Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
(Hb) that is chemically linked to a sugar. Most
monosaccharide
Monosaccharides (from Greek ''monos'': single, '' sacchar'': sugar), also called simple sugars, are the simplest forms of sugar and the most basic units (monomers) from which all carbohydrates are built.
They are usually colorless, water-solub ...
s, including
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
,
galactose
Galactose (, '' galacto-'' + '' -ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molec ...
and
fructose
Fructose, or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galacto ...
, spontaneously (i.e.
non-enzymatically) bond with hemoglobin when present in the bloodstream. However, glucose is less likely to do so than galactose and fructose (13% that of fructose and 21% that of galactose), which may explain why
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
is used as the primary metabolic fuel in humans.
The formation of the sugar-hemoglobin linkage indicates the presence of excessive sugar in the bloodstream, often indicative of
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
in high concentration (HbA1c ≥ 5.7%). A1C is of particular interest because it is easy to detect. The process by which sugars attach to hemoglobin is called
glycation
Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proces ...
. HbA1c is a measure of the component of hemoglobin.
HbA1c is measured primarily to determine the three-month average
blood sugar level and can be used as a diagnostic test for
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
and as an assessment test for
glycemic control
The term ''diabetes'' includes several different metabolic disorders that all, if left untreated, result in abnormally high concentration of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces ...
in people with
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
. The test is limited to a three-month average because the average lifespan of a red blood cell is four months. Since individual red blood cells have varying lifespans, the test is used as a limited measure of three months. Normal levels of glucose produce a normal amount of glycated hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. In diabetes, higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have been associated with
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
,
nephropathy
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can ...
,
neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...
, and
retinopathy
Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically inc ...
.
Terminology
Glycated hemoglobin is preferred over
glycosylated
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
hemoglobin to reflect the correct (non-enzymatic) process. Early literature often used ''glycosylated'' as it was unclear which process was involved until further research was performed. The terms are still sometimes used interchangeably in English-language literature.
The naming of HbA1c derives from hemoglobin type A being separated on
cation exchange chromatography. The first fraction to separate, probably considered to be pure hemoglobin A, was designated HbA0, and the following fractions were designated HbA1a, HbA1b, and HbA1c, in their order of
elution
In analytical and organic chemistry, elution is the process of extracting one material from another by washing with a solvent; as in washing of loaded ion-exchange resins to remove captured ions.
In a liquid chromatography experiment, for exam ...
. Improved separation techniques have subsequently led to the isolation of more
subfractions.
History
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
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
by Bookchin and Gallop in 1968.
Its increase in diabetes was first described in 1969 by
Samuel Rahbar Samuel Rahbar ( fa, سموئیلِ رهبر ''Samu'il-e Rahbar'' May 12, 1929 - November 10, 2012) was an Iranian scientist who discovered the linkage between diabetes and HbA1C, a form of hemoglobin used primarily to identify plasma glucose concen ...
''
et al
References
Notes
References
Further reading
*
*
{{Latin phrases
Lists of Latin phrases, E ...
.''
The reactions leading to its formation were characterized by Bunn and his coworkers in 1975.
The use of hemoglobin A1c for monitoring the degree of control of glucose metabolism in diabetic patients was proposed in 1976 by
Anthony Cerami
Anthony Cerami (born October 3, 1940) is an American entrepreneur and medical research scientist.
Biography
Anthony Cerami received his undergraduate degree from Rutgers University and received a Ph.D. in 1967 from Rockefeller University, New Y ...
, Ronald Koenig and coworkers.
Damage mechanisms
Glycated hemoglobin causes an increase of highly reactive
free radicals
In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron.
With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spont ...
inside blood cells, altering the properties of their
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s. This leads to
blood cell aggregation and increased blood
viscosity
The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water.
Viscosity quantifies the inte ...
, which results in impaired blood flow.
Another way glycated hemoglobin causes damage is via
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, which results in
atherosclerotic
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no sy ...
plaque (
atheroma
An atheroma, or atheromatous plaque, is an abnormal and reversible accumulation of material in the inner layer of an arterial wall.
The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount o ...
) formation. Free-radical build-up promotes the
excitation
Excitation, excite, exciting, or excitement may refer to:
* Excitation (magnetic), provided with an electrical generator or alternator
* Excite Ballpark, located in San Jose, California
* Excite (web portal), web portal owned by IAC
* Electron exc ...
of
Fe2+-hemoglobin through into abnormal
ferryl
A transition metal oxo complex is a coordination complex containing an oxo ligand. Formally O2-, an oxo ligand can be bound to one or more metal centers, i.e. it can exist as a terminal or (most commonly) as bridging ligands (Fig. 1). Oxo ligan ...
hemoglobin (Fe
4+-Hb). Fe
4+ is unstable and reacts with specific
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s in hemoglobin to regain its Fe
3+ oxidation state
In chemistry, the oxidation state, or oxidation number, is the hypothetical charge of an atom if all of its bonds to different atoms were fully ionic. It describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. C ...
. Hemoglobin molecules clump together via
cross-linking reactions, and these hemoglobin clumps (multimers) promote cell damage and the release of Fe
4+-hemoglobin into the
matrix
Matrix most commonly refers to:
* ''The Matrix'' (franchise), an American media franchise
** ''The Matrix'', a 1999 science-fiction action film
** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchis ...
of innermost layers (
subendothelium) of arteries and veins. This results in increased permeability of interior surface (
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
) of blood vessels and production of pro-inflammatory
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
adhesion
Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another).
The forces that cause adhesion and cohesion can be ...
proteins, which promote
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
accumulation in blood vessel surfaces, ultimately leading to harmful plaques in these vessels.
Highly glycated Hb-
AGEs go through
vascular smooth muscle
Vascular smooth muscle is the type of smooth muscle that makes up most of the walls of blood vessels.
Structure
Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood ...
layer and inactivate
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
-induced endothelium-dependent relaxation, possibly through binding to
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(NO), preventing its normal function. NO is a potent
vasodilator
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
and also inhibits formation of plaque-promoting
LDL
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
s (i.e. “bad cholesterol”)
oxidized
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
form.
This overall degradation of blood cells also releases
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
from them. Loose heme can cause oxidation of endothelial and LDL proteins, which results in plaques.
Principle in medical diagnostics
Glycation of proteins is a frequent occurrence, but in the case of hemoglobin, a nonenzymatic condensation reaction occurs between glucose and the N-end of the
beta chain
Hemoglobin subunit beta (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the ''HBB'' gene, which along with alpha globin ( HBA), makes up the most common form of haemoglobin in adult humans, hemogl ...
. This reaction produces a
Schiff base
In organic chemistry, a Schiff base (named after Hugo Schiff) is a compound with the general structure ( = alkyl or aryl, but not hydrogen). They can be considered a sub-class of imines, being either secondary ketimines or secondary aldimine ...
(R-N=CHR', R = beta chain, CHR'= glucose-derived), which is itself converted to 1-deoxyfructose. This second conversion is an example of an
Amadori rearrangement The Amadori rearrangement is an organic reaction describing the acid or base catalyzed isomerization or rearrangement reaction of the ''N''-glycoside of an aldose or the glycosylamine to the corresponding 1-amino-1-deoxy-ketose. The reaction is i ...
.
When blood glucose levels are high,
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
molecules attach to the hemoglobin in
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s. The longer hyperglycemia occurs in blood, the more glucose binds to hemoglobin in the red blood cells and the higher the glycated hemoglobin.
Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red cell, therefore, 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.
A1c is a weighted average of blood glucose levels during the life of the red blood cells (117 days for men and 106 days in women). Therefore, glucose levels on days nearer to the test contribute substantially more to the level of A1c than the levels in days further from the test.
This is also supported by data from clinical practice showing that HbA1c levels improved significantly after 20 days from start or intensification of glucose-lowering treatment.
Measurement
Several techniques are used to measure hemoglobin A1c. Laboratories may use
high-performance liquid chromatography
High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
,
immunoassay
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoass ...
,
enzymatic
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
assay,
capillary electrophoresis
Capillary electrophoresis (CE) is a family of electrokinetic separation methods performed in submillimeter diameter capillaries and in micro- and nanofluidic channels. Very often, CE refers to capillary zone electrophoresis (CZE), but other electr ...
, or
boronate affinity chromatography
Affinity chromatography is a method of separating a biomolecule from a mixture, based on a highly specific macromolecular binding interaction between the biomolecule and another substance. The specific type of binding interaction depends on the ...
.
Point of care
Clinical point of care (POC) is the point in time when clinicians deliver healthcare products and services to patients at the time of care.
Clinical documentation
Clinical documentation is a record of the critical thinking and judgment of a health ...
(e.g., doctor's office) devices use immunoassay boronate affinity chromatography.
In the United States, HbA
1c testing laboratories are certified by the National Glycohemoglobin Standardization Program to standardize them against the results of the 1993
Diabetes Control and Complications Trial
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased a ...
(DCCT). An additional percentage scale, Mono S has previously been in use by Sweden and KO500 is in use in Japan.
[HbA1c in a new way]
By the Swedish Diabetes Association. Retrieved Mars 2011
Switch to IFCC units
The American Diabetes Association,
European Association for the Study of Diabetes
The European Association for the Study of Diabetes (EASD) is a scientific association founded in Montecatini Terme, Italy in 1965 with Joseph Hoet as Founding President. The aims of the association are to encourage and support research in the fiel ...
, and
International Diabetes Federation
The International Diabetes Federation (IDF) is an umbrella organization of over 230 national diabetes associations in more than 160 countries and territories. The Federation has been leading the global diabetes community since 1950. It is headqua ...
have agreed that, in the future, HbA
1c is to be reported in the
(IFCC) units.
IFCC reporting was introduced in Europe except for the UK in 2003;
the UK carried out dual reporting from 1 June 2009 until 1 October 2011.
Conversion between DCCT and IFCC is by the following equation:
:
Interpretation of results
Laboratory results may differ depending on the analytical technique, the age of the subject, and biological variation among individuals. Higher levels of HbA
1c are found in people with persistently elevated blood sugar, as in
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
. While diabetic patient treatment goals vary, many include a target range of HbA
1c values. A diabetic person with good glucose control has an HbA
1c level that is close to or within the reference range.
The International Diabetes Federation and the American College of Endocrinology recommend HbA
1c values below 48 mmol/mol (6.5 DCCT %), while the
American Diabetes Association
The American Diabetes Association (ADA) is a United States-based nonprofit that seeks to educate the public about diabetes and to help those affected by it through funding research to manage, cure and prevent diabetes (including type 1 diabetes, ...
recommends HbA
1c be below 53 mmol/mol (7.0 DCCT %) for most patients. Results from large trials in suggested that a target below 53 mmol/mol (7 DCCT %) for older adults with type 2 diabetes may be excessive: Below 53 mmol/mol, the health benefits of reduced A1c become smaller, and the intensive glycemic control required to reach this level leads to an increased rate of dangerous hypoglycemic episodes.
A retrospective study of 47,970 type 2 diabetes patients, aged 50 years and older, found that patients with an HbA
1c more than 48 mmol/mol (6.5 DCCT %) had an increased mortality rate, but a later international study contradicted these findings.
A review of the
UKPDS
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, Action to Control Cardiovascular Risk in Diabetes (ACCORD), Advance and Veterans Affairs Diabetes Trials (VADT) estimated that the risks of the main complications of diabetes (
diabetic retinopathy
Diabetic retinopathy (also known as diabetic eye disease), is a medical condition in which damage occurs to the retina due to diabetes mellitus. It is a leading cause of blindness in developed countries.
Diabetic retinopathy affects up to 80 perc ...
,
diabetic nephropathy
Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease ...
,
diabetic neuropathy
Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic c ...
, and
macrovascular disease
Macrovascular disease is a disease of any large (''macro'') blood vessels in the body. It is a disease of the large blood vessels, including the coronary arteries, the aorta, and the sizable arteries in the brain and in the limbs.
This sometimes ...
) decreased by about 3% for every 1 mmol/mol decrease in HbA
1c.
However, a trial by ACCORD designed specifically to determine whether reducing HbA
1c below 6.0% using increased amounts of medication would reduce the rate of cardiovascular events found higher mortality with this intensive therapy, so much so that the trial was terminated 17 months early.
Practitioners must consider patients' health, their risk of hypoglycemia, and their specific health risks when setting a target HbA
1c level. Because patients are responsible for averting or responding to their own hypoglycemic episodes, their input and the doctors' assessments of the patients'
self-care
Self-care has been defined as the process of establishing behaviors to ensure holistic well-being of oneself, to promote health, and to actively management of illness when it occurs. Individuals engage in some form of self-care daily with food ...
skills are also important.
Persistent elevations in blood sugar (and, therefore, HbA
1c) increase the risk of long-term vascular complications of diabetes, such as
coronary disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves Ischemia, the reduction of blood flow to the myocardium, heart muscle due to build-up o ...
,
heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
,
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
,
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
,
kidney failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
,
blindness
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment ...
,
erectile dysfunction
Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...
,
neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...
(loss of sensation, especially in the feet),
gangrene
Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
, and
gastroparesis
Gastroparesis (gastro- from Ancient Greek γαστήρ – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis"), also called delayed gastric emptying, is a medical disorder consisting of weak muscular contractions (peristalsis) ...
(slowed emptying of the stomach). Poor blood glucose control also increases the risk of short-term complications of surgery such as poor
wound healing
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
.
Lower-than-expected levels of HbA
1c can be seen in people with shortened red blood cell lifespans, such as with
glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency (G6PDD), which is the most common enzyme deficiency worldwide, is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. ...
,
sickle-cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
, or any other condition causing premature red blood cell death. Blood donation will result in rapid replacement of lost RBCs with newly formed red blood cells. Since these new RBCs will have only existed for a short period of time, their presence will lead HbA
1c to underestimate the actual average levels. There may also be distortions resulting from
blood donation
A blood donation occurs when a person voluntarily has blood drawn and used for blood transfusion, transfusions and/or made into biopharmaceutical medications by a process called Blood fractionation, fractionation (separation of whole blood com ...
during the preceding two months, due to an abnormal synchronization of the age of the RBCs, resulting in an older than normal average blood cell life (resulting in an overestimate of actual average blood glucose levels). Conversely, higher-than-expected levels can be seen in people with a longer red blood cell lifespan, such as with iron deficiency.
Results can be unreliable in many circumstances, for example after blood loss, after surgery, blood transfusions, anemia, or high erythrocyte turnover; in the presence of chronic renal or liver disease; after administration of high-dose vitamin C; or
erythropoetin treatment.
In general, the
reference range
In medicine and health-related fields, a reference range or reference interval is the range or the interval of values that is deemed normal for a physiological measurement in healthy persons (for example, the amount of creatinine in the blood, o ...
(that found in healthy young persons), is about 30–33 mmol/mol (4.9–5.2 DCCT %). The mean HbA
1c for diabetics type 1 in Sweden in 2014 was 63 mmol/mol (7.9 DCCT%) and for type 2, 61 mmol/mol (7.7 DCCT%).
The approximate mapping between HbA
1c values given in DCCT percentage (%) and eAG (estimated average glucose) measurements is given by the following equation:
:eAG(mg/dL) = 28.7 × A1C − 46.7
eAG(mmol/L) = 1.59 × A1C − 2.59
Data in parentheses are 95%
confidence interval
In frequentist statistics, a confidence interval (CI) is a range of estimates for an unknown parameter. A confidence interval is computed at a designated ''confidence level''; the 95% confidence level is most common, but other levels, such as 9 ...
s
Normal, prediabetic, and diabetic range
The 2010
American Diabetes Association
The American Diabetes Association (ADA) is a United States-based nonprofit that seeks to educate the public about diabetes and to help those affected by it through funding research to manage, cure and prevent diabetes (including type 1 diabetes, ...
Standards of Medical Care in Diabetes added the =HbA
1c ≥ 48 mmol/mol (≥6.5 DCCT %) as another criterion for the diagnosis of diabetes.
Indications and uses
Glycated hemoglobin testing is recommended for both checking the blood sugar control in people who might be prediabetic and monitoring blood sugar control in patients with more elevated levels, termed diabetes mellitus. For a single blood sample, it provides far more revealing information on glycemic behavior than a fasting blood sugar value. However, fasting blood sugar tests are crucial in making treatment decisions. The American Diabetes Association guidelines are similar to others in advising that the glycated hemoglobin test be performed at least twice 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.
Glycated hemoglobin measurement is not appropriate where a change in diet or treatment has been made within 6 weeks. 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,
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
, or genetic differences in the hemoglobin molecule (
hemoglobinopathy
Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.
There are tw ...
) such as
sickle-cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
and other conditions, as well as those who have donated blood recently, are not suitable for this test.
Due to glycated hemoglobin's variability (as shown in the table above), additional measures should be checked in patients at or near recommended goals. People with HbA
1c values at 64 mmol/mol or less should be provided additional testing to determine whether the HbA
1c values are due to averaging out high blood glucose (
hyperglycemia
Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...
) with low blood glucose (
hypoglycemia
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
) or the HbA
1c is more reflective of an elevated blood glucose that does not vary much throughout the day. Devices such as continuous
blood glucose monitoring
Blood glucose monitoring is the use of a glucose meter for testing the concentration of glucose in the blood ( glycemia). Particularly important in diabetes management, a blood glucose test is typically performed by piercing the skin (typically, ...
allow people with diabetes to determine their blood glucose levels on a continuous basis, testing every few minutes. Continuous use of blood glucose monitors is becoming more common, and the devices are covered by many health insurance plans, but not by
Medicare in the United States. The supplies tend to be expensive, since the sensors must be changed at least every 2 weeks. Another useful test in determining if HbA
1c values are due to wide variations of blood glucose throughout the day is
1,5-anhydroglucitol, also known as
GlycoMark. GlycoMark reflects only the times that the person experiences hyperglycemia above 180 mg/dL over a two-week period.
Concentrations of hemoglobin A1 (HbA1) are increased, both in diabetic patients and in patients with
kidney failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
, when measured by
ion-exchange chromatography
Ion chromatography (or ion-exchange chromatography) separates ions and polar molecules based on their affinity to the ion exchanger. It works on almost any kind of charged molecule—including large proteins, small nucleotides, and amino a ...
. The thiobarbituric acid method (a chemical method specific for the detection of glycation) shows that patients with kidney failure have values for glycated hemoglobin similar to those observed in normal subjects, suggesting that the high values in these patients are a result of binding of something other than glucose to hemoglobin.
In
autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of ...
, concentrations of HbA1 is undetectable. Administration of
prednisolone
Prednisolone is a steroid medication used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers. Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthrit ...
will allow the HbA1 to be detected. The alternative
fructosamine
Fructosamines are compounds that result from glycation reactions between a sugar (such as fructose or glucose) and a primary amine, followed by isomerization via the Amadori rearrangement. Biologically, fructosamines are recognized by fructosamin ...
test may be used in these circumstances and it also reflects an average of blood glucose levels over the preceding 2 to 3 weeks.
All the major institutions such as the International Expert Committee Report, drawn from the International Diabetes Federation, the European Association for the Study of Diabetes, and the American Diabetes Association, suggest the HbA
1c level of 48 mmol/mol (6.5 DCCT %) as a diagnostic level. The Committee Report further states that, when HbA
1c testing cannot be done, the fasting and glucose-tolerance tests be done. Diagnosis of diabetes during pregnancy continues to require fasting and glucose-tolerance measurements for
gestational diabetes
Gestational diabetes is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms; however, it increases the risk of pre-eclampsia, depression, and of ...
, and not the glycated hemoglobin.
Modification by diet
Meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
has shown
probiotic
Probiotics are live microorganisms promoted with claims that they provide health benefits when consumed, generally by improving or restoring the gut microbiota. Probiotics are considered generally safe to consume, but may cause bacteria-host i ...
s to cause a statistically significant reduction in glycated hemoglobin in
type 2 diabetics.
Trials with multiple strains of probiotics had statistically significant reductions in glycated hemoglobin, whereas trials with single strains did not.
Standardization and traceability
Hemoglobin A1c is now standardized and traceable to IFCC methods HPLC-CE and HPLC-MS. The change to the newer unit of mmol/mol is part of this standardization. The standardized test does not test for iodine levels in the blood;
hypothyroidism
Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
or iodine supplementation are known to artificially raise the A1c.
Veterinary medicine
HbA1c testing has not been found useful in the treatment of cats and dogs with diabetes, and is not generally used;
fructosamine
Fructosamines are compounds that result from glycation reactions between a sugar (such as fructose or glucose) and a primary amine, followed by isomerization via the Amadori rearrangement. Biologically, fructosamines are recognized by fructosamin ...
is favoured instead.
See also
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Diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
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Hemoglobin A2
Hemoglobin A2 (HbA2) is a normal variant of hemoglobin A that consists of two alpha and two delta chains (α2δ2) and is found at low levels in normal human blood. Hemoglobin A2 may be increased in beta thalassemia or in people who are heterozygo ...
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Prediabetes
Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...
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Proteopedia
Proteopedia is a wiki, 3D encyclopedia of proteins and other molecules.
The site contains a page for every entry in the Protein Data Bank (>130,000 pages), as well as pages that are more descriptive of protein structures in general such as acetylc ...
Structure of glycated hemoglobin
References
External links
National Diabetes Information Clearinghouse
American Diabetes Association Standards of Medical Care 2007
{{DEFAULTSORT:Glycated Hemoglobin
Blood tests
Diabetes-related tests
Diabetes
Glucose
Hemoglobins
Medical tests