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World J Methodol. Jun 26, 2016; 6(2): 133-142
Published online Jun 26, 2016. doi: 10.5662/wjm.v6.i2.133
Methods, units and quality requirements for the analysis of haemoglobin A1c in diabetes mellitus
Ilkka Penttilä, Karri Penttilä, Päivi Holm, Harri Laitinen, Päivi Ranta, Jukka Törrönen, Rainer Rauramaa
Ilkka Penttilä, Jukka Törrönen, Rainer Rauramaa, Kuopio Research Institute of Exercise Medicine, University of Eastern Finland, 70100 Kuopio, Finland
Karri Penttilä, Finnish Medicines Agency FIMEA, 70210 Kuopio, Finland
Päivi Holm, Fimlab Laboratories Ltd., 30430 Tampere, Finland
Harri Laitinen, Päivi Ranta, Labquality Ltd., 00530 Helsinki, Finland
Author contributions: All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Conflict-of-interest statement: The authors indicate that none of the authors have no potential conflicts of interest related to the manuscript and that they have had not any financial support. Ilkka Penttilä, MD, PhD, Emeritus Professor is the survey expert for glycohemoglobin of Labquality Ltd, Harri Laitinen is PhM and the International relationship manager of Labquality Ltd., and Päivi Ranta is specialist of clinical biochemistry for HbA1c surveys of Labquality Ltd, Päivi Holm is the specialist in clinical biochemistry for mpere university hospital, Karri Penttilä, MD, PhD is specialist in internal medicine and hematology acting as the clinician for this report, and Rainer Rauramaa, MD, PhD professor as the chief of the Kuopio Research Institute of Exercise Medicine. The numerical data from Labquality Ltd. has been received with permission for this report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ilkka Penttilä, MD, PhD, Kuopio Research Institute of Exercise Medicine, University of Eastern Finland, Haapaniementie 16, 70100 Kuopio, Finland. ilkka.penttila@uef.fi
Telephone: +358-40-5825564
Received: September 19, 2015
Peer-review started: September 22, 2015
First decision: October 30, 2015
Revised: March 1, 2016
Accepted: March 24, 2016
Article in press: March 25, 2016
Published online: June 26, 2016
Processing time: 278 Days and 3.1 Hours
Abstract

The formation of glycohemoglobin, especially the hemoglobin A1c (HbA1c) fraction, occurs when glucose becomes coupled with the amino acid valine in the β-chain of Hb; this reaction is dependent on the plasma concentration of glucose. Since the early 1970s it has been known that diabetics display higher values OF HbA1C because they have elevated blood glucose concentrations. Thus HbA1c has acquired a very important role in the treatment and diagnosis of diabetes mellitus. After the introduction of the first quantitative measurement OF HbA1C, numerous methods for glycohemoglobin have been introduced with different assay principles: From a simple mini-column technique to the very accurate automated high-pressure chromatography and lastly to many automated immunochemical or enzymatic assays. In early days, the results of the quality control reports for HbA1c varied extensively between laboratories, therefore in United States and Canada working groups (WG) of the Diabetes Controls and Complications Trial (DCCT) were set up to standardize the HbA1c assays against the DCCT/National Glycohemoglobin Standardization Program reference method based on liquid chromatography. In the 1990s, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) appointed a new WG to plan a reference preparation and method for the HBA1c measurement. When the reference procedures were established, in 2004 IFCC recommended that all manufacturers for equipment used in HbA1c assays should calibrate their methods to their proposals. This led to an improvement in the coefficient of variation (CV%) associated with the assay. In this review, we describe the glycation of Hb, methods, standardization of the HbA1c assays, analytical problems, problems with the units in which HbA1c values are expressed, reference values, quality control aspects, target requirements for HbA1c, and the relationship of the plasma glucose values to HbA1c concentrations. We also note that the acceptance of the mmol/mol system for HbA1c as recommended by IFCC, i.e., the new unit and reference ranges, are becoming only slowly accepted outside of Europe where it seems that expressing HbA1c values either only in per cent units or with parallel reporting of percent and mmol/mol will continue. We believe that these issues should be resolved in the future and that it would avoid confusion if mmol/mol unit for HbA1c were to gain worldwide acceptance.

Keywords: Diabetes; Hemoglobin A1c; Glycohemoglobin; Glucose; International Federation of Clinical Chemistry and Laboratory Medicine; Reference values; Quality assurance; Recommendation; Target limits

Core tip: The aim of this review is to clarify methods, units, quality requirements, reference and cutoff limits for hemoglobin A1c (HbA1c) and ratio of blood glucose/HbA1c on the basis of the results from Finnish quality control surveys by comparing them to the literature. The HbA1c surveys of Labquality Ltd. (Helsinki, Finland) were started in 1986 by using two fresh EDTA-blood samples. From 1994, the number of the participating laboratories had risen to 139, of which 75 were Finnish and 64 from five other countries. In 2014, the number of the participating laboratories was total 214, 141 were Finnish and 73 from 13 other countries.