HbA1c for the Diagnosis of Diabetes Mellitus. Sam Rowe, MBBS, MAEd, FRCPC Banff, Alberta November 25, 2011

Transcription

1 HbA1c for the Diagnosis of Diabetes Mellitus Sam Rowe, MBBS, MAEd, FRCPC Banff, Alberta November 25, 2011

2 Disclosure last 2 years: Lilly HypoCCS Study Investigator Bristol-Myers Squibb - Speaker GlaxoSmith Kline Advisory Board

3 Objectives At the conclusion of this presentation participants will be familiar with: a) the history b) the limitations, and c) the potential usefulness of the A1c assay in the diagnosis of diabetes.

4 Hemoglobin A1c First reported 1968 Rahbar, University of Tehran Fast moving hemoglobin component on electrophoresis Moves faster than HbA, in the position of HbF Stable Not related to other known Hb variants such as HbS, HbC, HbD Formed by non enzymatic glycosylation the browinng (Maillard) reaction Termed glycation to distinguish from enzymatic glycosylation Glucose condenses with amino groups on ß chain proteins Found on early studies to be elevated two to threefold in diabetic patients Constitutes 60-80% of total glycated Hb

5 Hemoglobin A1c Began to be used as a marker for glucose control in the 70 s Koenig RJ, Peterson CM, Jones RL, Sandek C, Lehrman M, Cerami A. Correlation of glucose regulation and hemoglobin A1c in diabetes mellitus. NEJM 1976; 295: Bunn HF, Gabbay KM, Gallop, PM. The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 1978; 200: Gradually established as the gold standard in assessing glycemic control Began to be used by national bodies for target setting and to assess new therapies

6 1979 National Diabetes Data Group Criteria Diabetes diagnosed when 1. Classic symptoms 2. Venous FBS > 7.8 or 3. 2 hour PC on OGTT > 11.1

7 Expert Committee re-examined Criteria 1997 Examined epidemiologic studies of retinopathy in about 5000 patients Retinopathy appeared to increase when A1c reached 6.0 to 7.0% FBC 7.0 felt to represent similar degree of hypoglycemia to 2 hr OGTT 11.1 Diabetes could be diagnosed by one criterion or the other Terms IFG (FBS ) and IGT (2 hr PC OGTT ) were introduced FBS recommended rather than OGTT (cost, convenience, reproducibility) OGTT remained Gold Standard A1c not recommended as a diagnostic test

8 A1c Measurement as an Index of Control DCCT trial (1993) showed lower A1c levels were strongly associated with decreased microvascular complications in Type I diabetes. A1c from 9 to 7% over 6.5 years reduced retinopathy 76%, microalbuminuria 39% and neuropathy 60% ADA (1994) therefore recommended A1c values be optimized, and set a target of 7.0% But no reference method existed In 2004 there were still over 20 methods in use There were 3 basic types Immunoassay High Performance Light Chromatography (HPLC) Cation-exchange method Boronate affinity method

9 Standardization of A1c Measurement Methodology The DCCT method (ion exchange HPLC) was recommended in the mid 1990s in the USA This is now used nearly universally around the world IFCC (International Federation of Clinical Chemistry) developed a definitive reference method by introducting a sophisticated system to remove impurities from blood samples. Results using both methods are tightly correlated and can be converted by a formula

10 Interference with HbA1c Assays Ethnicity Different concentrations of Hb, rates of glycation and lifespan of red cells Different sensitivities and specificities for each group. Genetic variants e.g. HbS, HbC traits Modified derivatives of Hb Carbamylated Hb in renal failure Acetylated Hb in patients taking large doses of Aspirin Diseases that shorten erythrocyte survival/decrease mean RBC age Recovery from blood loss Haemolytic anaemia Transfusion Iron deficiency anaemia increases A1c results (prolonged RBC survival) Patients with sickle cell disease, High Fetal Hb may not be suitable for measurement

11 Interference with HbA1c Assays Hypertriglyceridemia lead to overestimation of Hb and Hyperbilirubinemia Aldimine (precursor of A1c, normally 5.8% total) can in diabetes to 30% and overstimate A1c Percentage of A1c said to be lower in whites than in black patients Vitamin E reduces glycation Long term alcohol abuse can interfere Loop diuretics in the elderly A1c A1c is lower in pregnancy A1c is lower in chronic liver disease A1c is lower in patients on anti retroviral therapy A1c is higher in patients with chrome opiate use

12 Where there is interference with the assay OR Where there is a discrepancy between clinical assessment and A1c measurement: 1. Use another A1c measurement method, or 1. Test for alternate markers or diabetes control - fructosamine (unaffected by hemoglobinopathies) anhydroglucitol

13 Adoption of A1c as a Criterion for Diagnosis of Diabetes Another International Expert Committee reviewed diagnostic criteria 2009 Concluded improvement and standardization of assays made A1c accurate and reliable enough for use in diagnosis of diabetes, as well as in follow-up ADA published revised criteria Diabetes diagnosed if DCCT standardized assay A1c measurement 6.5% (in the absence of unequivocal hyperglycemia, this should be confirmed by repeat testing)

14 Relationship between A1c and FBS Based on NHANES data, A1c 6.5% will identify one third less than FBS 7.0 Lorenzo and Haffner (2010) comparing FBS 7.0 vs 2 hr PC 11.1 vs A1c 6.5 found A1c diagnosed the smallest number of patients However in low and middle income settings (Peru) of 964 subjects 0.9% had diabetes using FBS 7.0 but 3.5% had diabetes using A1c 6.5. More than half the A1c diagnosed diabetics had normal FBS Subjects were older, poorer, thinner and more likely to be rural.

15 Advantages of A1c Stability Accuracy Convenience Correlation with risk of micro and macrovascular disease No need for fasting Gives a picture of control over time

16 Disadvantages of A1c Higher cost: $6 - $8 vs < $1 May need ethnic based, age related or other cut off adjustments in some populations Cannot be used in patients with hemoglobinopathies, hemolytic anaemia, liver or kidney disease Correlation with post load glucose is not as strong as with FBS.

17 There appears to be a continuum of blood sugar values from prediabetes to DM This may be the case for A1c Currently there is not enough evidence to recommend a prediabetes range for A1c measurement In diabetes, the stakes are high Intervention in persons at risk should not be delayed because of over reliance on diagnostic criteria A combination of tests may be necessary Convenience should not be the only concern

18 A1c Measurement in the Diagnosis of Diabetes There are patients for whom the test may not be suitable The test is more convenient than FBS or OGTT The test is more expensive than FBS or OGTT The test may/may not diagnose diabetes in the same patients vs FBS or OGTT Useful for ongoing follow-up and management If you think the patient is at risk treat Use more than one test modality

19 References 1. Huisman TMJ and Dozy AM (1962) Studies on the heterogeneity of hemoglobin V. Binding of hemoglobin with oxidised glutathione. J Lab Clin Med 60, Rahbar S (2005). The discovery of glycated hemoglobin: a major event in the study of nonenzymatic chemistry in biological systems. Ann N.Y. Acad. Sci. 1043: Rahbar S (1968) An abnormal hemoglobin in red cells of diabetics. Clin Chim Acta 22: Malkani S, Mordes JP (2011) Implications of Using Hemoglobin A1C for Diagnosing Diabetes Mallitus. AM J.Med 124, Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A (1976) NEJM 295: Bunn MF, Gabbay, KM, Gallop PM (1978) The Glycosylation of Hemoglobin, Relevance to Diabetes Mellitus. Science 200: Miranda JJ, Bernabe-Ortiz A, Stanojevic S, Malaga G, Gilman, RH, Smeeth L (2011) A1c as a Diagnostic Criteria for Diabetes in Low- and Middle-Income settings: Evidence from Peru. Plos One 6(3): e Manley SE, Sikaris KA, Lu ZX, Nightingale PG, Stratton IM, Round RA, Baskar V, Gought SCL, Smith, JM (2009) Validation of an algorithm combining haemoglobin A1c and fasting plasma glucose for diagnosis of diabetes mellitus in UK and Austrailian populations. Diabet. Med. 26, Bennett CM, Guo M, Dharmage SC (2007) HbA1c as a screening tool for detection of Type 2 diabetes: a systematic review. Diabet. Med 24, Home K, Majkowska L (2010) Difficulties in interpreting HbA1c results. Pol Arch Med Wewn 120 (4) Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet Feb 6;375(9713):481-9