Hemoglobin A1c

Hemoglobin A is comprised approximately 97% of total hemoglobin and undergoes glycation with non-enzymatic attachment of a sugar to its amino groups.

Hemoglobin A-1 C has glucose attached to the N terminus of beta chains.

Reflects 2-3 month average endogenous exposure to glucose, including postprandial blood glucose spikes.

The quantity of hemoglobin A-1 C is directly related to the glucose concentration that red blood cells are exposed to over their lifespan, making it a clinically useful measure of mean glycemic
during the preceding months.

Represents the percent of hemoglobin A with glucose bound to it.

Reflects average glucose over approximately hundred 120 days, the average red blood cell lifespan.

Has low intraindividual variablitiy, especially in nondiabetics.

While a reliable marker of glycemic control, it may explain less than 25% of the risk of developing diabetic microvascular complications.

Formed by the nonenzymatic attachment of glucose to hemoglobin and reflects the ambient glucose concentration of the previous 2 to 3 months.

The mean lifespan is increased with splenectomy so that hemoglobin A-1 C is increased because of increased RBC exposure time for glycation.

When the mean erythrocyte lifespan is decreased such as with hemolytic anemia hemoglobin A-1C is decreased because of the reduced RBC exposure time for glycation.

With decreased erythropoiesis such as with iron deficiency anemia increased mean age of red blood cells increases hemoglobin A-1 C levels.

Severe chronic kidney disease may increase RBC glycation through lipid peroxidation of hemoglobin and by extending erythrocytes lifespan due to decreased erythropoietin levels, causing false elevation of hemoglobin A-1 C level.

Optimal control of diabetes defined as HbA1c level of less than 6.5%.

HbA1c levels greater than 6.5% generally lead to a diagnosis of diabetes, and HbA1c levels between 5.7% and 6.5% are considered prediabetic

American Diabetes Association recommends the use of glycated analysis in the diagnosis of diabetes because of the association between this test and microvascular disease.

The A1c test fails to diagnose diabetes as often as cases detected by the oral glucose tolerance test.

In this study, 9,000 adults without a diabetes diagnosis were given an A1c test and an oral glucose tolerance test.

The A1c test failed to diagnose 73 percent of diabetes cases that were detected by the oral glucose tolerance test.

The A1c test more likely to detect abnormal glucose levels in non-Hispanic whites than in non-Hispanic blacks or Hispanics.

Elevated levels associated with microvascular and neuropathic complications.

Levels of HbA1C and fructosamine depend on ability of glucose to covalently bind to free amine groups on proteins.

Glycation of circulating proteins produces fructosamine, whereas glycation of the N-terminal valine of the hemoglobin beta chain produces HgbA1c.

Glycated hemoglobin has an advantage over fasting glucose levels in that it has higher repeatability, can be assessed in a nonfasting state and that is the preferred test for monitoring glucose control.

The rate limiting step in the formation of glycated hemoglobin and fructoseamine is the glucose level, and measurements of hemoglobin A1c and fructoseamine are useful in monitoring glycemic control in diabetes.

Levels correlate with the risk of developing diabetic complications such as retinopathy, neuropathy, and nephropathy.

Lowering the level delays the onset and slows the progression of microvascular complications.

A better predictor of coronary artery disease and coronary artery mortality than fasting or postload glycemia.

An increase of 1% is associated with a significant increase in risk of cardiovascular death in men without diabetes.

A 14% reduction in the risk of myocardial infarction for each 1% decrease in the mean level of HbA1c in patients with recent onset diabetes (Stratton IM et al).

Each 1% decrease in A1C is associated with a 21% decrease in the risk of any adverse clinical outcome related to diabetes, including myocardial infarction, stroke, peripheral vascular disease, and microvascular complications.

The relative risk of cardiovascular disease in type 2 diabetes increases approximate 16% for every percentage point increase in hemoglobin A-1 C.

In a study of 48,444 type 2 diabetics during a periof of 2.4 years was associated with an increased risk of myocardial infarction of 8% and 9% increase in stroke (Elley CR et al).

The United Kingdom Prospective Diabetes Study revealed a 0,9% reduction in hemoglobin A-1 C associated with a 25% reduction in microvascular complications, but only a 14% non significant reduction in macrovascular complications.

Each 1% reduction in HbA1c associated with a 37% decrease in risk of microvascular complications and a 21% decrease in risk of death related to diabetes.

Treatment goal for diabetes is <7% and as close to 6% as possible without significant hypoglycemia.

United Kingdom Prospective Diabetes Study for type two diabetes demonstrates a reduction in microvascular complications when hemoglobin A-1C levels reach below 7%.

Higher levels associated with lower cognitive function in men with type 2 diabetes and metabolic syndrome.

May be a risk factor for macrovascular disease.

More than 2.4 million people who do not have diabetes in the United States have a glycated hemoglobin of greater than 6.0%, and 7 million have a value higher than 6% (Selvin E).

Individuals with hemoglobin A1C of greater than 6% or higher are at higher risk for the development of diabetes and glycated is a marker of cardiovascular risk in such patients(Selvin E).

Patients with hemoglobin A1C results of 5.7-6.4% are conceded to be at high risk to develop diabetes, and therefore have prediabetes.

Individuals with prediabetes have an increased risk of developing type two diabetes, estimated at 5-10% annually and 70% in a lifetime.

Patients with a hemoglobin A1C of 6-6.5% are at particularly high risk to develop diabetes.

HA1C level are falsely low in diabetics with liver disease limiting the usefulness of this monitoring tool.

Glycated hemoglobin evaluation in non-diabetic adults is associated with a risk of diabetes, and a more strong association with a risk of cardiovascular disease and death from any causes, compared to fasting glucose levels (Selvin E).

Disorders that affect glycosylation of hemoglobin include: sickle cell disease, sickle cell trait and red blood cell turnover processes such as iron deficiency invalidate A1C results and require alternate testing.

HbA1C is a diagnostic test for type 2 diabetes mellitus, but the World Health Organization recommends that a confirmatory diagnostic test be used, either a second HbA1C or a plasma glucose test.

HbA1C is the result of glycation of hemoglobin, and can be falsely elevated in processes that prolong the lifespan of circulating erythrocytes, decrease erythrocyte clearance, or cause abnormal reticulocyte production.

Processes that decrease the lifespan of circulating erythrocytes, cause increased hemoglobin turnover, or result in increased reticulocyte production, can falsely depress HbA1C levels.

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

Severe hypertriglyceridemia and chronic alcoholism can interfere with the essay for hemoglobin A-1 C.

Individual variation occurs in HbA1C, not attributable to mean glucose values.

Individual variation in hemoglobin A-1 C is defined as the glycation gap which is associated with diabetic nephropathy.

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

Genes may preferentially affect red sell lifespan for glycation.

Recent blood transfusion have variable effects and may either increase or decrease HbA1C.

Blacks and Hispanics may have higher glycation rates.

HbA1C may vary in Indian populations, secondary to high rates of hemoglobinopathies.

May increase with age.

Medications lowering HbA1C are ones that can cause hemolysis such as quinine, or sulfonamides.

Medications that can increase HbA1C include high dose aspirin.

HbA1c predicts incident diabetes better than fructosamine and glycated albumin.

Assays for A1C must be approved by the National Glycohemoglobin Standardization Program and standardized to the Diabetes control and Complications Trial assay (ADA).

Estimated Average glucose conversion chart from HgA1C:
5.5%-111 mg/dL
6%-126 mg/dL
6.5%-140 mg/dL
7%-154 mg/dL
7.5%-169 mg/dL
8%-183 mg/dL
8.5%-197 mg/dL
9%-to 212 mg/dL
9.5%-226 mg/dL
10%-240 mg/dL
10.5%-255 mg/dL
11%-269 mg/dL
11.5%-283 mg/dL

Disorders that alter hemoglobin structurally a chemically affect the reliability of hemoglobin A-1 C testing, by altering hemoglobin glycolysylation to A-1C, by making red cells more prone to break down so there is less time for glycosylation or abnormal peak in chromatography so estimating the level is unreliable.

American Geriatrics Society recommends targeting hemoglobin A-1 C level of 7-7 1/2% in healthy adults older adults with a long life expectancy, 7 1/2-8% in adults with moderate comorbidity and a life expectancy of less than 10 years, and 8-9% in patients with multiple comorbidities and a shorter life expectancy.

More than 700 disorders with abnormal hemoglobin can affect A1 C levels, so alternative forms of glucose monitoring should be considered in such patients.

In a study of individuals without preexisting cardiovascular disease or diabetes, the additional use of the HbA1c analysis provides little benefit for prediction of cardiovascular disease risk (The Emerging Risk Factors Collaboration).

The use of glucosamine sulfate has no effect on mean hemoglobin A-1 C levels.


HbA1c Variability in First Two Years After Diabetes Diagnosis Helps Predict CVD Risk


An analysis of 29k patients with type 2 diabetes suggests increased HbA1c variability within the first 2 years of a diabetes diagnosis was associated with a 30-59% increase in risk of incident cardiovascular disease.


Its possible that episodes of severely low blood sugar may be the connection.


29,260 patients with at least 4 HbA1c measurements obtained within the first 2 years following a diagnosis of type 2 diabetes were followed.


Increased risk for incident cardiovascular disease among each increasing quartile of HbA1c variability, with the second, third, and fourth quartiles at a 30% and 59% increase in risk, respectively, when compared to the first quartile.


HbA1c variability was also associated with increased risk of first and recurrent severe hypoglycemic events. 




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