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β2 α2 γ2 α2 δ2 α2
Hb A Hb A0
93-95%
Hb A1 = GHb
Fast hemoglobins
Glycated Hemoglobins
5-7%
Hb A1a1 Hb A1b Hb A1c
HbA1a2 pyruvate glucose
Fructose-1,6-diphosphate
Hb A2
Glucose-6-phosphate
Hb F
+ + +
Definition of the Analyte
IFCC: HbA1c is defined as hemoglobin
molecules having a stable adduct of glucose
to the N-terminal valine of the hemoglobin β
chain
(βN-1-deoxyfructosyl-hemoglobin)
(nearly known as “DOF Haemoglobin”)
G G
N G
N N
G G G
G
N
G
N
G
Hb A1 = GHb
Fast hemoglobins
Glycated Hemoglobins
5-7%
Hb A1a1 Hb A1b Hb A1c
HbA1a2 pyruvate glucose
Fructose-1,6-diphosphate
Hb A2
Glucose-6-phosphate
Hb F
+ + +
What we actually measure:
Immunoassay:
HbA1c + HbA21c S1c + E1c etc / total Hb
Boronate affinity:
total glycated Hb / total Hb
HPLC:
HbA1c (+X) / (HbAo + Y + HbA1c + X)
NGSP IFCC
(%) mmol/mol
Afinion 1.4% 2.5%
Integra 1.4% 2.9%
Variant II 1.9% 3.3%
D10 1.8% 5.5%
9.0
Mean = 7.64 SDs: 2.7 / 3 = 0.9
SD = 2.7
CVs: 3.6 / 5 = 0.72
HbA1c (NGSP Standardisation, %)
CV = 3.6%
8.0
7.0
Mean = 4.9
6.0 SD = 1.4
CV = 2.8%
5.0
4.0
2.2
2.0 100
1.8
80
1.5
1.3
60
1.1
0.9
40
0.7
0.4 20
0.2
0.0 0
3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0
HbA1c (NGSP, %)
Current Role of HbA1c
• Managing patients with diagnosed
diabetes
Jones et al
Diagnosis
April 2011
HbA1c for Diagnosis
• Current Diagnostic Criteria
• Why might HbA1c be better?
• (or worse)
• Possible implementation
• Making it happen
Current Diagnostic Criteria
• Based on WHO/IDF 2006 Criteria
• Within setting of:
– Screening
– Testing
– Follow-up
• Plasma glucose is key parameter
NHMRC 2009
AUSDRisk ≥12 laboratory testing
Medicare Schedule of Benefits
• 66551 Quantitation of glycosylated haemoglobin
performed in the management of established diabetes -
WHO 2011
WHO
WHO
Less Assay Variation
• HbA1c assay improvement the product of
years of work
– NGSP
– IFCC
– CAP
– RCPA QAP
• Manufacturers
• Laboratories
HbA1c Variability
• Same sample to different laboratories
• CVi HbA1c: 2 – 3%
Decision point
• Convenience
• Compliance
• Also,
Intracellular pH
Appears on the WHO list
?
Assay Interferences
• Haemoglobinopathies
– Some assays not affected
– Some assays affected but can be seen
– Some assays affected and not seen
– Hb S, C, D E trait - use appropriate assays
• Eg Haemoglobin F and Immunoassay
– Less Beta chain (replaced by delta chain)
– Less HbA1c
– Same amount of Hb
– Lower HbA1c relative to total Hb
– SILENT in patient and assay!
So...
Opinion:
• Most patients likely to be OK for HbA1c
measurement
• Interferences: few outliers in method
comparison studies
• RBC factors: range of patients in trials
likely to include common factors
• But: some patients affected significantly
Implementation
• Need to turn current (limited) knowledge of
limitations into action plans
WHO 2011
Fructosamine
WHO criteria
• HbA1c ≥6.4% (48 mmol/L) diagnostic
• Should be repeated
• No “pre-diabetic” state
(ADA has HbA1c 5.7 to 6.4% as a risk
factor)