If A1C Results Are in Question, Can Fructosamine or Glycated Albumin Help?

Since 2010, the American Diabetes Association (ADA) has recommended HbA1C as the diagnostic test for type 2 diabetes mellitus (T2DM), while also advising that a confirmatory test be used in patients without overt clinical signs of hyperglycemia.¹ The World Health Organization recommends that a confirmatory diagnostic test be used, either a second HbA1C or a plasma glucose test.² The American Association of Clinical Endocrinologists (AACE) does not fully support these recommendations, allowing for the use of HbA1C as an adjunctive but not primary diagnostic test.³

Why such reservations about the A1C test?

When HbA1C Is Questionable

Since HbA1C is the result of glycation of hemoglobin, falsely elevated A1C values can be seen in processes that prolong the lifespan of circulating erythrocytes, decrease erythrocyte clearance, or cause abnormal reticulocyte production. Conversely, processes that decrease the lifespan of circulating erythrocytes, cause increased hemoglobin turnover, or result in increased reticulocyte production, can falsely depress HbA1C levels.⁴  

Specific pitfalls of the A1C test include^4-11:

- Falsely elevated HbA1C: seen in alcoholism, iron deficiency anemia, renal failure, liver disease, aplastic anemia, persistence of fetal hemoglobin, smoking.

- Falsely decreased HbA1C: seen in acute or chronic blood loss, hemolytic anemia, aplastic anemia, sickle cell anemia, hemoglobinopathies (eg, thalassaemias), glucose-6-phosphate dehydrogenase deficiency, splenectomy, malaria, HIV and other infections.

- Recent blood transfusion: complex effects-either increase or decrease.  

- Racial/ethnic variation: non-Hispanic blacks and Hispanic Americans may have higher glycation rates (research inconclusive); HbA1C may vary in some Asian Indian populations, secondary to high rates of hemoglobinopathies.  

- Age: may increase with age.

- Pregnancy: complex effects-either increase or decrease.

- Medication: can lower HbA1C levels (eg, drugs that cause hemolytic anemia, such as quinine antimalarial drugs, sulfonamides); or elevate HbA1C (eg, acetylated hemoglobin formed by very high–dose aspirin; metformin may increase glucose transport through erythrocyte membranes, although the clinical significance of this is unclear).

- Chronic kidney disease: complex effects related to iron deficiency, hemolytic anemia, hemodialysis, erythropoietin dose, recent transfusions, metabolic acidosis, etc.

- Standardization issues: recently improved, but variability still exists between methods and laboratories.

- Cost: runs high.

- Availability: unavailable in many countries.

- Slow Response: cannot be used to assess recent changes in therapy.

Other Options

Results of the Atherosclerosis Risk in Communities study (ARIC) study, combining researchers from Johns Hopkins, the University of Wisconsin, and the University of Minnesota, were recently published online in The Lancet Diabetes & Endocrinology.⁵ The study suggests that fructosamine and glycated albumin could be useful as adjunctive tests when HbA1C might not be valid, or when assessing short-term glycemic control. Key aspects of the study include⁵:

- Large, community-based sample of 11,348 adults free of diabetes and 958 adults with diabetes (both type 1 and type 2) were followed for nearly 2 decades.  

- HbA1c predicted incident diabetes better than fructosamine and glycated albumin.

- Fructosamine and glycated albumin were strongly associated with retinopathy (P<.0001) and predicted development of CKD nearly as well as HbA1C.

Fructosamine is formed when glucose binds to total serum proteins, mostly albumin. Glycated albumin is produced when glucose bonds to albumin. Neither are affected by erythrocyte or hemoglobin characteristics. Since serum proteins turn over every 10 to 14 days-faster than erythrocytes (every 120 days)-these tests can be used to measure short-term glucose control over 2- to 4-week periods. Like most tests, though, they’re not perfect.

Disadvantages:

- Alterations in serum protein turnover could affect results.

- Unclear whether there is a need to correct fructosamine for total serum protein concentration.

- Fructosamine and glycated albumin measurements could be affected by liver disease, hyperuricemia, acute illness or infection, and thyroid dysfunction.

Advantages:

- Low cost.

- Useful in settings where HbA1C is questionable, such as in HIV-infected patients.⁹

- Useful for assessing short-term (2- to 4-week) glycemic control.

More Work to Do

Fructosamine tests are widely available in many countries, although they have not caught on in clinical practice perhaps because of insufficient data about their usefulness in predicting long-term outcomes. Glycated albumin tests are commonly used in Japan for short-term monitoring of glycemia, but are not widely available in other countries. Although more work needs to be done, it is worth keeping the ARIC study and similar future studies on the radar as research that may help physicians manage patients with T2DM whose HbA1C values might not be telling the truth. 

References:

• American Diabetes Association. Standards of Medical Care in Diabetes 2010. Diabetes Care. 2010;33(suppl 1):S11-S61. doi:10.2337/dc10-S011. http://care.diabetesjournals.org/content/33/Supplement_1/S11.full#T2. Accessed January 27, 2014.
• World Health Organization. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus: abbreviated report of a WHO consultation 2011. Geneva, Switzerland.  http://www.who.int/diabetes/publications/report-hba1c_2011.pdf?ua=1. Accessed January 27, 2014.
• American Association of Clinical Endocrinologists/American College of Endocrinology. Position Statement on the Use of Hemoglobin A1C for the Diagnosis of Diabetes. Endocr Pract. 2010;16:155.  https://www.aace.com/files/position-statements/a1cpositionstatement.pdf. Accessed January 27, 2014.
• Reddy SA, Sachan A, Srinivasa Rao PVLN, Mohan A. Clinical applications of glycosylated haemoglobin. J Clin Sci Res. 2012;2:22-33.
• Selvin E, Rawlings AM, Grams M, et al. Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Lancet Diabetes Endocrinol. 2014 Jan 15; [Epub ahead of print]. doi:10.1016/S2213-8587(13)70199-2 (Abstract) http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70199-2/fulltext.
• Higgins T, Cembrowski G, Tran D, et al. Influence of variables on hemoglobin A1c values and nonheterogeneity of hemoglobin A1c reference ranges. J Diabetes Sci Technol. 2009;30:644–648.
• Haliassos A, Drakopoulos I, Katritsis D, et al. Measurement of glycated hemoglobin (HbA1c) with an automated POCT instrument in comparison with HPLC and automated immunochemistry method: evaluation of the influence of hemoglobin variants. Clin Chem Lab Med. 2006;44:223–227.
• Bonora E, Tuomilehto J. The pros and cons of diagnosing diabetes with A1C. Diabetes Care. 2011;34(suppl 2):S184-S190.
• Kim PS, Woods C, Georgoff P, et al. Hemoglobin A1c underestimates glycemia in HIV infection. Diabetes Care. 2009;32:1591-1593. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732167/pdf/zdc1591.pdf. (Full text)
• Egede LE, Gebregziabher M, Hunt KJ, et al. Regional, geographic, and racial/ethnic variation in glycemic control in a national sample of veterans with diabetes. Diabetes Care. 2011;34:938–943.  
• Zafon C, Ciudin A, Valladares S, et al. Variables involved in the discordance between HbA1c and fructosamine: the glycation gap revisited. PLoS One. 2013;8:e66696. doi:10.1371/journal.pone.0066696. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680426/pdf/pone.0066696.pdf. (Full text PDF)