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HbA1c: An effective screening tool for cystic fibrosisrelated diabetes?
JCF-01255; No of Pages 2
Journal of Cystic Fibrosis xx (2015) xxx – xxx www.elsevier.com/locate/jcf
Letter to the Editor
HbA1c: An effective screening tool for cystic fibrosis related diabetes? Marie-Angela Schnyder a , Christian Benden b , Christoph Schmid a a
Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, 8091 Zurich, Switzerland b Division of Pulmonary Medicine, University Hospital, 8091 Zurich, Switzerland Received 21 September 2015; accepted 15 October 2015 Available online xxxx
Dear Editor,
We have read with interest the article by Burgess et al. “HbA1c as a screening tool for cystic fibrosis related diabetes” [1]. The authors studied the relationship between glycosylated haemoglobin (HbA1c) and oral glucose tolerance test (oGTT) in a large number of adult (aged ≥ 16 years) patients with cystic fibrosis (CF) without a pre-existing diagnosis of CF related diabetes (CFRD). Recently, HbA1c has been accepted as a diagnostic criterion for type 1 and type 2 diabetes, if the value reads ≥ 6.5% (48 mmol/mol) [2]. With such a high cutoff, HbA1c has very poor sensitivity to detect CFRD in a patient previously not known for the disease; the same is also true for fasting plasma glucose (FPG) if a cutoff of ≥ 7 mmol/l is used. By contrast, a 2 h plasma glucose value (2hPG) ≥ 11.1 mmol/l remains an accepted criterion not only for type 1 and type 2 diabetes but also for CFRD, and thus, the oGTT has remained the gold standard for diagnosis of diabetes mellitus. Burgess et al. propose to use HbA1c as a screening tool in patients with CF, with a much lower cutoff, and to perform an oGTT only if the HbA1c is ≥ 5.8% (40 mmol/mol); an HbA1c b 5.8% would predict a negative oGTT, and therefore render an oGTT unnecessary. To reach a high sensitivity (93.8%), a low specificity (53%) would be accepted, and the use of the less patient-friendly oGTT could be reduced to half. Working at the Swiss Adult CF and Lung Transplant Centre in Zurich, we routinely screen our CF patients for CFRD by oGTT unless the diagnosis is already known (from previous testing or treatment; an oGTT was not performed in patients known for previous FPG ≥ 7.0 mmol/l). We thereby focus our attention particularly on patients with advanced lung disease and lung transplant assessment. Based on our clinical experience we believe that for these severely ill CF patients, HbA1c might be an inappropriate tool to detect impaired
glucose homoeostasis, and in particular, the underlying (potentially most harmful) impaired insulin secretion. With the aim of comparing our Zurich experience to that of the Royal Brompton Hospital in a somewhat distinct CF patient population, we collected oGTT and HbA1c data of CF patients referred to our centre between 2002 and 2015, in the majority to be evaluated for lung transplantation. Inclusion criteria were established CF, forced expiratory volume in 1 s (FEV1) ≤ 45%, and available oGTT and HbA1c data. 80 patients (39 females) were included, with a mean age of 26 years (range 12–47), a mean (± SD) FEV1 of 28 ± 8%, and a body mass index (BMI) of 18.5 ± 3.3 kg/m2, respectively. Forty-seven patients were delF508 homozygous, 25 heterozygous for delF508 genotype; seven had other genotypes (one patient's genotype was not known). According to the 2hPG value, CFRD was not diagnosed in 46 (58%) patients (age 25 ± 8 years, FEV1 30 ± 8%, BMI 19.1 ± 3.5 kg/m2); in 34 (42%) patients (age 28 ± 10 years, FEV1 26 ± 8%, BMI 17.6 ± 2.8 kg/m2), a new diagnosis of CFRD was made. This is in line with our previous observation that there is an intense clustering of a new diagnosis of CFRD in patients with advanced lung disease undergoing lung transplant assessment; the majority of these patients end up with a diagnosis of CFRD [3]. HbA1c was ≥ 5.8% in 62 (77.5%) and b 5.8% in 18 patients, as shown in Fig. 1. As judged by oGTT, 29 were true positive and 33 false positive. Among the 18 (22.5%) patients with HbA1c b 5.8%, omitting an oGTT would have been justified in 13 (true negative testing) but in five of them, the HbA1c would have been misleading (false negative), i.e. the diagnosis of CFRD would have been missed. The need for further testing would have been reduced by just 22.5% in our patient cohort in contrast to 51% in the study by Burgess and coworkers. We would propose that in CF patients, screening for CFRD should not only aim to identify patients for measures of their hyperglycaemia but also for impaired insulin secretion. According to our own unpublished data, impaired insulin
http://dx.doi.org/10.1016/j.jcf.2015.10.010 1569-1993© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Schnyder M-A, et al, HbA1c: An effective screening tool for cystic fibrosis related diabetes?, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.10.010
2
Letter to the Editor
HbA1c (%)
10
33
29
13
5
5
0 0
5
10
15
20
2hPG (mmol/L) Fig. 1. Distribution of venous plasma glucose values (measured by the hexokinase method in samples drawn into sodium fluoride-containing tubes) 2 h after oral glucose, plotted against HbA1c values (measured by immunoturbidimetric method in EDTA blood samples) in 80 patients with cystic fibrosis undergoing lung transplant assessment. The dotted horizontal line represents the proposed HbA1c threshold of 5.8%, the dotted vertical line the standard plasma glucose cutoff, 11.1 mmol/l.
appears that oGTT is superior to HbA1c in detecting insulinopenia. Overall, we concur that clinical criteria remain important in diagnostic strategies and treatment decisions, and that in CF patients in good clinical condition, low HbA1c could possibly serve as a tool to reduce the number of oGTTs; however, we strongly recommend oGTTs in patients with advanced CF lung disease and poor clinical condition with a high pretest probability of insulinopenia; since these patients may well benefit from insulin treatment, beyond the control of hyperglycaemia, ideally improving muscle and lung functions [3]. References [1] Burgess JC, Bridges N, Banya W, Gyi KM, Hodson ME, Bilton D, et al. HbA1c as a screening tool for cystic fibrosis related diabetes. J Cyst Fibros 2015. http://dx.doi.org/10.1016/j.jcf.2015.03.013. [2] Diabetes Care. 2015;38(Suppl. 1):S8–S16. [3] Hofer M, Schmid C, Benden C, Speich R, Inci I, Weder W, et al. Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation. J Cyst Fibros 2012;11(2):131–6 [Mar].
secretion is more reliably reflected and more readily detected by high 2hPG than by high FPG and high HbA1c, in particular, in the context of wasting, a common clinical sign in CF. It
Please cite this article as: Schnyder M-A, et al, HbA1c: An effective screening tool for cystic fibrosis related diabetes?, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.10.010
Journal of Cystic Fibrosis xx (2015) xxx – xxx www.elsevier.com/locate/jcf
Letter to the Editor
HbA1c: An effective screening tool for cystic fibrosis related diabetes? Marie-Angela Schnyder a , Christian Benden b , Christoph Schmid a a
Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, 8091 Zurich, Switzerland b Division of Pulmonary Medicine, University Hospital, 8091 Zurich, Switzerland Received 21 September 2015; accepted 15 October 2015 Available online xxxx
Dear Editor,
We have read with interest the article by Burgess et al. “HbA1c as a screening tool for cystic fibrosis related diabetes” [1]. The authors studied the relationship between glycosylated haemoglobin (HbA1c) and oral glucose tolerance test (oGTT) in a large number of adult (aged ≥ 16 years) patients with cystic fibrosis (CF) without a pre-existing diagnosis of CF related diabetes (CFRD). Recently, HbA1c has been accepted as a diagnostic criterion for type 1 and type 2 diabetes, if the value reads ≥ 6.5% (48 mmol/mol) [2]. With such a high cutoff, HbA1c has very poor sensitivity to detect CFRD in a patient previously not known for the disease; the same is also true for fasting plasma glucose (FPG) if a cutoff of ≥ 7 mmol/l is used. By contrast, a 2 h plasma glucose value (2hPG) ≥ 11.1 mmol/l remains an accepted criterion not only for type 1 and type 2 diabetes but also for CFRD, and thus, the oGTT has remained the gold standard for diagnosis of diabetes mellitus. Burgess et al. propose to use HbA1c as a screening tool in patients with CF, with a much lower cutoff, and to perform an oGTT only if the HbA1c is ≥ 5.8% (40 mmol/mol); an HbA1c b 5.8% would predict a negative oGTT, and therefore render an oGTT unnecessary. To reach a high sensitivity (93.8%), a low specificity (53%) would be accepted, and the use of the less patient-friendly oGTT could be reduced to half. Working at the Swiss Adult CF and Lung Transplant Centre in Zurich, we routinely screen our CF patients for CFRD by oGTT unless the diagnosis is already known (from previous testing or treatment; an oGTT was not performed in patients known for previous FPG ≥ 7.0 mmol/l). We thereby focus our attention particularly on patients with advanced lung disease and lung transplant assessment. Based on our clinical experience we believe that for these severely ill CF patients, HbA1c might be an inappropriate tool to detect impaired
glucose homoeostasis, and in particular, the underlying (potentially most harmful) impaired insulin secretion. With the aim of comparing our Zurich experience to that of the Royal Brompton Hospital in a somewhat distinct CF patient population, we collected oGTT and HbA1c data of CF patients referred to our centre between 2002 and 2015, in the majority to be evaluated for lung transplantation. Inclusion criteria were established CF, forced expiratory volume in 1 s (FEV1) ≤ 45%, and available oGTT and HbA1c data. 80 patients (39 females) were included, with a mean age of 26 years (range 12–47), a mean (± SD) FEV1 of 28 ± 8%, and a body mass index (BMI) of 18.5 ± 3.3 kg/m2, respectively. Forty-seven patients were delF508 homozygous, 25 heterozygous for delF508 genotype; seven had other genotypes (one patient's genotype was not known). According to the 2hPG value, CFRD was not diagnosed in 46 (58%) patients (age 25 ± 8 years, FEV1 30 ± 8%, BMI 19.1 ± 3.5 kg/m2); in 34 (42%) patients (age 28 ± 10 years, FEV1 26 ± 8%, BMI 17.6 ± 2.8 kg/m2), a new diagnosis of CFRD was made. This is in line with our previous observation that there is an intense clustering of a new diagnosis of CFRD in patients with advanced lung disease undergoing lung transplant assessment; the majority of these patients end up with a diagnosis of CFRD [3]. HbA1c was ≥ 5.8% in 62 (77.5%) and b 5.8% in 18 patients, as shown in Fig. 1. As judged by oGTT, 29 were true positive and 33 false positive. Among the 18 (22.5%) patients with HbA1c b 5.8%, omitting an oGTT would have been justified in 13 (true negative testing) but in five of them, the HbA1c would have been misleading (false negative), i.e. the diagnosis of CFRD would have been missed. The need for further testing would have been reduced by just 22.5% in our patient cohort in contrast to 51% in the study by Burgess and coworkers. We would propose that in CF patients, screening for CFRD should not only aim to identify patients for measures of their hyperglycaemia but also for impaired insulin secretion. According to our own unpublished data, impaired insulin
http://dx.doi.org/10.1016/j.jcf.2015.10.010 1569-1993© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Schnyder M-A, et al, HbA1c: An effective screening tool for cystic fibrosis related diabetes?, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.10.010
2
Letter to the Editor
HbA1c (%)
10
33
29
13
5
5
0 0
5
10
15
20
2hPG (mmol/L) Fig. 1. Distribution of venous plasma glucose values (measured by the hexokinase method in samples drawn into sodium fluoride-containing tubes) 2 h after oral glucose, plotted against HbA1c values (measured by immunoturbidimetric method in EDTA blood samples) in 80 patients with cystic fibrosis undergoing lung transplant assessment. The dotted horizontal line represents the proposed HbA1c threshold of 5.8%, the dotted vertical line the standard plasma glucose cutoff, 11.1 mmol/l.
appears that oGTT is superior to HbA1c in detecting insulinopenia. Overall, we concur that clinical criteria remain important in diagnostic strategies and treatment decisions, and that in CF patients in good clinical condition, low HbA1c could possibly serve as a tool to reduce the number of oGTTs; however, we strongly recommend oGTTs in patients with advanced CF lung disease and poor clinical condition with a high pretest probability of insulinopenia; since these patients may well benefit from insulin treatment, beyond the control of hyperglycaemia, ideally improving muscle and lung functions [3]. References [1] Burgess JC, Bridges N, Banya W, Gyi KM, Hodson ME, Bilton D, et al. HbA1c as a screening tool for cystic fibrosis related diabetes. J Cyst Fibros 2015. http://dx.doi.org/10.1016/j.jcf.2015.03.013. [2] Diabetes Care. 2015;38(Suppl. 1):S8–S16. [3] Hofer M, Schmid C, Benden C, Speich R, Inci I, Weder W, et al. Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation. J Cyst Fibros 2012;11(2):131–6 [Mar].
secretion is more reliably reflected and more readily detected by high 2hPG than by high FPG and high HbA1c, in particular, in the context of wasting, a common clinical sign in CF. It
Please cite this article as: Schnyder M-A, et al, HbA1c: An effective screening tool for cystic fibrosis related diabetes?, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.10.010