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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #5: Classification of Diabetes Mellitus and Other Categories of Glucose Intolerance Part 5 of 6

DeFronzoCoverDiabetes in children and youth

Type 1 diabetes in children and youth is typically characterized by weight loss, polyuria, polydipsia, blurring of vision, very high plasma glucose concentrations, and ketonuria. The diagnosis is usually very clear with high random glucose values, and there is rarely a need to investigate with an oral glucose tolerance text (OGTT). Type 2 diabetes in children is associated with milder symptoms and is often associated with obesity. In these cases, diagnosis is made using any one of OGTT, fasting plasma glucose, or HbA1c, with preference for HbA1c as there is no requirement to fast. However, there is still debate as to the use of the latter in children [65].

Classification of diabetes in youth poses special problems. Although type 1 diabetes remains the most common form of diabetes in youth of European background, type 2 diabetes is increasingly common, especially among adults at particularly high risk of type 2 diabetes. With the increase in obesity over the last 20 years, there has been an increase in type 2 diabetes in children especially among ethnicities at high risk as well as an increase in the number of children with type 1 who are overweight. Type 2 diabetes may also be present in youth with ketosis or ketoacidosis, which serves only to compound the problem further. While a practical delineation between these may be the use of insulin, it can no longer be assumed that those on insulin are type 1. Other investigations which could provide insight include measurement of C-peptide, characteristic type 1 antibodies, for example anti-GAD antibodies, and the monitoring of endogenous insulin secretion over time [17].

There has also been an increase in the number of children and adolescents with a mixture of the two types of diabetes, that is, subjects who are obese and/or with signs of insulin resistance as well as being positive for markers of autoimmunity to β cells. These cases present a problem under the current classification as they present with an overlapping phenotype of both type 1 and type 2 diabetes and have been referred to as hybrid diabetes, double diabetes, or latent autoimmune diabetes in youth (LADY) [66]. In such children, presentation of double diabetes is similar to LADA in adults.However, unlike LADA, little is known about the prevalence of double diabetes or the prevalence and significance of autoimmune markers in children. In addition, whether autoimmune-positive youth with double diabetes progress more rapidly to insulin dependence than those with type 2 diabetes without is not known. This is particularly important as these children/youth could be at risk for complications associated with β-cell dysfunction, as well as macro- and microvascular complications of type 2 diabetes. It has been suggested that the current classification of diabetes should be revised to include this new phenotype [66].

Another challenge among young people is the possibility of misdiagnosis of monogenic diabetes as type 1 and type 2. As noted previously, monogenic diabetes results from the inheritance of mutation(s) in a single gene that regulates β-cell function or less commonly in genes related to insulin resistance.

The clinical characteristics of a child with monogenic diabetes compared to children and youth with type 1 and type 2 are shown in Table 1.5. Monogenic diabetes should be considered in a child initially diagnosed as type 1 who has been diagnosed at less than 6 months of age, has a family history of diabetes with a parent affected, evidence of endogenous insulin production outside the “honeymoon” phase of diabetes with detectable C-peptide, and the absence of pancreatic islet autoantibodies (measured at diagnosis) [67].

ITDMTable1.5

In children with an initial diagnoses of type 2, a diagnosis of monogenic diabetes should be considered in the following circumstances: when the child is not obese or other diabetic family members have weight in the normal range, and the child does not have acanthosis nigricans; when the child is from an ethnic group with a low prevalence of type 2 diabetes and when there is no evidence of insulin resistance with normal fasting C-peptide levels [24,68].

In scenarios when monogenic diabetes is misdiagnosed as type 1 or 2, the aforementioned criteria should be considered as a whole rather than individually and are not absolute. DNA testing is now also available for diagnosis of monogenic diabetes.

DIAGNOSTIC CRITERIA

Diabetes is characterized by hyperglycemia, and thus diagnostic tests focus on establishing elevated blood glucose levels [69]. A casual blood glucose, fasting glucose or an OGTT of 75 grams may be performed. For children, the oral glucose load is proportional to body weight at 1.75 g per kg body weight. Recently, HbA1c has been added as an acceptable and reliable means of diagnosing diabetes (discussed later). The cutpoints for the diagnosis of diabetes are listed in Table 1.6.

ITDMTable1.6

In the absence of symptoms clearly attributable to diabetes, a diagnosis should not be based on a single measurement, but requires results within the diabetes range on two separate days.

The most notable change in diagnostic criteria in recent years is the recommendation by the ADA and WHO to use HbA1c for diagnosis of diabetes. A summary of the evolution of this decision is described in the following section.

Diagnosis of diabetes using HbA1c

HbA1c is a hemoglobin variant primarily composed of glycohemoglobin, which is formed by the nonenzymatic attachment of glucose to hemoglobin [70]. It was first identified in 1968 by Rabar, who noted it was associated with diabetes. By 1980, its clinical utility as a marker of glycemic control had been recognized. By the 1990s, supported by strong evidence from two studies, the Diabetes Control and Complications Trial [71] and the United Kingdom Prospective Diabetes Study [72], and the development of new high through put methods and improved coefficients of variation (CV), HbA1c had become the cornerstone marker in the monitoring of diabetes. In more recent years, a US national glycohemoglobin standardization program has been established and the International Federation of Clinical Chemistry (IFCC) has taken the lead to ensure that HbA1c assays are standardized. In 2011, the units of reporting were also changed from percentage points to IFCC mmol/mol. After a period of dual reporting, HbA1c will be reported in mmol/mol in many countries.

With some improvement in the assay and standardization of HbA1c, together with evidence from key trials demonstrating the importance of intensive glycemic control (as reflected by HbA1c levels) in reducing the risk of microvascular complications of diabetes, the move from using glucose for diagnosis to HbA1c had begun to gather support. However, concerns over standardization of the HbA1c assays and over other factors that may affect HbA1c continued to dampen the enthusiasm for use of HbA1c for diagnosis. In the last 10 years, however, several

developments have resulted in the incorporation of HbA1c into the diagnostic armamentarium.There has been significant improvement in the assays of HbA1c [73], analysis from eight different studies showed that HbA1c is as strongly related to the presence of diabetic retinopathy as are blood glucose levels [74], and HbA1c is strongly predictive of macrovascular outcomes and mortality [75,76].

The advantages of using HbA1c for diagnosis are clear. Firstly, HbA1c has far less day-to-day biological variation than fasting or 2-hour glucose [77]. Secondly, HbA1c is stable for one week at room temperature after collection while glucose is susceptible to glycolysis despite the use of fluoride oxalate to preserve the sample. Thirdly, unlike glucose measurement, there is no requirement for the patient to fast. Finally, glucose levels are also susceptible to modification by short-term lifestyle intervention while HbA1c reflects glycemia over a period of 3 to 4 months.

The major disadvantage of HbA1c is that there are a number of nonglycemic conditions that interfere with the assay. In particular, alterations of red blood cell turnover (e.g. kidney failure,

hematinic deficiencies, hemolysis, acute blood loss, pregnancy, and erythropoietin therapy) may affect the relationship between HbA1c and recent glycemia. The other important disadvantage is the need for a laboratory to use an IFCC aligned assay and be part of a standardization program, which may not be possible in developing countries.

Cutpoints of HbA1c have been set using similar methods to those adopted for the setting of blood glucose criteria. Cross-sectional data from 47,364 individuals from 12 countries reported that the threshold for diabetes-specific retinopathy was 6.3% (45 mmol/mol−1), with an optimal decision limit of 6.5% [74]. This latter cutpoint has been adopted by the ADA and WHO as an appropriate cutpoint for diabetes.

Although support for the use of HbA1c for diagnosis of diabetes has increased over the years, several questions about its suitability remain. For example, what should be the appropriate HbA1c ranges for pre-diabetes or intermediate glycemia? The ADA suggested that 5.7–6.5% (39–48 mmol/mol−1) should be used [5] to indicate intermediate glycemia while the WHO [78] suggested that levels of HbA1c below 6.5% may indicate intermediate glycemia but were reluctant to indicate a precise lower cutpoint. An international expert committee suggested that those with HbA1c between 6.0–6.5% (42–48 mmol mol−1) could be considered at high risk, and should be targeted for diabetes prevention activities [79].

A further concern about moving from glucose to HbA1c to diagnose diabetes is that we will observe a change in prevalence of diabetes, as an elevated HbA1c does not identify exactly the same individuals as does an elevated blood glucose. It should, however, be noted that a similar discrepancy in individuals identified also applies to diagnosis by fasting glucose compared to diagnosis by 2-hour plasma glucose in the OGTT.

In general, the use of HbA1c for diagnosis of diabetes results in a lower prevalence of diabetes with the magnitude of the difference between blood glucose-based prevalence and HbA1c-based prevalence varying widely between populations [80].

Diagnosis of diabetes using HbA1c is now recommended by both the ADA and WHO as detailed in Table 1.6. As discussed earlier, it is important to ensure that the HbA1c assay used meets stringent quality assurance test and is aligned with the IFCC standardization program. It is also important to ensure that there are no clinical conditions that preclude its accurate measurement.

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