Nutrition and Chronic Diseases

48 min read /

The fascinating and complex process of growth and the changes in body composition are subjected to alternations when facing chronic diseases during childhood and adolescence. Many chronic diseases can potentially result in growth impairment, due to numerous coexisting contributing factors that include suboptimal nutrition, high energy needs, chronic inflammation, and hormonal imbalance. Eight leading articles were selected and reviewed in this chapter, highlighting different aspects of growth and nutrition in 5 major chronic diseases of childhood: asthma, celiac disease, inflammatory bowel disease, cholestatic liver disease, and chronic kidney disease. We encourage the readers to explore the various topics discussed in this chapter, and to expand their knowledge in contemporary issues regarding pediatric chronic diseases and their interaction with the process of growth and nutritional status.

Download article Save (for later)

Introduction

The fascinating and complex process of growth and the changes in body composition are subjected to alternations when facing chronic diseases during childhood and adolescence. Many chronic diseases can potentially result in growth impairment, due to numerous coexisting contributing factors that include suboptimal nutrition, high energy needs, chronic inflammation, and hormonal imbalance. Eight leading articles were selected and reviewed in this chapter, highlighting different aspects of growth and nutrition in 5 major chronic diseases of childhood: asthma, celiac disease, inflammatory bowel disease, cholestatic liver disease, and chronic kidney disease. We encourage the readers to explore the various topics discussed in this chapter, and to expand their knowledge in contemporary issues regarding pediatric chronic diseases and their interaction with the process of growth and nutritional status.

Asthma

The influence of childhood asthma on adult height: evidence from the UK Biobank

Comments: Long-term use of inhaled corticosteroids (ICS) is widely common and is the preferred treatment in childhood asthma. Although the safety profile of ICS is significantly more favorable than that of oral corticosteroids, there is still uncertainty regarding the potential for systemic complications including growth alternation and bone health in children on continuous treatment [1, 2]. Young children might be particularly vulnerable to growth impairment, both due to repetitive corticosteroid or continuous treatment, as well as the negative effect of the inflammatory process, in the midst of a period of rapid growth.

In the study discussed herewith by Kunøe et al. over 1,000 children with asthma were followed prospectively from birth to the age of 6 years, and the cumulative dose of ICS was analyzed. The patients’ height z-score at 6 years of age was compared to the height/length z-score at 1 year, in 84% of the cohort. Dual-energy X-ray absorptiometry scans were performed at 6 years of age in 71% of the cohort. The results of this study demonstrated an inverse association between cumulative ICS use and height at 6 years. However, this finding was only significant among patients with continuous ICS exposure after the age of 5 years, which is 1 year prior to the height assessment, with a −0.31 cm (95% CI: −0.52 to −0.1) difference per year on standard treatment, p< 0.01. Children who were not treated continuously during the 6th year of life showed no significant decrease in height. Importantly, the cumulative ICS exposure was not associated with bone mineral content at the age of 6 years in any of the stratified ICS groups.

Despite the statistically significant association between ICS cumulative use and patients’ height, the magnitude of the reported effect was minimal. Moreover, the authors stressed in their discussion the reassuring observation that after 1 year of cessation of ICS use, even after several years of previous ICS treatment, there was no significant effect on children’s height. These findings support the results of previous studies that demonstrated the loss of negative effect on growth after ICS treatment cessation [3]. In an editorial published in response to Kunøe’s study, the potential effect of asthma severity as a confounder was discussed [4]. As asthma severity was not assessed in this observational study, the potential negative effect on growth of a poorly controlled disease by itself should be considered. Specifically, the subgroup of children that have stopped ICS treatment by the age of 5 years and reported stable growth trajectories may reflect the natural improvement in the asthma course.

Most studies so far have evaluated the growth of children with asthma along a few years of follow-up at the most, while longer-term longitudinal data are lacking. An Important study in twin pairs discordant for asthma [5] has found no significant effect of asthma on height in within-pair analyses, other than a transient effect attributed to a delay in puberty. Genetic factors might act as important confounders, which are difficult to control, in population-based studies.

The second study we discuss here is by Chen et al. where a large UK Biobank data was used to elucidate the influence of childhood asthma on adult height, while considering known genetic heterogeneity in height. The matched cohort study included 13,602 European adults who were diagnosed with asthma before the age of 18 years, compared to 136,008 controls. Overall, childhood asthma was associated with shorter height at adulthood, with an age-dependent trend toward a lower magnitude of association with increased age at asthma diagnosis. Reduction of 2–3% in height among men and women with asthma diagnosed before the age of 7 was observed. Moreover, the height deviation between actual attained height and each person's genetically determined height was only significant in individuals diagnosed with asthma before 4 years of age, with a stronger association among males. The height deficits were observed both in individuals that were treated and were not treated with ICS.

While considering the limitations of this community-based study (including self-reported diagnosis of asthma, missing data, and lack of information regarding symptoms or disease severity), the results suggest a stronger association between asthma and growth mainly in early life period, and highlight the need for more comprehensive longitudinal research as well as clinical surveillance of growth in children diagnosed with asthma.

Celiac Disease

Evaluation of parameters associated with growth retardation in children with coeliac disease

Comments: Celiac disease (CeD) is an immune-mediated enteropathy that affects the integrity of the intestinal mucosa and can present with a wide spectrum of signs and symptoms[6]. While the classical presentation of malabsorption and malnutrition was predominant in the past, a substantial proportion of children are currently diagnosed with nonspecific abdominal complaints or without any symptoms [7, 8]. Still, growth faltering and altered weight gain remain common and important parts in CeD presentation[9].

Taskin et al. have described, in this current publication, the prevalence and risk factors for growth retardation in a contemporary cohort of newly diagnosed children with CeD from Turkey. The study included 169 patients (64.5% females), with mean (SD)age at diagnosis of 8.3 (4.4) years. In this cohort, 42.6% presented with growth retardation, defined as height and/or weight below the 5th percentile for age. Vomiting Was the only gastrointestinal symptom that significantly correlated with growth retardation at presentation. In this study, longer symptom duration, but not age at diagnosis, had a positive correlation with growth retardation. Interestingly, CeD patients with growth retardation had shorter breastfeeding duration compared to patients without growth retardation; however, no significant correlation was found with the duration of gluten exposure.

This cohort, which included mostly Turkish and some Syrian pediatric patients, demonstrates that CeD may still be accompanied by high rates of undernutrition and growth delay. In this study population, the relatively advanced age at diagnosis and long duration of symptoms (17 months in patients with growth retardation, and 12 months without growth retardation) should be acknowledged. The accessibility of medical diagnosis and care, as well as food security, may be especially important in children with CeD worldwide.

The effect of gluten-free diet on body mass index in paediatric celiac disease

Comments: Contrary to the previous paper, it has already been reported over the past decade that overweight and obesity at disease onset is not unusual in children presenting with CeD [10–12]. Moreover, the rates of obesity in patients with CeD (after diagnosis) are rising, as reported recently in an adult population-based study from the USA [13]. Initiation of GFD in newly diagnosed patients can alter body weight and composition in various directions.

This study by Anafy et al. describes patterns of body mass index (BMI) in children with CeD at diagnosis and during follow-up with gluten-free diet (GFD). The study included 236 patients (62% females) with a median age 7.9 years. At diagnosis, the rates of underweight, normal weight, and overweight were 10.1, 76.3, and 13.6%, respectively. Overall, there was no significant change in BMI for the entire cohort, during a median follow-up of 16 months under GFD. However, a significant shift between categories of BMI was observed. Among patients who were overweight at diagnosis, 44.4%reached a normal BMI and 55.6% remained overweight under GFD. Among patients with normal weight at diagnosis, most remained in the same category, while 4.3 and6.9% became underweight and overweight, respectively. There were no shifts between underweight and overweight categories.

The interesting observations in this study stress the multidirectional changes in nutritional status that can occur in children with CeD after GFD initiation. Although the desired goal of achieving and maintaining normal body weight seems to dominate the significant changes in diet and habits can potentially cause reduction in weight among children with selective eating, as well as undesired excessive weight gain due to unbalanced diet. The normalization of BMI in a significant portion of children who are overweight at CeD diagnosis may reflect the positive effect of adopting healthier eating practices together with medical and nutritional follow-up. Either way, the important role of dietary and nutritional guidance and continuous follow-up cannot be overstressed in children with CeD

Inflammatory Bowel Disease

Pediatric-onset inflammatory bowel disease has only a modest effect on final growth: a report from the epi-IIRN

 

Comments: Growth retardation is common in pediatric inflammatory bowel disease (IBD), mostly in children with Crohn’s disease, and is influenced predominantly by the chronic inflammatory process that causes growth hormone (GH) resistance, in addition to malnutrition, malabsorption, and increased nutritional requirements and losses [14]. Although early data have suggested that pediatric-onset IBD negatively affects final height [15], there is a debate regarding the current evidence for final height impairment in the era of improved care and biologic treatments. Recent studies [16–18] report only mild or no decrease in the final height of patients diagnosed with IBD during childhood, with various identified risk factors for delayed growth.

In this study by Assa et al 2,229 patients with pediatric-onset IBD were identified in an Israeli national database and were matched to 4,338 non-IBD controls. No significant differences were found in final height between males with IBD and matched controls. Females with Crohn’s disease were marginally shorter than matched controls corresponding to a mean difference of 0.7 cm. There was no difference in final height for patients with ulcerative colitis, regardless of sex and age at diagnosis. No significant differences were observed in the rates of short stature between cases and controls. Although no significant difference was noted in final height for the entire cohort, when the adjusted mean difference was analyzed there was a significant reduction of −0.43 cm in both sexes. As for treatment with anti-tumor necrosis factor-α,there was no overall significant difference in the change of height z-score from diagnosis to adulthood between treated and untreated patients. However, in the subgroup of patients with growth impairment at diagnosis (defined as height z-score of<−1) treated with anti-tumor necrosis factor-α, absolute height improvement was significant, with 33% of these patients improving to z-score > −1 at the final height.Overall, this study is in line with the trend of results that appear in recent studies,where despite growth impairment in significant proportion of children with IBD, the effect on final height seems to be modest. This highlights the importance of identifying the subgroup of children with IBD with significant growth impairment, in order to personalize and adjust treatment goals including maximizing growth potential in the short window of opportunity to achieve adequate final height.

Moderate-to-vigorous physical activity is associated with higher bone mineral density in children with inflammatory bowel disease

Comments: There is a plethora of data on the effect of IBD on bone mineral density (BMD) as well as different alternation in body composition. However, the interplay between IBD and physical activity is still obscure. While IBD can have a negative effect on physical activity due to fatigue, gastrointestinal symptoms, and altered muscle mass and function, there is growing evidence that physical activity can be beneficial for patients with IBD[19, 20]. A recent study published this year has shown that children and adolescents with mild or inactive IBD have almost similar patterns of daily physical activity compared with healthy control, except for males who had reduced moderate-to-vigorous physical activity (MVPA) [21]. Most patients with IBD, similar to their matched healthy controls, did not fulfill the recommendation of adequate daily MVPA.

In this current study, Trivić et al. aimed to evaluate the relation between physical activity, body composition, and BMD in pediatric patients with IBD in remission. The study included 40 patients with IBD (mean age of 15 years, 60% males, 50% with Crohn’s disease). The prevalence of decreased BMD (z-score < −1) in this cohort was20%. Patients with Crohn’s disease had significantly lower BMD and lower lean body mass scores than patients with ulcerative colitis. Physical activity was assessed by a triaxial accelerometer worn over 5 consecutive days. The average time spent in physical activity was 247 min/day, with 46 min/day spent in MVPA. Only 15% of patients fulfilled the WHO’s recommendation of 60 min of MVPA daily [22]. The study reported a significant positive correlation between time spent in MVPA, and both BMD and lean body mass z-scores. In a multivariate analysis, only BMD remained significantly correlated with physical activity.

This study emphasizes the great importance of physical activity for BMD in children with IBD who are in remission. The strong correlation between MVPA and an increase in BMD may suggest a potentially valuable modifiable environmental factor that should further be explored in children with IBD.

Chronic Liver Disease

Body composition correlates with laboratory parameters and disease severity in infants with biliary atresia

Comments: Biliary atresia is the most common cause of cholestatic jaundice in the first months of life. Malnutrition is a major complication of chronic cholestatic liver disease (CLD),particularly in pediatric patients, with multiple factors involved in the pathogenesis[23, 24]. Poor intake is extremely common due to anorexia and recurrent vomiting, which together with the increased energy needs of a hypermetabolic state may lead to malnutrition and growth failure in these patients [25]. Furthermore, malabsorption and maldigestion play a major role in the disease as a result of the decreased bile pool in the bowel limiting fat absorption, as well as chronic enteropathy secondary to advanced portal hypertension. In CLD, the formation of IGF-1 and IGF-BP3 may be reduced, resulting in an impaired GH/IGF-1 axis. The assessment of nutritional status in children with CLD may be challenging, as fluid retention, ascites, and organomegaly make the conventional methods of weight and height measurements inaccurate for nutritional evaluation [24].

In this study by Marderfeld et al., various anthropometric measurements were used to assess malnutrition in 28 infants with biliary atresia treated in the single pediatric liver transplantation center in Israel. Nutritional assessment included dietary intake, serial anthropometric measurements including weight and length, as well as mid upper arm circumference, and skin-fold thickness. Fat-free mass and fat mass were measured using air displacement plethysmography (ADP). Based on the various measurement tools, malnutrition presented in 32–78% of the visits in this cohort, with the highest prevalence of malnutrition diagnosed using triceps skinfold thickness. The serum total bilirubin levels and the pediatric end-stage liver disease score were used to assess disease activity, which correlated best with the low mid-upper arm circumference z-score. Interestingly, fat-free mass and fat mass measured by ADP did not show any correlations with disease severity parameters. The results of this study recognize the complexity of assessing nutritional status in infants and children with CLD, influenced by the total body water and the mass of enlarged visceral organs. Body composition as measured by ADP, poorly correlated with disease severity, and further studies as well as specific reference values are much needed in this field.

Chronic Kidney Disease

Incidence of and risk factors for short stature in children with chronic kidney disease: results from the KNOW-Ped CKD

Comments: Growth impairment is common in children with chronic kidney disease (CKD), with a high prevalence of short stature in patients requiring renal replacement therapy during childhood [26, 27]. The etiology of growth retardation in children with CKD may be multifactorial, including genetic factors, delayed puberty, GH resistance, metabolic effect of chronic acidosis, inflammatory process, and malnutrition [28].

This study by Park et al. has evaluated the incidence and risk factors for short stature in pediatric patients with CKD in a large Korean multicenter cohort. The cross-sectional study included 432 children with CKD (median age of 10.9 years, 68% males), who were not on dialysis treatment and did not receive kidney transplantation. The prevalence of short stature and underweight in this cohort was 23 and 14%, respectively. Compared to normative data from Korean general population, children with CKD were shorter and had lower body weight. Recombinant GH (rGH) therapy was administered in only 14.3% of children with short stature in this cohort. Univariable and multivariable regression analyses were performed to examine risk factors for short stature. CKD stages 4 and 5, onset before 2 years of age, underweight, premature birth and low birth weight, and low household income were all identified as independent risk factors associated with short stature in these children.

This study highlights the high prevalence of growth impairment in a large cohort of children with CKD, with important comparisons not only to WHO standards but also to normative data of the specific local population. Notably, only a minority of children with short stature in this cohort received rGH therapy, similar to the results of a recent study from the USA [29], despite an established efficacy of GH treatment in children with renal impairment. Park et al. did not address the prevalence of metabolic acidosis, which is known to be a risk factor for growth impairment in CKD, as was also reported in another study published this year [30]. Nonetheless, of all the risk factors for short stature identified in Park et al.’s study, the authors rightly pointed that under-weight is the only potentially modifiable one. This emphasizes the importance of strict monitoring of body weight and composition in children with CKD as well as continuous nutritional assessment and management, in order to support adequate growth in this population.

References

  1. Kapadia CR, Nebesio TD, Myers SE, Willi S, Miller BS, Allen DB, et al. Endocrine effects of inhaled corticosteroids in children. JAMA Pediatr. 2016;170:163–70.
  2. Axelsson I, Naumburg E, Prietsch SO, Zhang L. Inhaled Corticosteroids in children with persistent asthma: effects of different drugs and delivery devices on growth. Cochrane Database Syst Rev. 2019;6:Cd010126.
  3. Guilbert TW, Mauger DT, Allen DB, Zeiger RS, Lemanske RF, Jr., Szefler SJ, et al. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. J Allergy Clin Immunol. 2011;128:956–63.e1–7.
  4. Standl M. Limited side effects of asthma treatment on growth and bone health in children. Thorax.2022;77:741.
  5. Protudjer JL, Lundholm C, Almqvist C. Asthma and height in twins: a cohort and within-pair analyses study. Twin Res Hum Genet. 2015;18:142–50.
  6. Husby S, Koletzko S, Korponay-Szabó I, Kurppa K, Mearin ML, Ribes-Koninckx C, et al. European Society Paediatric Gastroenterology, Hepatology and NutritionGuidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70:141–56.
  7. Størdal K. Growth and the changing faces of coeliac disease. Acta Paediatr. 2021;110:1987–88.
  8. Krauthammer A, Guz-Mark A, Zevit N, Marderfeld L,Waisbourd-Zinman O, Silbermintz A, et al. Two decades of pediatric celiac disease in a tertiary referral center: what has changed? Dig Liver Dis. 2020;52:457–61.
  9. Saari A, Harju S, Mäkitie O, Saha MT, Dunkel L,Sankilampi U. Systematic growth monitoring for the early detection of celiac disease in children. JAMA Pediatr. 2015;169:e1525.
  10. Diamanti A, Capriati T, Basso MS, Panetta F, Di Ciommo Laurora VM, Bellucci F, et al. Celiac disease and overweight in children: an update. Nutrients.2014;6:207–20.
  11. Valletta E, Fornaro M, Cipolli M, Conte S, Bissolo F,Danchielli C. Celiac disease and obesity: need for nutritional follow-up after diagnosis. Eur J Clin Nutr.2010;64:1371–72.
  12. Venkatasubramani N, Telega G, Werlin SL. Obesity in pediatric celiac disease. J Pediatr Gastroenterol Nutr.2010;51:295–97.
  13. Drosdak A, Satyavada S, Ismail M, Shah R, Cooper G. Obesity prevalence in celiac disease in the United States From 2014 to 2018. Int J Obes (Lond). 2022;46:441–43.
  14. Shamir R, Phillip M, Levine A. Growth retardation in pediatric Crohn’s disease: pathogenesis and interventions. Inflamm Bowel Dis. 2007;13:620–28.
  15. Sawczenko A, Ballinger AB, Savage MO, Sanderson IR. Clinical features affecting final adult height in patients with pediatric-onset Crohn’s disease. Pediatrics.2006;118:124–29.
  16. Mouratidou N, Malmborg P, Sachs MC, Askling J, Ekbom A, Neovius M, et al. Adult height in patients with childhood-onset inflammatory bowel disease: a nationwide population-based cohort study. Aliment Pharmacol Ther. 2020;51:789–800.
  17. Rinawi F, Assa A, Almagor T, Ziv-Baran T, Shamir R. Prevalence and predictors of growth impairment and short stature in pediatric-onset inflammatory bowel disease. Digestion. 2020;101:674–82.Shamir R, Koletzko B, Phillip M, Turck D (eds): Nutrition and Growth. Yearbook 2023. World Rev Nutr Diet. Basel, Karger, 2023,vol 126, pp 128–139 (DOI: 10.1159/000527947)Nutrition and Chronic Diseases 139
  18. Ghersin I, Khateeb N, Katz LH, Daher S, Shamir R, Assa A. Anthropometric measures in adolescents with inflammatory bowel disease: a population-based study. Inflamm Bowel Dis. 2019;25:1061–65.
  19. Cohen DL, Shirin H. Inflammatory bowel disease: itseffects on physical activity, sports participation, and athletes. Curr Sports Med Rep. 2021;20:359–65.
  20. Mareschal J, Douissard J, Genton L. Physical activity in inflammatory bowel disease: benefits, challenges and perspectives. Curr Opin Clin Nutr Metab Care.2022;25:159–66.
  21. Vanhelst J, Béghin L, Turck D, Labreuche J, Coopman S,Gottrand F, et al. Daily physical activity patterns in children and adolescents with inflammatory bowel disease. Pediatr Res. 2021;90:847–52.
  22. Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour.Br J Sports Med. 2020;54:1451–62.
  23. Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N,Mack CL, et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. JPediatr Gastroenterol Nutr. 2017;64:154–68.
  24. Tessitore M, Sorrentino E, Schiano Di Cola G, Colucci A,Vajro P, Mandato C. Malnutrition in pediatric chronic cholestatic disease: an up-to-date overview. Nutrients.2021;13:2785.
  25. DeRusso PA, Ye W, Shepherd R, Haber BA, Schneider BL, Whitington PF, et al. Growth failure and out comes in infants with biliary atresia: a report from the Biliary Atresia Research Consortium. Hepatology.2007;46:1632–38.
  26. Harambat J, Bonthuis M, van Stralen KJ, Ariceta G, Battelino N, Bjerre A, et al. Adult height in patients with advanced CKD requiring renal replacement therapy during childhood. Clin J Am Soc Nephrol. 2014;9:92–9.
  27. Salević P, Radović P, Milić N, Bogdanović R, ParipovićD, Paripović A, et al. Growth in children with chronic kidney disease: 13 years follow up study. J Nephrol.2014;27:537–44.
  28. Fernández-Iglesias Á, López JM, Santos F. Growth plate alterations in chronic kidney disease. Pediatr Nephrol.2020;35:367–74.
  29. Ng DK, Carroll MK, Kaskel FJ, Furth SL, Warady BA,Greenbaum LA. Patterns of recombinant growth hormone therapy use and growth responses among children with chronic kidney disease. Pediatr Nephrol.2021;36:3905–13.
  30. Brown DD, Carroll M, Ng DK, Levy RV, Greenbaum LA, Kaskel FJ, et al. Longitudinal associations between lowserum bicarbonate and linear growth in children with CKD. Kidney360. 2022;3:666–76.