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Christopher Saudek, M.D.
02-03-2011
- Hemoglobin A1c (HbA1c) is a stable adduct of glucose on the beta-chain of hemoglobin (N-[1-deoxyfructosyl]hemoglobin).
- Formed by a largely irreversible reaction, post-translationally and non-enzymatically, when hemoglobin circulating in a red blood cell is exposed to ambient glucose
- Alternate terms: "A1c" (preferred for use in communication with patients), "glycated hemoglobin" (the most accurate term), glycosylated hemoglobin.
- Expressed most often as the percent of hemoglobin that is glycated (alternatively, as mmol glycated hemoglobin per mole total hemoglobin).
- The single best test to monitor overall blood glucose control in diabetes (Saudek, 2006)
- Reflects the average blood glucose over about 3 months previously, although somewhat disproportionately weighted to recent blood glucose levels (Tahara)
- A strong indicator of risk for long-term diabetic complications, especially retinopathy, neuropathy and nephropathy (DCCT).
- Also an indicator of cardiovascular disease (CVD) risk, although glucose control is less strong of a risk factor for CVD than lipids, blood pressure and smoking (Selvin).
- Recently, HbA1c >6.5% is recommended as a criterion for diagnosing diabetes (International Expert Committee; Saudek, 2008).
- Many specific methods, divided into those that are based on charge (cation-exchange high pressure liquid chromatography (HPLC), electrophoresis, isoelectric focusing), structure (boronate-affinity chromatography , immunoassays) or chemical analysis (mass spectroscopy). Most commonly used methods in U.S. are HPLC and immunoassay.
- Hospital or commercial laboratory assays should be standardized through the National Glycohemoglobin Standardization Program (NGSP), a rigorous quality control program.
- Point-of-care equipment available for clinics and offices, requires careful standardization and quality control; often used for diabetes screening programs (Lenters-Westra).
- Generally, good correlation between point-of-care and laboratory A1c testing. However, 18% of patients with an HbA1c >7% by laboratory analysis were not similarly identified by the POC test (Schwartz).
- Kits for home use not recommended due to lack of quality control.
- Recommended for monitoring blood glucose control in all people with diabetes
- Recommended every 3-6 months, more often if treatment is changing rapidly
- Can be used for screening and diagnosis of people at high risk for diabetes (International Expert Committee).
- Directly correlated with average blood glucose over about 3 months' time
- Normal (non-diabetic) range is 4-6%
- Recommended A1c target for most people with diabetes is <6.5 - 7%, individualized according to the clinical situation.
- Over 8% generally considered poor blood glucose control; over 10% is very poor.
- Table describes relationship between A1c and average blood glucose
- Most accurate, recent equation to convert A1c to "estimated average glucose": eAG(mg/dl) = 28.7 × A1C - 46.7. eAG(mmol/l) = 1.59 × A1C - 2.59
- Be aware of confounders and effect modifiers (see Limitations and Confounders below, expanded in NGSP website).
- Not meaningfully affected by glycemic variability after accounting for mean blood glucose levels (Derr)
- Anything that lowers red blood cell survival time (such as hemolytic anemia) lowers A1c indpendent of blood glucose.
- Conversely, anything that increases the average age of red cells (such as aplastic anemia) increases A1c independent of blood glucose.
- Hemoglobinopathies interfere with valid A1c in some assays.
- For complete list of confounders and effect modifiers according to the method of assay, search NGSP website <http://www.ngsp.org/prog/index3.html>.
- Even in the case of hemoglobinopathies, measurements from most commonly used A1c assays are a valid reflection of glycemia, assuming red cell survival is normal.
- Laboratory quality control is essential. Normal values should be 4 to 6%.
- A1c is the test we use most often to indicate when treatment of blood glucose should be intensified.
- Not the preferred test for evaluating glycemic control in pregnancy, since A1c reflects control too slowly. In pregnancy, improvement of glucose control should be more quickly accomplished than possible based on A1c.
- Use of A1c in diagnosing diabetes is still new and controversial. Question about whether criteria should be adjusted according to racial/ethnic group.
- ADA statement in 2007 proposed worldwide use of International Federation of Clinical Chemistry (IFCC) new mass-spectroscopy-based reference method to standardize A1c assay; also recommended laboratory reporting value as conventional %, but also as mmol/mol, and as "estimated average glucose".
- Despite 2007 ADA statement, most clinicians continue reporting HbA1c as %.
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