techniques separate HbF
and gHbF from HbA and HbA1c, allowing for
accurate determinations of HbA1c(50). The chain in the
22 tetramer shares
only 4 of the first 10 amino acids with the ß chain of HbA and has
little to no immunoreactivity with most antibodies used in gHb assays.
However, if the immunoassay result is calculated relative to total Hb
in the sample, the calculation produces falsely decreased
HbA1c values. Recalculating
HbA1c relative to HbA gives more accurate
results, provided that the correction can be made (51).
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Summary |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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Although most modern chromatographic and immunoassay methods are either unaffected by common heterozygous variants such as HbAS, HbAC, and HbAE or give warning flags concerning the likelihood of an underlying variant, less common variants may give no such warnings. Furthermore, all gHb methods are inadequate for the assessment of long-term glycemic control in patients homozygous for HbS, HbC, or with HbSC disease. Although technologies such as boronate affinity chromatography and ES-MS provide a means of accurately determining gHb in these individuals, results are unlikely to accurately reflect long-term glycemic control due to pathological conditions that affect the formation and turnover of gHb in vivo.
In regions where populations have a high prevalence of variant Hbs, methods for the determination of gHb must be carefully selected to allow accurate determination of gHb in these individuals. When dealing with populations in which HbSS, HbCC, or HbSC disease are common and in which gHb determinations have limited utility, laboratories should offer alternative forms of testing, such as GSPs or GSA, to assist physicians with the determination of glycemic control in these individuals.
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Acknowledgments |
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Footnotes |
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2 The College of American Pathologists 1999 data were used to calculate relative percentages of methods in use as this survey provides a more accurate indication of current trends. During the time of the 2000 GH2-A Survey Set, Abbott had withdrawn their reagents for the IMx from the market. Many laboratories using the IMx as their primary method thus switched to an alternative method for measuring gHb during this period, significantly affecting the ratios of methods in use.
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References |
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TopAbstractIntroductionHb Variants and DerivativesgHbsLaboratory Methods for...Methods of gHb Determination...Effect of Commonly Encountered...SummaryReferences |
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2ß2(FG4)HisTyr substitution at the 1-ß2 interface. Hemoglobin 1989;13:367-376.[ISI][Medline]
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C. B. Hart Race Differences in Long-Term Diabet |
