HbA1c Diagnostic value

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The Value of Screening: HbA1c as a Diagnostic Tool : 

1 The Value of Screening: HbA1c as a Diagnostic Tool Dr. Hussam Elmouzi Clinical pathologist Alborg Laboratory

What is Diabetes Mellitus? : 

What is Diabetes Mellitus? Diabetes Mellitus is a group of metabolic diseases characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both. Two main types: – Type 1 diabetes : pancreatic β-cells unable to synthesize and secrete insulin more prominent symptoms. (10%) – Type 2 diabetes : combination of insulin resistance and inadequate insulin secretion less prominent symptoms. (90%) Symptoms: if present, may include thirst, frequent urination, irritability, increased fatigue, weight loss, blurry vision As a result, the disease may be diagnosed several years after onset, once complications have already arisen.


Hyperglycemia Hyperglycemia!! – not diagnosis of Diabetes!! This includes people in ‘at risk’ catagories that are often underrated such as “pre-diabetes .” >95% of ‘pre-diabetics’ become diabetics New & existing data confirms that diabetic complications are occurring at this stage!

Complications of Diabetes: 

Complications of Diabetes Diabetes can cause long-term complications such as Heart kidney Eye Foot Skin and nerve disease 4 25% of diabetics manifest complications at diagnosis 7-year gap (onset diagnosis) Adults with diabetes are at high risk for cardiovascular disease (CVD). In fact, at least 65 percent of those with diabetes die from heart disease or stroke.

The global burden: 

The global burden 366 million people have diabetes in 2011; by 2030 this will have risen to 552 million Every 10 seconds two people develop diabetes The number of people with type 2 diabetes is increasing in every country 80% of people with diabetes live in low-and middle-income countries The greatest number of people with diabetes are between 40 to 59 years of age 183 million people (50%) with diabetes are undiagnosed Diabetes caused 4.6 million deaths in 2011 every 10 seconds a person dies from diabetes-related causes Diabetes is the fourth leading cause of global death by disease. Diabetes caused at least USD 465 billion dollars in healthcare expenditures in 2011; 11% of total healthcare expenditures in adults (20-79 years)

Diabetes in the MENA region (2011) : 

Diabetes in the MENA region (2011) Number of people with diabetes in MENA up by 94% in the next 20 years Number of people with IGT in MENA up by 77% in the next 20 years

PowerPoint Presentation: 

OBESITY IN SAUDI ARABIA 2007 Diabetics attending Diabetic Center KSU.

PowerPoint Presentation: 

Controls DM FAMILY HISTORY IN SAUDI ARABIA: + ve FAMILY HISTORY in general population = 32% +ve FAMILY HISTORY in diabetic population = 38% 2007 Diabetics attending Diabetic Center KSU.


HOW CAN THE BURDEN OF DIABETES BE REDUCED? Early diagnosis can be accomplished through relatively inexpensive blood testing. Treatment of diabetes involves lowering blood glucose and the levels of other known risk factors that damage to blood vessels.

PowerPoint Presentation: 

All adults who are overweight and have additional risk factors: Physical inactivity First degree relative with diabetes Members of a high risk population groups Women diagnosed with gestational diabetes or who delivered a baby weighing >9 lb. Hypertension (high blood pressure) or cholesterol abnormality Other clinical conditions associated with resistance to the effects of insulin In the absence of the above criteria, testing should begin at age 45 years If results are normal, testing should be repeated at least at 3 year intervals, with consideration of more frequent testing depending on initial results and risk status. 10 Who Should Be Screened for Diabetes?

Previous Criteria: 

Previous Criteria IFG IGT

Fasting glucose: 

Fasting glucose Advantages Cheapest ,Measurement is easy and widely available One specimen needed Single cut off >126 mg/dl Disadvantage Requires fasting Large biological variability 􀂃 Intra-individual CV 5%-8% 􀂃 Inter-individual CV 7%-13% Less sensitive than OGTT Preanalytic variability

Glucose tolerance testing: 

Glucose tolerance testing Advantages Gold standard for accuracy Disadvantage Logistically most challenging 2 hour wait Fasting 2 blood samples

PowerPoint Presentation: 

Should we use HbA1c to screen for and diagnose diabetes?

PowerPoint Presentation: 

What is HbA1c Adult Hemoglobin 97% Hb A 2.5% Hb A2 0.5% Hb F HbA1c ≠ Hb A1 Hb A1 =Hb A1a, Hb A1b, and Hb A1c HbA1c ~80% of Hb A1 Also known as fast hemoglobins, glycohemoglobins, glycated hemoglobin

PowerPoint Presentation: 

HbA1c is Glycosylated Haemoglobin 14% 7% 9% The HbA1c test reports the amount of HbA1c as a proportion of the total haemoglobin Glucose + haemoglobin Red blood cell Glycohaemoglobin HbA1c is simply haemoglobin to which circulating glucose has bound

PowerPoint Presentation: 

March February May April May 6.25% April March Feb March April April May 8.33% May 12.5% May 25.0% May 52% April 27% March 14.5% Feb 6.5% Test at end May What period is measured ? Month red blood cell produced Total influence of monthly blood glucose on HbA1c

Methodological Differences in HbA1c Testing : 

Methodological Differences in HbA1c Testing Separation based on charge differences between modified and unmodified hemoglobin (electrophoresis, ion-exchange chromatography) Substances with the same mobility as HbA1c will be recognized as HbA1c Separation based on structural differences that recognize glucose-modified from nonglucose- modified hemoglobin – Boronate affinity detects total glycated hemoglobin – Immunoassays use antibodies that recognize the glycated aminoterminus of the Hb beta chains including four or more amino acids

A Typical Patient Encounter: 

A Typical Patient Encounter “ What’s a hemoglobin A…whatever you said? I remember my hemoglobin was low when I was pregnant. What were those other numbers? What do you mean, 7%...of what?”

A1c Derived Average Glucose (ADAG) Study Diabetes Care, August 2008 Translating the A1c assay into estimated average glucose: 

A 1c D erived A verage G lucose (ADAG) Study Diabetes Care, August 2008 Translating the A1c assay into estimated average glucose Increased accuracy of HbA1c in reflecting the true average glycemia Results reported as A1c-derived average glucose “estimated average glucose” – eAG A1C eAG % mg/dl 6 126 6.5 140 7 154 7.5 169 8 183 8.5 197 9 212 9.5 226 10 240

ADAG Study Conclusion: HbA1c Correlates Highly With AG: 

ADAG Study Conclusion: HbA1c Correlates Highly With AG 50 100 150 200 250 300 350 400 450 AG (mg/dl) AG (mg/dl) = 28.7 x HbA1c – 46.7 3 4 5 6 7 8 9 10 11 12 Measured HbA1c (%)



New reference standards : 

New reference standards DCCT, the method used then for measuring HbA1c has been found to have interferences causing a falsely high number. Scientists and clinicians have been working for more than 10 years to produce a gold-standard, interference free method for HbA1c called International Federation of Clinical Chemistry (IFCC) Expressed as mmol/mol of Hb Measures “ pure” A1c

Why change from DCCT Alignment?: 

Why change from DCCT Alignment? Original DCCT method New modern methods DCCT aligned 8.0% 6.4% 8.0% 1.6% Interferences

Converting DCCT to IFCC - A quick trick : 

7% = 53mmol/mol Converting DCCT to IFCC - A quick trick For whole numbers between 4 and 13 Minus two, minus two... 7 - 2 = 5

Converting DCCT to IFCC - A quick trick : 

7% = 53mmol/mol Converting DCCT to IFCC - A quick trick For whole numbers between 4 and 13 Minus two, minus two... 7 - 2 = 5 5 - 2 = 3

Conversion table DCCT to IFCC : 

Conversion table DCCT to IFCC DCCT % HbA1c IFCC mmol/mol HbA1c 4 20 4.5 26 5 31 5.5 37 6 42 6.5 48 7 53 7.5 58 8 64 8.5 69 9 75 9.5 80 10 86 10.5 91 11 97 11.5 102 12 108 12.5 113 13 119 13.5 124 14 130 14.5 135 15 140 15.5 146 16 151 16.5 157 17 162

Reporting Formats: 

Reporting Formats HbA1c level = 8.0% (DCCT aligned) HbA1c level = 64 mmol/mol (IFCC aligned) This is the format which will appear in primary care reporting systems Internal hospital reports and results printed directly from HbA1c analysers may appear in a slightly different format

Current Status of HbA1c Reporting: 

Current Status of HbA1c Reporting The US will continue to report %HbA1c. Reporting of eAG has also been recommended by the ADA and AACC but will be calculated and reported by the laboratory (US only). Most other countries have decided to change to IFCC numbers – most will dual report for at least 1-2 years UK Ireland The Netherlands Scandinavia Italy Australia New Zealand Germany Canada

PowerPoint Presentation: 

A1c testing does not require overnight fast Increase rate of screening during non-fasting hours HbA1c reflects long-term glycemic burden Relatively less affected by acute (e.g., stress or illness related) perturbations in glucose levels Accepted and current guide in management of diabetes A1c laboratory methods well standardized and reliable Greater stability in tube (no rushing to the lab) Optimal assay standardization ≥ 6.5% seems to be a reasonable cut-point to avoid over-diagnosis. An A1c 5.7-6.4% indicates high risk for developing diabetes: “pre-diabetes” 30 Factors Supporting Use of A1C for Screening and Diagnosis International Expert Committee Report on the Role of the A1C Assay in the Diagnosiso Diabetes. DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009

Factors affecting HbA1c: 

Factors affecting HbA1c A1C values influenced by red cell survival. falsely high values -- low red cell turnover- -disproportionate number of older red cells Such as iron, vitamin B12, or folate deficiency anemia. falsely low values -- rapid red cell turnover – greater younger red cells such as hemolysis ,chronic blood loss sickle cell anaemia, thalassaemias and hereditary spherocytosis Interference from Hb variants is still of concern but at the present time most laboratories are using methods that show no interference from the most common variants .

PowerPoint Presentation: 

Improvement in Standardization of Hemoglobin A 1 c Assays 1993-2006 (99% in USA ,CANADA,UK) 1997 Expert Committee recommended against using A1C values for diagnosis in part because of the lack of assay standardization

Recommendation of the International Expert Committee for the Diagnosis of Diabetes: 

Recommendation of the International Expert Committee for the Diagnosis of Diabetes Levels at which the Dx is made based on when the risk for retinopathy goes up A1c > 6.5% = Diabetes

PowerPoint Presentation: 

There was a stronger correlation between A1C and retinopathy than between fasting glucose levels and retinopathy Similar correlation between A1c and Retinopathy has been seen in DCCT/ UKPDS trials

Diabetes, CVD and Death: 

Diabetes, CVD and Death HbA1c (5.5-6.5) HbA1c (6.0-6.5) IFG (100-125 mg/dl) Diabetes 1.9 4.5 2.2 CHD 1.3 1.9 1.0 Stroke 1.2 2.2 0.9 Death 1.2 1.6 1.1 The Atherosclerosis Risk in Communities (ARIC) Community-based prospective cohort 15,792 middle-aged adults from four U.S. communities. Whites and Blacks only 15 years follow-up Selvin, E., M. W. Steffes, et al. (2010). N Engl J Med 362(9): 800-811.

PowerPoint Presentation: 

A1C Risk of Diabetes 5.0% 0.1% 5.5-6.0% 9 - 25% 6.0-6.5% 25 - 50% Meta-analysis of 16 studies 44,203 participants Follow-up 5.6 years Zhang, X., E. W. Gregg, et al. (2010). Diabetes Care 33(7): 1665-73.

Performance of HbA1c for the Classification and Prediction of Diabetes: 

Performance of HbA1c for the Classification and Prediction of Diabetes For HbA1c, using a cutoff point of 5.9% to identify types 2 diabetes sensitivity (to determine true positives) is reported to be in the range of 76-95% and specificity (to determine true negatives) is 67-86%., When aligning optimum cutoff values with the Diabetes Control and Complications Trial (DCCT) at 6.1-6.2%, corresponding sensitivity is 43%-81% and specificity is 79%-99%. * implications for the use of FPG and HbA(1c) for cost-effective screening. Diabetes Care 2003;26:485-90. * Efficient cutoff points for three screening tests for detecting undiagnosed diabetes and prediabetes. Diabetes Care 2005;28(6):1321-5. * Combined use of a fasting plasma glucose concentration and HbA1c for fructosamine predicts the likelihood of having diabetes in high-risk subjects. Diabetes Care 1998;21:1221-5. According to some good-quality studies cited in the evidence HbA1c values in the range of 5.6-6.0% appear to predict a higher incidence of future diabetes in prediabetic patients and seem to be the most cost-effective for diagnosing type 2 diabetes

PowerPoint Presentation: 

Microvascular complications 37% 14% Deaths related to diabetes Microvascular complications HbA 1c 37% 14% Deaths related to diabetes Microvascular complications HbA 1c 37% 14% Deaths related to diabetes Microvascular complications HbA 1c 37% 14% Deaths related to diabetes 21% Microvascular complications HbA 1c 37% 14% Deaths related to diabetes 21% Microvascular complications HbA 1c 37% 14% Deaths related to diabetes 21% 1% Myocardial infarction DCCT showed that HbA1c is the best long-term marker of diabetes control Better control of HbA1c leads to better outcomes in people with diabetes Stratton IM, et al . BMJ 2000; 321:405–412.

Laboratory changes What’s going on : 

Laboratory changes What’s going on • ADA revisions to Clinical Practice Recommendations – Include the use of HbA1c to diagnose diabetes (> 6.5%) – Include HbA1c to identify individuals at increased risk for diabetes (5.7-6.4%)

ADA Diagnostic Criteria: Normal, Diabetes, and Pre-diabetes Clinical Practice Recommendations 2010: 

ADA Diagnostic Criteria: Normal, Diabetes, and Pre-diabetes Clinical Practice Recommendations 2010 Parameter Normal Diabetes Pre-diabetes Method 1 Fasting Plasma Glucose (mg/dl) <100 ≥126 100–125 No caloric intake for at least 8 h 2 2-h plasma glucose on OGTT (mg/dl) <140 ≥200 140–199 WHO method: 75 g glucose load 3 Random plasma glucose (mg/dl) <140 ≥200 - with classic symptoms of hyperglycemia or crisis 4 A1C % <5.7 ≥6.5 5.7 – 6.4 NGSP certified method standardized to the DCCT assay

Screening test face-off: 

Screening test face-off Glucose tolerance Fasting Glucose A1C Convenience Cost Accuracy Technical factors Each test identifies overlapping subsets of pre-diabetes Each becomes positive at a different time in the progression to diabetes, unique to each person Each reflects a different relative prominence of the mechanisms underlying diabetes (B-cell failure, insulin resistance, etc.)

What Should We do?: 

U.S. National Health and Nutrition Examination Survey (NHANES) data revealed that 50-60 % of patients with fasting plasma glucose ≥126 mg/dL had A1C <6.5%, suggesting that A1C might reduce the number of people diagnosed. Measuring fasting and 2-h glucose values to diagnose diabetes…has limitations, but there may be less risk…to an individual being misdiagnosed as could occur with A1C based on age, ethnicity, renal disease, anemia, or hemoglobinopathy.” What Should We do? Diabetes care 2009;32:e141-e147

What Should We do?: 

What Should We do? 2 hr PP glucose has the highest specificity Hard to do in office practice FPG is better than A1c as single test A1c is easy to do and has a high specificity More expensive Effected by hemoglobinopathies, hemolysis and anemia

Screen with combination strategy: 

Screen with combination strategy If FPG < 100 mg/dl and A1c <6.0%: Normal glucose tolerance If FPG > 126 and A1c > 6.5%: Dx diabetes If one is diagnostic of DM and other is not: repeat the high test and if still positive: Dx diabetes If one or both in Prediabetic (FPG >100 and <126 mg/dl) or At risk range (A1c >6.0 and <6.5), do a 2hr PP glucose after 75 gm of glucose If > 200 mg/dl repeat to confirm Dx DM If >140 and <200 mg/dl Dx with IGT, prediabetes or at risk for diabetes Follow carefully * DIABETES TECHNOLOGY & THERAPEUTICS Volume 13, Number 12, 2011 Mary Ann Liebert, Inc. DOI: 10.1089/dia.2011.0074 * Diabetes Care 2010;33:S62-S69

Take Home Message: 

Take Home Message Diabetes mellitus is the most challenging problem in the 21 century with nearly 50% undiagnosed cases usually 25% represent with complications at the time of diagnoses with high cost medically and finically . Six countries in the MENA region are among the world’s ten highest for prevalence rates for both diabetes and impaired glucose tolerance mainly due to obesity ,lack of activity and genetic ability. ADA in 2010 recommended HBA1c test not only for diabetic control but also as early diagnostic tool due to it’s accuracy , simplicity and rapid testing ability. Combined screening strategy of diabetes for more accurate diagnosis. HbA1c should be reported with estimated average glucose for easy meaning and follow up. IFCC a new reference range in mmol/mol should be applied in HbA1c reporting beside % of glycated Hb ( duel report ) for better accuracy .