This study demonstrated significant improvements in body composition parameters in incident CD subjects from diagnosis throughout a period of extended follow-up. Additionally, the study identified the following determinants of improvements in LM-ht Z-score following diagnosis: increases in FM-ht Z-score and albumin; decreases in ESR, IL-6, and LBP; and infliximab therapy. Increases in albumin and GHBP, presentation with weight loss at diagnosis; and use of glucocorticoids, methotrexate, and infliximab were associated with greater increases in FM-ht Z-score. The data reported here differ significantly from prior reports and also provide new findings regarding determinants of changes in body composition in pediatric CD from diagnosis. First, our study is the first longitudinal study to show improvements in body composition parameters. Second, the inclusion of a robust contemporary reference population allowed for sex- and race-specific assessment of body composition relative to height, with further adjustment for Tanner stage. Additionally, the inclusion of the subset of controls with baseline, 6- and 12-month body composition data allow for the assessment of changes in LM relative to FM during the first 12 months of therapy in CD subjects. Third, to our knowledge, our study is the first to show improvements in LM-ht Z-score associated with improvements in IL-6 and LBP, as well as infliximab use.
A prior study of changes in body composition during two years after CD diagnosis, limited by a small cross-sectional reference population (n=81), did not show improvements in LM, did not note sex differences in body composition changes, and did not include measures of FM.20
In male CD subjects, we noted cachexia at baseline, with complete recovery of LM deficits at LTFU. In fact, increases in FM in males resulted in significantly greater FM in male CD subjects at LTFU compared with controls. In contrast, female CD subjects presented with LM and FM deficits at baseline and demonstrated complete recovery of FM deficits but persistent LM deficits despite improvement in LM-ht Z-scores at LTFU. The patterns of progressing from cachexia to excess adiposity in males and from wasting to cachexia in females over the study interval are not captured by examining differences in BMI Z-score (). These findings highlight the importance of assessing lean and fat compartments individually as indicators of nutritional status.
Although improvements in PCDAI were not associated with improvements in LM-ht Z-score, improvements in albumin and ESR, components of the PCDAI, and reductions in IL-6 and LBP, were associated with improvements in LM-ht Z-score. In fact, serum cytokines remained elevated six months following diagnosis, despite improvements in clinical disease activity, suggesting that therapies used to induce remission were not immediately effective in suppressing systemic inflammation. We were able to demonstrate a relationship between improvements in height Z-scores and reductions in PCDAI , IL-6, TNF-α, and LBP, though not infliximab therapy. The lack of an association between infliximab therapy and improvement in height Z-score is consistent with a similar study in an inception cohort of children with Crohn’s disease initiating infliximab therapy over a varied interval following disease diagnosis.36
Two prior studies that reported an association between infliximab therapy and changes in height Z-score were based on subjects’ enrollment at the time of initiation of infliximab therapy and did not include untreated Crohn’s disease controls.37–38
Recent studies using murine models of CD have elucidated the roles of IL-6 in growth failure.39–40
Although it is well recognized that sarcoactive cytokines41–42
induce myoblast apoptosis43
and stimulate protein degradation with resultant decreases in muscle mass, the association between improvements in LM deficits and IL-6 in incident pediatric CD has not been previously reported. LBP is an acute phase protein that is upregulated in the liver in response to endotoxin and IL-6 exposure. Additionally, a recent study of cross-sectional measures of LBP in a prevalent pediatric CD cohort demonstrated an association between elevated LBP and lower height Z-scores, suggesting that increased exposure to endotoxin results in immune-mediated growth hormone resistance.44
The study reported here is the first to examine changes in LBP and associated improvements in height and LM-ht Z-scores. Although TNF-α decreased significantly from baseline to LTFU, these changes were not associated with improvements in LM-ht Z-score. However, interval increases in LM-ht Z-score were associated with infliximab therapy. Together, the associations between improvements in LM deficits, reductions in IL-6 and LBP, and infliximab use emphasize the role of inflammation as an etiology for LM deficits.
We demonstrated decreased IGF-1 in CD subjects compared with controls but did not show significant increases over time or a relationship with LM deficits. However, increases in height Z-score were associated with increases in IGF-1. The predominant source of circulating IGF-1 is the liver, and recent murine studies have shown that hepatic IGF-1 is dispensable for many aspects of postnatal growth.45
Therefore, local IGF-1 action, not reflected in serum measurements, may be sufficient for attainment of LM.46
Under normal conditions, IGFBP-3 is produced by hepatic Kupffer cells in association with IGF-1 production by hepatocytes. We observed increased IGFBP-3 in CD subjects compared with controls at baseline, which normalized during long-term follow-up. This was unexpected, as serum IGFBP-3 is typically reduced during catabolism. However, IL-6 has been shown to induce IGFBP-3 secretion by Kupffer cells in vitro; this may explain the increase observed in the serum at earlier time points when IL-6 was elevated.47
The net effect of an increase in total IGF-1, and decrease in IGFBP-3, during LTFU would have been to increase the relative amount of free IGF-1 available to promote accrual of LM. GHBP is produced in humans from cleavage of the extra-cellular domain of the growth hormone receptor and release into the serum.48
Under normal conditions, serum GHBP is positively associated with FM.49
Therefore, it was surprising to observe increased in GHBP at baseline in CD patients, compared with controls. This may reflect an increase in GHR cleavage under inflammatory conditions, as we recently demonstrated in a murine model of acute endotoxin exposure.50
We did observe the expected positive association between increases in FM-ht Z-score and GHBP during therapy.49
Our study has some limitations, including the lack of dietary and physical activity data. For example, the associations between infliximab therapy and lean mass may be mediated by improved physical activity and dietary intake. There was loss to follow-up during the study interval, but subjects who did and did not complete all 4 study visits were no different in terms of demographics, disease activity, anthropometry, or body composition at baseline, minimizing potential bias. In addition, mucosal, as opposed to serum, levels of inflammatory cytokines such as TNF-α, were not available and may have correlated better with body composition outcomes. Finally, the biologic and clinical significance of the observed relations between the changes in cytokines and growth factors and associated changes in growth and body composition is unknown; however, our findings support the hypothesis that alterations in these biomarkers may directly impact growth and body composition.
In summary, this study demonstrated significant improvements in body composition over a median of 43 months following CD diagnosis. These observational data suggest that biologic therapies targeting inflammatory cytokines and the intestinal microbiome (e.g. LBP) may benefit patients presenting with linear growth failure, cachexia or wasting at diagnosis. However, randomized clinical trials are needed to determine if early use of such therapies will affect growth and body composition in pediatric Crohn’s disease.