Nutrition and Growth in Chronic Diseases

Anat Guz-Mark, Raanan Shamir
Introduction Chronic diseases that occur during childhood and adolescence can be associated with adverse effects on nutritional status, body composition, bone health, and growth patterns throughout this period of life. Growth impairment is a common feature of different chronic diseases in children, resulting from various contributing factors, including inflammatory processes, inadequate intake or absorption of macro- and micronutrients, high energy requirements during illness, and treatment-related adverse effects. We have selected and reviewed nine leading articles for this chapter, published over the last year, focusing on different nutritional and growth aspects in several childhood chronic diseases: celiac disease, inflammatory bowel disease, and attention-deficit/hyperactivity disorder. From a plethora of published research, these articles provide a diverse representation of different contemporary issues including topics on micronutrient deficiencies, metabolic bone disease, as well as growth patterns and challenges in different diseases. We hope that this small selection of papers will stimulate our readers to explore other papers in the selected topics as well as the effect of nutrition on growth in other chronic diseases that were not covered this year due to limited space. Celiac Disease Micronutrient deficiencies in children with coeliac disease; a double-edged sword of both untreated disease and treatment with gluten-free diet Comments: Celiac disease (CD) is an autoimmune enteropathy that develops in genetically predisposed individuals upon ingestion of gluten. As villous atrophy develops, patients with CD can present with symptoms of malabsorption and exhibit macro- and micronutrient deficiencies. A strict gluten-free diet (GFD) is the only treatment for patients with CD, leading to the resolution of symptoms and resolution of mucosal injury (villous atrophy) and disease complications. However, cereals are an important source for various minerals and trace elements in a Western diet, and the paucity of fortified gluten-free foods might lead to micronutrient deficiencies in patients following GFD [1, 2]. Children, whether on a GFD or not, are at particular risk of consuming excessive quantities of fat and insufficient amounts of dietary fibers as well as some vitamins and trace elements [2]. This current study by McGrogan et al. aimed to specify and compare different patterns of micronutrient deficiency between children with CD at diagnosis (while still consuming a gluten-containing diet), and children with established CD consuming a GFD during follow up. At the time of CD diagnosis, low levels of micronutrients were frequent (≥10% of patients) for: vitamins E (88%), B1 (71%), D (24%), K (21%), A (20%), and B6 (12%), ferritin (79%), and zinc (33%). In patients following GFD longer than 12 months, the micronutrients that improved the most were vitamins K, E, B1 and ferritin. On the contrary, the status of vitamins B6 and vitamin D deteriorated over follow-up with GFD and low levels were associated with a longer duration of disease. Deficiencies in vitamin A, zinc, copper, selenium, and magnesium did not differ significantly between diagnosis and follow-up. There were no associations between the micronutrient status and fecal gluten immunogenic peptide measurements (used as a marker of GFD adherence). As suggested by its title, this paper represents the so-called double-edged sword of GFD treatment in CD. The study nicely highlights the frequent micronutrient deficiencies in children with newly diagnosed CD as a common complication of intestinal mucosal damage and malabsorption. On the other hand, it demonstrates how a GFD may fail to change the status of some of these nutrients over a 1-year period, or even lead to micronutrient deficiency by itself. Nutritional counseling is of great importance and should be an integral component of treating and following children with CD, not only for the guidance and assessment of practicing GFD, but rather for the assessment and monitoring of the nutritional adequacy of the child’s diet.   Significant improvement in bone mineral density in pediatric celiac disease: even at six months with gluten-free diet Comments: CD-related malabsorption can cause an alternation in the calcium and vitamin D balance, and is associated with poor skeletal maturation and metabolic bone disease [3, 4]. The prevalence of reduced bone mineral density (BMD) in CD varies between studies and age groups, and is roughly estimated to be present in about 30–50% of patients at the time of diagnosis [5]. Follow-up is recommended in patients with CD and reduced BMD, after 1–2 years of strict GFD adherence [5, 6]. In the study by Gerenli et al., BMD was assessed in 46 pediatric patients with CD, both at the time of diagnosis and after 6 months from initiating GFD. No correlations were found in this study between vitamin D or parathyroid hormone levels and BMD values. At the time of diagnosis only 22% of patients had normal BMD (Z-score above –1 SDS). Another 22% of patients normalized their BMD at the 6-month follow-up. At diagnosis of CD, 34.8% demonstrated osteoporosis with a BMD Z-score below –2 SDS, while 31.2% of this group gained more than 1 SDS at the 6-month follow-up. Both weight and height Z-scores significantly increased during the period of follow-up on GFD with no significant change in BMI Z-scores. This study reported a relatively high prevalence of reduced BMD compared to most studies in pediatric CD, and also a significant portion of them had vitamin D deficiency. The importance of this study is the demonstration of a rapid increase in BMD over  a short period of time on a GFD, even before the period of recommended time for reevaluation of BMD after treatment initiation. It provides another example and emphasis on the efficacy of maintaining a GFD for the correction of metabolic complications of CD. Childhood growth prior to screen-detected celiac disease: prospective follow-up of an at-risk birth cohort based studies have shown signs of early growth retardation in young children later diagnosed with CD [7, 8]. In the previous yearbook we discussed the findings from the longitudinal PreventCD study, which identified slower growth rates in infants at genetic risk of CD who developed CD by 6 years of age, compared to those who did not develop CD [9]. That study identified lower growth rates in CD before diagnosis, although growth was usually within “clinical standards” [9]. This current study by Stahl et al. presents a sub-analysis from The Diabetes Autoimmunity Study in the Young (DAISY) cohort, which followed children genetically at risk for type 1 diabetes and CD, including annual growth and CD antibody measurements from the age of 9 months until 10 years. Out of 1,979 children, 120 developed CD autoimmunity and 71 were diagnosed with CD during follow-up. No significant associations were found in this study between weight, height, and BMI and the risk of screening- detected CD or autoimmunity. A weak association was surprisingly found between increased height velocity and CD development. The results of this prospective trial contradict most other studies in this field. However, this prospective cohort used early and relatively more frequent serologic assessments compared to other studies, which could perhaps lead to the early detection of CD before significant damage has occurred. It is important to also acknowledge the negative results, with no indication according to this study for any impairment in childhood growth before the development of CD and CD autoimmunity. Another interpretation of these results is in the potential benefit of screening for CD during early childhood in order to minimize the negative impact of late diagnosis of CD on children’s growth. Inflammatory Bowel Disease Trends in anemia, iron, therapy, and transfusion in hospitalized pediatric patients with inflammatory bowel disease Comments: Comments on this article are incorporated in the comments on the following article by Goyal et al. Anemia in children with inflammatory bowel disease: a position paper by the IBD committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition Comments: Iron deficiency and iron deficiency anemia are common in patients with inflammatory bowel disease (IBD) [10]. A multifactorial etiology combines malabsorption of iron due to intestinal epithelial damage, chronic gastrointestinal blood losses, and mainly the negative effect of proinflammatory cytokines on iron absorption and utilization. Proinflammatory cytokines (especially interleukin-6) upregulate the transcription and expression of hepcidin, resulting in the downregulation of ferroportin. The reduction of ferroportin results in reduced duodenal iron absorption and iron export by macrophages [11]. The high circulation hepcidin levels in active inflammation may cause functional iron deficiency due to insufficient iron utilization despite   adequate iron stores [12]. Anemia of chronic diseases is also common in IBD, caused by the direct inhibitory effect of inflammatory cytokines on erythropoietin levels and erythropoietic activity in the bone marrow [13]. In the retrospective multicenter study by Jacobson-Kelly et al., data regarding iron deficiency anemia among hospitalized pediatric patients with IBD were evaluated. The cohort included 8,007 and 28,260 hospitalizations over a 7-year period. The rate of anemia during admission in this population was 29.8%, with an increase in prevalence during the study period. Laboratory evaluation for iron deficiency was performed only in 12.6% of the cases. Treatments with red cell transfusions, intravenous (IV) iron and oral iron were given in 7.4, 6.3, and 18.4% of admissions, respectively. Interestingly, there was a significant decrease in the use of red cell transfusions between the years 2012 and 2018, and a significant increase in the use of IV iron during this period. Iron sucrose was the most commonly used IV iron formulation. Coadministration of iron (either oral or IV) in patients receiving red cell transfusion was documented in 41.8%; however, these data are limited only to treatments given in an inpatient hospitalization setting. This study well demonstrated the high prevalence of anemia in pediatric patients with IBD during hospital admissions, although the study population most likely represent a subgroup of patients with more severe active disease that require hospitalization. The trends towards an increase in IV iron treatments over time, and a decrease in the use of red blood cell transfusion in these patients, reflect the changes in common practice of therapeutic approach in patients with IBD and anemia, and are in concordance with current professional recommendations. The second article by Goyal et al. is a position paper published last year by the IBD Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition. The article reviews the current knowledge on anemia in pediatric patients with IBD, stating a prevalence of up to 74–78% of newly diagnosed children with IBD in different studies. Anemia and iron deficiency can be used as markers for disease activity in IBD, and are also considered as comorbid conditions that require identification and treatment. Both iron deficiency and anemia can cause disabling symptoms and also affect quality of life as well as impairment of concentration and cognitive function. According to the position statement, iron deficiency anemia should be treated with a combination of iron supplementations, control of disease activity, and optimization of dietary intake. Despite some concerns previously raised regarding oral iron supplementation in IBD, it is the recommended route of treatment in mild anemia (hemoglobin ≥10 g/dL). Oral iron may occasionally be poorly tolerated because of gastrointestinal side effects. Moreover, a dysbiotic effect of unabsorbed iron on gut microbiota has been demonstrated mainly in animal models with IBD, while only a single human adult study has shown a differential shift in gut bacterial diversity based on the route of iron administration [14]. Treatment with IV iron is indicated when oral iron is ineffective or poorly tolerated in patients with moderate to severe anemia (hemoglobin ≤10 g/dL) and in patients with active inflammation. The suboptimal utilization of IV iron could be attributed to concerns regarding adverse effects, limited availability, and cost. Despite these concerns, all current IV iron products are considered to be safe overall when administered by trained personnel, and are efficient in treating iron deficiency in pediatric patients with IBD. The position paper also provides practical guidance for the calculation of iron deficit and administration of various iron products. Growth, puberty, and bone health in children and adolescents with inflammatory bowel disease Comments: Comments on this article are incorporated in the comments on the following article by Ricciuto et al. Diagnostic delay is associated with complicated disease and growth impairment in paediatric Crohn’s disease Comments: Growth impairment is a common feature of pediatric IBD, more common in Crohn’s disease than in ulcerative colitis, and can occasionally be the presenting symptom of the disease. There are numerous factors contributing to impaired growth in these patients, including reduced intake of nutrients due to anorexia and digestive symptoms, malabsorption as a result of intestinal epithelial damage, high energy requirements in active disease, increased losses of energy and nutrients, a direct negative effect of inflammatory pathways on growth, and treatment-related factors such as the effect of steroids on the GH-IGF 1 axis [15]. Pubertal delay is also a concern in the pediatric age group and is sometimes observed in adolescents with IBD due to abnormalities of sex steroid production or activity caused by the effect of proinflammatory cytokines [16]. The study by Jin et al. aimed to investigate their definition of “endocrine complications” of pediatric IBD, including impaired growth, delayed puberty, and low BMD. In  with moderate to severe disease activity scores compared to the group with a mild activity range. BMD was assessed at the time of diagnosis in 119 patients, and demonstrated a Z-score below –1 in 50.4% and below –2 in 21% of patients. BMD Z-scores were significantly lower in patients with delayed puberty. Although this is a small study, it provides a comprehensive assessment of metabolic and endocrine complications of IBD in children and adolescents. As the vast majority of patients in this cohort had Crohn’s disease, the results cannot be generalized to all types of IBD. In addition, data regarding different stages of puberty at the time of diagnosis were lacking. Despite these limitations, the study highlights potential complications of IBD regarding growth, puberty, and decreased BMD, and stresses the importance of achieving adequate control of disease activity in the pediatric age group. The widescale multicenter study by Ricciuto et al. assessed the effect of diagnostic delay on growth and disease complication among 1,399 patients with pediatric-onset Crohn’s disease. Although the various aspects of IBD complications are not part of the scope of this current review, we have incorporated this well-designed study in our chapter for its important findings regarding growth impairment. The definition of “diagnostic delay” was determined as time interval between symptom onset and diagnosis above the 75th percentile in the cohort. The median time from symptom onset to diagnosis for the overall cohort was 4.2 (2.0–9.2) months, and a diagnostic delay was >9.2 months. The study demonstrated a significant association between longer time to diagnosis and lower height Z-score, after adjusting for patient demographics and small bowel involvement. For every additional month of symptoms before diagnosis, the height Z-score decreased by 0.013 standard deviations (p = 0.001). This original study puts the previous report by Jin et al. in the appropriate context, demonstrating the importance of early diagnosis of pediatric IBD. It highlights its effect on growth impairment, which is still a common and potentially modifiable complication in children with chronic inflammatory disease. Attention-Deficit/Hyperactivity Disorder Long term methylphenidate exposure and growth in children and adolescents with ADHD: a systematic review and meta-analysis  Comments: Comments on this article are incorporated in the comments on the following article by Waxmonsky et al. A randomized controlled trial of interventions for growth suppression in children with attention-deficit/hyperactivity disorder treated with central nervous system stimulants Comments: Attention-deficit/hyperactivity disorder (ADHD) is commonly diagnosed during childhood and adolescence, treated with a combination of psycho-behavioral and pharmacological approaches. The most frequently used treatment for ADHD is the psychostimulant methylphenidate (MPH) [17, 18], which, besides its positive effect on ADHD symptoms, may also be accompanied by several adverse effects, including reduced appetite, gastrointestinal discomfort, sleep disturbance, anxiety, and restlessness [19, 20]. The negative impact of stimulant medications on growth trajectories has been a matter of concern for many years, although the clinical and practical significance of this effect on long-term growth and final height is debatable [21]. The study by Carucci et al. provides a current meta-analysis of the association of prolonged exposure (>6 months) to MPH with height, weight, and timing of puberty, based on 18 studies and 4,868 children and adolescents with ADHD. The meta-analysis found an association between long-term MPH exposure and statistically significant impact on height and weight, but effect sizes were small, with possible minimal clinical effect. The most prominent impact on weight was found during the first 12 months of treatment, and on height within the first 24–30 months, with a plateau thereafter. No significant effects were found regarding the dose or formulation of MPH, patient age, and being drug-naïve (without ADHD medication prior to MPH). Data on the impact of either ADHD or MPH on the timing of puberty was found to be limited. The second article, by Waxmonsky et al., describes a randomized controlled trial comparing three methods for weight recovery interventions in 71 children experiencing a decline in BMI Z-score of at least 0.5 after 6 months of treatment with neuro-stimulants. The median period of intervention was 15 months. The three interventions were monthly monitoring of weight and height, a daily caloric supplementation of a 150- kcal drink, and drug holidays limiting medication to school days. Across all three interventions, weight and weight-velocity increased significantly over 10 months of follow-up. Drug holidays and caloric supplementation were more efficient in weight gain than monthly monitoring. There was no increase in height velocity over the study period. Despite the significant improvement, standardized weight and height overall decrease over the study period compared to a control group of children with ADHD without medications. This important and well-designed study demonstrates the efficacy of different methods of interventions in controlling and limiting the decline in growth trajectories in children receiving CNS stimulants. The most effective methods that allowed for an increase in the overall caloric intake were adding energy supplementation formula or practicing drug holidays. These methods enabled an increase in appetite and caloric intake in weekends and school breaks. 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