Impaired growth and altered body composition are common and major complications in children and adolescents with inflammatory bowel disease, which may precede the diagnosis (1) and also may occur in the absence of proven malabsorption (2,3) or reduced caloric intake (4). Although the pathogenesis is thought to be multifactorial, several investigators have reported that those affected with Crohn's disease (CD) have more impaired growth than those with ulcerative colitis (4–6). Limited sample sizes in many studies bar generalizations about gender differences in the impact of CD on growth and long-term prognosis in children and adolescents.
Ferguson and Sedgwick (7) in a retrospective study that included 60 British subjects with CD, used both measured and self-reported heights and found that despite the growth retardation observed during the teenaged years, most patients eventually achieved heights within the normal range for the general population. Griffiths et al. (8) retrospectively reviewed the linear growth of 67 subjects with CD from childhood into adulthood and also reported a favorable prognosis. In addition, they observed that females achieved greater catch-up growth than males. Motil et al. (4) prospectively measured linear growth in 69 children with inflammatory bowel disease (34 with CD, 68% male) over a 3-year period and found 24% to 39% with impaired growth regardless of pubertal development. The genetic component of linear growth was not evaluated in the above studies. Markowitz et al. (9) retrospectively analyzed the heights of 48 adults (38 with CD) with juvenile-onset inflammatory bowel disease. Using the National Center for Health Statistics height percentiles and two height prediction methods (those of Bailey and Pinneau  and Roche et al. ), they found that 31% had permanently impaired linear growth. Most of the subjects had CD, and 73% were males. These results show the association between CD and impaired growth and also suggest that there may be gender differences in the impact of CD on growth.
The purpose of our study was to examine growth and body composition in a large sample of children, adolescents, and young adults with CD using anthropometry and dual-energy x-ray absorptiometry (DEXA). The severity of impaired linear growth in relation to genetic potential was assessed using the parent-specific adjusted heights by the method of Himes et al. (12) These variables were examined in relation to measures of disease activity. Special attention was given to evaluating the question of gender differences in the patterns of growth.
PATIENTS AND METHODS
Subjects invited to participate were selected by a randomly generated computer list of patients with CD aged 5 to 25 years who received care at The Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania. Children and young adults with CD diagnosed by radiologic, histologic, and clinical parameters were enrolled. Subjects were excluded if they had any other chronic illness known to affect growth, pubertal development, or body composition. A group of 66 control subjects of similar age was recruited from a convenience sample of friends and family of hospital staff and nearby area residences. Of these, 75% were primarily recruited for this study, and the remaining 25% were participating in other ongoing studies in which similar recruitment and measurement techniques had been applied. Informed consent was obtained before the study from the subject and parent(s) or guardian(s), and assent was obtained from subjects less than 18 years of age. The Institutional Review Board at The Children's Hospital of Philadelphia approved the study.
Anthropometric, Body Composition, and Disease Activity Measurements
Using the methods described by Lohman et al. (13), one observer obtained all anthropometric measurements in triplicate. Height and weight were recorded using a digital scale accurate to 0.1 kg (Scaltronix, White Plains, NY, U.S.A.) and a stadiometer accurate to 0.1 cm (Holtain, Crymych, UK). Pubertal stage was determined (by a single investigator, EJS) by physical examination of pubic hair pattern in males and females, breast development in females, and penile development in males, according to the criteria of Tanner (14). The scores for genital and hair development were averaged, and the value was used to categorize them into three groups: prepubertal: Tanner stage I; peripubertal: stages II–IV; and postpubertal: stage V.
Using a flexible plastic measuring tape (Ross Laboratories, Columbus OH, U.S.A.) upper arm circumference was measured. A skinfold caliper (Holtain), was used to measure the biceps, triceps, subscapular, and suprailiac skinfolds on the right side. Elbow diameter was measured using a sliding caliper (Holtain). Total upper arm muscle area (UAMA) was calculated from upper arm circumference and triceps skinfold (15). The fat patterning (centripetal fat ratio) was calculated as the subscapular skinfold divided by the sum of the triceps and subscapular skinfolds (16). A high centripetal fat ratio would be suggestive of increased axial compared with peripheral subcutaneous fat stores such as occurs in a cushingoid body habitus. Weight and height values were compared with National Center for Health Statistics reference standards for percentiles, and z-scores for weight (WAZ) and height (HAZ) were computed using the Centers for Disease Control's Anthropometric Software Program (version 3.1, 1988, Division of Nutrition, Centers for Disease Control and Prevention, Atlanta, GA, U.S.A.). For subjects aged 18 years and older, height and weight z-scores were calculated using an age of 17.9 years. Z-scores for skinfolds, arm circumference, UAMA, and elbow breadth were calculated using National Center for Health Statistics reference data published by Frisancho (15,17).
Height was adjusted for genetic potential using the parental height adjustment method of Himes et al. (12). In this method, the subject's measured height and the measured or estimated height of both parents are used to obtain a midparent height. The parent-specific adjusted height is then calculated and is applicable in children aged birth to 18 years. It is based on 586 midparent–child pairs who participated in the Fels Longitudinal Study, and on more than 16,000 serial measurements of recumbent length and stature (12). Because no radiographic studies are required, adjusted height can be readily and repetitively used in clinical practice. An adjusted height-for-age z-score (AHAZ) was then computed. Using age and gender-specific equations, percentage of body fat (BF), fat mass in kilograms (FM), and fat-free mass in kilograms (FFM) were calculated from four skinfolds (18–20). Body composition was also assessed by whole-body DEXA scan (QDR-2000, Hologic, Inc., Walthman, MA, U.S.A.). The results were reported as FM, BF, and FFM.
Age at diagnosis was obtained by medical chart review. Site of disease was obtained from endoscopic, histologic, and radiologic reports in the medical record and categorized as follows: upper gastrointestinal Crohn's when involvement was limited to the esophagus, stomach, duodenum, jejunum, small intestine, and terminal ileum; lower GI Crohn's for involvement limited to the colon; and mixed if both upper gastrointestinal site and colon were involved. Disease activity was assessed at enrollment using the Pediatric Crohn's Disease Activity Index (PCDAI) (21). The PCDAI score is based on history (30%), physical examination (30%), laboratory data (20%), and height velocity (20%). The scores range from 0 to 100. Scores of 0 to 10 correspond to no disease activity, 11 to 30 to mild activity, and more than 30 to moderate to severe activity. The PCDAIs obtained during earlier outpatient visits were abstracted by one investigator from the patients' medical records, and the average was calculated. Steroid exposure was calculated as the total lifetime exposure for each subject including oral and intravenous forms of steroids. All dosage forms, except steroid enemas, were converted to oral prednisone equivalent. Total exposure in days or months was also calculated and was based on total number of days or months of steroid exposure and not duration of disease. Therefore, steroid exposure was expressed as cumulative dose in milligrams per day.
Skeletal age was obtained in subjects with CD by the Tanner–Whitehouse 2 (TW2) method (22), in which radiographs of the left hand and wrist are used. Subjects in pubertal stage Tanner V were excluded, because growth was assumed to be complete. Also, subjects in Tanner stage IV but with no linear growth for a period of at least 12 months were assumed to have completed growth. Therefore, skeletal age was not measured in this group.
All analyses were performed by computer (Stata 5.0; Stata, College Station, TX, U.S.A.) for males and females separately. Statistical comparisons of growth, nutritional status, and body composition variables were examined with unpaired t-tests. Pearson correlations were used to determine the associations between disease severity variables and growth and nutritional status outcomes. To explore the contribution of pubertal stage, two-way analysis of variance was used to determine whether group (CD vs. control) and puberty status were associated with growth and nutritional status. The interaction term group vs. pubertal stage was included in the analyses to determine whether group differences were consistent across pubertal developmental stages. Multiple and polynomial regression analyses were used to test for group differences in FFM and FM after adjusting for the age-related increases in these variables. For all analyses, statistical significance was defined as P <= 0.05.
One hundred thirty-two subjects with CD (36% females) and 66 control subjects (56% females) were enrolled in the study. Their clinical characteristics are displayed in Table 1. The males with CD outnumbered the females by a ratio of 1.7:1. There were no gender differences in age, duration of disease, or average PCDAI.
Growth, Nutritional Status, Skeletal Maturation, and Pubertal Stage
When the groups were compared on the basis of z-scores for growth and nutritional status (Table 2), which adjusts for the age-and gender-related trends in anthropometric dimensions, a pattern of deficits in growth and nutritional status emerged in the males. There were significant differences in z-scores for growth (HAZ, AHAZ, and WAZ) and nutritional status (elbow breadth, arm circumference, and UAMAZ) in males with CD compared with control subjects. Similar differences were not observed between the females with CD and control subjects.
Skeletal age assessment was completed for the subsample of 60 subjects with CD who met the assessment criteria. There was no significant difference between skeletal age and chronological age by paired t-test for the 19 females for whom skeletal age was measured. However, skeletal age was significantly delayed by an average of 0.9 ± 1.6 years (P = 0.001) in the 41 males in whom the measurement was obtained.
The subjects with CD and control subjects were similar in distribution by puberty stage. For females, the pre-, peri-, and postpubertal subjects with CD and control subjects were similar in age. However, for males with CD, the peripubertal group was significantly older than control subjects (14.6 vs. 12.7 years, P = 0.02). To determine whether differences between the CD and control subjects in growth or nutritional status z-scores were influenced by pubertal stage, two-way analysis of variance tests were used to compare subjects with CD and control subjects across pubertal stages. Among females with CD, adjusted height improved with advancing puberty (Fig. 1). Females with CD did not significantly differ from control subjects in HAZ, AHAZ, and UAMAZ across pubertal stages. For males with CD, there were significant differences in AHAZ by pubertal stage (P = 0.02) and between groups (P = 0.04), so that control subjects had significantly higher AHAZ (P < 0.001) than the CD group. Males with CD had significantly lower HAZ (P < 0.001), AHAZ (P < 0.001), and UAMAZ (P = 0.02), regardless of pubertal stage and did not improve with completion of puberty (Fig. 2).
Body composition was assessed by DEXA and by anthropometric prediction equations using four skinfolds. Results of both methods were highly correlated with FFM (r = 0.98), FM (r = 0.95), and BF (r = 0.89), and these associations were similar for males and females and in the CD and control groups. Although the results were highly correlated, comparisons of the results of the two methods by paired t-test indicated that the skinfold prediction method consistently overestimated FFM and underestimated FM compared with the DEXA method (Table 3). In general, there were no differences in absolute values of FFM and FM and the percentage of BF between males with CD and control subjects. However, there were group differences in measures of body fat by anthropometry and DEXA in the females. Measures of adiposity (triceps skinfold z-score) in both males and females with CD were significantly correlated with steroid exposure (females r = 0.40, P = 0.01; males r = 0.30, P = 0.002). Nevertheless, they did not differ from control subjects in body fat patterning as indicated by the centripetal fat ratio (Table 2).
Because FM and FFM increase with age, a more appropriate group comparison requires adjustment for the age-related changes in body composition. Suitable reference data for body composition measures (BF, FM, and FFM) are not available for computation of z-scores. Therefore, as an alternative, multiple regression analysis was used in which age and, where appropriate, age squared terms were entered into the model so that more meaningful group comparisons could be made for males and females separately. The results for DEXA body composition measures are presented (Fig. 3). For both males and females, the CD groups had significantly lower FFM than control subjects (P = 0.05). Overall, males with CD had 3.5 kg less FFM and females 2.9 kg less than control subjects. Males with CD and control males had similar amounts of body fat at all ages, but females with CD had 3.7 kg more body fat mass than control subjects (P = 0.04), a difference of approximately 6%.
Data for site of disease were available in 119 subjects: 9 (8%) had CD limited to the upper gastrointestinal tract, 31 (26%) had CD limited to the colon, and 79 (66%) had CD involving both upper and lower gastrointestinal sites. No significant association occurred between site of disease and any of the growth parameters. Only 83 subjects (33 female) had medical records that were adequate for calculation of an average PCDAI. The average PCDAI was the same in both genders (P = 0.6) and was in the mild disease activity range. For both males and females with CD, delayed skeletal age (skeletal age minus chronological age) was inversely associated with HAZ and WAZ, indicating that to some degree, poor growth status in children with CD is related to delayed maturation. Average PCDAI was inversely correlated with UAMAZ (males, r = -0.34, P = 0.02; females, r = -0.39, P = 0.03), thereby associating increasing disease activity with reduced muscle mass. In females, lifetime steroid exposure was inversely associated with delayed skeletal age (r = -0.45, P = 0.05) and HAZ (r = -0.34, P = 0.02). In males, there was no significant association between lifetime steroid exposure and HAZ or delayed skeletal age. Therefore, in general, impaired growth in females was more consistently associated with disease severity indicators than in males.
The findings of this large study of 132 subjects with CD are in agreement with results in previous studies that have shown that CD is associated with impaired linear growth and decreased muscle mass (1,4,5,9,23,24). This is the first report to specifically describe gender differences in the severity of impaired growth in children, adolescents and young adults with CD. Impaired growth in males with CD was present regardless of pubertal stage and also occurred among young adults.
Because there is a significant genetic component contributing to height, determining adjusted height is a more powerful way of assessing height status (12). For both males and females with CD, z-scores based on adjusted heights were significantly lower than z-scores based on measured height. These findings suggest that children with CD do not attain their genetic potential for linear growth. Furthermore, males seem to be more severely affected than females. The average AHAZ for males was -1.0, which is one standard deviation less than expected. In addition, males with CD were significantly shorter than control subjects regardless of pubertal stage.
Delayed skeletal age was also more prevalent in males with CD, and in both genders it was associated with small body size. It is unlikely that a type II error prevented detection of delayed skeletal age in the females, because the subsample of 19 females was sufficient for detection of a one standard deviation difference between chronological age and skeletal age (power 99.6%, P = 0.05). These cross-sectional observations suggest that poor growth status in males with CD cannot be fully explained by delayed maturation, because mature males did not differ in status from immature males. Male gender per se has been found by other investigators to confer greater risk for complications of CD and its therapy (25). These findings suggest that delayed skeletal age and puberty in CD may not be assurances for future prolonged and/or greater linear growth as occurs in healthy children (26), but rather may be more of an index of the disease's impact on growth. Therefore, longitudinal study is required to verify the long-term impact of disease severity on delayed maturation and growth status.
On average, females with CD did not differ from control subjects in height, HAZ, or AHAZ. Nevertheless, 23% of the females with CD had heights below the 5th percentile for age, and 25% were below the 5th percentile of their adjusted height. In males, 26% had heights below the 5th percentile for age, and 33% were below the 5th percentile of their adjusted height (data not presented). Thus, growth failure is also common in females, but not as severe as in males. In healthy children, the average age of peak height velocity growth in females is 11.5 years, whereas in males it occurs at the age of 13.5 years (27). Because the mean age at diagnosis for both genders in our study was 12 years, females tended to acquire CD after the age at which peak height velocity usually occurs, whereas males acquired CD before the average age of peak height velocity. Therefore, the time of onset of CD in relation to age of peak height velocity may in part explain the gender differences seen in the disease's impact on growth. Children acquiring CD just before the age of peak height velocity may be at greater risk for impaired linear growth and therefore warrant special attention to growth issues while treating the CD.
Although body weight and height are useful in clinical care, the information they provide about nutritional status is incomplete. Assessing body composition allows description of the BF and FFM tissue compartments. Fat tissue makes up the body's energy stores and is laid down when ingested calories are greater than those required for an individual's body size, physical activity, and health status (28) (positive energy balance). The FFM represents the body protein resources and functional capacity and is composed of water, lean tissue, organs, and bone. UAMAZ is a proxy measure of muscle mass and correlates very well with total body FFM and with functional measures such as forearm muscle grip strength (29). After adjustment was made for age, subjects with CD had normal body fat stores but less FFM than the control subjects. There was a negative correlation between disease activity and UAMAZ, thereby associating chronic inflammation with low muscle mass. Increased tissue and systemic levels of proinflammatory cytokines may mediate impaired accretion of lean tissue during chronic inflammation (30–32). Inadequate caloric intake has also been implicated as an important cause for impaired growth in CD (1,33). Normal body fat stores in the presence of decreased muscle mass implies that factors other than primary malnutrition were responsible for the impaired growth in our study subjects. Body fat was significantly correlated with steroid exposure; however, there was no correlation between UAMAZ and lifetime steroid exposure. Therefore, lifetime steroid exposure did not satisfactorily explain these body composition differences. These findings are consistent with the multifactorial origin of the impaired growth and body composition in CD.
The highest incidence of CD is reported in the Scandinavian countries. In the literature women are generally considered to be at a 20% to 30% greater risk than men for development of CD (34). In the United States, surveys provide conflicting data regarding gender distribution ranging from female predominance (35) to no difference (36). Because most surveys have been conducted among adults with CD, the results may have limited generalizability to the pediatric age range. We previously reported a male predominance in pediatric CD by a ratio of 1.7:1. This analysis came from a data pool of 192 patients with confirmed CD who were observed at our institution (37). Many other independent studies involving pediatric subjects with CD have also had a predominance of male subjects (1,4,8,38,39). A reason for this discrepancy in adult versus pediatric gender distribution may be later age of disease onset of CD or its diagnosis in females; yet, the average age of diagnosis for both genders in our study was 12 years. However, among the females it was more variable (wider standard deviation in age of diagnosis) than among males. It is possible that the social impact of impaired growth is more obvious in male children and adolescents. Kanof et al. (1) found that 88% of children with CD experience a decrease in linear growth velocity before diagnosis. The greater concern about height among males may influence referral patterns and contribute to earlier diagnosis of CD in males. This may in turn result in the gender prevalence pattern of CD in the pediatric age group.
The main limitation of our study is that it was cross-sectional. Therefore, inferences about long-term impact on growth are limited. However, the findings reported here are based on a large sample of patients with pediatric-onset CD and a comprehensive battery of growth and nutritional status measurements. Only a proportion of the subject (60% of the males and 69% of the females) had sufficient documentation in their records for retrospective calculation of an average PCDAI. Because these were outpatient records they may have underrepresented periods of severe illness requiring hospital admission. Although this may have limited our assessment about the disease's impact on growth, it is unlikely to have influenced the gender differences we observed. Finally, the type of comparison group (control subjects) may have influenced the severity of our findings (i.e., very well-nourished control subjects could exaggerate the disparity in growth and nutritional status measurements). However, it is unlikely that this influenced our findings, because the control subjects were generally of similar age and had normal distribution in growth and nutritional status measures. Also, the z-scores used to compare both groups with the national reference data support the findings of growth and body composition deficits in subjects with CD.
In summary, these data confirm the association between CD and impaired growth in children, adolescents, and young adults. The use of parent-specific adjusted-heights that predict genetic potential for linear growth is a more powerful method of assessing impaired growth. Body composition should be an important consideration in planning and assessing growth and nutritional outcomes in children with CD. Furthermore, despite similarities in age at diagnosis, duration of disease, and disease activity, growth in males with CD was more severely impaired than in females. For females the disease severity indicators were more consistently associated with growth and nutritional status. This suggests that factors other than disease severity may influence growth and nutritional status in males with CD. The time of onset of CD in relation to the age at peak height velocity may confer risk for impaired linear growth. These findings call for special attention to growth and development issues of those with disease diagnosed in childhood and early adolescence. Future studies of pre-and peripubertal males and females with CD are needed to more fully understand the gender specific abnormalities and risk factors for impaired growth and also to evaluate various interventions.
Supported by the General Clinical Research Center, National Institutes of Health (grant RR-00240) and by the Nutrition Center at The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.
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Keywords:© 2000 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
Adolescents; Anthropometry; Body composition; Children; Crohn's disease; Dual-energy x-ray absorptiometry; Gender; Growth