Abstract
Background:
Impaired glucose metabolism and cystic fibrosis (CF)-related diabetes (CFRD) are associated with insufficient weight gain and impaired lung function in children and adolescents with CF. We have asked whether imminent CFRD may be a cause of poor growth in children and adolescents.
Methods:
A retrospective case control study including 32 patients with CF with or without diabetes was conducted. Sixteen pairs, matched according to age, gender and exocrine pancreatic insufficiency, were analysed. Standard deviation scores (SDS) of height, growth, weight, body mass index (BMI), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and forced expiratory flow at 75% of expired FVC (FEF75) were recorded during a mean observation period of 13 years per patient.
Results:
SDS of height and weight were reduced in CF patients with diabetes compared to those without, not only at the point of diagnosis (both p<0.05) but years before the evidence of diabetes. Afterwards there was a significant decline in height (p<0.001) and weight (p<0.01) SDS in CFRD patients and an increasing difference between the height and weight of CF patients with or without diabetes. In contrast, no significant reduction of BMI-SDS was observed in CFRD patients. All analysed lung function parameters showed a marked decline in CFRD patients starting 1 year prior to the diagnosis of diabetes.
Conclusions:
Deteriorating growth, reduced weight and impaired lung function are related to the development of CFRD and are obvious several years before the actual diagnosis of diabetes.
Introduction
As opposed to children without cystic fibrosis (CF), young individuals with CF are frequently affected by an abnormal glucose metabolism [1], [2]. This, and its progression towards a CF-related diabetes (CFRD) is due to reduced or delayed insulin secretion, combined with insulin resistance [1], [3], [4]. Worsening of glucose metabolism leads to increased bacterial growth in the lungs and thus infections of the airways, which limit lung function and life expectancy [5], [6], [7]. Hence, early recognition and treatment of an altered glucose tolerance is of clinical relevance [3], [8], [9]. Although more prospective studies are needed to address a possible advantage of insulin treatment over oral hypoglycaemic agents, there are signs of better glycaemic control and improved weight gain when using insulin [10], [11], [12]. This is why insulin has become the preferred therapeutic agent in patients with CFRD [13]. Former studies have shown that a decline of nutritional status, as evidenced by weight reduction, may occur several years prior to the diagnosis of CFRD by an oral glucose tolerance test (OGTT) [14], [15]. Only limited data is available as to the impact of CFRD on growth in children. Cheung et al. observed a decreased growth of CF patients with diabetes at the time of the first diabetic OGTT as well as 2 years later [16]. Moreover, Bizzarri et al. described a lower final height in adolescents suffering from CFRD, compared to CF patients without diabetes [17]. Therefore we have asked: does reduced growth in paediatric CFRD patients precede the diagnosis of diabetes, as shown for poor weight gain? If so, growth might be useful as a marker of the onset of diabetes and indicate the imminent development of diabetes in paediatric CF patients.
Materials and methods
This was a retrospective study set at the Hospital for Children and Adolescents of the University of Leipzig. Data were collected from hospital records and the Leipzig auxological network CrescNet, from all patients with CF who had been treated during 25 years (January 1990 till December 2014) [18], [19]. One hundred and twenty-six patients, 60 females and 66 males, were included. Patients were divided into two groups, one group with CFRD [following the diagnostic criteria in regards to Moran et al. 2014, i.e. in all cases 2-h OGTT plasma glucose >200 mg/dL (11.1 mmol/L) during stable baseline health; in our clinic routine OGTT are performed yearly from the age of 10 years] and the other without CFRD [13]. Matched pairs according to gender, sufficient observational period before and after age of diagnosis of CFRD and exocrine pancreatic insufficiency were established. Order of matching was alphabetical by surname. Patients without sufficient documentation were excluded.
Height-standard deviation scores (SDS), weight-SDS and body mass index (BMI)-SDS as well as Z-scores of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and forced expiratory flow at 75% of expired FVC (FEF75) (according to Quanjer et al. 2012) were recorded [20]. Lung function tests had to fulfil the American Thoracic Society and the European Respiratory Society (ATS/ERS) acceptability and repeatability criteria [21]. Of all lung function results per year, the median one of each patient was included.
The study period included a minimum of 3 years prior to the diagnosis of diabetes and a minimum of 3 years after diagnosis (up to the maximum age of 19 years, as only data within the period of growth were supposed to be analysed). From the diagnosis of diabetes, HbA1c values of all CFRD patients were measured at least twice a year. The values during a period of 3 years after diagnosis were included.
The trends for height, weight, and BMI SDS were analysed using linear mixed models (LMM) using age centred with respect to the age of diagnosis and a grouping factor including their interactions as fixed effects. Therefore the values were categorised into three groups: (a) measurements of patients without CFRD (b) measurements of patients with diabetes but before diagnosis and (c) measurements of patients with diabetes after diagnosis. Values from 1 year before diagnosis to 0.25 years after diagnosis were excluded from weight related analyses for the CFRD group. Therefore weight related values for the point of diagnosis were estimated from values before and after this period to correct for excessive weight loss caused by diabetes. We allowed the intercept as well as the slope to vary by person. The correlation between slopes and intercepts was only significant and therefore included for BMI-SDS. The respective slopes were tested against each other using a χ2 test. p-Values regarding differences in intercepts were calculated using F-statistics. The confidence level α was set to 0.05.
Results
Patient characteristics and treatment
Sixteen of the patients with CF from the study cohort developed diabetes by the age of 19. Of these, 10 (62.5%) were girls (Table 1; Supplemental Data, Tables 1 and 2). The mean age at the time of diagnosis of diabetes was 14.4±4.4 years. The mean observational period was 13.9 years in the CFRD group and 13.2 years in the group of the matched CF patients without diabetes. Data from a period of at least 3 years prior to the age of diagnosis of diabetes were available for all patients. The related data from the subsequent period were partly discarded when the patients’ age exceeded 19 years, which applied to five of the CFRD patients. For the other 11 patients with diabetes, data from a period of at least 3 years after the diagnosis of diabetes were available. Fourteen (88%) of the 16 patients with diabetes as well as 14 of the matched patients carried a delF508 [according to Human Genome Variation Society (HGVS): p.Phe508del, c.1521_1523delCTT] variant in a homozygous or compound-heterozygous form. Twenty-five percent of the patients with CFRD were chronically infected by Pseudomonas aeruginosa at the age of diabetes onset, as were 31% of the matched patients at the same age (Table 1; Supplemental Data, Tables 3 and 4). One patient (7%) of the CFRD group had undergone an allergic bronchopulmonary aspergillosis (ABPA), treated with glucocorticosteroids, before the diagnosis of diabetes, in comparison to none of the matched patients. During the observational period, two (13%) of the CFRD patients and one (7%) of the matched patients developed sonographic signs of liver cirrhosis with a Child Pugh score A.
Patient characteristics of CFRD patients and matched CF patient group including mean age of diagnosis of diabetes (years), gender, mean length of observational period (years), number of patients exhibiting only class 1 or 2 mutations of the CFTR gene, number of patients with start of chronic Pseudomonas aeruginosa infection pre/post age of diagnosis of CFRD, number of patients with sonographic signs of liver cirrhosis (Child Pugh score A), number of patients with allergic bronchopulmonary aspergillosis (ABPA) pre/post age of diagnosis of CFRD, number of patients receiving insulin therapy, number of patients first treated with oral antidiabetics, mean HbA1c post diagnosis of CFRD (%).
| Group | CFRD patients | Matched CF patients |
|---|---|---|
| Age of diagnosis of CFRD, mean, years | 14.3 | – |
| Gender (female/male) | 10/6 | 10/6 |
| Observational period, mean, years | 13.9 | 13.2 |
| CFTR mutations: only class 1/2 | 13 | 11 |
| Chronic P. aeruginosa infection (pre/post age of diagnosis of CFRD) | 4/3 | 5/1 |
| Liver cirrhosis (Child Pugh A) | 2 | 1 |
| ABPA (pre/post age of diagnosis of CFRD) | 1/1 | 0/1 |
| Insulin therapy | 8 | – |
| Primary therapy with oral antidiabetics | 7 | – |
| HbA1c post diagnosis of CFRD, mean, % | 6.5 | – |
Fifty percent of the CFRD patients were treated with insulin (intensified conventional treatment) during the observational period. The treatment of 19% of the CFRD group first consisted of oral antidiabetics (glibenclamide and/or repaglinide) and was later switched to insulin. Twenty-five percent of the patients with diabetes received only oral antidiabetics during the observational period. Treatment with glibenclamide or repaglinide was only undertaken before 2002, i.e. evidence of a superiority of insulin. For 19% of the CFRD patients there was no need to treat or the patients refused pharmacological treatment. In the cases treated, the treatment was initiated at an average of 7.5 months after the diagnosis of diabetes. Mean HbA1c values of all but one exceptional patient (10.8%) during 3 years following the diagnosis of CFRD ranged from 5.6% to 6.9%. Taking all patients’ mean HbA1c values into account, the mean HbA1c was 6.5% (Table 1; Supplemental Data, Table 3).
Auxological parameters in relation to CFRD
In our patient group, CF is related to decreased height in general, when compared to the standard German growth chart (Figure 1A). Moreover, SDS of height differ when comparing CF patients with and without diabetes. The median height-SDS of the CFRD patient group are lower in every single year, from 11 years before to 7 years after the age of diagnosis of diabetes. At the point of diagnosis the mean height-SDS was 0.66 SD lower in the CFRD group (−0.91 vs. −0.27; p<0.047). This is not only applicable to the patient-dependent analysis (LMM) (Figure 1A), but also to a simple group-dependent analysis of the samples. Starting at the time of diagnosis, the height-SDS of the CFRD patients significantly decrease (β=−0.1, p<0.001), and the difference between the values of the patients with and without diabetes simultaneously increases. We also observe a slightly (but not significantly) decreasing trend in height-SDS of the patients with diabetes during all analysed years before the time of diagnosis (β=−0.02).
Trends for height (A), weight (B) and BMI (C) SDS in the described linear mixed models (LMM) in CF patients with diabetes before and after the point of diagnosis of diabetes, in comparison to the related trends of the matched patients of the same age.
The graphs concerning the patients with diabetes are split into the trends pre and post diagnosis. The related graphs concerning the patients without diabetes are not split, as to the lack of an equivalent change in disease progress in the matched patients. Both height- and weight-SDS are higher in patients with diabetes compared to the matched controls. This is observed before and after the diagnosis of diabetes, but with a more substantial decrease in CFRD patients after the diagnosis. Concerning BMI-SDS, a decreasing difference between the values in patients with and without diabetes during the whole observational period is noticeable.
Most of the above also apply to weight-SDS. We observe negative SDS for weight in the majority of CF patients in general as well as lower weight-SDS of the CFRD patients, when compared to the matched controls (Figure 1B). The mean weight at the point of diagnosis is 0.6 SD lower for the CFRD patients in comparison to their matched controls (−1.12 vs. −0.52; p=0.027). The weight-SDS of both CFRD and non-CFRD patients decrease over time. Again the weight-SDS of the patients with diabetes significantly decrease after the diagnosis of diabetes (β=−0.09, p<0.01), leading to an increasing difference between the weight-SDS of the CF patients with and without diabetes. In contrast to the results concerning height-SDS, we do not observe an increase in this difference before the time of diagnosis of diabetes.
When comparing the BMI-SDS of CF patients with and without diabetes, we notice slightly reduced scores of the CFRD patient group at the beginning of the observational period (Figure 1C) and 0.25 SD lower BMI-SDS at the point of diagnosis (p<0.26). However, and in contrast to the SDS for height and weight, this difference is not significant and is diminished during adolescence.
Lung function parameters in relation to CFRD
The included spirometric parameters (Z-scores of FVC, FEV1, FEF75) show, as expected, lower median values as compared to a healthy population for the whole group of CF patients throughout the observational period (Figure 2). Furthermore, lower median values in the CF patient group with diabetes than in the group without are noticeable. Median FVC Z-scores worsen over time in the CFRD group, starting already several years before the diagnosis of diabetes (Figure 2A). In contrast, FVC scores in the group of the matched patients indicate a subtle to no change in vital capacity. All of this also applies to the Z-scores of FEV1, one of the measures of an obstructive component of the disease (Figure 2B). There is a decrease of the FEV1 Z-scores in the CFRD group already before the diagnosis of diabetes, but nearly none in the matched patient group without diabetes. The Z-scores of the other marker of an obstructive lung disease, FEF75, decrease in both groups in the same manner up to 1 year after the point of diagnosis of diabetes (Figure 2C). From then on a more marked decrease in FEF75 Z-scores is observed in the CFRD group.
Median and standard error bars of the Z-scores of FVC (A), FEV1 (B) and FEF75 (C) in CF patients with diabetes before and after the point of diagnosis of diabetes, in comparison to the related values of the matched patients of the same age.
The graphs show lower and decreasing FVC and FEV1 Z-scores of the CFRD patients, whereas there is no substantial decrease of the related scores of the matched patients during the whole observational period. In both groups a decrease of FEF75 Z-scores is noticeable, with more severely decreasing scores in the group of CF patients with diabetes, beginning 2 years after the diagnosis of diabetes.
Discussion
In addition to the reduced final height observed by Bizzarri et al. and the decline in growth in the 2 years following the first diabetic OGTT described by Cheung et al., the results of this study indicate reduced growth years before and after a diagnosis of diabetes in CFRD patients [16], [17]. Furthermore, our results confirm previously published data which show a reduced gain in weight in paediatric CF patients already years before evidence of diabetes [15]. Altogether the data link the well-established association between early life growth and later lung function to the development of CFRD: once a child does not grow according to his or her own growth trajectory, diabetes might well occur within only a few years [22]. Hence, monitoring growth and weight attainment in children and adolescents with cystic fibrosis might be even more important than previously thought.
In contrast to former studies, we do not observe a reduced BMI in CF patients at the onset of diabetes. This can be explained by the parallel decrease in weight as well as height scores. Previous studies have related the development of CFRD to deterioration in lung function [23], [24], [25]. This relation is confirmed by our results. FVC and FEV1 remained largely stable in the non-CFRD group whereas there was a parallel decrease of FEF75 in both groups. This might be explained by a higher sensitivity of FEF75 as a marker of early CF lung disease [26]. Notably, worsening of FEV1 seems to be a better marker of an imminent development of CFRD than worsening of FEF75 in our patients.
Growth and weight gain, as well as the lung function of the patients who develop CFRD during childhood or adolescence are compromised years before the diagnosis of diabetes. The reason can be either a direct impact of an early, subclinical development of diabetes in these parameters, or a different underlying, not yet known factor which disrupts body growth and the development of the lungs and, independently from these, leads to the development of diabetes. In the former case, there would be a need to establish new diagnostic methods to detect patients who might benefit from early insulin therapy, e.g. continuous glucose monitoring [27]. In the latter case, the paediatric CFRD patients would represent a subgroup of CF patients – not only from the onset of diabetes, but from the day of birth onwards.
The effect of the development of CFRD on growth trajectories might be confounded by disease-related factors such as the bacterial colonisation of the lung or the number of exacerbations the patients have undergone. However, such confounders could neither support nor contradict the observation that paediatric CFRD is associated with a worse course of CF in general. In contrast to disease-related parameters, patient-related factors, including a later onset of pubertal development, lower predicted height or a different social background, possibly interfere with the results of this study. Because of the relatively small group of patients, they cannot be ruled out at this time.
Conclusions
Monitoring growth and weight attainment is crucial in patients with CF. Deceleration of growth, as evidenced by a decline in height-SDS, may well precede the manifestation of diabetes by several years. A decrease in weight and BMI-SDS is reason for concern and should be prompted by stepped-up nutritional and pulmonary treatment. Concerning lung function parameters, specific thresholds that predict occurrence of CFRD should be evaluated, to enable early preventive actions that may delay the onset of diabetes or relieve its sequelae.
Acknowledgments
We thank the patients and their families for their patience and consent. We also wish to express our gratitude to all doctors and nurses who care for the patients.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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Supplemental Material:
The online version of this article offers supplementary material (DOI: https://doi.org/10.1515/jpem-2017-0005).
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