Nutrition and Growth in Chronic Diseases (N&G 2024)

Nutrition and Growth in Chronic Diseases

Introduction

Nutrition plays a pivotal role in enabling adequate growth and achieving the full growth
potential. This optimal growth requires proper intake of macro- and micronutrients and
hormonal axis that acts in its full capacity without interruption. Unfortunately, in chronic
diseases, children suffer from inadequate intake of nutrients and insufficient utilization of
energy and nutrients, while inflammation interferes with the proper action of hormonal
stimuli. For this chapter, we have selected and reviewed 12 leading articles published over
the last year, evaluating different nutritional and growth aspects in some major chronic
diseases of childhood: celiac disease, cystic fibrosis, inflammatory bowel disease, and
chronic kidney disease. These articles are a selected sample of manuscripts published this
year on the interplay between chronic disease, nutrition, and growth and are an appetizer
for the reader to dive into this intriguing aspect of nutrition and growth.

Celiac Disease

Factors associated with low bone mineral density at the time of diagnosis in children with celiac disease

Comments: The association between celiac disease (CeD) and poor bone health is well reported, and in children and adolescents, it is manifested as reduced bone mineral density (BMD) in newly diagnosed CeD [1]. The etiology may be multifactorial combining intestinal and nonintestinal factors, including malabsorption of macro- and micronutrients, as well as increased production of pro-inflammatory cytokines causing bone turnover and remodeling imbalance [2, 3].

In this study by Çamtosun et al. [4], 86 newly diagnosed children with CeD (mean age
8.06 ± 4.08 years) were retrospectively evaluated for BMD and possible risk factors.
BMD Z-scores were calculated according to both chronological age (CA) and height
age (HA).

The BMD Z-score according to CA was found to be ≤−2 in 26.7% of the patients, and the BMD Z-score according to HA was found to be ≤−2 in 12.8%. A positive correlation was found between the BMD Z-score CA and both weight-for-age and height-for-age Z-scores (rs: 0.373 and 0.380, respectively). When BMD was evaluated based on HA, no association was found between BMD and clinical parameters (presenting symptoms), laboratory parameters (celiac serology levels, vitamins and micronutrients levels, liver enzymes), or histopathological stage. A positive correlation was only found with age at diagnosis (rs: 0.269).

The correction of BMD Z-score according to HA is especially important in children with short stature, which was prevalent in one-third of this cohort. These findings emphasize the importance of BMD result interpretation, because without this correction, BMD Z-scores might be misleadingly low [5]. Nonetheless, this study highlights the significant prevalence of reduced BMD in children with a new diagnosis of CeD, regardless of clinical symptoms of malabsorption or different laboratory parameters, emphasizing the current lack of established risk factors in this population.

Nutrient deficiencies in children with celiac disease during long term follow-up

Nutritional imbalances in Polish children with coeliac disease on a strict gluten-free
diet

Risk of obesity during a gluten-free diet in pediatric and adult patients with celiac
disease: a systematic review with meta-analysis

Comments: Gluten-free diet (GFD) is currently the sole treatment for celiac disease (CeD), and life-long strict adherence is recommended to avoid persistent intestinal inflammation and CeD-related complications. As gluten-containing grains serve as the primary grain in most cereal-based foods nowadays, following a GFD often involves major changes in dietary patterns, and can be challenging for patients and families alike. The 2022 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper on the management and follow-up of children and adolescents with CeD [6] recommends testing for micronutritional status at time of diagnosis, correcting deficiencies, and continued follow-up until normalization of celiac serology. Although maintaining GFD results in improvement of most nutritional deficiencies in patients with CeD, there is some concern about the nutritional balance of GFD, especially when relying on commercial and processed gluten substitutes [7–
9].

In the current study by Kreutz et al. [10], serial data were retrospectively analyzed from 130 children with CeD, followed by a single center in the Netherlands. Follow-up visits were performed from 3 months after CeD diagnosis, and then yearly up to 10 years. The mean age at diagnosis was 6.2 years, with 59% girls. Celiac antibody normalization was documented in 66, 75, and 77% of patients after 1, 2, and 3 years of GFD, respectively. Overall, no vitamin B6 deficiency or hypocalcemia was found. Low levels of ferritin, vitamin D, vitamin B12, folate, and zinc were present in 22, 21, 2, 4, and 8% of measurements, respectively. The frequency of a ferritin and iron deficiency decreased over time in this cohort. Low ferritin prevalence declined from 36% at 3 months after GFD initiation to 9.5% after 5 years of follow-up. Vitamin D insufficiencies and deficiencies seemed to arise randomly with no specific trend over time. The frequencies of deficiency in vitamin B12, folate, and zinc were too sporadic to identify a trend overtime. As some of the deficiencies observed after 3 months were also reported at the time of diagnosis, that could have influenced the pooled results of this study. Moreover, there were some missing data with limited availability of measurements per nutrient.

Szaflarska-Popławska et al. [11] reported data from a single-center prospective cohort in Poland, comparing 48 children with CeD on a strict GFD (mean duration 5.02 ± 3.87 years) with 50 children without CeD. The study included anthropometric measurements, 3-day food records, and laboratory tests of hemoglobin, calcium, magnesium, folic acid, and vitamin B1, B2, B6, and B12 level. Compared to children with no CeD, children with CeD had significantly lower levels of serum calcium, vitamin B1, and folic acid. Mean calcium, folic acid, and vitamin D intake was below the dietary recommendations in both CeD and non-CeD subjects. The mean dietary intake of proteins and carbohydrates in the CeD group exceeded the recommended levels, but was similar to controls. The prevalence of underweight was significantly higher, and the prevalence of overweight/obesity was significantly lower among patients with CeD, compared to controls. There was no effect of GFD duration on the intake of most macro and micronutrients, except for vitamin B1 that declined overtime.

The systematic review and meta-analysis by Barone et al. [12] aimed to assess the prevalence of body mass index (BMI) categories at disease presentation and their variation in patients on a GFD overtime, among children and adults with CeD. A total of 45 studies (22 in pediatric patients and 23 in adults) met the eligibility criteria and were included in the meta-analysis. The analysis included 7,959 patients with CeD and 20,524 healthy individuals. The mean BMI of patients at diagnosis was significantly lower than that of controls, with an overall reduced risk to be in the overweight/obese category at diagnosis. During follow-up on a GFD, patients with CeD significantly increased their mean BMI. The pooled prevalence of patients in different BMI categories during a GFD showed that the percentages of patients in the overweight and obese categories remained similar to those observed at disease presentation: 13 and 7%, respectively. The data demonstrated that only 9% have changed to a higher BMI category during GFD; however, it was significantly more common in adults than in children (12 vs. 6%, respectively, p = 0.013). However, 20% of the entire population changed from the overweight/obese category to the underweight/normal category, more commonly in the pediatric vs adult population (34 vs. 8%, respectively, p <0.001). The results emphasize that after initiation of GFD, an increase in BMI category is significantly more frequent in adults, while the opposite is observed in children. Overall, this current meta-analysis shows that GFD does not increase the risk of developing overweight or obesity.

All three publications highlight the importance of a comprehensive dietary consultation when initiating GFD in patients with CeD, in order to guide how to not only eliminate gluten from the diet but also maintain a balanced and nutritionally adequate diet supporting normal body weight and growth and avoiding long-term nutritional deficiencies.

Cystic Fibrosis

Trajectories of early growth and subsequent lung function in cystic fibrosis: an
observational study using UK and Canadian registry data

Early life growth trajectories in cystic fibrosis are associated with lung function at
age six

Nutritional status and lung function in children with pancreatic-sufficient cystic
fibrosis

Comments: Cystic fibrosis (CF) is strongly associated with poor nutritional status, caused by the underlying genetic mutation, malabsorption and decreased nutrient intake, higher energy needs and increased losses, as well as recurrent infections [13]. As poor nutritional status is associated with lower lung function and long-term morbidity and mortality, optimizing nutritional status and adequate growth is one of the most important management goals in CF. Moreover, CF guidelines recommended monitoring patients’ growth trajectories aiming for target weight-for-length Z-score or body mass index (BMI) Z-score (before and after the age of 2 years, respectively) above the 50th percentile, to prevent disease progression [14].

In the first study, Macdougall et al. [15] have used data from two national CF registries (1,974 patients from the United Kingdom and 791 patients from Canada) to characterize the association between weight trajectories in early childhood (1–5 years) and lung function at age 6 years. In both registries, weight-for-age Z-score at age 1 year (intercept) and change over time (slope) were associated with forced expiratory volume in 1 s percent predicted (FEV1pp) later at 6 years. At 1 year, an increase in one weight-for-age Z-score was associated with an increase of 3.2–3.8 FEV1pp, and an increase of one BMI Z-score was associated with an increase of 3.7–4.1 FEV1pp. These results are consistent with previous studies and highlight the importance of nutrition status of patients with CF during infancy, considering later disease outcomes.

In the second study [16], Psoter et al. have used a group-based trajectory modeling to
characterize early life growth patterns and their association with lung function at the
age of 6 years, utilizing data from the Cystic Fibrosis Foundation Patient Registry in the United States. Patients (n = 6809) were divided to six groups by growth trajectories: three groups that began with growth parameters >50th percentile, termed “always high,” “gradual decliner,” and “rapid decliner,” and three groups that began with growth parameters <50th percentile, termed “rapid riser,” “gradual riser,” and “always low.” Trajectories consistently above the 50th percentile (always high and gradual decliner) had higher FEV1pp at age 6 compared to trajectories consistently below the 50th percentile (always low), with nearly 10% difference in FEV1pp between always high and always low trajectory. The different trajectory classes were associated with sex, ethnicity, newborn screening, and pancreatic function.

The third interesting study by Madde et al. [17] focuses on patients with CF without pancreatic insufficiency (PI). It is known that only 10–15% of children with CF retain pancreatic sufficiency (PS) overtime, and hence this subgroup is poorly represented in CF cohort studies. As PI leads to intestinal malabsorption, it is a major cause of malnutrition and poor growth in children with CF. This is the first large cohort study to evaluate the association between BMI and FEV1pp in children with PS-CF, and to compare to the association in PI-CF. The study included children diagnosed with CF before the age of 2 years, who had data on BMI and FEV1pp after the age of 6 years. Overall, 424 children with PS-CF and 7,849 children with PI-CF were identified from the Cystic Fibrosis Foundation Patient Registry. Pancreatic status was defined based on pancreatic enzyme replacement therapy.

The association between BMI and FEV1 differed significantly by pancreatic status:
each 10% higher BMI was associated with 2% higher FEV1pp in PI-CF, compared to just 0.9% in PS-CF. Moreover, in PS-CF, overweight/obesity was associated with decreasing FEV1pp. In addition, the decline in lung function between 6 and 20 years of age was evaluated according to pancreatic status and BMI groups. In the PI cohort, all BMI groups showed a significant decline in FEV1 with age (−1.34% per year), with steeper decline in the lower BMI groups. However, among the PS cohort, the FEV1 decline with age was modest (−0.48% per year), and mean FEV1pp remained >90% by age 20 years regardless of BMI group. This study highlights the importance of maintaining good nutritional status in CF to benefit lung function over time, in both pancreatic subgroups; however, the effect in PS patients is more modest. Finally, the finding of a decrease in FEV1 among PS patients with BMI above 85th percentile should be taken into consideration in this specific group, to avoid overweight and obesity, which
could be detrimental to lung function.

Inflammatory Bowel Disease

Can we rely on resting metabolic rate equations? Large variance in Crohn disease
pediatric patients

Comments: Resting metabolic rate (RMR), which represents resting energy expenditure, is the energy required by the body in resting conditions and is the largest component of the total energy expenditure. Multiple factors can impact RMR, including age, sex, genetic factors, and endocrine function. However, it has become clear that fat-free mass (FFM) is the best single determinant of RMR, accounting for the majority of its between-subject variance [18].

The RMR characteristics in children with inflammatory bowel disease (IBD), and specifically Crohn disease (CD), are poorly established. A reduction in RMR in CD [19] can result from anorexia or food avoidance, as well as from poor nutritional state that may alter body composition. On the contrary, RMR may also be elevated in patients with IBD due to active inflammation and increased metabolic requirements. Determining resting energy expenditure and total energy requirements is particularly important in children with IBD, both for nutritional management and rehabilitation, as well as for specific treatments in CD using enteral nutrition.

In this study by Marderfeld et al. [20], RMR was evaluated in pediatric patients with CD using an indirect calorimetry, and the results were compared to estimated RMR using the Schofield equation (which considers the patient’s age, sex, weight, and height). FFM was measured by bioelectrical impedance analysis. The study included 73 children, aged 7–18 years, with various stages of CD. Of the total, 29% patients were underweight, 2.8% were overweight, and 9.7% had short stature at the time of assessment. Children with moderate/severe disease score had lower weight Z-scores, lower body mass index Z-scores, and lower RMR. No association was found between RMR/FFM ratio and disease activity. There was a wide variance in RMR in the study population, and the ratio of measured RMR to estimated RMR varied between 0.7 and 1.5. This ratio was higher than 1 in the mild CD group and highest among patients in remission. This study highlights the wide variation and the limited ability to predict RMR in this population, implying that accurate individual assessment using the appropriate equipment and trained personnel is needed for establishing energy needs in CD.

Sex-specific pathways lead to statural growth impairment in children with Crohn’s
disease

Growth after menarche in pediatric inflammatory bowel disease

Comments: Growth impairment is common in pediatric inflammatory bowel disease (IBD), mostly in children with Crohn disease (CD) [21, 22]. The growth impairment is a result of multifactorial pathophysiology combining the effects of the chronic inflammatory process, chronic malnutrition, and treatment-related factors including the use of corticosteroids. The growth hormone (GH)–insulin-like growth factor 1 (IGF-1) axis is negatively affected by the elevation of pro-inflammatory cytokines, causing GH resistance and impaired linear growth [23, 24]. In addition, chronic malnutrition may occur due to decreased dietary intake and intestinal malabsorption, as well as an increase in energy requirements. The impact of pediatric-onset IBD on final height in modern era, however, is debatable [25–27].

It has been suggested that statural growth impairment is more common in male patients with CD than in females [28], although other studies showed different results [27]. This current study by Gupta et al. [29] prospectively examined serum cytokines and hormone levels in pediatric CD multicenter longitudinal cohort. Height Z-score difference was computed as height Z-score based on chronological age minus height Z-score based on bone age.

Overall, 122 children with CD (63% male) were included. The magnitude of the mean height Z-score difference was greater in females (±0.94) than males (−0.87 vs. −0.27; p = 0.005), indicating growth was better in females. Specific serum cytokine levels did not differ by sex; however, different associations were found between specific cytokines and hormones levels (evaluated as bone age Z-scores) in males and females. Among females, negative associations were identified between interleukin (IL)-8 and IL-12p70 with gonadotropin; IL-8, IL-12p70, and interferon-γ with sex hormone; and IL-8 and interferon-γ with IGF-1. Among males, IL-1β and IL-6 were negatively associated with IGF. These findings suggest that the primary pathway of growth impairment is the GH–IGF-1 axis in males and the hypothalamic-pituitary-gonadal axis in females. It also highlights the need to include specific serum inflammatory proteins
in risk models to establish which males and which females are at greatest risk for
growth impairment in CD.

In the second study by Salguero et al. [30], the impact of age at menarche on final height was investigated in female patients with IBD diagnosis prior to menarche. The study identified 146 patients (76% with CD), with mean age at diagnosis of 10.7 years, mean age at menarche of 14.3 years, and mean age upon final height of 19.6 years (with no significant differences between patients with CD and ulcerative colitis). There was a significant negative correlation between age of menarche and magnitude of linear growth after menarche. Patients who had menarche before 12.5 years had significantly increased linear growth than those who had menarche after 13.5 years. However, there was a significant positive association between age at menarche and final height, but not the final height Z-score. Delayed menarche (age ≥ 14.5 years) occurred in 41 and 35% of patients with CD and ulcerative colitis, respectively, and was associated with maternal delayed menarche and with lower weight Z-score at diagnosis.
Growth impairment was associated with surgery before menarche, jejunal disease,
low mid-parental height, hospitalization (only for CD), and recurrent corticosteroid or anti–tumor necrosis factor alpha therapy. The study highlights the multifactorial etiology for growth impairment in IBD, irrespective of age at menarche.

Chronic Kidney Disease

Associations of longitudinal height and weight with clinical outcomes in pediatric
kidney replacement therapy: results from the ESPN/ERA Registry

Comments: There is a significant high burden of morbidity and mortality among pediatric patients with end-stage kidney disease on kidney replacement therapy (KRT, i.e., hemodialysis, peritoneal dialysis, hemofiltration, and hemodiafiltration) [31]. Short stature in these patients is common, reported in approximately 40% [32, 33], and results from numerous factors including genetic alternations, malnutrition, growth hormone re-sistance and delayed puberty, inflammatory process, and chronic acidosis [34]. Previous studies have suggested association between both extremes of body mass index (BMI), as well as short stature, and higher mortality risk in pediatric KRT [35, 36].

In this study, Bonthuis et al. [37] have evaluated the association of height and BMI with clinical outcomes, in a large European cohort of pediatric patients with KRT (33 countries, 11,873 patients). During a median follow-up of 4.7 years, short stature was observed in 42.7% of patients, whereas only 1.4% had tall stature. Most patients had normal weight (67.7%), followed by overweight (17.9%), obesity (9.6%), and underweight (4.9%). Patients with both short and tall statures had a lower likelihood of receiving kidney transplantation compared to patients with normal stature, as were patients with underweight compared to patients with normal weight. Moreover, kidney transplant recipients with short or tall statures had an increased risk of graft failure. All-cause mortality was associated with short stature, underweight, and obesity. Specifically, patients with short stature showed an increased risk of death from infections. The risk of cardiovascular mortality was also higher among patients with short stature, underweight, overweight, and obesity.

The major limitation of this registry-based observational study is the inability to determine causality, while the course of disease and complications could influence growth and weight, rather than the opposite direction. In addition, in children with end-stage kidney disease, characteristics of the underlying disease could influence anthropometric indices, including genetic etiologies and height or fluid balance and weight. Nevertheless, this is an important large-scale multicenter study that demonstrates that extremities of height and BMI are associated with poorer outcomes in children with KRT. These results suggest the need for a multidisciplinary approach in this population, including close nutritional management, possibly growth hormone treatment in persistent short stature, and lifestyle modification.

Evaluation of height centile growth patterns compared with parental-adjusted
target height following kidney transplantation

Comments: Kidney transplantation (KT) is effective in correcting metabolic and endocrine disorders contributing to uremic growth failure in children with end-stage kidney disease. However, catch-up growth following KT has been infrequently observed [38]. In this current study, Ng et al. [39] have evaluated growth of children after KT, compared to their target height, which was defined as parental-adjusted height standard deviation score (SDS) within ±1.55. Height SDS was assessed at the time of transplant and at 1, 2, 3, and 5 years following KT. The study included 48 children (29% females), with median age of 5.3 years at first KT. Children with conditions known to have genetic predisposition to short stature were excluded. At the time of KT, 60% of children had normal height (SDS ≥−1.88), with only 48% children achieving their target height based on adjusted parental height. The percentage of children achieving normal height increased to 75, 83.3, 86.5, and 88% at 1, 2, 3, and 5 years following KT, respectively. The percentage of children achieving target height increased to 68.8, 73.8, 73, and 80% at 1, 2, 3, and 5 years after KT, respectively (p = 0.01). Although children aged <6years at KT had the highest prevalence of growth impairment at time of transplant, they also demonstrated the most significant increase in the proportion of children achieving their target height at 1, 2, 3, and 5 years after KT (72, 81.8, 85, and 92.3%, respectively, p = 0.023). Only 16% of children with short stature at the time of KT received growth hormone therapy after KT. Maintenance steroid immunosuppression was given to 42% of the cohort at latest follow-up; however, it was not associated with failure to achieve target height. The only identified risk factor of failure to achieve target height was duration of dialysis >12 months.

Although this study reports encouraging results as the vast majority of children attained normal height during the first 5 years after KT, still 20% had not achieved their target height. Since dialysis prior to KT was identified as the major risk factor for failure to achieve target height, a focus should be given to obtain adequate growth prior to KT in children with advanced kidney disease.

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