Original Paper
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2015;83:45–54 DOI: 10.1159/000369457
Received: June 6, 2014 Accepted: October 28, 2014 Published online: December 20, 2014
A Prospective Longitudinal Study of Growth and Pubertal Progress in Adolescents with Inflammatory Bowel Disease Avril Mason a Salma Malik a Martin McMillan a Jane D. McNeilly c J. Bishop b Paraic McGrogan b Richard K. Russell b S. Faisal Ahmed a a c
Child Health, School of Medicine, University of Glasgow, b Department of Paediatric Gastroenterology and Department of Paediatric Biochemistry, Royal Hospital for Sick Children, Glasgow, UK
Key Words Adolescence · Chronic disease · Hypogonadism · Growth · Inflammation
delay, adolescents with IBD display growth retardation which may be associated with raised ESR, adverse quality of life measures and an abnormality of IGF-1 bioavailability. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1663–2818/14/0831–0045$39.50/0 E-Mail [email protected] www.karger.com/hrp
Introduction
Children with inflammatory bowel disease (IBD), and particularly Crohn’s disease (CD), often present during early adolescence and have been reported to display delayed puberty [1]. It is possible that chronic inflammation may lead to wide-ranging effects, including hypogonadotropic hypogonadism [2], an abnormality of sex steroid synthesis [3–5] or an abnormality of sex steroid action [6]. Pubertal delay is often associated with growth retardation but previous studies suggest that adolescents with IBD seem to have more profound short stature than expected simply for delayed puberty [1]. In addition, adults with a history of pubertal delay are often shorter as adults than their predicted height (Ht) but the discrepancy between target Ht and final Ht seems to be greater in adults with childhood onset IBD compared to healthy adults with a history of delayed puberty [7–9]. As sex steroid-induced growth acceleration is dependent on increased growth hormone (GH) and IGF-1 production [10], it is possible that poorer growth during puberty and shorter final adult Ht may be due to the effect of Professor S. Faisal Ahmed, MD, FRCPCH Child Health, School of Medicine, University of Glasgow Royal Hospital for Sick Children, Yorkhill Glasgow G3 8SJ (UK) E-Mail faisal.ahmed @ glasgow.ac.uk
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Abstract Background: Puberty and growth may be affected in inflammatory bowel disease (IBD) but the extent is unclear. Methods: We performed a prospective study over 12 months in 63 adolescents (Crohn’s disease, CD, n = 45; ulcerative colitis/ IBD unclassified, UC, n = 18) with a median age of 13.4 years (range 10–16.6). Assessment included anthropometry, biochemical markers of growth and puberty and an assessment of quality of life by IMPACT-III. Results: Compared to the normal population, boys with CD were shorter, with a median height SDS (HtSDS) of –0.13 (–2.52 to 1.58; p < 0.05). In addition, the study cohort had a lower median IGF-1 SDS of –0.29 (–4.53 to 2.96; p = 0.008) and a higher median IGFBP3 SDS of 0.45 (–3.15 to 2.55; p = 0.002). Over the study period, the median Ht velocity (HV) was 5 cm/year (0.2–8.7) and the change in HtSDS was 0.06 (–0.48 to 0.57). The median difference between the chronological and bone age was 0.3 years (–2.5 to 3.0) and pubertal examination was not delayed. In the whole group, the erythrocyte sedimentation rate (ESR) showed an inverse association with HV (r = –0.29; p = 0.025) and IGF1:IGFBP3 (r = –0.34; p = 0.016). The score in the body image domain, IMPACT-III, was inversely associated with HtSDS (r = –0.31; p = 0.03). Conclusion: Despite no evidence of pubertal
Methods Patients Between December 2009 and December 2011, adolescents were recruited after obtaining informed consent whilst attending the gastroenterology clinic at the Royal Hospital for Sick Children, Glasgow if they were over 10 years old and if they had a diagnosis of IBD confirmed by standard diagnostic criteria. Of the 150 eligible patients who were attending the clinic, 12 were excluded as they had a history of an endocrine disorder, an additional chronic inflammatory disease such as juvenile idiopathic arthritis or had been diagnosed with a congenital disorder known to be associated with short stature. Of the remaining 138 adolescents, 63 were recruited into the study and consisted of 45 cases of CD (23 males) and 18 cases of ulcerative colitis/IBD unclassified (UC; 12 males; fig. 1). For the purpose of analysis children with UC and IBD unclassified were analysed together. The median age of the study population at diagnosis was 11.0 years (range 2.2–15.5) and the median age at study baseline was 13.4 years (10–16.6; table 1). Of the 63 cases, all had anthropometry at baseline, 58 (92%) had biochemical markers of growth at baseline and 52 (83%) had anthropometry at both 0 and 12 months. The Ht of patients who declined participation in the study was similar to those who were recruited (fig. 1).
46
Horm Res Paediatr 2015;83:45–54 DOI: 10.1159/000369457
Auxology Anthropometric data including Ht, weight, parental Ht and calculated body mass index (BMI) were collected from the clinical records of the recruited children at the time of diagnosis. At baseline (T0) and 12 months (T12), the following data were obtained by the same researcher (A.M.) – Ht and sitting Ht (SH), using a Harpenden stadiometer, and weight, BMI and pubertal status by physical examination. The BMI and Ht at diagnosis (HtDiag), Ht at baseline (Ht0) and Ht at 12 months (Ht12) were converted into SDS using 1990 British children standards [19]. SH was converted to SDS using the 1978 Tanner-Whitehouse standards [20]. Bone age was determined at T0 and T12 using the Tanner (TW2) RUS method. Ht velocity (HV) was converted into SDS for bone age with reference to sex-matched Tanner-Whitehouse HV charts, allowing for the HV to be evaluated in the context of maturity rather than chronological age. In addition to assessing bone age, pubertal progress was also assessed by comparison to established age norms by assessing pubertal status according to Tanner staging in girls and boys [21, 22]. The pubertal growth spurt is an important hallmark of puberty and can be used as a valid proxy of pubertal onset in retrospective studies [23, 24]. Cross-sectional growth data, corrected for skeletal maturation (bone age), were collated at 12 months and superimposed on HV charts for the normal female and male population to assess peak HV magnitude and timing. To assess selection bias, details of Ht, age and disease duration at the time of recruitment into the study were collected from the clinical records of all patients and the data for those who entered the study were similar to those who did not enter the study (fig. 1). Markers of Disease Activity Data for C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, platelets and haematocrit were collected from the clinical records. CRP levels of 7 mg/l, % Platelets, 109/l
Subjects, n Median age, years
T0
T0
T12
CDF
CDM
Table 1. Clinical details of children with IBD
Pubertal Growth in IBD
Horm Res Paediatr 2015;83:45–54 DOI: 10.1159/000369457
Downloaded by: University of Nebraska-Lincoln Libraries 129.93.16.3 - 4/3/2015 7:54:32 PM
49
23 13.3 (10.4–16.6) 13.0 (8.6–18.2) –0.15 (–2.6 to 1.5) 0.0 (–1.5 to 2.1)
1 4 5 8 1
19 14.1 (11.5–17.6) 13.7 (9.3–18) –0.14 (–2.5 to 1.6) –0.56 (–2.2 to 2.4) 0.05 (–0.3 to 0.4) 4.8 (0.8–7.6) 0.07 (–2.3 to 3.6)
3 4 7 6 2
–0.26 (–4.5 to 1.0) 0.77 (–1.2 to 2.1) 1,901 (1,125–2,776) 477 (164–941)
22 13.9 (10.0–16.5) 13.2 (9.6–16) –0.33 (–2.5 to 2.1) –0.04 (–1.7 to 2.8)
1 3 7 5 3
19 14.8 (12.1–17.5) 13.4 (10.1–16) 0.55 (–3.0 to 2.1) –0.14 (–2.3 to 1.6) 0.07 (–0.5 to 0.6) 2.8 (0.2–8.3) –0.4 (–4 to 4.7)
T12
3 2 5 2 –
–0.27 (–1.2 to 1.0) 0.51 (–2.0 to 2.4) 1,724 (1,119–2,041) 415 (180–979)
9/3 13.4 (10.0–16.5) 13.8 (9.2–15.9) 0.27 (–1.7 to 2.7) 1.17 (–1.0 to 3.2)
T0
UCM/IBDU
2 3 2 1 1
6/3 13.9 (10.8–16.8) 13.5 (10–17.1) 0.27 (1.6 to 2.2) 0.68 (–1.1 to 3.2) 0.09 (–0.5 to 0.3) 5.4 (3.6–8.7) 0.3 (–4.6 to 2.3)
T12
– 2 3 1 –
–0.6 (–1.9 to 0.0) –0.18 (–3.2 to 0.6) 1,730 (981–2,043) 500.3 (220–623)
5/1 13.2 (11.2–14.7) 13.4 (11.4–15.1) 0.18 (–1.8 to 1.1) –0.21 (–1.9 to 2.2)
T0
UCF/IBDU
2 1 2
5/0 14.2 (12.1–15.7) 14.6 (12.9–15.7) 0.39 (–1.3 to 0.6) –0.03 (–1.9 to 2.1) 0.18 (0.0 to 0.4) 5.2 (1.4–7.7) 2.5 (–2 to 8.2)
T12
T12 63 52 13.4 14.2 (10.0–16.6) (10.8–17.6) 13.2 13.6 (8.6–18.2) (9.3–18) –0.08 –0.06 (–2.6 to 2.7) (–3.0 to 2.2) 0.17 –0.06 (–1.9 to 3.2) (–2.3 to 3.2) 0.06 (–0.5 to 0.6) 5 (0.2–8.7) 0.14 (–4.6 to 8.2)
T0
All
For continuous variables, data are expressed as medians (with ranges). CDM = Male subjects with CD; CDF = female subjects with CD; UCM = male subjects with UC; UCF = female subjects with UC; IBDU = IBD unclassified; BA = bone age.
–0.31 (–3.0 to 3.0) IGFBP3 SDS for BA 0.22 (–1.7 to 2.6) ALS, mU/ml 1,888 (544–2,719) IGFBP2, ng/ml 435 (223–435) Tanner stage: 3 I 7 II 7 III 4 IV 2 V
IGF-1 SDS for BA
HVSDS for BA
HV, cm/year
ΔHtSDS
BMISDS
HtSDS
BA, years
Subjects, n Age, years
T0
T0
T12
CDF
CDM
Table 2. Clinical assessment of growth and puberty of children with IBD
2
HtSDS Diag
0
–2
–2 CDM n = 23
CDF 22
UCM 12
UCF 6
CDM n = 23
CDF 22
UCM 12
UCF 6
CDF 19
UCM 9
UCF 5
2
HtSDS 12 m
2
HtSDS 0m
0
0
–2
* 0
–2 CDM n = 23
CDF 22
UCM 12
UCF 6
CDM n = 19
(0 months) and 12 months in male and female patients with CD and UC. MPHtSDS = Mid-parental HtSDS (see legend to fig. 1 for
other abbreviations). Numbers on x-axis refer to number of patients at each time point. * p < 0.05 compared to the normal population.
had HtDiagSDS
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2015;83:45–54 DOI: 10.1159/000369457
Received: June 6, 2014 Accepted: October 28, 2014 Published online: December 20, 2014
A Prospective Longitudinal Study of Growth and Pubertal Progress in Adolescents with Inflammatory Bowel Disease Avril Mason a Salma Malik a Martin McMillan a Jane D. McNeilly c J. Bishop b Paraic McGrogan b Richard K. Russell b S. Faisal Ahmed a a c
Child Health, School of Medicine, University of Glasgow, b Department of Paediatric Gastroenterology and Department of Paediatric Biochemistry, Royal Hospital for Sick Children, Glasgow, UK
Key Words Adolescence · Chronic disease · Hypogonadism · Growth · Inflammation
delay, adolescents with IBD display growth retardation which may be associated with raised ESR, adverse quality of life measures and an abnormality of IGF-1 bioavailability. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1663–2818/14/0831–0045$39.50/0 E-Mail [email protected] www.karger.com/hrp
Introduction
Children with inflammatory bowel disease (IBD), and particularly Crohn’s disease (CD), often present during early adolescence and have been reported to display delayed puberty [1]. It is possible that chronic inflammation may lead to wide-ranging effects, including hypogonadotropic hypogonadism [2], an abnormality of sex steroid synthesis [3–5] or an abnormality of sex steroid action [6]. Pubertal delay is often associated with growth retardation but previous studies suggest that adolescents with IBD seem to have more profound short stature than expected simply for delayed puberty [1]. In addition, adults with a history of pubertal delay are often shorter as adults than their predicted height (Ht) but the discrepancy between target Ht and final Ht seems to be greater in adults with childhood onset IBD compared to healthy adults with a history of delayed puberty [7–9]. As sex steroid-induced growth acceleration is dependent on increased growth hormone (GH) and IGF-1 production [10], it is possible that poorer growth during puberty and shorter final adult Ht may be due to the effect of Professor S. Faisal Ahmed, MD, FRCPCH Child Health, School of Medicine, University of Glasgow Royal Hospital for Sick Children, Yorkhill Glasgow G3 8SJ (UK) E-Mail faisal.ahmed @ glasgow.ac.uk
Downloaded by: University of Nebraska-Lincoln Libraries 129.93.16.3 - 4/3/2015 7:54:32 PM
Abstract Background: Puberty and growth may be affected in inflammatory bowel disease (IBD) but the extent is unclear. Methods: We performed a prospective study over 12 months in 63 adolescents (Crohn’s disease, CD, n = 45; ulcerative colitis/ IBD unclassified, UC, n = 18) with a median age of 13.4 years (range 10–16.6). Assessment included anthropometry, biochemical markers of growth and puberty and an assessment of quality of life by IMPACT-III. Results: Compared to the normal population, boys with CD were shorter, with a median height SDS (HtSDS) of –0.13 (–2.52 to 1.58; p < 0.05). In addition, the study cohort had a lower median IGF-1 SDS of –0.29 (–4.53 to 2.96; p = 0.008) and a higher median IGFBP3 SDS of 0.45 (–3.15 to 2.55; p = 0.002). Over the study period, the median Ht velocity (HV) was 5 cm/year (0.2–8.7) and the change in HtSDS was 0.06 (–0.48 to 0.57). The median difference between the chronological and bone age was 0.3 years (–2.5 to 3.0) and pubertal examination was not delayed. In the whole group, the erythrocyte sedimentation rate (ESR) showed an inverse association with HV (r = –0.29; p = 0.025) and IGF1:IGFBP3 (r = –0.34; p = 0.016). The score in the body image domain, IMPACT-III, was inversely associated with HtSDS (r = –0.31; p = 0.03). Conclusion: Despite no evidence of pubertal
Methods Patients Between December 2009 and December 2011, adolescents were recruited after obtaining informed consent whilst attending the gastroenterology clinic at the Royal Hospital for Sick Children, Glasgow if they were over 10 years old and if they had a diagnosis of IBD confirmed by standard diagnostic criteria. Of the 150 eligible patients who were attending the clinic, 12 were excluded as they had a history of an endocrine disorder, an additional chronic inflammatory disease such as juvenile idiopathic arthritis or had been diagnosed with a congenital disorder known to be associated with short stature. Of the remaining 138 adolescents, 63 were recruited into the study and consisted of 45 cases of CD (23 males) and 18 cases of ulcerative colitis/IBD unclassified (UC; 12 males; fig. 1). For the purpose of analysis children with UC and IBD unclassified were analysed together. The median age of the study population at diagnosis was 11.0 years (range 2.2–15.5) and the median age at study baseline was 13.4 years (10–16.6; table 1). Of the 63 cases, all had anthropometry at baseline, 58 (92%) had biochemical markers of growth at baseline and 52 (83%) had anthropometry at both 0 and 12 months. The Ht of patients who declined participation in the study was similar to those who were recruited (fig. 1).
46
Horm Res Paediatr 2015;83:45–54 DOI: 10.1159/000369457
Auxology Anthropometric data including Ht, weight, parental Ht and calculated body mass index (BMI) were collected from the clinical records of the recruited children at the time of diagnosis. At baseline (T0) and 12 months (T12), the following data were obtained by the same researcher (A.M.) – Ht and sitting Ht (SH), using a Harpenden stadiometer, and weight, BMI and pubertal status by physical examination. The BMI and Ht at diagnosis (HtDiag), Ht at baseline (Ht0) and Ht at 12 months (Ht12) were converted into SDS using 1990 British children standards [19]. SH was converted to SDS using the 1978 Tanner-Whitehouse standards [20]. Bone age was determined at T0 and T12 using the Tanner (TW2) RUS method. Ht velocity (HV) was converted into SDS for bone age with reference to sex-matched Tanner-Whitehouse HV charts, allowing for the HV to be evaluated in the context of maturity rather than chronological age. In addition to assessing bone age, pubertal progress was also assessed by comparison to established age norms by assessing pubertal status according to Tanner staging in girls and boys [21, 22]. The pubertal growth spurt is an important hallmark of puberty and can be used as a valid proxy of pubertal onset in retrospective studies [23, 24]. Cross-sectional growth data, corrected for skeletal maturation (bone age), were collated at 12 months and superimposed on HV charts for the normal female and male population to assess peak HV magnitude and timing. To assess selection bias, details of Ht, age and disease duration at the time of recruitment into the study were collected from the clinical records of all patients and the data for those who entered the study were similar to those who did not enter the study (fig. 1). Markers of Disease Activity Data for C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, platelets and haematocrit were collected from the clinical records. CRP levels of 7 mg/l, % Platelets, 109/l
Subjects, n Median age, years
T0
T0
T12
CDF
CDM
Table 1. Clinical details of children with IBD
Pubertal Growth in IBD
Horm Res Paediatr 2015;83:45–54 DOI: 10.1159/000369457
Downloaded by: University of Nebraska-Lincoln Libraries 129.93.16.3 - 4/3/2015 7:54:32 PM
49
23 13.3 (10.4–16.6) 13.0 (8.6–18.2) –0.15 (–2.6 to 1.5) 0.0 (–1.5 to 2.1)
1 4 5 8 1
19 14.1 (11.5–17.6) 13.7 (9.3–18) –0.14 (–2.5 to 1.6) –0.56 (–2.2 to 2.4) 0.05 (–0.3 to 0.4) 4.8 (0.8–7.6) 0.07 (–2.3 to 3.6)
3 4 7 6 2
–0.26 (–4.5 to 1.0) 0.77 (–1.2 to 2.1) 1,901 (1,125–2,776) 477 (164–941)
22 13.9 (10.0–16.5) 13.2 (9.6–16) –0.33 (–2.5 to 2.1) –0.04 (–1.7 to 2.8)
1 3 7 5 3
19 14.8 (12.1–17.5) 13.4 (10.1–16) 0.55 (–3.0 to 2.1) –0.14 (–2.3 to 1.6) 0.07 (–0.5 to 0.6) 2.8 (0.2–8.3) –0.4 (–4 to 4.7)
T12
3 2 5 2 –
–0.27 (–1.2 to 1.0) 0.51 (–2.0 to 2.4) 1,724 (1,119–2,041) 415 (180–979)
9/3 13.4 (10.0–16.5) 13.8 (9.2–15.9) 0.27 (–1.7 to 2.7) 1.17 (–1.0 to 3.2)
T0
UCM/IBDU
2 3 2 1 1
6/3 13.9 (10.8–16.8) 13.5 (10–17.1) 0.27 (1.6 to 2.2) 0.68 (–1.1 to 3.2) 0.09 (–0.5 to 0.3) 5.4 (3.6–8.7) 0.3 (–4.6 to 2.3)
T12
– 2 3 1 –
–0.6 (–1.9 to 0.0) –0.18 (–3.2 to 0.6) 1,730 (981–2,043) 500.3 (220–623)
5/1 13.2 (11.2–14.7) 13.4 (11.4–15.1) 0.18 (–1.8 to 1.1) –0.21 (–1.9 to 2.2)
T0
UCF/IBDU
2 1 2
5/0 14.2 (12.1–15.7) 14.6 (12.9–15.7) 0.39 (–1.3 to 0.6) –0.03 (–1.9 to 2.1) 0.18 (0.0 to 0.4) 5.2 (1.4–7.7) 2.5 (–2 to 8.2)
T12
T12 63 52 13.4 14.2 (10.0–16.6) (10.8–17.6) 13.2 13.6 (8.6–18.2) (9.3–18) –0.08 –0.06 (–2.6 to 2.7) (–3.0 to 2.2) 0.17 –0.06 (–1.9 to 3.2) (–2.3 to 3.2) 0.06 (–0.5 to 0.6) 5 (0.2–8.7) 0.14 (–4.6 to 8.2)
T0
All
For continuous variables, data are expressed as medians (with ranges). CDM = Male subjects with CD; CDF = female subjects with CD; UCM = male subjects with UC; UCF = female subjects with UC; IBDU = IBD unclassified; BA = bone age.
–0.31 (–3.0 to 3.0) IGFBP3 SDS for BA 0.22 (–1.7 to 2.6) ALS, mU/ml 1,888 (544–2,719) IGFBP2, ng/ml 435 (223–435) Tanner stage: 3 I 7 II 7 III 4 IV 2 V
IGF-1 SDS for BA
HVSDS for BA
HV, cm/year
ΔHtSDS
BMISDS
HtSDS
BA, years
Subjects, n Age, years
T0
T0
T12
CDF
CDM
Table 2. Clinical assessment of growth and puberty of children with IBD
2
HtSDS Diag
0
–2
–2 CDM n = 23
CDF 22
UCM 12
UCF 6
CDM n = 23
CDF 22
UCM 12
UCF 6
CDF 19
UCM 9
UCF 5
2
HtSDS 12 m
2
HtSDS 0m
0
0
–2
* 0
–2 CDM n = 23
CDF 22
UCM 12
UCF 6
CDM n = 19
(0 months) and 12 months in male and female patients with CD and UC. MPHtSDS = Mid-parental HtSDS (see legend to fig. 1 for
other abbreviations). Numbers on x-axis refer to number of patients at each time point. * p < 0.05 compared to the normal population.
had HtDiagSDS
