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ORIGINAL ARTICLES Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications Part 1: Diagnosis and Classification of Diabetes Mellitus Provisional Report of a WHO Consultation K.G.M.M. Alberti*1, P.Z. Zimmet2 for the WHO Consultation3 1Department of Medicine, University of Newcastle upon Tyne, UK 2International Diabetes Institute, Caulfield, Australia The classification of diabetes mellitus and the tests used for its diagnosis were brought into order by the National Diabetes Data Group of the USA and the second World Health Organization Expert Committee on Diabetes Mellitus in 1979 and 1980. Apart from minor modifications by WHO in 1985, little has been changed since that time. There is however considerable new knowledge regarding the aetiology of different forms of diabetes as well as more information on the predictive value of different blood glucose values for the complications of diabetes. A WHO Consultation has therefore taken place in parallel with a report by an American Diabetes Association Expert Committee to re-examine diagnostic criteria and classification. The present document includes the conclusions of the former and is intended for wide distribution and discussion before final proposals are submitted to WHO for approval. The main changes proposed are as follows. The diagnostic fasting plasma (blood) glucose value has been lowered to $7.0 mmol l21 (6.1 mmol l21). Impaired Glucose Tolerance (IGT) is changed to allow for the new fasting level. A new category of Impaired Fasting Glycaemia (IFG) is proposed to encompass values which are above normal but below the diagnostic cut-off for diabetes (plasma $6.1 to ,7.0 mmol l21; whole blood $5.6 to ,6.1 mmol l21). Gestational Diabetes Mellitus (GDM) now includes gestational impaired glucose tolerance as well as the previous GDM. The classification defines both process and stage of the disease. The processes include Type 1, autoimmune and non-autoimmune, with beta-cell destruction; Type 2 with varying degrees of insulin resistance and insulin hyposecretion; Gestational Diabetes Mellitus; and Other Types where the cause is known (e.g. MODY, endocrinopathies). It is anticipated that this group will expand as causes of Type 2 become known. Stages range from normoglycaemia to insulin required for survival. It is hoped that the new classification will allow better classification of individuals and lead to fewer therapeutic misjudgements. ª 1998 WHO Diabet. Med. 15: 539–553 (1998) KEY WORDS diabetes mellitus; classification; diagnosis; Type 1 diabetes; Type 2 diabetes; gestational diabetes mellitus Received 24 April 1998; accepted 24 April 1998 3Contributors: K.G.M.M. Alberti, University of Newcastle upon Tyne, UK (Co-Chairman); P.Z. Zimmet, International Diabetes Institute, Caulfield, Australia (Co-Chairman); A. Alwan, World Health Organiza- tion, Alexandria, Egypt; P. Aschner, ACD and Javerlana University, Bogota, Colombia; J.-P. Assal, University Hospital, Geneva, Switzerland; P.H. Bennett, NIDDK, Phoenix, AZ, USA; L. Groop, University of Lund, Malmo¨, Sweden; J. Jervell, Rikshospitalet, Oslo, Norway; Y. Kanazawa, Jichi Medical School, Omiya, Japan; H. Keen, Guy’s Hospital and Medical School, London, UK; H. King, World Health Organization, Geneva, Switzerland; R. Klein, University of Wisconsin Medical School, Madison, WI, USA; J.-C. Mbanya, Centre Hospitalier et Universitaire de Yaounde´, Cameroon; A. Motala, University of Natal, Congella, South Africa; Pan X.-R., China-Japan Friendship Hospital, Beijing, China PR (deceased 8 July 1997); A. Ramachandran, Diabetes Research Centre, Madras, India; N. Samad, Dow Medical College & Civil Hospital, Karachi, Pakistan; P. Vardi, Schneider Children’s Centre, Petah-Tikvah, Israel. 539CCC 0742–3071/98/070539–15$17.50 Ó 1998 WHO DIABETIC MEDICINE, 1998; 15: 539–553 Observers: D. McCarty, International Diabetes Institute, Caulfield, Australia (Rapporteur); N. Unwin, University of Newcastle upon Tyne, UK (Rapporteur); R. Kahn, American Diabetes Association, USA; R.A. Rizza, Americna Diabetes Association, USA; M. Berrens, Bayer, Germany; J. Nolan, Institute for Diabetes Discovery, USA; S. Pramming, Novo Nordisk, Denmark. Note: This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organization. The views expressed in documents by named authors are solely the responsibility of those authors. Sponsors: Bayer, UK; Bayer, Germany; Novo Nordisk, Copenhagen, Denmark; Institute for Diabetes Discovery, New Haven, USA *Correspondence to: Professor George Alberti, Department of Medicine, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK ORIGINAL ARTICLES Introduction In the late 1970s both WHO1 and the National Diabetes Data Group2 produced new diagnostic criteria and a new classification system for diabetes mellitus. This brought order to a chaotic situation in which nomencla- ture varied and diagnostic criteria showed enormous variations using different oral glucose loads. In 1985 WHO slightly modified their criteria to coincide more closely with the NDDG values.3 NDDG later modified their diagnostic requirements for diabetes mellitus in adults, dropping the intermediate sample and becoming identical with WHO. There are now many data available, and much more aetiological information has appeared. It seemed timely to re-examine the issues and to update and refine both the classification and the criteria. In particular it has seemed necessary to modify the diagnos- tic fasting plasma glucose level and to look at intermediate non-diagnostic, but not normal, fasting levels. It also seemed reasonable to place the classification system on a more aetiological basis. Both the American Diabetes Association (ADA) and a WHO working group met separately to discuss these issues. Fortunately there was cross-representation on the two groups and, in general, similar conclusions were reached. The ADA published their recommendations in 1997,4 while the WHO group present their conclusions below for consultation and comment. It should be added that the WHO group has also developed proposals for the diagnosis and classification of the complications of diabetes, and these will be published shortly. At this juncture we are seeking comments and constructive suggestions with the aim of modifying the document. It should be noted that, unlike the ADA, we do not make recommendations about screening as these will vary widely according to local factors. We would urge you to send comments to the Co-Chairmen of the WHO group before the end of September 1998. Definition and Diagnostic Criteria for Diabetes Mellitus and Other Categories of Glucose Intolerance Definition The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hypergly- caemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non-ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. Often symptoms are not severe, 540 K.G.M.M. ALBERTI ET AL. Ó 1998 WHO Diabet. Med. 15: 539–553 (1998) or may be absent, and consequently hyperglycaemia of sufficient degree to cause pathological and functional changes may be present for a long time before the diagnosis is made. The long-term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular, and cerebro- vascular disease. Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action. The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin. Diagnosis and Diagnostic Criteria Diagnosis If a diagnosis of diabetes is made, the clinician must feel confident that the diagnosis is fully established since the consequences for the individual are considerable and lifelong. The requirements for diagnostic confirmation for a person presenting with severe symptoms and gross hyperglycaemia differ from those for the asymptomatic person with blood glucose values found to be just above the diagnostic cut-off value. Severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. For the asymptomatic person, at least one additional plasma/blood glucose test result with a value in the diabetic range is essential, either fasting, from a random (casual) sample, or from the oral glucose tolerance test (OGTT). If such samples fail to confirm the diagnosis of diabetes mellitus, it will usually be advisable to maintain surveillance with periodic re-testing until the diagnostic situation becomes clear. In these circumstances, the clinician should take into consideration such additional factors as family history, age, adiposity, and concomitant disorders, before deciding on a diagnostic or therapeutic course of action. It should be reiterated that the diagnosis of diabetes in an asymptomatic subject should never be made on the basis of a single abnormal blood glucose value. An alternative to the single blood glucose esti- mation or OGTT has long been sought to simplify the diagnosis of diabetes. Glycated haemoglobin, reflecting average glycaemia over a period of weeks, was thought to provide such a test. Although in certain cases it gives equal or almost equal sensitivity and specificity to glucose measurement, it is not available in many parts of the world and is not sufficiently well standardized for its use to be recommended at this time. ORIGINAL ARTICLES Diabetes in Children Diabetes in children usually presents with severe symptoms, very high blood glucose levels, marked glycosuria, and ketonuria. In most children the diagnosis is confirmed without delay by blood glucose measurements, and treatment (including insulin injection) is initiated immediately, often as a life-saving measure. An OGTT is neither necessary nor appropriate for diagnosis in such circumstances. A small proportion of children and adolescents, however, present with less severe symptoms and may require a fasting blood glucose and/or an OGTT for diagnosis. Diagnostic Criteria The clinical diagnosis of diabetes is often prompted by symptoms such as increased thirst and urine volume, recurrent infections, unexplained weight loss and, in severe cases, drowsiness and coma; high levels of glycosuria are usually present. A single blood glucose estimation in excess of the diagnostic values indicated in Figure 1 (black zone) establishes the diagnosis in such cases. Figure 1 also defines levels of blood glucose below which a diagnosis of diabetes is unlikely in non- pregnant individuals. These criteria are as in the 1985 report.3 For clinical purposes, an OGTT to establish diagnostic status need only be considered if casual blood glucose values lie in the uncertain range (i.e. between the levels that establish or exclude diabetes). If an OGTT is performed, it is sufficient to measure the blood glucose values while fasting and at 2 h after a 75 g oral glucose load (Annexes 1 and 2). For children the oral glucose load is related to body weight: 1.75 g kg21. The diagnostic criteria in children are the same as for adults. Diagnostic Figure 1. Unstandardized (casual, random) blood glucose values in the diagnosis of diabetes in mmol l21 (mg dl21). Taken from the 1985 WHO Study Group Report3 541DIAGNOSIS AND CLASSIFICATION OF DIABETES MELLITUS Ó 1998 WHO Diabet. Med. 15: 539–553 (1998) interpretations of the fasting and 2-h post-load concen- trations in non-pregnant subjects are shown in Table 1. Change in Diagnostic Value for Fasting Plasma/Blood Glucose Concentrations The major change in the diagnostic criteria for diabetes mellitus from the previous WHO recommendation3 is the lowering of the diagnostic value of the fasting plasma glucose concentration to 7.0 mmol l21 (126 mg dl21) and above, from the former level of 7.8 mmol l21 (140 mg dl21) and above. For whole blood the proposed new level is 6.1 mmol l21 (110 mg dl21) and above, from the former 6.7 mmol l21 (120 mg dl21). The new fasting criterion is chosen to represent a value which in most persons is of approximately equal diagnostic significance to that of the 2-h post-load concentration, which is not changed. This equivalence has been established from several population-based studies5–7 and it also represents an optimal cut-off point to separate the components of bimodal frequency distributions of fasting plasma glucose concentrations seen in several populations. Furthermore, several studies have shown increased risk of microvascular disease in persons with fasting plasma glucose concentrations of 7.0 mmol l21 (126 mg dl21) and over,6 and of macrovascular disease in persons with such fasting concentrations, even in those with 2-h values of ,7.8 mmol l21 (140 mg dl21).8 Epidemiological Studies For population studies of glucose intolerance and diabetes, individuals have been classified by their blood glucose concentration measured after an overnight fast and/or 2 h after a 75 g oral glucose load. Since it may be difficult to be sure of the fasting state, and because ORIGINAL ARTICLES Table 1. Values for diagnosis of diabetes mellitus and other categories of hyperglycaemia Glucose concentration (mmol l21 (mg dl21)) Whole blood Plasmaa Venous Capillary Venous Diabetes Mellitus: Fasting $6.1 ($110) $6.1 ($110) $7.0 ($126) or 2-h post glucose load $10.0 ($180) $11.1 ($200) $11.1 ($200) or both Impaired Glucose Tolerance (IGT): Fasting concentration (if measured) ,6.1 (,110) ,6.1 (,110) ,7.0 (,126) and 2-h post glucose load $6.7 ($120) and $7.8 ($140) and $7.8 ($140) and ,10.0 (,180) ,11.1 (,200) ,11.1 (,200) Impaired Fasting Glycaemia (IFG): Fasting $5.6 ($100) and $5.6 ($100) and $6.1 ($110) and ,6.1 (,110) ,6.1 (,110) ,7.0 (,126) 2-h (if measured) ,6.7 (,120) ,7.8 (,140) ,7.8 (,140) aCorresponding values for capillary plasma are: for Diabetes Mellitus, fasting $7.0 ($126), 2-h $12.2 ($220); for Impaired Glucose Tolerance, fasting ,7.0 (,126) and 2-h $8.9 ($160) and ,12.2 (,220); and for Impaired Fasting Glycaemia $6.1 ($110) and ,7.0 (,126) and if measured, 2-h ,8.9 (,160). For epidemiological or population screening purposes, the fasting or 2-h value after 75 g oral glucose may be used alone. For clinical purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day unless there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms. Glucose concentrations should not be determined on serum unless red cells are immediately removed, otherwise glycolysis will result in an unpredictable underestimation of the true concentrations. It should be stressed that glucose preservatives do not totally prevent glycolysis. If whole blood is used, the sample should be kept at 0–4 ° C or centrifuged immediately, or assayed immediately. of the strong correlation between fasting and 2-h values, epidemiological studies or diagnostic screening have in the past been restricted to the 2-h values only (Table 1). If the OGTT is difficult to perform for any reason (e.g. logistical, economic) it is now recommended that fasting plasma glucose alone can be used for epidemiological purposes. It should be recognized that some of the individuals identified by fasting values may be different from those identified by the 2-h values, and that overall prevalence may be somewhat different,9 although not always.5,10 Ideally both the 2-h and the fasting value should be used. Classification Earlier Classifications The first widely accepted classification of diabetes mellitus was published by WHO in 19801 and, in modified form, in 1985.3 The 1980 and 1985 classi- fications of diabetes mellitus and allied categories of glucose intolerance included clinical classes and two statistical risk classes. The 1980 Expert Committee proposed two major classes of diabetes mellitus and named them IDDM or Type 1, and NIDDM or Type 2. In the 1985 Study Group Report the terms Type 1 and Type 2 were omitted, but the classes IDDM and NIDDM were retained, and a new class of Malnutrition-related 542 K.G.M.M. ALBERTI ET AL. Ó 1998 WHO Diabet. Med. 15: 539–553 (1998) Diabetes Mellitus (MRDM) was introduced. In both the 1980 and 1985 reports other classes of diabetes included Other Types and Impaired Glucose Tolerance (IGT) as well as Gestational Diabetes Mellitus (GDM). These were reflected in the subsequent International Nomenclature of Diseases (IND) in 1991, and the tenth revision of the International Classification of Diseases (ICD-10) in 1992. The 1985 classification was widely accepted and is used internationally. It represented a compromise between clinical and aetiological classification and allowed classi- fication of individual subjects and patients in a clinically useful manner even when the specific cause or aetiology was unknown. The classification or staging of diabetes mellitus based on clinical descriptive criteria is continued in the proposed classification, but a complementary classification according to aetiology is now recommended. Proposed Classification The proposed classification encompasses both clinical stages and aetiological types of diabetes mellitus and other categories of hyperglycaemia, as suggested by Kuzuya and Matsuda.11 The clinical staging reflects that diabetes, regardless of its aetiology, progresses through several clinical stages during its natural history. Moreover, individual subjects may move from stage to stage in either direction. Persons who have, or who are developing, diabetes mellitus ORIGINAL ARTICLES can be categorized by stage according to the clinical characteristics, even in the absence of information concerning the underlying aetiology. The classification by aetiological type results from improved understanding of the causes of diabetes mellitus. Application of the New Classification The new classification contains stages which reflect the various degrees of hyperglycaemia in individual subjects with any of the disease processes which may lead to diabetes mellitus. All subjects with diabetes mellitus can be categorized according to clinical stage, and this is achievable in all circumstances. The stage of glycaemia may change over time depending on the extent of the underlying disease processes (Figure 2). A disease process may be present but may not have progressed far enough to cause hyperglycaemia. The aetiological classification reflects the fact that the defect or process which may lead to diabetes may be identifiable at any stage in the develop- ment of diabetes—even at the stage of normoglycaemia. Thus the presence of islet cell antibodies in a normo- glycaemic individual makes it likely that that person has the Type 1 autoimmune process. Unfortunately there are few good highly specific indicators of the Type 2 process at present, although these no doubt will be revealed as aetiology is more clearly defined. The same disease process can cause impaired fasti