Background study is to mainly focus on the use,

BackgroundInformation:Recent studies from different experts have helpedclarify the role and use of glycated haemoglobin in the management of diabetes. Diabetes,being one of the rapidly arisen diseases over the world can have massive consequencesin the future as according to WHO organisation, diabetes has affected over 400 millionpeople worldwide and the numbers are predicted to nearly double to it andbecome the seventh leadingcause of death in 2030 (WHO, 2016).  Diabetesmellitus (DM) is a metabolic disorder with heterogenous causes, which ischaracterised by chronic hyperglycaemia due to defects in insulin action,secretion or the combination of them both. This abnormality of insulin resultsin affecting the metabolism of carbohydrates, protein and fat (World HealthOrganisation, 2011). There are two main types of diabetes; type 1 diabetes,which is depended on insulin and type 2 diabetes which is not dependant oninsulin (Ahmed, 2011). Type 1 diabetes is an autoimmune disorder, which is aconsequence of an absolute insulin deficiency as a result of pancreatic betacell destruction by T-cell mediation (Kawasaki, 2014). Type 2 on the other hand is caused by insulinresistance. The pancreas produces insulin but it either is not enough or the insulinis not used by the body effectively (Isley and Molitch, 2005).

Overall, thisindicates that the body will build up glucose as there won’t be enough ofinsulin to process glucose or the body becomes resistance to the effect ofinsulin. This build up can lead to an increased risk of microvascular andmacrovascular diseases or other serious health complications such as, blindness,kidney failure and lower limbs amputation etc. Therefore, it is crucial to usehighly standardised tests such, as HbA1c as this test can provide strongindication of both diabetes and pre-diabetes in a timeframe, where actions canbe made immediately (Niflioglu et al., 2012)The aim of this study is to mainly focus on the use, powerand efficacy of the glycated haemoglobin (HbA1c) in the diagnosis of diabetesmellitus.Diagnostic criteria for DM:Asmentioned above that hyperglycaemia is a sign of diabetes, it will end up showinga few major symptoms like diabetic retinopathy and diabetic keto acidosis intype 1 diabetes. Diabetes patients can also experience polyuria, polydipsia,fatigues and weight loss (Ahmed, 2011). For manyyears, the main option carried out for the diagnosis of diabetes have been themeasurement of the glycaemic control level that individual exhibits, whichindicates the presence of glucose in their blood (American Diabetes Association,2013).

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Tests included in this option are fasting plasma glucose (FPG) test andOral glucose tolerance test (OGTT). HbA1c was later introduced and approved byWHO in 2011. The results of these obtained from WHO can be seen in table 1.The OGTT wasconsidered as a “gold standard” test, which made it possible to assess patients’ability to metabolise glucose (Sacks, 2011). OGTT is a two hours plasma glucoseindication. It requires patients to fast overnight in order to measure theirvenous plasma glucose concentration. A load of 75g anhydrous glucose is thenconsumed by patients and a glucose concentration after 2 hours is re-measured (WHO,2016). There are two categories where patients may fall into; IGT or IFG.

 These individuals are described as having prediabetesand are at significant risk of developing DM (mostly Type 2) and thecomplications associated with it. Table 1:WHO recommendations for the diagnostic criteria for diabetes or pre-diabetes(WHO, 2016).              * Valuesof venous plasma glucose after 2 hours of ingestion of 75 g oral glucose load Thelimitation with OGTT and FPG tests is that even though blood sugar levels canvary throughout the day and over time, these tests only measure blood glucose atone point at time. This indicate that a good measure of average plasma sugarover a particular time is not provided (Sacks, 2011). Therefore, the use of glycated haemoglobin HbA1c was introduced, whichgives more accurate diabetes diagnosis. HbA1c is not only helpful for the diagnosisof diabetes but it also manages the glycaemic control without any specialpreparation such as fasting. Thus, it has been deemed as a new “gold standard” diagnostictool for diabetes mellitus because of its properties (Alqahtani et al.

, 2013). In 2005,when WHO revealed their criteria, it included a statement that HbA1c should notbe adopted as a diagnostic test as the challenges of measurement accuracyoutweighed the convenience of its use. However later in 2011, they reviewedtheir previous decision to recommend HbA1c as diagnostic marker for diabetesand they came up with a conclusion that HbA1c can be used as a diagnostic testfor diabetes. Avalue of 6.5% (48mmol/L) is recommended as the cut-off point for diagnosingdiabetes. A value less than 6.

5% or to be more precise, a value between 5.7%and 6.4% indicates pre-diabetes.

If the value undercomes between 6.6.5, thereis a high risk of developing diabetes.

More than 7% is considered to be highthus risky. t is important to consider that HbA1c values below 6.5% and 5.7%do not reliably exclude the presence of diabetes and prediabetes,  Structure and process of the GlycatedHaemoglobin:HbA1c issynthesised by a non- enzymatic reaction of glucose molecule binding withN-terminal valine of the haemoglobin beta chains. This binding forms analdimine (Schiff base or labile HbA1c) which itselfis converted to 1-deoxyfructose. Schiff base then undergoes an Amadori rearrangement to form amore stable ketoamine (HbA1c) (Hare, Shaw and Zimmet, 2012). As seen in figure1, the two extra products i.

e., the formation of intermediate and advanced glycosylationproducts can be produced if diabetes is not diagnosed and treated on time.These extra products are considered to cause further complications fordiabetics as there will be a high risk of retinopathy and neuropathy (Singhet al., 2014).     Inaddition to HbA1c, as known that Red blood cells carry oxygento the tissues through the blood flow of the circulatory system, they containhaemoglobin and when the haemoglobin binds with glucose in the blood over the timeof 4 – 12 weeks, it becomes glycated.

 Thismeans that with more glucose present inthe blood, it is more likely that the glucose will interact with the haemoglobinand make more glycated haemoglobin. This formation decreases oxygen carrying capacity and limits thetissue oxygen delivery (Kilpatrick, 2000).Therefore, HbA1c is carried in order to prevent further damage. HbA1c providesan average glucose concentration over a period of 8-12 weeks (3 months). As haemoglobinglycation occurs over the life span of 120 days of red blood cells and becauseof this lifespan of erythrocytes, HbA1c is limited to 3 months… Measurementof HbA1c:There are various assays carried out to measure HbA1c. The principle of all these methods is to detach theglycated haemoglobin from non-glycated haemoglobin. Unlike other glycatedhaemoglobin fractions, HbA1c can be separated easily based on differences in netcharge (usually by HPLC) or structure (usually immunoassays or boronateaffinity chromatography). HPLC is the most commonly used assay for measuringHbA1c as Hb species are eluted from the exchange column at different rates due tocharge variability between HbA1c and other haemoglobin.

Spectrometry is thenused to calculate the concentration of HbA1c. However, interference with HBScan occur during this method. Immunoassays is another methodwhich involves the measurements of HbA1c specifically of antibodies in order torecognise the structure of the N- terminal glycated (usually first 4 – 10 aminoacids) of the Hb beta chain. This method allows the use of the PCO device,established by WHO. This device can measure the HbA1c concentration in ahospital rather than laboratories however, the disadvantage of this assay canbe the variable interference of haemoglobinopathies with altered amino acids onbinding sites.

Boronate affinity method is the less common one, which uses m-aminophenylboronicacid to react specifically with the cis-diol groups of glucose on Hb. This method measurestotal glycated GHB, including HbA1c and Hb glycated at other sites, and tendsto demonstrate the least interference from the presence of Hb variants andderivatives. The enzymatic method currently available measures HbA1c by usingan enzyme that specifically cleaves the N-terminal valine. Nevertheless, this methoddoes not only measure the glycationof N-terminal valine on ? chain, but also ? chains glycated at other sites andglycated ? chains.Total GHB is a term used to refer to all glycated Hb species. Total GHBis composed of HbA1c, and Hb glycated with glucose at other sites, includingthe glycated N terminus of the ? chain and the glycated ? amino groups oflysine residues.

It can be measured by affinity chromatographic methods. Circumstancesin which HbA1c should not be usedFor the vast majority of individuals withdiabetes, HbA1c is considered to be an excellent measurement ofthe glycaemic control. However, WHO provided a few clinical scenarios in which hbA1ctesting is considered unreliable (summarised in table 2 below). Most commonly,conditions that alter erythrocytes lifespan, glycation rate and availability ofglucose can significantly affect the accuracy of HbA1c.

These conditions mayeither result in decreased or increased hbA1c value. Whenerythrocyte lifespan is shortened, the HbA1c level is lowered, thus providing afalse negative result but when the lifespan is extended, the HbA1c isincreased, which also gives a falsely positive result (Florkowski, 2013).   Conditions Effect on HbA1c haemolytic anaemia lowers HbA1c concentration due to the lysis of erythrocytes.

Severe iron-deficiency anaemia causes 1-1.5% rise in HbA1c due to lengthened erythrocyte lifespan Pregnant individuals Lowers hba1c due to extended erythrocyte lifespan Individuals on medication, which increases glucose concentration due to insulin resistance e.g. steroids (Ahmed, 2011). Increases A1c thus would give falsly high hba1c children and young people under 18 or Type 1 diabetes patients. Decreases A1c due to rise in plasma glucose therefore, would give falsely low hba1c. Any type of haemoglobinopathies patients A1c is decreased due to an increased amount of non-HbA haemoglobin thus would result in low hba1c levels.  Advantages and Disadvantages ofHbA1cThe following table summarises the advantages and disadvantages of using HbA1c.

Advantages Disadvantages Can measure chronic glycaemia levels. Results can be misleading in certain physiological and disease states   It can be done at any time of the day. Still not available worldwide HbA1c is not disturbed by temporary lifestyle alterations unlike FPG and OGTT (Saudek et al., 2008)   HbA1c is more convenient than other glucose tests as there is no requirements for pre-test preparations such as fasting. Does not directly indicate the measurement of glycaemia.              Limitations of HbA1c:Glycation being not a direct measurement of glycaemia can beaffected by other factors, which would give incorrect hbA1c readings. Factors such as race or age are also reported toinfluence HbA1c.

For example, the level of HbA1c is higher inpeople from Asia and Africa compared to Caucasians. This means that differentcut off points for varying ethnicities must be assigned as individuals could beunder and over diagnosed if the same value is used. Therefore, it isrecommended that an alternative measure of glycaemic control is used in suchcircumstances, where HbA1c methods are invalidated. More research needs to be done in order to provide more accurate,reliable and variable reference values of HbA1c for various ethnicities anddifferent ages. Those different values can then be used worldwide to evaluatesuccessful diagnosis of diabetes Mellitus.

 HbA1c assays needs to be standardised internationally (by following IFCCand NGSP guidelines) to improve the accuracy of the diagnosis of diabetesMellites.