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IMMUNOLOGIC
& GENETIC TESTING IN DIABETES NON & MINIMALLY INVASIVE GLUCOSE ANALYSIS Monitoring of Patients with Diabetes INSULIN & PRECURSORS, LEPTIN & AMYLIUN: IS THERE A ROLE?
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Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus The
Role of Glucose Management in David Sacks,
MB, ChB A.Diagnosis/screeningRecommendation: Glucose should be measured in plasma in an accredited laboratory both to establish the diagnosis of diabetes and for population screening. Analysis in an accredited laboratory is not necessary for routine monitoring. The diagnosis of diabetes is established exclusively by the documentation of hyperglycemia (increased glucose concentrations in the blood). In 1997, the earlier diagnostic criteria 1 were modified 2 to better identify subjects at risk of retinopathy and nephropathy. The revised (current) criteria include: (a) symptoms of diabetes and casual (i.e., regardless of the time of the preceding meal) plasma glucose "e 11.1 mmol/L (200 mg/dL), (b) fasting plasma glucose (FPG) "e 7 mmol/L (126 mg/dL) or (c) 2-h postload glucose "e 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance test (OGTT) 2. If any one of these three criteria is met, confirmation by repeat testing on a subsequent day is necessary to establish the diagnosis. Although included as a criterion, the OGTT was not recommended for routine clinical use in non-pregnant individuals (see below). Population screening for diabetes, previously controversial, is now recommended2. The ADA propose that FPG should be measured in all asymptomatic people aged 45 years or more. If results are normal, testing should be repeated at 3-year intervals. Screening should be considered at a younger age or be carried out more frequently in individuals at increased risk of diabetes (see Ref 2 for conditions associated with increased risk). Despite these recommendations, there is no published evidence that treatment based on screening has value. Furthermore, the cost-effectiveness of screening is unknown. B. Monitoring/Prognosis Recommendation: Although there is evidence linking high glucose concentrations to adverse outcome, substantially more data are available that directly correlate increased glycated hemoglobin with diabetic complications. Routine measurement of plasma glucose concentrations in an accredited laboratory is not recommended as the primary means of monitoring or evaluating therapy in individuals with diabetes (? Of value in patients who respond to diet/exercise).There is a direct relationship between the degree of blood glucose control and the risk of late renal, retinal and neurological complications. This correlation has been demonstrated for type 1 3 and more recently for type 2 4 diabetes. Type 1 diabetic persons who maintained lower average blood glucose concentrations exhibited a significantly lower incidence of diabetic retinopathy, nephropathy and neuropathy 3. Although intensive insulin therapy reduced hypercholesterolemia by 34%, the risk of macrovascular disease was not significantly decreased. Similar results were obtained in patients with type 2 diabetes 4. Intensive blood glucose control in patients with type 2 diabetes significantly reduced microvascular complications, but no significant difference was detected for macrovascular disease (myocardial infarction or stroke) 4. In both studies, patients in the intensive group maintained lower median plasma glucose concentrations. Analyses of the outcomes were linked to Hb A1c, which was used to evaluate glycemic control, rather than glucose concentration. Moreover, most clinicians use the ADA recommendations which define a target Hb A1c concentration as the goal for optimum glycemic control 5. There is some evidence directly linking higher glucose concentrations to a poor prognosis. For example, the 10 year survival of 6681 people in a Japanese town was reduced if FPG "e 140 mg/dL 6. Similar findings were obtained in 1939 patients with type 2 diabetes followed for a mean of 15 years where multiple logistic regression revealed that the risk of death was significantly increased if FPG "e 140 mg/dL 7. Type 2 diabetic subjects with FPG "e 140 mg/dL had increased cardiovascular mortality 8. Furthermore, comparison of 300 patients with a first myocardial infarction and 300 matched controls revealed that a moderately increased FPG was a risk factor for infarction 9. Notwithstanding these observations, neither random nor fasting glucose concentrations should be measured in an accredited laboratory as the primary means of routine monitoring. Laboratory blood glucose testing can be used to supplement information from other testing, to test the accuracy of self-monitoring (see below) or when adjusting the dose of oral hypoglycemic agents 10. A possible exception is the rare situation where no access to Hb A1c is available. 2. Rationale The disordered carbohydrate metabolism that underlies diabetes manifests as hyperglycemia. Therefore, measurement of blood glucose is the sole diagnostic criterion. This strategy is indirect as hyperglycemia reflects the consequence of the metabolic derangement, not the cause. However, until the underlying molecular pathophysiology of the disease is identified, blood glucose concentrations are likely to remain the exclusive diagnostic modality. B. Screening: Screening is recommended for several reasons. The onset of diabetes is estimated to occur ~10 years before clinical diagnosis 11 and epidemiological evidence indicates that complications may begin several years before clinical diagnosis. Furthermore, 50% of people in the U.S. with type 2 diabetes are undiagnosed 12. Notwithstanding this recommendation, there is no evidence that population screening of blood glucose concentrations provides any benefit. Outcome studies should be performed to justify screening.2. Analytical Issues
Recommendation: Blood for fasting plasma glucose analysis should be drawn after the subject has fasted overnight (at least 8 h). Plasma should be separated from the cells within 60 min; if this is not possible, a tube containing sodium fluoride should be used for collecting the sample. Blood should be drawn after an overnight fast (no caloric intake for at least 8 h) during which time the subject may consume water 2. Glucose concentrations decrease ex vivo with time in whole blood due to glycolysis. The rate of glycolysis—reported to average 5-7% (~10 mg/dL) per hour 13—varies with the glucose concentration, temperature, white blood cell count and other factors 14. Glycolysis can be attenuated by inhibition of enolase with sodium fluoride or, less commonly, lithium iodoacetate. These reagents can be used alone or, more commonly, with anticoagulants such as potassium oxalate, EDTA, citrate or lithium heparin. Although fluoride maintains long-term glucose stability, the rates of decline of glucose in the first hour after sample collection in tubes with and without fluoride are virtually identical 13. (Note that leukocytosis will increase glycolysis even in the presence of fluoride if the white cell count is very high.) After 4 h, the glucose concentration is stable for 72 h at room temperature in the presence of fluoride 13. In separated, nonhemolysed sterile serum without fluoride the glucose concentration is stable for 8 h at 25 °C and 72 h at 4 °C 15. Glucose can be measured in whole blood, serum or plasma, but plasma is recommended for diagnosis. Although red blood cells are freely permeable to glucose, the water content of plasma is approximately 12% higher than that of whole blood. The glucose concentrations during an OGTT in capillary blood are significantly higher than those in venous blood (mean of 30 mg/dL, equivalent to 20-25%) 16, but the mean difference in fasting samples is 2 mg/dL 16, 17. Reference values: Glucose concentrations in healthy individuals vary with age. Neonatal fasting glucose values are low — 20-60 mg/dL in premature infants and 30-60 mg/dL at term 15. Reference intervals in children are 60-100 mg/dL, similar to the adult range of 74-106 mg/dL 15. Note that the ADA criteria 2, not the reference values, are used for the diagnosis of diabetes. Moreover, the threshold for diagnosis of hypoglycemia is variable. The reference values are not useful to diagnose these conditions. In adults, mean fasting plasma glucose increases with increasing age from the third to the sixth decade 18, but does not increase significantly with age beyond 60 years 19, 20. By contrast, glucose concentrations after a glucose challenge are substantially higher in older individuals 19, 20.
Recommendation: Enzymatic methods for glucose analysis are relatively well standardized. Despite the low imprecision at the diagnostic decision limits (126 mg/dL and 200 mg/dL), classification errors may occur. Because of the relatively large intraindividual biological variability (CVs of ~ 5-15%), individuals with FPG of 105-125 mg/dL should be considered for follow-up at intervals shorter than the current ADA recommendation of every 3 years. Glucose is measured almost exclusively by enzymatic methods. Analysis of proficiency surveys conducted by the College of American Pathologists (CAP) reveals that hexokinase or glucose oxidase is used in virtually all the analyses performed in the U.S. 15. A few laboratories use glucose dehydrogenase. At a plasma glucose concentration of ~147 mg/dL, imprecision among laboratories using the same method had a CV <4% (excluding glucose dehydrogenase) and among the different methods the range of variability was 145.7-151.9 mg/dL (4%) 15. Similar findings have been reported for glucose analysis in blood samples from patients. For example, comparison of plasma samples from 240 subjects revealed mean glucose concentrations of 101.6 ± 4 and 96.7 ± 3.9 mg/dL (5% difference) using hexokinase and glucose oxidase, respectively 21. No consensus has been achieved on the analytical goals for glucose analysis. Numerous criteria have been proposed to establish analytic goals. These include expert opinion (consensus conferences), opinion of clinicians, regulation, state of the art and biological variation 22. A rational and realistic recommendation that has received some support is to use biological criteria as the basis for analytic goals. It has been suggested that imprecision should not exceed one half of the within-subject biological CV 23, 24. For plasma glucose, a CV "d 2.2% has been suggested as a target for imprecision 24 (seems too low?). Although this recommendation was proposed for within-laboratory error, it would be desirable to achieve this goal for inter-laboratory imprecision to avoid variability among laboratories in the diagnosis of diabetes in individuals whose glucose concentrations are close to the threshold value.3. Interpretation Knowledge of intraindividual variability of FPG concentrations is essential for meaningful interpretation of patient values. An early study, which repeated the OGTT in 31 nondiabetic adults at 48 h intervals, revealed that FPG in 22 (71%) subjects varied by <10% and 30 (97%) varied by <20% 25. Biological variation includes variation in assay, blood drawing technique, measurement conditions and intraindividual variation 26. Careful evaluation over several consecutive days revealed that intraindividual variation of FPG in 12 healthy subjects (mean glucose of 89 mg/dL) exibited a biological CV of 4.8-6.1 % 27, 26. Larger studies have revealed 14% CV of FPG in 246 normal 28 and 193 newly diagnosed untreated type 2 diabetic subjects 29. The latter study, which measured FPG by glucose oxidase on two consecutive days, obtained 95% confidence intervals (CI) of 13.7% for biological variability. If this figure of 14% is applied to a true glucose concentration of 126 mg/dL, the 95% CI would encompass glucose concentrations of 108-144 mg/dL. If the CV of the glucose assay (~4%) is included, the 95% CI is ~ 18%. Thus, the 95% CI for a fasting glucose concentration of 126 mg/dL would be 126 ± 18%, namely 103-149 mg/dL. Using assay imprecision only (excluding biological variability) would yield 95% CI of 116-136 mg/dL among laboratories for a true glucose concentration of 126 mg/dL. One should bear in mind that these ranges include 95% of subjects and other individuals will be outside this range. A short turnaround time for glucose analysis is not usually necessary for the diagnosis and management of diabetes. In some clinical situations, such as acute hyper- or hypoglycemic episodes in the Emergency Department or treatment of diabetic ketoacidosis, rapid analysis is desirable. A turnaround time of 30 min has been proposed (Howanitz 93), but no outcome data have been published that validate this figure. Frequency of measurement The frequency of measurement of blood glucose is dictated by the clinical situation. To establish the diagnosis of diabetes, the ADA recommends that FPG should be measured on two occasions 2. Screening by FPG is recommended every 3 years if normal, more frequently in high-risk individuals. Monitoring is performed by patients themselves who measure blood glucose with meters and by assessment in an accredited laboratory of Hb A1c (see below). The frequency of measurement of glucose in acute clinical situations (e.g., diabetic ketoacidosis, neonatal hypoglycemia, etc.) is highly variable, ranging from every 30 min to once a day.4. Emerging considerations Non- or minimally-invasive analysis of glucose is addressed below. Self-Monitoring of Blood GlucosePortable meters for measurement of blood glucose concentrations are used in three major settings: i) in hospitals (at the patient’s bedside and in clinics); ii) in physicians’ offices and iii) by patients at home. The last, self-monitoring of blood glucose (SMBG), is performed at least once a day by 40% and 26% of individuals with type 1 and 2 diabetes, respectively 30. The worldwide market for SMBG is $2.7 billion-per-year, with annual growth estimated at 10-12% 31. The ADA lists the following indications for SMBG: i) achievement and maintenance of glycemic control; ii) prevention and detection of hypoglycemia; iii) avoidance of severe hyperglycemia; iv) adjusting to changes in life-style and v) determining the need for initiating insulin therapy in gestational diabetes mellitus (GDM) 32. It is recommended that most individuals with diabetes attempt to achieve and maintain blood glucose levels as close to normal levels as is safely possible 2. 1. Use
Recommendation: There are no published data to support a role for portable meters in the diagnosis of diabetes or for population screening. The imprecision of the meters, coupled with the substantial differences among meters, precludes their use in the diagnosis of and screening for diabetes. (How to deal with meters in physicians’ offices?). The criteria for the diagnosis of diabetes are based upon outcome data (the risk of micro- and macrovascular disease) correlated with plasma glucose concentrations—both fasting and 2 h after a glucose load—assayed in a central laboratory 2. Whole blood is used in portable meters. Although many portable meters have been programmed to report a plasma glucose concentration, the imprecision of the current meters (see below) precludes their use in the diagnosis of diabetes. Similarly, screening by portable meters, although attractive because of convenience, ease and accessibility, would generate many false positives and false negatives. B. Prognosis/Monitoring Recommendation: SMBG should be performed once to several times per day by patients with diabetes treated with insulin or sulfonylureas. Insulin-requiring patients adjust the dose of insulin based on SMBG. Both groups of patients use SMBG to detect asymptomatic hypoglycemia. In patients with type 2 diabetes, SMBG facilitates better control, particularly when therapy is initiated or changed. The role of SMBG in patients with stable type 2 diabetes controlled by diet alone is not known.SMBG is recommended for all patients with diabetes who are receiving insulin. Tight glycemic control can decrease microvascular complications in individuals with type 1 3 or type 2 4 diabetes. Intensive blood glucose control in patients with type 1 diabetes was achieved in the Diabetes Control and Complications Trial (DCCT) by participants performing SMBG at least four times per day 3. Therapy in patients with type 2 diabetes in the UK Prospective Diabetes Study 4 was adjusted according to FPG concentrations – SMBG was not evaluated. A literature review was performed of studies, published between 1976 and 1996, that evaluated SMBG in patients with type 2 diabetes 33. Only one of the published studies reported that SMBG produced a significantly positive improvement, namely lower Hb A1c. The authors of the review concluded that the efficacy of SMBG in type 2 diabetes is questionable 33. Although SMBG may be useful in initiating or changing therapy in patients with type 2 diabetes, clinical studies are needed to define its role in outcome in patients with type 2 diabetes. 2. Rationale SMBG allows patients with diabetes to achieve and maintain specific glycemic goals. Knowledge of blood glucose concentrations is necessary for insulin-requiring patients to determine appropriate insulin doses at different times of the day 32. Patients adjust the amount of insulin according to their blood glucose concentration. Frequent SMBG is particularly important for tight glycemic control. Hypoglycemia is a major, potentially life-threatening complication of the treatment of diabetes. The risk of hypoglycemia increases significantly with pharmacologic therapy directed towards maintaining the glycemic range as close to normal as possible 3, 4. The incidence of major hypoglycemic episodes—requiring third-party help or medical intervention—was 2- to 3-fold higher in the intensive group than in the conventional group in clinical trials of patients with type 1 and type 2 diabetes 3, 4. Furthermore, many diabetic patients, particularly those with type 1 diabetes, lack the autonomic warning symptoms that normally precede neuroglycopenia (“hypoglycemic unawareness”) 34, increasing the risk of hypoglycemia. SMBG can be useful for detecting asymptomatic hypoglycemia and allowing patients to avoid major hypoglycemic episodes. 3. Analytical Issues
Recommendation: Patients should be instructed in the correct use of glucose meters, including quality control. Comparison between SMBG and concurrent laboratory glucose analysis should be performed at regular intervals to evaluate the accuracy of patient results. Multiple factors can interfere with glucose analysis with portable meters. Several of these, such as proper application, timing and removal of excess blood 15, have been eliminated by advances in technology. Important variables that may influence the results of bedside glucose monitoring include changes in hematocrit, altitude, environmental temperature or humidity, hypotension, hypoxia and high triglyceride concentrations 35. Furthermore, most meters are inaccurate at very high or very low glucose concentrations. Another important factor is variability of results among different glucose meters. Different assay methods and architecture result in lack of correlation among meters, even from a single manufacturer. In fact, two meters of the same brand have been observed to differ in accuracy 36. B. Analytical Recommendation: Multiple performance goals for portable glucose meters have been proposed. These targets vary widely and are highly controversial. No published study has achieved the goals proposed by the ADA. Manufacturers should work together to improve the imprecision of current meters. We recommend meters that measure and report plasma glucose concentrations to facilitate comparison with the vast body of literature in which complications and outcomes are correlated with plasma glucose concentrations. (What to do with meters that measure whole blood, but use “fudge factor” to report plasma glucose?). At least 25 different meters are commercially available. Virtually all the meters use strips that contain glucose oxidase or hexokinase. A drop of whole blood is applied to a strip that contains all the reagents necessary for the assay. The technology used is reflectance photometry or electrochemical analysis, both of which can measure the rate of the reaction or the final concentration of the products. The meter provides a digital readout of blood glucose concentration. Most meters claim a reportable range of 30-600 mg/dL, with a few having a lower limit of zero. Several important technological advances that decrease operator error have been made in the last few years. These include “no wipe” strips, automatic commencement of timing when both the sample and the strip are in the meter, smaller sample volume requirements, no results if sample volume is inadequate, “lock out” if controls are not assayed, bar code readers and the ability to store up to several hundred results that can subsequently be downloaded for analysis. Together these improvements have resulted in superior performance by new meters 37. Several analytical goals have been proposed for the performance of glucose meters. The rationale for these is not always clear. In 1987 the ADA recommended a goal of total error (user plus analytical) of < 10% at glucose concentrations of 30-400 mg/dL 100% of the time 38. In addition, it was proposed that values should differ by "d 15% from those obtained by a laboratory reference method. The recommendation was modified in response to the significant reduction in complications by tight glucose control in the DCCT. The revised performance goal, published in 1996 32 is for analytic error < 5%. To our knowledge, there are no published studies of glucose meters that have achieved the ADA goal of analytic error of <5%. The CLIA 88 goal is less stringent than the ADA; results with meters should be within 10% of target values or ± 6 mg/dL, whichever is larger. NCCLS recommendations (1994) are ± 20% of laboratory glucose at >100 mg/dL and ±15 mg/dL of laboratory glucose if the glucose concentration is "d 100 mg/dL. A different approach was proposed by Clarke 39 who developed an Error Grid that attempts to define clinically important errors by identifying fairly broad target ranges. There is a very large variability in the performance of different meters. Although current meters, as predicted, exhibit performance superior to prior generations of meters 37, imprecision remains high. For example, a study conducted under carefully controlled conditions where all assays were performed by a single medical technologist resulted in only ~ 50% of analyses meeting the ADA criterion of < 5% deviation from reference values 37. Performance of older meters was substantially worse with 2 of the 4 meters able to achieve results < 5% of reference values in only 33% of analyses. Another recent study evaluated meter performance in 226 hospitals by split samples run simultaneously on meters and laboratory glucose analyzers revealed that 45.6%, 25% and 14% differed from each other by > 10%, > 15% and > 20%, respectively 40. Recent analysis of the clinical and analytical accuracy of portable glucose meters (all measurements done by one person) demonstrated that none of the meters met the ADA criterion and only 2 meters had 100% of the estimations in the clinically acceptable zones by Error Grid analysis 41. Recommendation: Clinical studies are needed to determine the analytic goals for glucose meters. At a minimum, the end-point should be hemoglobin A1c. Ideally, outcomes (e.g., long-term complications and hypoglycemia) should also be examined. Frequency of measurement SMBG should be performed at least four times per day in insulin-deficient patients with type 1 diabetes. Monitoring less frequently than four times a day results in a deterioration of glycemic control 32. The optimal frequency of SMBG for patients with type 2 diabetes is unknown. Current ADA recommendations suggest daily SMBG for patients treated with insulin or sulfonylureas 5 to detect hypoglycemia. There is no known role for SMBG in patients with type 2 diabetes who are treated with diet alone. Issues for the Committee 1. How to deal with meters in physician’s offices? 2. Should meters report whole blood or plasma glucose? 3. Should criteria for meter performance (including operator) by patients at home be different from those in a medical setting? 4. What imprecision is necessary/achievable for meters? References 1.National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28:1039-1057. 2. American Diabetes Association. 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