Glycosylated hemoglobin


 * Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [mailto:psingh@perfuse.org];

Overview
Glycosylated (or glycated) hemoglobin (hemoglobin A1c, Hb1c, or HbA1c) is a form of hemoglobin used primarily to identify the average plasma glucose concentration over prolonged periods of time. Its name is sometimes abbreviated to A1C. It is formed in a non-enzymatic pathway by hemoglobin's normal exposure to high plasma levels of glucose. Glycosylation of hemoglobin has been implicated in nephropathy and retinopathy in diabetes mellitus. Monitoring the HbA1c in type-1 diabetic patients may improve treatment.

Historical Perspective
Hemoglobin A1c was first separated from other forms of hemoglobin by Huisman and Meyering in 1958 using a chromatographic column. It was first characterized as a glycoprotein by Bookchin and Gallop in 1968. Its increase in diabetes was first described in 1969 by Samuel Rahbar and coworkers The reactions leading to its formation were characterized by Bunn and his co-workers in 1975. The use of hemoglobin A1c for monitoring the degree of control of glucose metabolism in diabetic patients was proposed in 1976 by Koenig and coworkers.

Pathophysiology
In the normal 120-day life span of the red blood cell, glucose molecules join hemoglobin, forming glycated hemoglobin. In individuals with poorly controlled diabetes, increases in the quantities of these glycated hemoglobins are noted.

Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red cell reflects the average level of glucose to which the cell has been exposed during its life cycle. Measuring glycated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose regulation. The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months. Some researchers state that the major proportion of its value is related to a rather short term period of two to four weeks.

Interpretation of results
Laboratory results may differ depending on the analytical technique, the age of the subject, and biological variation among individuals. Two individuals with the same average blood sugar can have A1C values that differ by as much as 1 percentage point. In general, the reference range (that found in healthy persons), is about 4%–5.9%.

Higher levels of HbA1c are found in people with persistently elevated blood sugar, as in diabetes mellitus. While diabetic patient treatment goals vary, many include a target range of HbA1c values. A diabetic person with good glucose control has a HbA1c level that is close to or within the reference range. The International Diabetes Federation and American College of Endocrinology recommend HbA1c values below 6.5%, while American Diabetes Association recommends that the HbA1c be below 7.0% for most patients. A high HbA1c represents poor glucose control. Persistent elevations in blood sugar (and therefore HbA1c) increase the risk for the long-term vascular complications of diabetes such as coronary disease, heart attack, stroke, heart failure, kidney failure, blindness, erectile dysfunction, neuropathy (loss of sensation, especially in the feet), gangrene, and gastroparesis (slowed emptying of the stomach). Poor blood glucose control also increases the risk of short-term complications of surgery such as poor wound healing.

Lower than expected levels of HbA1c can be seen in people with shortened red blood cell life span, such as with glucose-6-phosphate dehydrogenase deficiency, sickle-cell disease, or any other condition causing premature red blood cell death. Conversely, higher than expected levels can be seen in people with a longer red blood cell life span, such as with Vitamin B12 or folate deficiency.

The approximate mapping between HbA1c values and average blood glucose measurements over the previous 4-12 weeks is shown in the table.

Indications
Glycosylated hemoglobin is recommended for both
 * Checking blood sugar control in people who might be pre-diabetic and
 * Monitoring blood sugar control in patients with more elevated levels, termed diabetes mellitus.

For a single blood sample, it provides far more diagnostic information regarding glycemic behavior than a fasting blood sugar value. That being said, fasting blood sugar tests are crucial in making treatment decisions. The American Diabetes Association guidelines are similar to others in advising that the glycosylated hemoglobin test be performed at least two times a year in patients with diabetes who are meeting treatment goals (and who have stable glycemic control) and quarterly in patients with diabetes whose therapy has changed or who are not meeting glycemic goals.

Changes in Diet and Treatment
Glycosylated hemoglobin measurement is not appropriate where there has been a change in diet or treatment within 6 weeks.

Abnormalities in Hemoglobin and Red Blood Cell Production
Likewise the test assumes a normal red blood cell aging process and mix of hemoglobin subtypes (predominantly HbA in normal adults). Hence people with recent blood loss or hemolytic anemia, or genetic differences in the hemoglobin molecule (hemoglobinopathy) such as sickle cell disease and other conditions are not suitable for this test. The alternative fructosamine test may be used in these circumstances and it similarly reflects an average of blood glucose levels over the preceding 2 to 3 weeks.

Variability Across Laboratories
There is variation among laboratories and a lack of consensus on a diagnostic threshold for glycosolated hemoglobin. For these and other reasons, no medical organization recommends the use of this test alone to diagnose diabetes. Instead, fasting plasma glucose or an oral glucose tolerance test are used.