(Glycosylated) Hemoglobin: Hba1c New Directions to Diagnose Diabetes

Article 368 1 Clock Hour Glycated (Glycosylated) Hemoglobin: HbA1c New directions to diagnose diabetes

Joseph Balatbat

2nd Place Winner 2010 AMT Technical Writing Contest

Also known as hemoglobin A1c, HbA1c, A1C or es the effectiveness of therapy by monitoring long- Hb1c, Glycated (Glycosylated) Hemoglobin is a term serum glucose regulation. In individuals with form of hemoglobin used primarily to identify the av- poorly controlled diabetes, the quantities of this erage plasma glucose concentration over a prolonged glycated hemoglobin are much higher than in period of time. Increased levels of glycated hemoglo- healthy people. bin has been associated with cardiovascular disease, Using the conversion table (See table 1) from the nephropathy, and retinopathy in diabetes mellitus. American Diabetes Association’s (ADA) 2005 posi- Monitoring the level of HbA1c in juvenile onset (type tion statement on Standards of Medical Care in Dia- 1Ð autoimmune) diabetes may improve treatment.1 betes, the 7.5% A1C reading would equate to an average blood glucose of about 168mg/dL. Bear in mind Background that the correlation between mean plasma glucose lev- In 1958, hemoglobin A1C was first separated els and A1C levels is an estimation only, dependent on from other forms of hemoglobin (Huisman and Me- methodology used for the calculation as well as other tering) using a chromatographic column.2 Ten years factors, such as the red blood cells’ life span. A 1 per- later, hemoclobin A1C was characterized as a glyco- cent change in an A1C result reflects a change of about protein (non-enzymatic attachment of glucose to pro- 30mg/dL (1.67 mmol/L) in average blood glucose. tein) by Bookchin and Gallop.3 Ralibar and cowork- ers4 wrote that the blood level of A1C is found to be Indications and Use elevated in diabetes and seven years thereafter, for- Glycated hemoglobin values reflect the 2-3 mally recommended its use to monitor the degree of month average endogenous exposure to glucose in- control of glucose metabolism in diabetic patients cluding postprandial spikes in the blood glucose (Cerami, Koenig, etal.).5 level, and have low intraindividual variability, par- ticularly in persons without diabetes.7, 8 These char- Principle and Measures acteristics may contribute to the superiority of gly- During the normal 120-day life span of the red cated hemoglobin over fasting glucose for long-term blood cell (RBC), glucose molecules react with he- macrovascular risk stratification. moglobin, forming glycated hemoglobin. Once a hemoglobin molecule is glycated, it remains in this TABLE 1: Mapping between HBA1c values and form. In people without diabetes, about 4% to 6% of Estimated Average Glucose (EAG) measurements their hemoglobin is glycosylated. Red blood cells (RBCs) that contain the hemoglobin circulate in the HbA1c Estimated Average Glucose (EAG) Mean Plasma Glucose (MPG) bloodstream for three to four months before being broken down and replaced. During that time, the % mg/dL Mmol/L RBC can bond, irreversibly, to glucose in the blood- 5 97 (76-120) 5.4 stream. A buildup of glycated hemoglobin within the 6 126 (100-152) 7.0 red blood cell therefore reflects the average level of 7 154 (123-185) 8.6 glucose to which the cell has been exposed during its 8 183 (147-217) 10.2 Dr. Joseph H. life cycle. Thus, A1C readings higher than about 6% 9 212 (170-249) 11.8 Balatbat, RMA, indicate higher than normal amounts of glucose 10 240 (193-282) 13.4 RPT, AHI, Vice- roaming the blood stream in the past 120 days. President for 11 269 (217-314) 14.9 Academic Affairs, Other studies state that the major proportion of its 12 298 (240-347) 16.5 Sanford-Brown value is related to a rather shorter period of two to Adapted: American Diabetes Association Standards of Medical Care Institute, New York four weeks.6 Measuring glycated hemoglobin assess- in Diabetes- 2009, Diabetes Care; 32: Suppl 1:S13-S61.14

112 August 2010 • Continuing Education Topics & Issues Recommendations for the diagnosis of diabetes point of diagnosis, however, the origin of diabetes is are based on the relations of fasting glucose and gly- an academic debate because the use or production of cated hemoglobin with microvascular disease, typi- insulin cannot realistically be measured on a popula- cally retinopathy.9, 10 Nonetheless, cardiovascular dis- tion-wide basis. Thus, we rely on the result of the ease is the leading cause of illness, death, and dysfunction-hyperglycemia to characterize and diag- hospitalization in persons with diabetes.11, 12 In a re- nose diabetes. In the United States, diagnosis is typi- cent study by Selvin et al,13 it was suggested that gly- cally made on the basis of fasting plasma glucose cated hemoglobin values in the normal range can (FPG), while in Europe and in clinical trials, an oral identify persons at increased risk for coronary heart glucose tolerance test (OGTT) is the preferred disease, stroke, and death before the diagnosis of method. Unfortunately, both tests have rather limited diabetes, indicating that glycated hemoglobin is a overlap, meaning that most persons diagnosed by an useful marker of cardiovascular risk and death from FPG would not be diagnosed by an OGTT and vice- any cause. versa.21 Furthermore, the two tests can produce dif- There is a significant proportion of people who are ferent results for the same person on different days.19 unaware of their elevated HbA1C level before they As if that weren’t sufficiently confusing, consider that have blood lab work.14, 15 For a single blood sample, it the level of hyperglycemia necessary to diagnose di- provides far more revealing information on glycemic abetes, by either test, is somewhat arbitrary. Because behavior than a fasting blood sugar value. That being it is not clear what level of hyperglycemia represents said, fasting blood sugar tests are crucial in making a given level of insulin use or production, once diag- treatment decisions. The American Diabetes Associ- nosed, we rely on A1C.9 ation guidelines are similar to others in advising that Use of A1C to diagnose diabetes has been consid- the glycosylated hemoglobin test be performed at ered by the expert panels in the past, but the idea has least twice a year in patients with diabetes who are been rejected.22, 23 The primary obstacle was a lack of meeting treatment goals, with stable glycemic con- standardization of the assay, but that is no longer the trol, and quarterly in patients with diabetes whose case.24 In fact, A1C is better standardized than other therapy has changed or who are not meeting measurements of glucose.17 Other advantages of A1C glycemic goals.16 Glycated hemoglobin measurement include the fact that it is a better indication of overall is not appropriate where there has been a change in glycemic exposure over time and that there is sub- diet or treatment within 6 week. Likewise, the test as- stantially less day-to-day variability.7 From a practical sumes a normal blood cell aging process and mix of standpoint, A1C is much easier to measure because it hemoglobin subtypes, predominantly HbA in normal does not require fasting or timed samples, and it is adults. Hence, people with recent blood loss, donated currently used to manage diabetes. The attractiveness blood recently or have hemolytic anemia or genetic of a single test to both diagnose and manage diabetes, differences in the hemoglobin molecule (hemoglo- especially while the test is easy to administer and binopathy) such as sickle-cell disease and other con- largely reproducible, suggests that greater reliance on ditions, are not suitable for this test. the A1C assay is inevitable. The expert panel followed the methods used to de- New Directions fine diagnostic thresholds for the FPG and OGTT, In July 2009, an international expert committee identifying 6.5% as the A1C level at which the preva- (appointed by the American Diabetes Association lence of diabetic retinopathy begins to rise above that (ADA), International Diabetes Federation (IDF) and of nondiabetic patients. the European Association for the Study of Diabetes The purpose in making diagnosis is to initiate (EASD) published a report that made the case for treatment. Whether early treatment reduces the risk using HbA1C assay to diagnose type 2 diabetes.17 Al- for microvascular and macrovascular complications though met with road blocks and controversies, in associated with diabetes has not yet been determined January 2010, the ADA now includes A1C as an ap- but knowing that early treatment can reduce those propriate diagnostic test,18 reversing its previous po- complications, diagnosis of diabetes must be done sition that recommended against it. sooner. Even it complications aren’t avoided with Chronic diseases imply damaged or dysfunctional early treatment, other benefits of lifestyle can cer- body parts. In the case of diabetes, the dysfunction is tainly accrue. Thus, there is little reason to delay di- in the body’s ability to make or use insulin. Whether agnosis (and treatment) until A1C reaches 6.5%. diabetes begins with the inability to properly use in- In summary, the expert panel has suggested that sulin (insulin resistance) or with inadequate produc- the A1C assay may be used to diagnose diabetes, rec- tion of insulin (beta-cell failure) is controversial but ommending 6.5% as the diagnostic threshold, and the most diabetic patients experience both problems ear- ADA has now accepted the suggestion. Regardless lier rather than later in the disease.19, 20 From the stand- of which test one decides to use, it is apparent that

Continuing Education Topics & Issues • August 2010 113 many factors play into account than just the result 13. Selvin, E, Steffes MW, et al. Glycated Hemoglobin, Diabetes, of the test in assessing a patient’s health risk and in and Cardiovascular Risk in Nondiabetic adults. N Eng J Med selecting the next treatment approach. If an expert 2010 362:800-11 14. Executive summary: Standards of Medical Care in Diabetes- panel wanted to take on the topic of diagnosing dia- 2010. Current criteria for the diagnosis of diabetes. Diabetes betes, perhaps it is time to run away from the glucose- Care. January 2010 33:S4-S10 centric definition to one that more clearly represents 15. Walid MS, Newman BF, et al. Prevalence of previously un- the full cardiometabolic risk of the individual patient. known elevation of glycosylated hemoglobin HbA1c in spine surgery patients and impact on length of stay and total cost. J Hosp Med. References 16. American Diabetes Association Standards of medical care in 1. Larsen ML, Horder M, et al. Effect of long-term monitoring of diabetes 2007. Diabetes Care 30 Suppl 1: S4-S41 glycosylated hemogolobin levels in insulin-dependent diabetes 17. The International Expert Committee. International Expert mellitus. N Engl J Med. 323 (15); 1021-15 Committee Report on the role of the A1C assay in the diagno- 2. Huisman TH, Martis EA, Dozy A. Chromatography of hemo- sis of diabetes,. Diabetes Care, 2009; 32; 1327-1334. Abstract globin types on carboxymethylcellulose. J. Lab Clin Med 52 18. American Diabetes Association. Diagnosis and classification (2): 312-27 of diabetes mellitus. Diabetes Care. 2010; 33:S62-S69. Ab- 3. Bookchin RM, Gallop PM. Structure of hemoglobin A1c: Na- stract. ture of the N=terminal beta chain blocking group. Biochem 19. Nathan DM, Davidson NB, DeFronco RA, et al. Impaired glu- Biophys Res. Common. 32 (1): 86-93 cose and impaired glucose tolerance: Implications for care. Di- 4. Rahbar S, Blumenfeld O, Ramney HM. Studies of an unusual abetes Care, 2007; 30:753-759. Abstract. hemoglobin in patients with diabetes mellitus. Biochem Phy 20. Kahn SE. The relative contributions of insulin resistance and Res. Commun, 36 (5): 838-43 beta-cell dysfunction to the pathophysiology of type 2 dia- 5. Koenig RJ, Petersen CM, Jones RL et al. Correlation of glu- betes. Diabetologia. 2003, 46:3-19. Abstract. cose regulation and hemoglobin A1c in diabetes mellitus. N 21. Unwin N, Shaw J, Zimmel P, et al Impaired glucose tolerance Eng J Med. 295 (8):417-20 and impaired fasting glycemia. The current status on defini- 6. Hemoglobin A1c Fact Sheet. Michigan Diabetes Research and tion and intervention. Diabet Med: 2002; 19:708-723. Ab- Training Center. stract. 7. Selvin E, Crainiceanau CM, Brancati FL. Short-term variabil- 22. American Diabetes Association. Report of the expert on the ity in measures of glycemia and implications for the classifi- diagnosis and classification of diabetes mellitus. Diabetes cation of diabetes. Arch Intern Med. 2007; 167:1545-1551. Care, 1997; 20:S1-S12. Abstract. 8. Meigs BJ, Nathan DM, et al. Tracking of glycated hemoglobin 23. American Diabetes Association. Report of the Expert Com- in the original cohort of the Framingham Heart Study J Clin mittee in the Diagnosis and Classification of Diabetes Mellitus. Epidemio 1996; 49; 411-7. Diabetes Care, 2003;26: S5-S20. Abstract. 9. American Diabetes Association Standards of medical care in 24. Consensus Committee. Consensus statement on the worldwide diabetes- 2009, Diabetes Care; 32: Suppl 1:S13-S61. standardization of the hemoglobin A1C measurement: the 10. American Diabetes Association Diagnosis and Classification American Diabetes Association, European Association for the of diabetes mellitus- Diabetes Care 2010; 33: Suppl 1:S62- Study of Diabetes, International Federation of Clinical Chem- S69. istry and Laboratory Medicine, and International Diabetes Fed- 11. Engelgau MM, Geiss LS,et al. The evolving diabetes burden in eration. Diabetes Care. 2007; 30:2399-2400. Abstract the United States. Ann Intern Med 2004:140: 945-50. 12. Bertoni AG, KropJS, et al. Diabetes-related morbidity and mortality in a national sample of U.S. elders. Diabetes Care 2002. 25:471-5.

114 August 2010 • Continuing Education Topics & Issues Questions for STEP Participants Article 368 1 Clock Hour You can submit your answers either online or manually. To submit your answers online, go to www.amt1.com, click on AMT Store on the top navigation bar. Click on STEP Online, then select the article number and purchase the relevant test (member fee is $3/online test, no cost for download of article — don't forget to login with your member ID to receive the discounted $3 online test fee; nonmember fee is $5 for download of article, $10 for online test). If you wish to submit answers manually (only available to AMT members — member fee is $6/manual test), please submit answers on official AMT answer sheets only. Request answer sheets by email: [email protected]; by fax: 847-823-0458; or by mail: STEP Program Answer Sheets, American Medical Technologists, 10700 W. Higgins Road, Suite 150, Rosemont, IL 60018. When submit- ting answers manually, please be sure to include all the required information on the answer sheet and the $6 processing fee per article. In the following, choose the one best answer for each question.

1 Glycated hemoglobin is also known as 6 The leading cause of illness, death, and A. HbA1C hospitalization in persons with diabetes is: B. Hb1c A. nephropathy C. Hemoglobin A1c B. cardiovascular disease D. All of the above C. retinopathy D. liver disease 2 Normal life span of an erythrocyte A. 30 days 7 A person is not suitable to test for HbA1c B. 24 hours when the individual has: C. 120 days A. recent blood loss D. 3Ð6 months B. hemoglobinopathy (variant Hgb molecule) 3 For people without diabetes, the average level C. sickle-cell disease of gylcosylated Hb is: D. All of the above A. below 4 % B. 4 to 6 % 8 In January 2010, the American Diabetes C. Above 10% Association (ADA) includes A1C assay as an D. 70 to 120 mg% appropriate diagnostic test for type 2 diabetes. A. True 4 A 1 percent change in an A1C result reflects a B. False change of about ______in average blood glucose. 9 Laboratory diagnosis of diabetes is obtained A. 5.5 % by: B. 30 mg/dl A. FPG C. 5.4 Mmol/l B. OGTT D. 120 mg % C. HBA1c D. All of the above 5 Glycated hemoglobin values reflect the two to three month average endogenous exposure to 10 Advantages of A1C assay: glucose including postprandial spikes in the A. does not require fasting blood glucose level. B. used to diagnose diabetes A. True C. used to manage diabetes therapy B. False D. All of the above

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